JP2000273076A - Retinoid agonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having the action to regulate the physiological activity of retinoid, and usable as a retinoid action regulator or intranuclear receptor ligand action regulator. SOLUTION: This new compound is a compound of formula I [X is a linkage group such as NH-CO or CO-NH, or single bond; n is 1-5; R is a group of formula II (R1 is H or a lower alkyl) or the like] or a salt thereof, e.g. 4-[(3,4- bis(trifluoromethyl)phenylcarboxamido)benzoic acid of formula III. The compound of formula III is obtained by reaction of methyl p-aminobenzoate with 3,4-bis(trifluoromethyl)benzoyl chloride to form methyl 4-[(3,4-bis(trifluoromethyl) phenylcarboxamido)benzoate, which is then reacted with sodium hydroxide to effect demethylation. The compound of formula I is useful in treating or preventing overretinoid disease or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a retinoic acid or a compound having a retinoic acid-like physiological activity (retinoid)
And compounds having an effect of regulating the physiological activity of a nuclear receptor ligand represented by

[0002]

2. Description of the Related Art Retinoic acid (vitamin A acid) is an active metabolite of vitamin A, and acts to differentiate developing immature cells into mature cells having specific functions.
It has extremely important physiological actions such as cell growth promoting action and life sustaining action. Various vitamin A acid derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and Journal of Chemistry (1988) ,
Vol. 31, No. 11, p. 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 "retinoids".

[0003] For example, all-trans
Retinoic acid is a nuclear receptor present in the cell nucleus.
Superfamily (Evans, RM, Science, 240, p.
889, 1988), which has been shown to bind to retinoic acid receptor (RAR) belonging to the group and regulate the growth, differentiation, or death of animal cells (Petko
vich, M., et al., Nature, 330, pp. 444-450, 1987)
. The above compound having retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid: Am80, etc.) Have also 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. Comm., 166, pp.
1300-1307, 1990). These compounds have been found clinically 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. ing.

[0004] Several compounds that act antagonistically on such retinoids and attenuate the typical actions of the above retinoids are known (Eyrolles, L., et al. Journal of
Medicinal Chemistry, 37 (10), pp. 1508-1517, 199
Four). Further, as compounds that enhance the action of retinoids, compounds described in JP-A-10-59951 and JP-A-10-338658 are known.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound having an action of regulating the physiological activity of retinoid. The present inventors have previously reported retinoic acid receptor (RA
R) (Renaud, J.-P., et al. Nature, 378, p
p. 681-689, 1995), constructing the three-dimensional structure on a computer, and using the program ADAM & EVE (International Publication WO96 / 13785) developed by the present inventors so far, A compound capable of stably binding to the ligand binding site of the RAR was searched from the dimensional structure database. As a result, they have found that the compound represented by the following formula (I) stably binds to RAR, and that these compounds have an effect of regulating the physiological activity of retinoid, and have completed the present invention. .

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

Embedded image Wherein, X is -NH-CO -, - CO- NH-, or -C (NH ₂₎ = NO-
A linking group represented by CO— or a single bond; n
Represents an integer of 1 to 5; R represents the following formula:

Embedded image (Wherein, R ¹ , R ² , or R ³ represents a hydrogen atom or a lower alkyl group, and one or more substituents may be present on the aromatic ring) Or a salt thereof.

[0007] In another aspect, the present invention provides a method comprising:
A medicament comprising the compound represented by (I) or a physiologically acceptable salt thereof is provided. The medicament of the present invention can be used as a retinoid action regulator or a nuclear receptor ligand action regulator, and more preferably as a retinoid action inhibitor or a nuclear receptor ligand action inhibitor. According to a preferred embodiment of the present invention, the above-mentioned medicine used as an action regulator of a physiologically active substance which exerts a physiological action by binding to a nuclear receptor belonging to the nuclear receptor superfamily, preferably as an action inhibitor; The above medicine wherein the physiologically active substance is a retinoid is provided.

According to yet another aspect of the present invention, the use of the above-mentioned compound or a salt thereof for the manufacture of the above-mentioned medicament, preferably in the form of a pharmaceutical composition, and in vivo in mammals including humans. A method for regulating the action of a retinoid, preferably a method for suppressing the action of a retinoid, wherein an effective amount of a substance selected from the group consisting of the compounds or physiologically acceptable salts thereof is administered to mammals including humans. A method is provided that includes the step of: Further, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound or a physiologically acceptable salt thereof and a retinoid.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), n is 1 to 5
Where (CF ₃ ) _n indicates that there are n trifluoromethyl groups on the benzene ring. The position of the trifluoromethyl group is not particularly limited, but is preferably in the meta position with respect to the bond or group represented by X, and more preferably two trifluoromethyl groups are present in the meta position. preferable. When X represents a single bond, the group represented by R is directly bonded to the benzene ring.

In the above group represented by R, as the lower alkyl group represented by R ¹ , R ² or R ^3, a linear or branched alkyl group having about 1 to 6 carbon atoms can be used.
More specifically, a methyl group, an ethyl group, an n-propyl group,
An isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like can be used. One or more substituents may be present on the aromatic ring of the group represented by R, and when two or more substituents are present, they may be the same or different. Although the type of the substituent is not particularly limited, for example, a lower alkyl group (eg, a methyl group or an ethyl group), a lower alkoxy group (eg, a methoxy group, an ethoxy group), or a halogen atom (eg, a fluorine atom, a chlorine atom, or a bromine atom) may be used. Can be mentioned.

The compound of the present invention represented by the formula (I) may exist in the form of a salt such as an acid addition salt or a base addition salt, and any salts are included in the scope of the present invention. Acid addition salts include mineral acid salts such as hydrochloride or hydrobromide, or organic acid salts such as p-toluenesulfonate, methanesulfonate, oxalate, or tartrate. . As the base addition salt, for example, 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 salt such as a triethylamine salt or an ethanolamine salt can be used. It can also be present as an amino acid salt such as a glycine salt. Further, the compound of the present invention or a salt thereof may exist as a hydrate or a solvate, and these substances are also included in the scope of the present invention.

The compound of the present invention may have one or more asymmetric carbons depending on the type of the substituent, but may have stereoisomers such as optically active isomers and diastereomers,
Any mixtures, racemates and the like of the stereoisomers are included in the scope of the present invention. Further, in addition to geometric isomers based on double bonds (syn- or anti-isomers) or any mixtures thereof, tautomers, if any, are also included in the scope of the present invention. .

Among the compounds of the present invention represented by the above general formula (I), preferred compounds include the following compounds and C ₁ -C ₆ alkyl esters of these compounds. It is not limited to the compound of.

[0014]

Embedded image

The working examples of this specification illustrate the preparation of the above preferred compounds encompassed by formula (I) of the present invention. Accordingly, any of the compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials, reaction reagents, reaction conditions, and the like used in these production methods. However,
The method for producing the compound of the present invention is not limited to those specifically described in Examples.

The compound represented by the formula (I) or a salt thereof has an activity of regulating the physiological activities of retinoids (typically, cell differentiation activity, cell growth promoting activity, life sustaining activity, etc.). And preferably has the effect of remarkably suppressing the physiological activity of retinoids. Further, the above-mentioned compound or a salt thereof is a substance which expresses a physiological activity by binding to a receptor belonging to the nuclear receptor superfamily existing in the nucleus of a cell (for example, a steroid compound,
Vitamin D compounds such as vitamin D _3, or acts to modulate the biological activity of thyroxine, etc.), preferably has an action to suppress the physiological activity. Furthermore, it can regulate the action of orphan receptors of unknown ligand present in the nucleus.

Accordingly, the compound of the present invention or a salt thereof is used, for example, for the prevention and / or treatment of diseases associated with abnormal biological actions involving one or more nuclear receptors belonging to the nuclear receptor superfamily. be able to.

When the compound of the present invention is used as a medicament, it is selected from the group consisting of the compound represented by the above formula (I) and physiologically acceptable salts thereof, and hydrates and solvates thereof. One or two or more substances may be administered as they are, but preferably one or two or more of the above substances are used.
It can be administered in the form of a pharmaceutical composition comprising more than one species and a pharmaceutical additive. In addition, one or more active ingredients such as retinoids and steroid compounds may be further blended with the above-mentioned pharmaceutical composition, and used as a so-called pharmaceutical composition. The pharmaceutical composition can be prepared in any form for oral or parenteral administration.

Pharmaceutical compositions suitable for oral administration include:
For example, tablets, capsules, powders, fine granules, granules, solutions, syrups and the like can be mentioned. Examples of the pharmaceutical composition suitable for parenteral administration include injections, drops, suppositories, Examples include inhalants, eye drops, nasal drops, ointments, creams, patches, transdermal absorbents, and transmucosal absorbents. Examples of the pharmaceutical additives used for producing the above pharmaceutical composition include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, and dissolving agents. Or a solubilizing agent, a tonicity agent, a pH adjuster, a stabilizer, a propellant, and an adhesive, which can be appropriately selected by those skilled in the art according to the form of the pharmaceutical composition. Alternatively, two or more kinds may be used in combination.

The dose of the medicament of the present invention is not particularly limited.
In the case where a drug containing a retinoid such as retinoic acid as an active ingredient and a drug of the present invention are used in combination to regulate and preferably control the action of a retinoid, or when a drug containing a retinoid is not used in combination, the drug already exists in a living body In any administration method such as administration of the medicament of the present invention for controlling the action of retinoic acid, preferably for controlling the action, an appropriate dose can be easily selected. When a drug containing a retinoid as an active ingredient and the drug of the present invention are used in combination,
The medicament of the present invention can be administered at any time or period, such as during the retinoid administration period, or one or both periods before and after the retinoid administration period.

[0021]

EXAMPLES Hereinafter, the present invention will be described in more detail 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 shown above as preferred compounds.

Example 1: 4-[(3,4-bis (trifluoromethyl)
Preparation of phenylcarboxamide] benzoic acid (compound 3) Methyl p-aminobenzoate (606 mg) was added to anhydrous benzene (15
dissolved in pyridine (3 mL) and 3,4-bis (trifluoromethyl) benzoic acid chloride (1.1 g) with stirring
Was added in anhydrous benzene (2 mL). After stirring overnight at room temperature, the reaction mixture was poured into 2N aqueous hydrochloric acid and extracted with methylene chloride. The organic layer was washed sequentially with 2N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, and dried over Na ₂ SO ₄ . After distilling off the solvent, the residue methylene chloride - was recrystallized from hexane mixed solution, 4 -. Was obtained [(3,4-bis (trifluoromethyl) phenyl carboxamide] benzoate (1.34 g) ¹ H-NMR (400 MHz, CDCl ₃ ) 8.34 (2 H, br s), 8.10 (2
H, d, J = 8.8 Hz), 8.09 (1 H, br s), 8.00 (1 H, br
s), 7.77 (2 H, d, J = 8.8 Hz), 3.93 (3 H, s) Anal.Calcd. for C ₁₇ H ₁₁ F ₆ NO ₃ , C: 52.19%, H: 2.83%,
N: 3.58%; Found C: 52.15%, H: 3.10%, N: 3.59%

Methyl 4-[(3,4-bis (trifluoromethyl) phenylcarboxamide] benzoate (150 mg) was dissolved in methanol (8 mL), and a 2N aqueous sodium hydroxide solution (2 mL) was added. After the disappearance of the raw materials, the reaction mixture was added with a 2N aqueous hydrochloric acid solution to adjust the pH to 7 or less, and extracted with ethyl acetate.The organic layer was washed successively with water and dried over Na2SO4. The residue was recrystallized from an ethyl acetate-hexane mixed solution to give 4-[(3,4-bis (trifluoromethyl)
Phenylcarboxamide] benzoic acid (compound 3) (137m
g) was obtained. Colorless prisms (ethyl acetate-hexane); mp 256-257
° C ¹ H-NMR (400 MHz, DMSO-d ₆ ) 10.88 (1 H, s), 8.62 (2
H, s), 8.38 (1 H, s), 7.98 (2 H, d, J = 8.8 Hz), 7.
90 (2 H, d, J = 8.8 Hz) Anal.Calcd. For C ₁₆ H ₉ F ₆ NO ₃ , C: 50.94%, H: 2.40%,
N: 3.71%; Found C: 50.84%, H: 2.67%, N: 3.59%

Example 2: 4-[(3,4-bis (trifluoromethyl)
Preparation of phenylcarbamoyl] benzoic acid (compound 4) Dissolve 3,4-bis (trifluoromethyl) aniline (917 mg) in anhydrous benzene (15 mL) and pyridine (3 mL), and stir terephthalic acid monomethyl chloride (3 800
mg) in anhydrous benzene (2 mL). After adding 4- (dimethylamino) pyridine (3 mg), the mixture was stirred overnight at room temperature. The reaction mixture was poured into 2N aqueous hydrochloric acid and extracted with methylene chloride. The organic layer was washed sequentially with 2N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, and dried over Na ₂ SO ₄ . After distilling off the solvent, the residue ethyl acetate - was recrystallized from hexane mixed solution, 4 -. Was obtained [(3,4-bis (trifluoromethyl) phenylcarbamoyl] benzoic acid (1.34 g) ¹ H-NMR (400 MHz, CDCl ₃ ) 8.20 (2 H, br s), 8.18 (2
H, d, J = 8.8 Hz), 8.10 (1 H, br s), 7.95 (2 H, d,
J = 8.4 Hz), 7.68 (1 H, br s), 3.98 (3 H, s) Anal.Calcd. For C ₁₇ H ₁₁ F ₆ NO ₃ , C: 52.19%, H: 2.83%,
N: 3.58%; Found C: 52.20%, H: 2.97%, N: 3.30%

Methyl 4-[(3,4-bis (trifluoromethyl) phenylcarbamoyl] benzoate (106 mg) was dissolved in methanol (8 mL), and a 2N aqueous sodium hydroxide solution (2 m
L) was added and the mixture was stirred at room temperature. After the disappearance of raw materials, 2
The pH was adjusted to 7 or less by adding an aqueous solution of N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed successively with water and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was recrystallized from a mixed solution of ethyl acetate-hexane to give 4-[(3,4-bis (trifluoromethyl) phenylcarboxamide] benzoic acid (compound 4) (91 mg).
I got Colorless prisms (ethyl acetate-hexane); mp 274-275
° C ¹ H-NMR (400 MHz, CDCl ₃ ) 10.96 (1 H, s), 8.52 (2 H,
br s), 8.10 (4 H, s), 7.83 (1 H, br s) Anal.Calcd. for C ₁₆ H ₉ F ₆ NO ₃ , C: 50.94%, H: 2.40%,
N: 3.71%; Found C: 50.96%, H: 2.67%, N: 3.51%

Example 3: Preparation of 5- [4-[(3,4-bis (trifluoromethyl) phenylcarboxamidobenzylidene] -2,4-dioxothiazolidine (compound 5) 4-[(3,4-bis (Trifluoromethyl) phenylcarboxamide] methyl benzoate (1.0 g, 3.0 mmol) in anhydrous THF 20
Dissolve at -20 ° C in 9 ml of DIBAL (1 M toluene solution, 9
mmol) was added slowly. One hour later, the reaction solution was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 8: 1) to give 750 mg of 3,4-bis (trifluoromethyl) -N- [4- (hydroxymethyl) phenyl] benzenecarboxamide. Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 8.33 (2 H, s), 8.07 (1 H,
s), 7.93 (br s, 1 H), 7.64 (d, 2 H, J = 1.8 Hz),
7.41 (d, 2 H, J = 8.4 Hz), 4.71 (s, 2 H), 1.37 (s,
18 H)

3,4-bis (trifluoromethyl) -N- [4- (hydroxymethyl) phenyl] benzenecarboxamide 750
mg (2.07 mmol) of methanol-free methylene chloride 50
The mixture was dissolved in ml, and 500 mg of PCC was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (methylene chloride), and purified using 4-[(3,4-bis
(Trifluoromethyl) phenylcarboxamide] benzaldehyde (522 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.99 (s, 1 H), 8.35 (2 H,
s), 8.12 (br s, 1 H), 8.10 (br s, 1 H), 7.96 (d, 2
H, J = 8.4 Hz), 7.88 (d, 2 H, J = 8.8 Hz)

4-[(3,4-bis (trifluoromethyl) phenylcarboxamide] benzaldehyde 180 mg (0.5 mmo
l) 58 mg of 2,4-thiazolidinedione in anhydrous toluene 10
and add 13 mg of piperingin and 9 mg of acetic acid.
The mixture was refluxed at 120 ° C. for 5 hours. Pour the reaction solution into ice water,
Extracted with ethyl acetate. Wash the organic layer with saline and add Na ₂ SO ₄
After dehydrating with a solvent and concentrating the solvent, recrystallized from methanol to give 5- [4
-[(3,4-bis (trifluoromethyl) phenylcarboxamidobenzylidene] -2,4-dioxothiazolidine (compound
5) got. Yellow needles (methanol); mp> 300 ° C ¹ H-NMR (400 MHz, DMSO-d ₆ , 30 ° C) 12.54 (1 H, br s),
10.89 (s, 1 H), 8.61 (br s, 2 H), 8.38 (br s, 1
H), 7.95 (d, 2 H, J = 8.8 Hz), 7.76 (s, 1 H), 7.65
(d, 2 H, J = 8.8 Hz)

Example 4: 5- [4- [N-methyl-[(3,4-bis (trifluoromethyl) phenyl] carboxamidobenzylidene]-
Production of 2,4-dioxothiazolidine (compound 6) NaH (20 mg) was washed twice with n-hexane (1 mL) and suspended in anhydrous dimethylformamide (DMF, 2 mL). Four-
[(3,4-bis (trifluoromethyl) phenylcarboxamide] benzaldehyde (180 mg, 0.5 mmol) was added to anhydrous DMF (2
ml) and slowly added to the above suspension. After 30 minutes, methyl iodide (1 mL) was added, and the mixture was further stirred for 1 hour. After excess methyl iodide and DMF were distilled off under reduced pressure, water and methylene chloride were added to the residue. The organic layer is washed with water, dehydrated with Na ₂ SO ₄ , concentrated, and then silica gel column chromatography (methylene chloride)
To give 4- [N-methyl-[(3,4-bis (trifluoromethyl) phenyl] carboxamide] benzaldehyde (118 m
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.95 (s, 1 H), 7.82 (d, 2
H, J = 8.8 Hz), 7.79 (br s, 1 H), 7.75 (br s, 2
H), 7.21 (d, 2 H, J = 8.4 Hz), 3.58 (s, 3 H)

4- [N-methyl-[(3,4-bis (trifluoromethyl) phenyl] carboxamide] benzaldehyde 80 m
g (0.22 mmol) and 25 mg of 2,4-thiazolidinedione in 8 ml of anhydrous toluene.
g was added and the mixture was refluxed at 120 ° C. overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. Wash the organic layer with saline,
After dehydration with Na ₂ SO ₄ and concentration of the solvent, recrystallization from a mixed solution of ethyl acetate and hexane gave 5- [4- [N-methyl-[(3,4-bis (trifluoromethyl) phenyl] carboxamidobenzylidene]. -2,4-Dioxothiazolidine (compound 6) was obtained Pale yellow prisms (ethyl acetate / n-hexane);
4-226 ° C 1H-NMR (400 MHz, DMSO-d ₆ , 30 ° C) 8.06 (s, 1 H), 7.9
5 (s, 2 H), 7.71 (s, 1H), 7.51 (d, 2 H, J = 8.8 H
z), 7.43 (d, 2 H, J = 8.3 Hz).

Test Example: Assay for Inducing Cell Differentiation in HL-60 Cells Using each of the compounds obtained in Examples 1 to 4, the effects of the compounds alone on the cell differentiation inducing action and the effects of retinoids on the cell differentiation inducing action were examined. . Am80 as retinoid [4-
[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid was used at a concentration of 3 × 10 ⁻¹⁰ M. According to the method described in JP-A-61-76440, using the promyelocytic leukemia cell line HL-60, the differentiation into granulocytic form and nitroblue tetrazolium
Percentage of differentiated cells determined by measuring (NBT) reducing ability
(%) Was calculated from the NBT reducing ability. Table 1 shows the differentiation-inducing effect of the compound alone (the ratio of the cells induced to differentiate (%)), and Table 2 shows the ratio (%) of the cells induced to differentiate in the presence of 3 × 10 ⁻¹⁰ M Am80. .

[0032]

[Table 1]

[0033]

[Table 2]

[0034]

The compound of the present invention has a function of regulating the physiological activity of retinoid, and is useful as a medicament for treating and / or preventing diseases such as retinoid excess.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/341 A61K 31/34 601 4H006 31/4245 31/41 603 31/426 31/425 601 C07C 233 / 65 C07C 233/65 233/66 233/66 C07D 271/12 C07D 271/12 277/34 277/34 307/54 307/54 F term (reference) 4C033 AD01 AD09 AD17 AD20 4C037 HA15 HA31 HA32 4C056 AA01 AB02 AC04 AD03 AE03 FA17 FB01 FC07 4C086 AA01 AA02 AA03 BC66 BC82 BC99 MA04 NA14 ZA96 ZB13 ZB15 ZC02 4C206 AA01 AA02 AA03 DA17 GA34 MA04 NA14 ZA96 ZB13 ZB15 ZC02 4H006 AA01 AA03 AB20 BM10 BM71 BS30 B30B

Claims (6)

[Claims] (1) The following formula (I): Wherein, X is -NH-CO -, - CO- NH-, or -C (NH ₂₎ = NO-
A linking group represented by CO— or a single bond; n
Represents an integer of 1 to 5; R represents the following formula: (Wherein, R ¹ , R ² , or R ³ represents a hydrogen atom or a lower alkyl group, and one or more substituents may be present on the aromatic ring) Or a salt thereof. 2. The following formula: The compound according to claim 1, which is selected from the group consisting of compounds represented by the formula: C ₁ -C ₆ alkyl esters of these compounds, and salts of these compounds. 3. A medicament comprising the compound according to claim 1 or a physiologically acceptable salt thereof. 4. The medicament according to claim 3, which is in the form of a pharmaceutical composition comprising the compound according to claim 1 or 2, which is an active ingredient, or a physiologically acceptable salt thereof, and a pharmaceutical additive. 5. The medicament according to claim 3, wherein the medicament is used as an inhibitor of a physiologically active substance which exerts a physiological action by binding to a nuclear receptor belonging to the nuclear receptor superfamily. 6. The medicament according to claim 5, wherein the physiologically active substance is a retinoid antagonist.