WO2002055525A1 - Retinoid agonists - Google Patents

Abstract

Compounds represented by the general formula (I) or salts thereof, having an ability to potentiate the physiological activities of retinoic acid or retinoids: (I) [wherein R1 is hydrogen or C¿1-6? alkyl; R?2 and R3¿ are each hydrogen, C¿1-6? alkyl, or the like; R?4, R5, and R6¿ are each hydrogen, halogeno, C¿1-6? alkyl, or the like; Y is phenylene or pyridinediyl; X is S- or N(R?7¿)- (wherein R7 is hydrogen or C¿1-6? alkyl); and Z is C-R?8¿ (wherein R8 is hydrogen, halogeno, or the like) or N], mor e specifically, compounds represented by the general formula (I) or salts thereof [wherein (1) Z is N, or (2) R1 is hydrogen or C¿1-6? alkyl; R?2 and R3¿ together with the ring-constituent carbon atoms to which they are bonded form a six-membered ring bearing one or more C¿1-4? alkyl groups; R?4, R5, and R6¿ are each hydrogen; Y is pyridinediyl; X is S-; and Z is CH].

Description

 Description Retinoid active substance Technical field

 The present invention relates to a novel compound, and more particularly to a novel compound that enhances the physiological action of a nuclear receptor receptor ligand represented by a compound (retinoid) having retinoic acid-retinoic acid-like physiological activity.冃,

 Retinoic acid (Vitamin A acid) is an active metabolite of Vitamin A. It has the effect of differentiating developing immature cells into mature cells with unique functions, as well as promoting cell growth and maintaining life. It has a very important physiological effect. Various biminmin A derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047, JP-A-61-76440, and Journal of Medicinal Chemistry ( The compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, .2182) have been shown to have similar physiological effects. The above compounds having retinoic acid and retinoic acid-like biological activity are collectively referred to as "retinoides".

For example, all-trans retinoic acid is a retinoic acid receptor that is present in the cell nucleus and belongs to the nuclear receptor Receptinoic acid belonging to the superfamily (Evans, RM, Science, 240, p.889, 1988). It has been shown that binding to Yuichi (MR) as a ligand regulates the growth of animal cells or cell death (Petkovich, M., et al., Nature, 330, pp. 444 -450, 1987). The above compounds having retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl) rubamoyl] benzoic acid : Am80, etc.) have been suggested to bind to RAR and exert physiological activity similarly to retinoic acid (Hashimoto, Y., Cell struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al "Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990). Clinically, it has been found to be useful in the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissue, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers. Compounds that act antagonistically on such retinoids and attenuate the typical effects of the above-mentioned retinoids are known (Eyrolles, L. et al., Journal of Medicinal Chemistry, 37 (10), pp. 1508 -1517, 1994) However, almost no substance is known that enhances the action of retinoids, such as retinoic acid, even though it does not have retinoid action by itself or its retinoid action is weak. For example, EP 694,301 A1 does not include special features for RXR Reception Yuichi. It has been suggested that a heterologous ligand compound has an effect of enhancing the action of Am80, a specific ligand compound for RAR-Hyceptin, and Japanese Patent Application Laid-Open No. 10-59951 discloses that Compounds that enhance the action are disclosed.

 An object of the present invention is to provide a compound having an action similar to that of a retinoic acid such as retinoic acid, and a compound having an enhanced action of a retinoide. More specifically, it is an object of the present invention to provide a compound which itself has a retinoide action and a compound which can remarkably enhance the action of retinoide.

 The present inventors have made intensive efforts to solve the above problems, and as a result, have found that a compound represented by the following general formula is useful as a retinoid and has a property of enhancing the action of the retinoid, and completed the present invention. I came to.

 That is, according to the present invention, the following formula (I):

(I)

Wherein, R ¹ represents a hydrogen atom or ₍₆ alkyl group; R ² and R ³ which it independently or showing a water atom or ₍₆ alkyl group, or R ² and R ³ are such together connexion They may form a 5- or 6-membered ring with the carbon atom on the benzene ring to which they are attached (the above-mentioned ring may have one or more (or _four alkyl groups) on the ring); ⁴ , R ⁵ , and R ⁶ each independently represent a hydrogen atom, a halogen atom, (a ₆ alkyl group, or a halogenated Ci-e alkyl group; Y represents a phenylene group or a pyridinediyl group; X represents —S -Or-N (R ⁷ )-(R ⁷ represents a hydrogen atom or ( ₆ alkyl group); Z is CR ⁸ (R ⁸ is hydrogen atom, halogen atom, C _1-6 alkyl group, or halogenated _{Represents a} C _1-6 alkyl group) or represents N)

 (1) a compound wherein Z is N or a salt thereof;

(2) ^ is a hydrogen atom or a ( ₆ alkyl group, and R ² and R ³ are linked together with one or more ( ₄ alkyl groups) on the ring together with the carbon atom on the benzene ring to which they are bonded. Wherein R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms, Y is a pyridinediyl group, X is -S-, and Z is CH; or a salt thereof;

(3) ^ is a hydrogen atom or a ( ₆ alkyl group, and R ² and R ³ are-緖 together with a carbon atom on the benzene ring to which they are bonded, and one or more ( ₄ alkyl groups A compound or a salt thereof, wherein R ⁴ and R ⁶ are hydrogen atoms, R ⁵ is a halogen atom, Y is a phenylene group, and Z is CH;

(4) a compound or a salt thereof in which at least two or more of R \ R ⁵ , R ⁶ , and R ⁸ are groups other than hydrogen atoms; or

(5) a compound or a salt thereof, wherein at least one of R \ R ⁵ , R ⁶ and R ⁸ is a halogenated C _1-6 alkyl group;

Is provided.

From another viewpoint, according to the present invention, a medicament containing the above compound or a physiologically acceptable salt thereof as an active ingredient, a retinoide action enhancer containing the above compound or a physiologically acceptable salt thereof as an active ingredient And a nuclear receptor receptor-enhancing agent comprising the above compound or a physiologically acceptable salt thereof as an active ingredient. Is done.

 In still another aspect, the present invention provides use of the above-mentioned compound or a physiologically acceptable salt thereof for the manufacture of the above-mentioned medicament; enhancing the effect of retinoid in the body of mammals including humans. A method comprising administering to a mammal, including a human, an effective amount of the compound or a physiologically acceptable salt thereof; the action of a nuclear receptor receptor ligand in the body of a mammal, including a human. And administering to a mammal, including a human, an effective amount of the compound or a physiologically acceptable salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION

R ¹ represents a hydrogen atom or an alkyl group having ₆ (1 to 6 carbon atoms). In the present specification, the alkyl group is any of linear, branched, cyclic, or a combination thereof. The same applies to the alkyl moiety of a substituent having an alkyl moiety (eg, a halogenated alkyl group, etc.) Examples of the alkyl group include a methyl group, an ethyl group, a II-propyl group, an isopropyl group, and an n-butyl group. Groups, sec-butyl group, tert-butyl group and the like, and preferably a methyl group.

R ² and R ³ each independently represent a hydrogen atom or a C _1-6 alkyl group. As the alkyl group, for example, those exemplified above can be used, but preferably, an ethyl group, an isopropyl group, a tert-butyl group and the like can be used. The substitution positions of R ² and R ³ are not particularly limited, and can be independently substituted at any position. For example, R ² and R ³ or in the para position and main evening position respectively is X, and R ³ may be that it main evening position及Pi ortho position relative to X, or and R ³ May be in the para position and the main position with respect to X, respectively.

Also, becomes R ² and R ³ gar緖, together with two carbon atoms on the benzene ring to which R ² and are attached respectively, may form a 5- or 6-membered ring. The ring formed may have one or two or more ( ₄ alkyl groups, for example, may have 2 to 4 methyl groups, preferably 4 methyl groups. , R ² and R ³ Is substituted by R ² and R ³ to form a 5,6,7,8-tetrahydronaphthylene ring or 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthane Preferably, a ren ring or the like is formed.

l \ R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a ( ₆ alkyl group or a halogenated C _1-6 alkyl group. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom Or an iodine atom, but a fluorine atom is preferable. (As the ₆ alkyl group, for example, those exemplified above can be used, but a methyl group, The halogen atom constituting the halogenated alkyl group may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, but is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom. Examples of the halogenated alkyl group include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, and a dichloromethyl group. Examples thereof include a fluoromethyl group and a tetrafluoroethyl group.

X is a nitrogen atom substituted with R ⁷ - shows a or a sulfur atom (-S-) (-NR ^7). R ⁷ represents a hydrogen atom or a C _1H3 alkyl group. (As the ₆ alkyl group, those exemplified above can be used, for example, a methyl group is preferable. The nitrogen atom or the sulfur atom may be N-oxide or sulfoxide, respectively.

Y represents a phenylene group or a pyridinediyl group. For example, P-phenylene group, m-phenylene group, 0-phenylene group, pyridine-2,4-diyl group, pyridine-2,5-diyl group, pyridine-3,5-diyl Any phenylene group or pyridinediyl group such as a group can be used. Preferably, a P-phenylene group or a pyridine-2,5-diyl group can be used. Pyridine - 2,5 Jiiru case of using group, the 2-position or 5-position any position of the pyridine - group represented by C00R ¹ may be substituted. The compound of the present invention is represented by the formula (I):

 (1) a compound wherein Z is N;

(2) ^ is a hydrogen atom or a ( ₆ alkyl group, and R ² and R ³ are linked together with one or more ( ₄ alkyl groups) To A compound which forms a 6-membered ring, wherein R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms, Y is a pyridinediyl group, X is —S—, and Z is CH;

(31 ¹ is a hydrogen atom or ( ₆ alkyl group, and R ² and 緖 have one or more C _w alkyl groups on the ring together with the carbon atom on benzene to which they are bonded. A compound which forms a membered ring, R ⁴ and R ⁶ are hydrogen atoms, R ⁵ is a halogen atom, Y is a phenylene group, and Z is CH;

(4) a compound in which at least two or more of R ⁴ , R ⁵ , R ⁶ , and R ⁸ are groups other than hydrogen atoms; or

(5) a compound wherein at least one of R \ R ⁵ , \ and R ⁸ is a halogenated- ₆ alkyl group;

Is one of

In the compounds of the above (1) to (5), it is preferable that R ² and R ³ together form a 6-membered atom together with the carbon atom on the benzene ring to which they are bonded, Preferably has 2 to 4 ( ₄ alkyl groups. The alkyl group present on the ring is preferably a methyl group. Most preferably, there are 4 methyl groups on the ring. .

In the compound of the above (1), R ⁴ , R ⁵ , and R ⁶ are preferably a hydrogen atom, Y is preferably a phenylene group, and X is preferably —S—.

In the above compound (2), Y is preferably a 2,5-pyridinediyl group. In the compound of the above (3), R ⁵ is a fluorine atom, Y is a P-phenylene group, and X is -Ν (Β · ⁷ )-(R ⁷ is a hydrogen atom or a methyl group) or -S -Is preferred. In the compound of the above (4), R ⁵ and R ⁸ are preferably a group other than a hydrogen atom, and more preferably, and are both a hydrogen atom or a halogen atom, and R ⁵ and R ⁸ are This is the case when the group is other than a hydrogen atom. More preferably, both R ⁵ and R ⁸ are halogen atoms, and most preferably, both R ⁵ and R ⁸ are fluorine atoms. It is also preferred that R ⁵ , R ⁶ , and R ⁸ are all fluorine atoms.

In the compound of the above (5), it is preferred that Y is a phenylene group and X is -S-. New It is preferred that at least one of R ⁴ , R ⁵ , R ⁶ , and R ^{8 is} a trifluoromethyl group. More preferably, R ⁵ is a trifluoromethyl group, and even more preferably, B ⁵ is a trifluoromethyl group, and R ⁴ , R ⁶ , and R ⁸ are hydrogen atoms.

The compounds of the present invention may exist as acid addition salts or base addition salts, and the substances in the form of salts are also included in the scope of the present invention. Examples of the acid addition salts include mineral acid salts such as hydrochloride and bromide hydrochloride, and organic acid salts such as P-toluenesulfonate, methanesulfonate, oxalate and tartrate. it can. A base addition salt is formed when R ¹ represents a hydrogen atom, and is a metal salt such as a sodium salt, a potassium salt, a magnesium salt, or a calcium salt, an ammonium salt, or an organic amine such as a triethylamine salt or an ethanolamine salt. Salts and the like can be mentioned.

 The compound of the present invention may have one or more asymmetric carbons depending on the kind of the substituent, and the optical isomer in a pure form based on such asymmetric carbon is diastereomeric. In addition to stereoisomers such as isomers, any mixtures of the stereoisomers, racemates and the like are all included in the scope of the present invention. It goes without saying that any hydrate or solvate of the compound in the form of a free compound or salt is also included in the scope of the present invention.

 The production method of the compound of the present invention is not particularly limited, but it can be produced, for example, according to the production method described in JP-A-10-59951. In the examples of the present specification, the methods for producing the compounds of the present invention are specifically and in detail described.Therefore, the methods used in these methods will be referred to the above-mentioned publications and the examples of the present specification. Any of the compounds included in the scope of the present invention can be produced by appropriately changing the starting materials, reagents, reaction conditions, and the like, and by appropriately modifying or modifying these methods as necessary. .

The compound of the present invention is a compound having substantially no retinoid-like action itself, or having a weak or moderate retinoid-like action. When the compound is allowed to coexist with a retinoic acid such as retinoic acid, the physiological activity (typically, cell differentiation action, cell growth promoting action, and life-sustaining action) of retinoid is markedly enhanced. While not wishing to be bound by any particular theory, it is understood that the compounds of the present invention may include retinoide receptor (the term "retinoid receptor" as used herein includes retinoic acid receptor RAR and MR. Retinoids such as retinoic acid can interact with one or more of the receptors that are capable of interacting with each other.) It exerts an effect or enhances the physiological activity of retinoid. Also, without wishing to be bound by any particular theory, when the compound of the present invention itself has a retinoid action, the action is a synergistic action.

 Therefore, the compound of the present invention is a compound of the above type having a retinoic acid-retinoic acid-like biological activity (eg, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthalenyl) rubumoyl] benzoic acid: Am80, etc., as well as biminmin A deficiency, keratosis of the epidermal tissue, psoriasis, allergic diseases, immunological diseases such as rheumatism, bone diseases, leukemia, diabetes , Or as a medicament for the prophylaxis / treatment of diseases such as cancer, or when administering retinoid for the prophylaxis / treatment of the above-mentioned diseases, the compound of the present invention may be administered as a medicament. It can be used as a retinoid action enhancer.

In addition, the compound of the present invention enhances the action of retinoic acid already present in the body even when retinoids are not administered for the treatment and prevention of the above-mentioned diseases. It is also possible to administer the compounds of the invention themselves. In addition, the compounds of the present invention not only have an effect of enhancing action on retinoids, but also have a nuclear receptor 1-super-family 1 present in the nucleus of cells (Evans, ILM., Science, 240, p. 889). , 1988 steroids compounds exerting a physiological effect by binding to the receptions evening one belonging to), vitamins such as vitamin D _3: D compound, or use the effect enhancer of the physiologically active substances such as thyroxine may Rukoto.

A medicament comprising the compound of the present invention or a physiologically acceptable salt thereof, It may be administered, but is preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art. Further, it can be used as a pharmaceutical composition in the form of a so-called combination drug by mixing it with a drug containing retinoid such as retinoic acid as an active ingredient. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups. Pharmaceutical compositions suitable for parenteral administration include Examples thereof include injections, suppositories, inhalants, eye drops, nasal drops, ointments, creams, transdermal absorbents, transmucosal absorbents, and patches. The active ingredient of the medicament of the present invention may be a free form compound or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

The above-mentioned pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, Examples include solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants, and adhesives. As the active ingredient of the medicament of the present invention, one or two selected from the group consisting of a free form of the conjugate and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof are provided. The above substances can be used, and the dosage of the medicament of the present invention is not particularly limited.In the case where the action of a retinoid is enhanced by using a medicament of the present invention in combination with a medicament containing a retinoid such as retinoic acid as an active ingredient. In the case of administering the medicament of the present invention to enhance the action of retinoic acid already present in the living body without using a medicament containing a retinoid, an appropriate dose can be easily selected in any administration method. it can. For example, in the case of oral administration, it can be used in the range of 0.01 to 1,000 mg per adult per day. When a medicament containing a retinoid as an active ingredient and a medicament of the present invention are used in combination, the medicament of the present invention can be administered during, before, or after the administration of retinoid. Example

 Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers in the examples correspond to the compound numbers in the following scheme. Example 1: Synthesis of HX900

Fe / aq.HCl / EtOH

 1-5 HX900

To a suspension of NaH (351 mg, 8.78 ol) in dry dimethylformamide (DMF, 25 mL) was added 5,6-, 7,8-tetrahydro-5,5,5,0-5 ° C under salt-ice bath cooling. A solution of 8,8-tetramethylnaphthalene-2-thiol (compound 1-1: J.Med.Chem., 38, pp.3163-3173, 1995, 1.935, 8.78 benzyl) in dry DMF (5 mL) was added dropwise. did. After gradually warming to room temperature and stirring for 1 hour, A solution of 2-chloro-3-nitropyridine (1.325 g, 8.36 t) in dry DMF (5 mL) was added dropwise at 0-5 ° C under cooling with a salt-ice bath. After gradually warming to room temperature and stirring for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The dry燥後solvent was evaporated under reduced pressure with the organic phase was washed with water and saturated brine MgSO _4. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 40/1) to obtain Compound 1-2 (2.755 g, 96.2%).

¾-thigh (CDC1 ₃ ) d8.52 (dd, 1H, J = 1.8, 4.8Hz), 8.48 (dd, 1H, J = l, 8, 8.4Hz), 7.46 (d, 1H, J = 1.8Hz) , 7.37 (d, 1H, J = 8.1Hz), 7.29 (dd 5 1H, J = 1.8, 8.4Hz), 7.17 (dd, 1H, J = 4.5, 8.1Hz), 1.71 (s, 4H), 1.32 ( s, 6H), 1.28 (s, 6H) .Compound 1-2 (2.687 g, 7.85 tmol) was suspended in ethanol (26 mL) and water (2.6 mL), and concentrated hydrochloric acid (6.5 mL) was added. . Iron powder (2.192 g, 39.25 mol) was added to the mixture, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction solution was poured into a mixed solution of NaOH (10.0 g, 250 mL), dichloromethane (125 mL) and water (250 mL), 15 g of celite was added, and the mixture was stirred and filtered through celite. The aqueous phase of the filtrate was extracted with dichloromethane, and the combined organic phases were washed with water and saturated saline, dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain compound 1-3 (1.056 g, 43.0%).

¾ - jobs _{(CDC1 3) 68.20 (dd,} 1H, J = 1.5, 4.5Hz), 7.27 (d, 1H, J = 2.4Hz), 7.19 (d, 1H, J = 8.1Hz), 7.06 (dd, 1H , J = 4.5, 7.8Hz), 7.00 (dd, 2H, J = 1.8, 8.1Hz), 4.20 (brs, 2H), 1.64 (s, 4H), 1.23 (s, 6H), 1.21 (s, 6H) Compound 1-3 (183 mg, 0.586 ol) and triethylamine (65.2 mg, 0.645 mmol) were dissolved in dry dichloromethane (5 mL), and terephthalic acid monomethyl chloride (0-5 ° C) was cooled in a salt-ice bath with cooling at 0-5 ° C. A solution of 128 mg (0.645 t) of dry dichloromethane (2 mL) was added dropwise. The temperature was gradually raised to room temperature and stirred for 15 hours. The reaction was diluted with dichloromethane, water and dried and then the solvent washed MgSO ₄ with saturated brine and evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 5/1). Purification yielded compound 1-4 (216 mg, 77.7%).

¾-NMR (CDCl ₃ ) 58.84 (brs and dd ₃ 1H + 1H, J = 1.5 ₃ 8.4Hz), 8.38 (dd, 1H, J = 1.5, 4.5Hz), 8.12 (d, 2H, J = 8.4Hz) , 7.74 (d, 2H, J = 8.7Hz) ₅ 7.35 (dd, 1H, J = 4.5 ₅ 8.1Hz), 7.26 (d, 1H, J = 1.5Hz), 7.23 (d, 1H, J = 8.1Hz) , 7.04 (dd, 1H, J = 1.8, 8.4Hz), 3.96 (s, 3H), 1.63 (s, 4H), 1.21 (s, 6H) ₅ 1.15 (s, 6H) .Compound 1-4 (192 mg Was dissolved in dichloromethane (1 mL), polyphosphoric acid (PPA, 4.50 g) was added, and the mixture was heated and stirred at 120 ° C for 1 hour. Water was added to the reaction solution, which was extracted with dichloromethane. The organic phase was removed by water and reduced圧留After drying solvent washed MgSO ₄ with brine. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain Compound 1-5 (93.4 mg, 50.5%).

¾- thigh _{(CDC1 3) 68.32 (dd,} 1H, J = 1.8, 4.5Hz), 8.11 (d, 2H, J = 8.7Hz) 3 7.90 (d, 2H, J = 8.7Hz), 7.66 (dd, 1H , J = 1.8, 8.1Hz), 7.57 (s, 1H), 7.29 (dd, 1H, J = 4.5, 8.4Hz), 7.08 (s, 1H), 3.96 (s, 3H), 1.66 (s, 4H) , 1.31 (s, 3H), 1.28 (s, 3H), 1.15 (s, 3H), 1.09 (s, 3H). Compound 1-5 (80.8 mg, 0.175 t) was added to tetrahydrofuran (THF, 3 mL). After dissolving in MeOH (1 mL), 2N NaOH (0.88 mL, 1.76 mL) was added, and the mixture was heated with stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 2N HC1 (1 mL) was added to the residue, diluted with water, and extracted with ethyl acetate. The organic phase Shi removed by drying after solvent distillation under reduced pressure at washing MgSO ₄ with water and saturated brine HX900 (71.0mg, 91.7%) was obtained. The purified product was obtained by recrystallization from toluene. mp - thigh (picture _{- d 6) 68.31 (dd,} 1H, J = 1.5, 4.5Hz), 8.06 (d, 2H, J = 8.4Hz), 7.84 (d, 2H, J = 8.4Hz), 7.77 (dd , 1H, J = 1.5, 8.1Hz), 7.59 (s, 1H), 7.47 (dd, 1H, J = 4.5, 8.1Hz), 7.19 (s, 1H), 1.63 (s, 4H), 1.28 (s, 6H), 1.14 (s, 3H), 1.07 (s, 3H). Example 2: Synthesis of HX901

 HX901

2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) thio] aniline (Compound-1: J. Med. Chem., 40, pp.4222- 4243, 1997, 218 mg, 0.70 olol) and 5-ethyl-2,5-pyridinedicarboxylate (Nippon Kagaku Zasshi, 88, 553-556, 1967, 273 mg, 1.40 olol) in dry dichloromethane. (3.5 mL) suspension was added with hydrochloric acid (3-dimethylaminopropyl) -3-ethylcarboimide (269 mg, 1.40 lotol) and stirred at room temperature for 4 hours. The reaction was diluted with Jikurorume Yun, water and dried and then the solvent washed MgSO ₄ with saturated brine and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain Compound 2-2 (306 mg, 89.5%).

¾- Anonymous _{(CDC1 3) d ll.14 (brs} , 1H), 9.20 (d, 1H, J = 1.8Hz), 8.66 (dd, 1H, J = 1.2 3 8.1Hz), 8.46 (dd, 1H, J = 1.8, 8.1Hz), 8.31 (d, 1H, J = 8.1Hz), 7.65 (dd, 1H, J = 1.8 ₃ 7.5Hz), 7.43-7.49 (m, 1H), 7.26-7.27 (m, 1H) , 7.13-7.18 (m, 1H), 7.12 (d, 1H, J = 8.4Hz), 6.95 (dd, 1H 3 J = 1.8, 8.1Hz), 4.45 (q, 2H, J = 7.2Hz), 1.59 ( s, 4H), 1.44 (t, 3H, J = 7.2Hz), 1.16 (s, 6H), 1.12 (s, 6H). Compound 2-2 (280 mg, 0.572 t) was added to dichloromethane (1 mL). Dissolve and add PPA (5.28 g) was added and the mixture was heated and stirred at 120 ° C for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was evaporated under reduced pressure and dried and then the solvent washed MgSO ₄ with water and brine. The obtained residue was purified by silica gel column chromatography (dichloromethane / methyl alcohol / acetic acid = 380/20/1) to obtain HX901 (153 mg, 60.4%). The purified product was obtained by recrystallization from toluene. mp 283 ° Co

-Accessories (thigh 0-d ₆ ) d9.03 (dd, 1H ₅ J = 1.2, 2.1Hz), 8.51 (dd, 1H, J = 1.2, 8.1Hz), 8.47 (dd, 1H, J = ZA, 8.4 Hz), 7.52 (dd, 1H, J = 0.9, 7.8Hz), 7.46 (s, 1H), 7.37-7.44 (m, 2H), 7.20-7.26 (m, 1H), 7.15 (s, 1H), 1.61 (s, 4H), 1.26 (s, 6H), 1.13 (s, 3H), 1.04 (s, 3H). Example 3: Synthesis of HX902

 HX 02

2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) thio] aniline (compound 2-1, 202 mg, 0.65 mmol) and 2-ethyl-2 1,5-pyridinedicarboxylate (Nippon Kagaku Zasshi, 88, pp.553-556, 1967, 253 mg, 1.30 fraction 1) in dry dichloromethane (3.5 mL) was added to a suspension of 1- (3-dimethylaminopropyl hydrochloride). ) -3-Ethyl carbodiimide (249 mg, 1.30 mol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with dichloromethane, reduced the dried solvent was washed with water and brine MgSO ₄ The pressure was distilled off. The resulting residue was obtained by silica gel column chromatography (hexane / acetic acid Echiru = 4/1) give to compound 3-2 (300 mg ₅ 94.4%).

- Anonymous _{(CDC1 3) 59.10 (brs,} 1H), 9.03 (d, 1H, J = 2.4Hz), 8.62 (d, 1H, J = 8.4Hz), 8.15 (d, 1H, J = 7.8Hz), 7.99 (dd, 1H, J = 2.4 , 8.1Hz), 7.67 (dd, 1H 5 J = 1.5, 7.8Hz), 7.49-7.55 (m, 1H), 7.22 (dd, 1H 3 J = 1.5, 7.8Hz), 7.18 (d, 1H, J = 8.1Hz) ₅ 7.07 (d, 1H, J = 1.8Hz), 6.81 (dd, 1H, J = 2.1, 8.4Hz), 4.50 (q, 2H, J = 7.2Hz), 1.61 (s, 4H), 1.46 (t, 3H, J = 7.2Hz), 1.19 (s, 6H), 1.13 (s, 6H). Compound 3-2 (258 mg, 0.527 tmol) was added to dichloromethane (1 mL). ), PPA (6.05 g) was added, and the mixture was heated with stirring at 120 ° C for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was evaporated under reduced pressure and dried and then the solvent washed GS0 ₄ with water and brine. The obtained residue (140 mg) was recrystallized from hexane-ethyl acetate to obtain HX902 (110 mg, 47.2%). mp 154-155 ° Co

¾ -舰_{(CDC1 3) d9.07 (dd,} 1H, J = 0.9, 2.1Hz), 8.37 (dd, 1H, J = 2.1, 8.1Hz), 8.28 (dd, 1H, J = 0.9, 7.8Hz) , 7.48-7.53 (m, 1H), 7.47 (s, 1H), 7.37-7.38 (m, 2H), 7.14-7.20 (m, 1H), 7.01 (s, 1H), 1.66 (s, 4H), 1.31 (s, 3H), 1.29 (s, 3H), 1.16 (s, 3H), 1.08 (s, 3H).

Example 4: Synthesis of HX903

 HX903-H

4-6a R ⁸ = H

HX904 R ⁸ = F

4-6b R ⁸ = F

6-bromo-1,2,3 ₃ 4 - tetrahydro - 1,1 ₃ 4 ₃ 4-tetramethyl-naphthoquinone evening Len 1 · 00 g (3.74 Face ol), 4-Furuoro - 2 two Trois diphosphorus (Compound 4 - la) 0.58 g (3.71 mol ), K 2 C0 3 0.57 g (4 · 12顏ol), Cul 0.04 g (0.21 thigh ol) in o- xylene 20 nil and the mixture was heated under reflux for 9 hours. Xylene was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 15) to obtain compound 4-2a (1.04 g, 81%).

-Hidden (CDC1 ₃ ) 9.35 (s, 1 H), 7.90 (dd, J = 9.2, 2.4 Hz, 1 H) ₃ 7.33 (d, J = 8.4 Hz, 1 H), 7.14-7.21 (m, 3 H), 7.01 (dd, J = 8.4, 2.4 Hz, 1 H) ₃ 1.71 (s, 4 H), 1.30 (s, 6 H) ₃ 1.28 (s, 6 H) 0.18 g (4.5 mmol) of NaJi (60% in oil) was washed with n-hexane, suspended in 3 mL of DMF, cooled in an ice bath, and 1.04 g (3.03 mmol) of compound 4-2a was added to 30 mL of DMF. And stirred at room temperature for 30 minutes. To this mixture was added 0.4 mL of CII (6.42 mmol), and the mixture was stirred for 5 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure to obtain compound 4-3a (1.05 g, 98%).

_{¾-NM (CDC1 3) 7.57} (dd, J = 7.6, 2.8 Hz, 1 H), 7.35 (dd, J = 9.2, 4.8Hz, 1 H), 7.29 (m, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 6.51 (dd, J = 8.4, 2.4 Hz, 1 H), 3.25 (s, 3 H), 1.63 (s, 4 H) ), 1.22 (s, 6H), 1.18 (s, 6H) Dissolve 1.05 g (2.98 ol) of compound 4-3a in 30 mL of ethyl acetate, add 10% Pd / C 0.1, and add Stir vigorously for hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain compound 4-4a (0.61 g, 6350).

_{- NMR (CDC1 3) 7.11 (} d, J = 8.8 Hz, 1 H), 6.97 (dd, J = 8.4, 6.0 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 6.50 (dd , J = 10.4, 2.8 Hz, 1 H), 6.43 (dd, J = 8.8, 2.4 Hz, 1 H), 6.41 (dd, J = 6.0, 2.8 Hz, 1 H), 3.95 (brs, 2 H), 3.14 (s, 3 H), 1.65 (s, 4 H) ₅ 1.23 (s, 6 H) ₅ 1.22 (s, 6 H) Compound 4-4aO.61 gU.87 tmol) was dissolved in 15 mL of dry benzene, 1.5 iL of pyridine was added. After cooling in an ice bath, terephthalic acid monomethyl ester chloride (0.41 g, 2.06 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 4) to obtain compound 4-5a (0.91 g, quant) ₀

¾-NMR (CDCI3) 8.58 (brs, 1H), 8.44 (dd, J = 10.8, 2.8 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 1 H), 7.18 (dd, J = 8.8, 5.6 Hz, 1 H), 6.87 (dt, J = 8.0, 3.2 Hz, 1 H), 6.65 (d, J = 2.8 Hz, 1 H), 6.57 (dd, J = 8.8, 2.8 Hz, 1 H), 3.93 (s, 3 H) , 3.27 (s, 3 H), 1.65 (s, 4 H), 1.25 (s, 6 H), 1.17 (s, 6 H) Compound 4-5a 0.91 g (1.86 t) dissolved in a small amount of dry dichloromethane Then, PPA 10 was added, and the mixture was stirred at 110 ° C for 1 hour. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane> = 1: 4) to obtain compound 4-6a (0.71 g, 81%).

_{¾-NMR (CDC1 3) 8.08} (d, J = 8.8 Hz, 2 H), 7.86 (d, J = 8.8 Hz, 2 H), 7.01 (dd, J = 9.6, 2.8 Hz, 1 H), 6.92 ( s, 1 H), 6.88 (s, 1 H), 6.81-6.69 (m, 2 H), 3.95 (s, 3 H), 3.23 (s, 3 H), 1.63-1.68 (m, 4 H), 1.32 (s, 3 H), 1.27 (s, 3 H), 1.13 (s, 3 H) ₅ 1.05 (s, 3 H) Compound 4-6a 0.71 g (1.50 t ol) of compound 10 mL And 2% of 20% NaOH and stirred at room temperature for 5 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to obtain HX903 (0.62 g, 90%). ¾-NMR (DMS0-d ₆ ) 13.1 (brs, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2 H), 6.98-7.09 (m, 4 H), 6.86 (s, 1 H), 3.19 (s, 3 H), 1.59 -1.61 (m, 4 H), 1.29 (s, 3 H), 1.25 (s, 3 H), 1.10 (s, 3 H) . H), 1.01 (s, 3 H) Anal Calcd for C 29 H 29 FN 2 0 23 C: 76.29%, H: 6.40%, N: 6.14%; Found C: 76.00%, H: 6.39% N: 6.02 % Example 5: Synthesis of HX90

6-Bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthylene 1.53 g (7.52 麵 ol), 2,4-difluoro-6-ditroaniline (compound 4-lb) 1.00 g (5.74 reference ol), K ₂ C0 ₃ 0.90 g (6.51 thigh ol), Cul 0.055 g (0.29 ol) was added with 20 mL of o-xylene and heated under reflux for 24 hours. Xylene was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 60 → 1: 10) to obtain compound 4-2b (1.82 g, 88%). ).

_{-NMR (CDC1 3) 8.54 (brs} , 1 H), 7.75 (ddd, J = 8.4, 3.2, 2.0 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 7.14 (ddd, J = 11.2, 7.6, 3.2 Hz, 1 H), 6.88 (dd, J = 2.8, 2.4 Hz, 1 H), 6.74 (ddd, J = 8.4, 2.8, 2.4 Hz, 1 H), 1.68 (s, 4 H) , 1.27 (s, 6 H) ₅ 1.25 (s, 6 H)

0.33 g (8.3% ol) of NaH (60% in oil) was washed with n-hexane, suspended in 5 mL of DMF, and 1.97 g (5.47 t) of compound 4-2b was dissolved in 40 mL of DMF and added. The mixture was stirred at room temperature for 30 minutes. It was stirred at room temperature for 1 hour added CH ₃ I 0.7 mL (11.2 thigh ol) to the mixture. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 4-3b (2.04 g, quant

¾-NMR (CDCI3) 7.39 (ddd, J = 7.6, 3.2, 2.0 Hz, 1 H), 7.18 (ddd, J = 9.6, 8.0, 2.8 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 6.41 (dd, J = 8.8, 2.8 Hz, 1 H), 3.24 (s, 3 H), 1.63 (s, 4 H) ₅ 1.22 (s , 6H), 1.18 (s, 6H) Compound 4-3b 2.04 g (5.4 t ol) was dissolved in 30 mL of ethyl acetate, 0.8 g of 10% Pd / C was added, and the mixture was vigorously stirred for 13 hours under a hydrogen atmosphere. . The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure to obtain compound 4-4b (1.19 g, 63%).

¾- thigh _{(CDC1 3) 7.12 (d,} J = 8.8 Hz, 1 H), 6.56 (d, J = 2.8 Hz, 1 H), 6.41 (dd, J = 8.8, 2.8 Hz, 1 H), 6.28 ( ddd, J = 10.0, 2.8, 1.6 Hz, 1 H), 6.23 (ddd, J = 10.4, 9.2, 2.8 Hz, 1 H), 4.10 (brs, 2 H), 3.18 (s, 3 H), 1.65 (s, 4 H), 1.23 (s, 12 H) Compound 4-4b 1.19g (3.45 mol) was dissolved in 15 mL of dry benzene, and 1.5 mL of pyridine was added. After cooling in an ice bath, terephthalic acid monomethyl ester chloride (0.75 g, 3.77 tmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7 → 1: 4) to obtain a disulfide compound 4-5b (1.66). g, 95%).

_{-NR (CDC1 3) 8.58 (brs} , 1 H), 8.30 (ddd, J = 10.8, 2.4, 2.0 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 1 H), 6.70 (ddd, J = 10.8, 8.8, 2.8 Hz, 1 H), 6.62 (d, J = 2.8 Hz, 1 H), 6.53 (dd, J = 8.4, 2.8 Hz, 1 H), 3.93 (s, 3 H), 3.29 (s, 3 H), 1.65 (s, 4 H), 1.25 (s, 6 H), 1.18 (s , 6H) Compound 4-5b 1.66 g (3.27 fold) was dissolved in a small amount of dry dichloromethane, 15 g of PPA was added, and the mixture was stirred at 110 ° C for 2 hours. After cooling, ice water was added to the reaction mixture, followed by extraction with acetic acid E Ji Le, the organic layer was washed with water, brine, and dried over anhydrous N S0 _4. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 4-6b (1.15 g, 72 72).

¾-NMR (CDGI3) 8.08 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H), 7.11 (s, 1 H), 6.87 (s, 1 H), 6.82 ( ddd, J = 9.2, 2.8, 1.6 Hz, 1 H) ₃ 6.64 (ddd, J = 11.6, 8.0, 2.8 Hz, 1H), 3.95 (s, 3H), 3.37 (d, J = 4.8 Hz, 3H), 1.64-1.72 (m ₃ 4 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H), 1.06 (s, 3 H) Compound 4-6b 0.88 g (1.80 ol) was suspended in 15 mL of ethanol and 3 mL of 20% NaOH, and the mixture was stirred at room temperature for 5 hours. After acidifying the reaction mixture, it was extracted with ethyl acetate, The organic layer was washed with water and saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure to obtain a HX904 by obtained residue was recrystallized from E evening Nord (0.81 g, 95%) o ^ -NMR (DMS0-d 6) 13.1 (brs, 1 H), 8.02 (d, J = 8.4 Hz, 2 H) ₃ 7.75 (d, J = 8.0 Hz, 2 H), 7.23 (s, 1 H), 7.08 (ddd, J = 11.6, 8.8, 3.2 Hz, 1 H) , 6.92 (dd, J = 9.6, 1.6 Hz, 1 H), 6.89 (s, 1 H), 3.33 (d, J = 5.2 Hz, 3 H), 1:60 -1.62 (m, 4 H), 1.30 (s, 3 H), .1.27 (s, 3 H), 1.11 (s, 3 H), 1.01 (s, 3 H) Anal.Calcd for C ₂₉ ¾ ₈ F _z N _z 0 ₂₃ C: 73.40% H : 5.95%, N: 5.90%; Found G: 73.27% H: 6.11% N: 5.87%

Example 6: Synthesis of HX905

5-la R ⁴ , R ⁶ , ⁸ = H, R ⁵ = CF ₃ , X = C1 5-2a ⁴ , R ⁶ , R ⁸ = H, R ⁵ = CF ₃

5-lb R ⁴ , ⁵ , R ⁶ , R ⁸ , X = F S-2b R ⁴ , R ⁵ , R ⁶ , R ⁸ = F

5-lc R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = F, X = I 5-2c R ⁴ , R ⁶ , R ⁸ = H, ⁵ = F

5-4c R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = F

5-5a R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = CF ₃ HX905 R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = CF ₃ 5-5bR ⁴ , R ⁵ , R ⁶ , R ⁸ = F HX 06R ⁴ , R ⁵ , R ⁶ , R ^S = F 5-5c R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = F HX 07 R ⁴ , R ⁶ , R ^S = H, R ⁵ = F

Dissolve 0.50 g (2.27 face) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthylene-2-thiol in 10 mL of dry benzene, cool in an ice bath, 0.27 g (2.41 liter) of tert-butoxylium was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled in an ice bath, and 0.51 g (2.26 t ol) of 4-chloro-3-nitrobenzotrifluoride (compound 5-la) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice water, neutralized, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . Solvent The residue was purified by vacuum gel chromatography (ethyl acetate: n-hexane = 1: 50 → 1: 30) to obtain compound 5-2a (0.90 g, 97%).

- thigh _{(CDC1 3) 8.51 (d,} J = 0.8 Hz, 1 H), 7.56 (dd, J - = 8.8, 2.0 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.44 ( d, J = 8.0 Hz, 1 H), 7.28 (dd, J = 8.0, 2.0 Hz, 1 H), 7.00 (d, J = 8.8 Hz, 2 H), 1.73 (s, 4 H), 1.33 (s , 6H), 1.28 (s, 6H) Compound 5-2a (0.90 g, 2.19 fold) was suspended in water (3 mL) and ethanol (15 mL), and concentrated hydrochloric acid (0.8 mL) was added. To this mixture was added iron powder 0.9, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain a di-conjugated product 5-3a (0.54 g, 65%).

_{l-NMR (CDC1 3) 7.46} (d, J = 7.6 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.17 (d, J = 2.8 Hz, 1 H), 6.96 (m, 1H), 6.93 (d, J = 8.4 Hz, 1 H), 6.82 (dd, J = 8.4, 2.0 Hz, 1 H), 4.42 (brs, 2 H), 1.65 (s, 4 H), 1.23 ( s, 6H), 1.22 (s, 6H) Compound 5-3a 0.54 g (1.42 fold) was dissolved in 10 mL of dry benzene, and 1.0 mL of pyridine was added. To this, terephthalic acid monomethyl ester chloride (0.31 g, 1.56 ref.) Was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 5-4a (0.64 g, 84%).

¾- thigh _{(CDC1 3) 8.97 (brs,} 1 H), 8.95 (s, 1 H), 8.08 (d, J = 8.0 Hz, 2 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H) , 6.88 (dd, J = 8.0, 2.0 Hz, 1 H), 3.95 (s, 3 H), 1.63 (s, 4 H), 1.22 (s, 6 H), 1.16 (s, 6 H) Compound 5-4a 0.64 g (1.18 t ol ) Was dissolved in a small amount of dry dichloromethane, 10 g of PPA was added, and the mixture was stirred at 110 ° C for 8 hours. After cooling, ice water was added to the reaction mixture, followed by extraction with acetic acid E Ji Le, the organic layer was washed with water, brine, and dried with anhydrous ₂ 30 _4. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain compound 5-5a (0.22 g, 36%).

_{ΐ-ΝΜ (CDC1 3) 8.11} (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 1.2 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.44 (s, 1 H), 7.33 (dd, J = 8.0, 2.0 Hz, 1 H), 7.05 (s, 1 H), 3.96 (s, 3 H), 1.64- 1.65 (m, 4 H), 1.31 (s, 3 H), 1.29 (s, 3 H), 1.15 (s, 3 H), 1.08 (s, 3 H) Compound 5-5a 0.22 g (0.42 thigh ol) Was suspended in 10 mL of ethanol and 2 mL of 2N NaOH, and the mixture was stirred at room temperature for 16 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol to obtain HX905 (0.10 g, 47%).

-NMR (DMSO- d ₆ ) 13.2 (brs, 1 H), 8.05 (d, J = 8.0 Hz, 2 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.71 (d, J = 8.0 Hz , 1 H), 7.66 (s, 1 H), 7.54 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.14 (s, 1 H), 1.61 (brs, 4 H), 1.27 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H)

Anal. Calcd for C ₂₉ ¾ ₆ F ₃ N0 ₂ S ₅ C: 68.35% H: 5.14%, N: 2.75%; Found C: 68.54%, H: 5.09% N: 2.11% Example Ί: Synthesis of HX906

0.12 g (3.0 t ol) of NaH (60¾ in oil) was washed with n-hexane, suspended in 5 mL of dry benzene, cooled in an ice bath, and then cooled with 5,6,7,8-tetrahydro-5, 5,8,8-tetramethylnaph 0.52 g (2.36 t ol) of Yuren-2-thiol was dissolved in 5 mL of dry benzene and added, followed by stirring at room temperature for 15 minutes. To this mixture, 0.50 g (2.35 liters) of pentafluorofluoronitrobenzene (compound 5-lb) dissolved in 3 mL of dry benzene was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, neutralized, extracted with acetic acid Echiru, the organic layer was washed with water, brine, and dried over anhydrous N S0 _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane) to obtain compound 5-2b (0.53 g, 55%).

-NR (CDC1 ₃ ) 7.46 (d, J = 1.6 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.17 (dd, J = 8.4, 2.0 Hz, 1 H), 1.66 (s, 4 H), 1.26 (s, 6 H), 1.24 (s, 6 H) Compound 5-2b 0.81 g (1.96 t ol) was suspended in 15 mL of ethanol, and 3 mL of 2N hydrochloric acid was added. . 0.9 g of iron powder was added to this mixture, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous N S0 _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 5-3b (0.69 g, 92%).

¾-NMR (CDCI3) 7.19 (d, J = 2.0 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.93 (dd, J = 8.4, 2.0 Hz, 1 H), 4.52 (brs, 2H), 1.64 (s, 4H), 1.22 (s, 12H) Compound 5-3b 0.69 g (1.80 liter) was dissolved in dry benzene (15 mL), and pyridine (1.5 mL) was added. added. 0.39 g (1.96 mol) of terephthalic acid monomethyl ester chloride was added thereto, and the mixture was stirred at room temperature for 14 hours, and then heated and refluxed for 2 hours. The reaction mixture was poured into 2N HC1, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 4) to obtain Compound 5-4b as a crude product.

E - thigh _{(CDC1 3) 8.09 (d,} J = 8.4 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.78 (s, 1 H), 7. 14 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 8.4, 2.4 Hz, 1 H), 3.96 (s, 3 H), 1.61 (s, 4 H), 1.20 (s, 6 H), 1.10 (s, 6 H) Dissolved in dry dichloromethane, added PPAIOg and stirred at 110 ° C for 14 hours. After cooling, ice water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and crystallized to give et the residue in main evening Knoll, to give the compound 5- 5b (0.61 g, 65% [2steps]) ¾-NMR (DMS0-d 6) 8.09 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 8.8 Hz, 2 H), 7.58 (s, 1 H) ₅ 7.21 (s, 1 H), 3.89 (s, 3 H), 1.62 (s, 4 H), 1.28 (s, 3 H), 1.26 (s, 3 H) ₃ 1.13 (s, 3 H), 1.06 (s, 3 H) Compound 5-5b 0.61 g (1.15 thigh ol) in ethanol 20 mL And 5 mL of 2N NaOH, and stirred at room temperature for 16 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol to obtain HX906 (0.50 g, 83%).

-Thigh (DMS0-d ₆ ) 13.2 (brs, 1 H), 8.06 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.58 (s, 1 H), 7.21 (s, 1 H), 1.62 (s, 4 H), 1.28 (s, 3 H), 1.26 (s, 3 H), 1.14 (s, 3 H), 1.07 (s, 3 H)

Anal. Calcd for C ₂₈ H ₂₃ F ₄ N0 ₂ S ₃ C: 65.49%, H: 4.51%, N: 2.73%; Found C: 65.24% H: 4.63%, N: 2.62% Example 8: Synthesis of HX907

5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthylene-2-thiol 0.50 g (2.27 ol) was dissolved in 20 mL of dry benzene, cooled in an ice bath, -Butoxycalime (0.28 g, 2.50 t) was added and stirred at room temperature for 15 minutes. This mixture was cooled in an ice bath, and 0.60 g (2.25 mmol) of 5-fluoro-2--2-nitronitrobenzene (5-drug conjugate 5-lc) was added, followed by stirring at room temperature for 5 hours. Pour the reaction mixture into ice water, neutralize, and add ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 20) to obtain compound 5-2c (0.57 g, 70 ° / o) o

_{¾-NMR (CDC1 3) 7.95} (dd, J = 8.4, 2.8 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.27 ( dd, J = 8.0, 2.0 Hz, 1 H), 7.12 (ddd, J = 9.2, 7.2, 2.8 Hz, 1 H), 6.88 (dd, J = 9.2, 5.6 Hz, 1 H), 1.72 (s, 4 H), 1.32 (s, 6H), 1.27 (s, 6H) Compound 5-2c 0.56 g (1.57 mmol) was dissolved in ethanol (10 mL), and 2N hydrochloric acid (3 mL) and iron powder (0.5 g) were added. Heated to reflux for an hour. After cooling, the reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-dioxane = 1: 20) to obtain compound 5-3c (0.37 g, 72%).

¾- thigh _{(CDC1 3) 7.41 (dd,} J = 8.4, 6.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.05 (d, J = 2.0 Hz, 1 H), 6.74 ( dd, J = 8.4, 2.0 Hz, 1 H), 6.48 (dd, J = 10.8, 2.8 Hz, 1 H), 6.45 (td, J = 8.4, 2.4 Hz, 1 H), 4.40 (brs, 2 H) , 1.64 (s, 4H), 1.22 (s, 6H), 1.20 (s, 6H) Compound 5-3c 0.37 g (1.13 tmol) was dissolved in 10 mL of dry benzene, and 1 mL of pyridine was added. . To this, terephthalic acid monomethyl ester chloride (0.25 g, 1.26 t ol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 5) to obtain compound 5-4c (0.49 g, 88%).

¾- thigh _{(CDC1 3) 9.12 (brs,} 1 H), 8.52 (dd, J = 10.8, 2.8 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 2 H), 7.65 (dd, J = 8.8 , 6.4 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 2.4 Hz, 1 H), 6.90 (td , J = 8.0, 2.8 Hz, 1 H), 6.80 (dd, J = 8.4, 2.4 Hz, 1 H) ₃ 3.95 (s, 3 H), 1.62 (s, 4 H), 1.20 (s, 6 H), 1.14 (s, 6H) The compound 5-4c (0.49 g, 0.99 mol) was dissolved in dry dichloromethane (2 mL), PPA10 was added, and the mixture was stirred at 110 ° C for 8 hours. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 5) to obtain compound 5-5c (0.34 g, 72%).

_{Ή - NMR (CDC1 3) 8.07} (d, J = 8.8 Hz, 2 H), 7.86 (d, J = 8.8 Hz, 2 H), 7.41 (s, 1 H), 7.40 (dd, J = 8.8, 5.6 Hz, 1 H) ₃ 7.04 (dd, J = 10.0, 2.8 Hz, 1 H), 7.01 (s, 1 H), 6.81 (td, J = 8.0, 2.8 Hz, 1 H), 3.94 (s, 3 H ), 1.63 -1.67 (m, 4 H), 1.29 (s, 3 H), 1.27 (s 5 3 H), 1.13 (s, 3 H), 1.06 (s 5 3 H) compound 5-5c 0.34 g ( 0.72) was suspended in ethanol (10 mL) and 2N NaOH (1.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was acidified, extracted with acetic acid Echiru, the organic layer was washed with water, brine, and dried over anhydrous ¾ ₂ 80 _4. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / n-hexane to obtain compound HX907 (0.23 g, 71%).

Ή-NMR (DMS0-d ₆ ) 13.1 (brs, 1 H), 8.04 (d, J = 8.0 Hz, 2 H) ₅ 7.82 (d, J = 8.4 Hz, 2 H), 7.52 (dd, J = 8.4 , 6.4 Hz, 1H), 7.51 (s, 1H), 7.19 (dd, J = 10.0, 2.8Hz, 1H), 7.12 (s, 1H), 7.04 (td, J = 8.4, 2.8Hz, 1H) , 1.61 -1.62 (m, 4 H), 1.27 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3H), 1.05 (s, 3H) Anal. Calcd for C ₂₈ H ₂₆ FN0 ₂ S, C: 73.18%, H: 5.70% N: 3.05%; Found C: 72.92% H: 5.99%, N: 2.95¾ Test example 1: Cell differentiation induction assay in HL-60 cells

Using each of the compounds produced in the examples, the cell differentiation induction action alone and coexistence The effect of retinoid on cell differentiation induction was examined. Am80 [4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthenyl)] rubamoyl] benzoic acid was used as a retinoide for comparison and coexistence. According to the method described in JP-A-61-76440, the differentiation into granulocytic cells was performed using the promyelocytic leukemia cell line HL-60 and the morphological changes and the two-mouth blue tetrazolium (NBT ) Was determined by measuring the reducing ability. The percentage (%) of the divided cells shown in the following table was calculated from the NBT reducing ability. The results are shown in Tables 1-3. The structures of the compounds tested are as follows: o

 HX600 HX630 HX650

HX902 HX904 R = F HX906 R ⁴ , R ⁵ , R ⁶ , R ⁸ = F

HX907 R ⁴ , R ⁶ , R ⁸ = H, R ⁵ = F The proportion of the partial I spoon guide cells during co-exist with differentiation induction 1x10 ⁰ M Am80 with compound compound alone (%) percentage of induced cells (%) Concentration (M) Concentration (M)

^{10- 8 It) - 7 10- 6} none 10- 10 10- 9 10 one ⁸ It) - ⁷ 10- ⁶

ΗΧ600 0.5 0.8 0.5 53.5 60 79 90

 ΗΧ650 1,3 0.2 0.2 53.5-55 66 87

Compound compound alone differentiation in induction 3x10 - ¹⁰ M Am80 Coexistence upon partial I spoon

 Percentage of induced cells (%) Percentage of induced cells) Concentration (M) Concentration (M)

_{10 -8 10 -7 10 -6 none 10} "10 10- 9 10- 8 10- 7 10- 6

ΗΧ630 1 1 1 13.5 19 24 59 87-

ME21 0.5 0.4 1.4 22-40 74 87

ΗΧ900 0.8 0.8 0.4 13.5 24 23 45 88

 HX901 0.6 1.1 0.2 13.5 25 29 40 80

Compound Induction of differentiation by compound alone Differentiation in the presence of 3xl0 " ¹⁰ M Am80

 Percentage of induced cells (%) Percentage of induced cells (%) Concentration (M) Concentration (M)

10 " ⁸ 10— ⁷ 10— ⁶ none 10— ¹⁰ 10—9 10— ⁸ 10- ⁷

ΗΧ903 0.8 0.8 1.6 28 35 38 61 83

 ΗΧ904 0.9 1 1.2 28 32 30 40 40

 ΗΧ905-0.3 0.9 13 15 18 9 16

 ΗΧ906 1.1 1.8 1.1 13 17 21 25

 ΗΧ907 1.1 .8 1.1 23.5-73 93 Industrial applicability

 The compound of the present invention is useful as an active ingredient of a medicament as a compound having a retinoid action and a compound capable of remarkably enhancing the action of retinoid.

Claims

Claims 1- The following formula (I): wherein represents a hydrogen atom or (6 alkyl group; R2 and B3 each independently represent a hydrogen atom or (6 alkyl group, or R2 And R3 may be taken together to form a 5- or 6-membered ring together with the carbon atom on the benzene ring to which they are attached (the above ring has one or more (4 alkyl groups on the ring) R4, R5, and R6 each independently represent a hydrogen atom, a halogen atom, a (6alkyl group, or a halogenated (6alkyl group; Y represents a phenylene group or a pyridinediyl group; X represents -S- or -N (R7)-(R7 represents a hydrogen atom or (indicating a 6-alkyl group); Z represents C-R8 (R8 represents a hydrogen atom, a halogen atom, a (6-alkyl group, or a halogenated (6 Represents an alkyl group) or represents N))

 (1) a compound wherein Z is N or a salt thereof;

(2) ^l is a hydrogen atom or a ( ₆ alkyl group, and R ² and R ³ are-緖 together with a carbon atom on the benzene ring to which they are bonded, and one or more ( ₄ alkyl groups Wherein R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms, Y is a pyridinediyl group, X is -S-, and Z is CH; or a salt thereof;

(m ¹ is a hydrogen atom or a ( ₆ alkyl group, and R ² and R ³ together have one or more ( ₄ alkyl groups on the ring together with the carbon atom on the benzene ring to which they are attached) A compound or a salt thereof, which forms a 6-membered ring, and wherein R ⁶ is a hydrogen atom, R ⁵ is a halogen atom, Y is a phenylene group, and Z is CH;

(4) a compound or a salt thereof in which at least two or more of R \ R ⁵ , R ⁶ , and R ⁸ are groups other than hydrogen atoms; or

(5) at least one of R \ R ⁵ , R ⁶ , and R ⁸ is halogenated (a ₆ alkyl group; Certain compounds or salts thereof.

 2. A medicament comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.

 3. A retinoid action enhancer comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.

 4. A nuclear receptor-ligand action enhancer comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.