WO1998045242A1 - Retinoid activity regulators - Google Patents

Abstract

Compounds represented by general formula (I), wherein R1 represents hydrogen or C¿1-6? alkyl; R?2, R3 and R4¿ represent hydrogen, C¿1-6? alkyl, etc.; and X represents a divalent group -C(R?5)(R6¿)- or -NR7- (wherein R5 represents hydrogen or hydroxy; R6 represents phenyl or a 5- or 6-membered, saturated or unsaturated nitrogen-containing heterocycle; and R7 represents hydrogen, C¿1-12? alkyl optionally having one or more unsaturated bonds, etc.). Because of the effect of regulating the expression of the physiological activities of retinoids such as retinoic acid, these compounds are useful as retinoid activity regulators.

Description

 Description Retinoid action regulator Technical field

 The present invention relates to a novel compound, and more particularly to a novel compound which regulates a physiological action of a nuclear receptor monoligand represented by a compound having a retinoic acid-like retinoic acid-like physiological activity (retinoide). . The compound of the present invention is useful as an active ingredient of a medicament such as a retinoid action regulator. Background art

 Retinoic acid (vitamin A acid) is an active metabolite of vitamin A. It acts to differentiate developing immature cells into mature cells with unique functions, promote cell growth, It has extremely important physiological functions such as life support. Various vitamin A derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and journals' Ob 'Medicinal' Chemistry (Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p. 2182) have been shown to have similar physiological effects. Such compounds having retinoic acid and retinoic acid-like biological activity are collectively referred to as "retinoides".

 For example, all-trans 'retinoic acid is a nuclear receptor present in the cell nucleus', a retinoic acid receptor belonging to the superfamily (Evans, RM, Science, 240, p. 889, 1988). (RAR) as a ligand has been shown to regulate the proliferation, differentiation, or cell death of animal cells (Petkovich,

M., et al., Nature, 330, pp. 444-450, 1987). The above-mentioned compounds having retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyDcarbamoyl] benzoic acid: Am80, etc.) are also used. Similar to retinoic acid, it has been suggested that it binds to RAR and exerts physiological activity (Hashimoto, Y., Cell struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Co., Ltd., 166, pp. 1300-1307, 1990). These compounds have been found clinically to be useful in the treatment and prevention of vitamin A deficiency, epithelial keratosis, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers. ing.

 Compounds that act antagonistically on such retinoids and attenuate the typical actions of the above-mentioned retinoids are known (Eyrolles, L., et al., Journal of Medicinal Chemistry, 37 (10) ), pp. 1508-1517, 1994). On the other hand, there are few reports on substances that enhance the action of retinoids, such as retinoic acid, even though they do not have retinoid action by themselves or their retinoid action is weak. For example, Japanese Patent Application Laid-Open No. 8-59511 discloses that a compound which is a specific ligand for RXR receptor has an action of enhancing the action of Am80 which is a specific ligand compound for RAR-receptor. Is suggested. This publication states that 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbonyl] benzoic acid-ethylene acetal induces the differentiation of Am80. It has been suggested to enhance the effect. Further, the present inventor has proposed that 4-H-2,3- (2,5-dimethyl-2,5-hexano) 5-methyldibenzo [b, e] [1,4] dazepine-1 trityl Benzodiazepine compounds such as benzoic acid (HX600) were found to enhance the action of retinoids (Umemiya et al., Chem. Pharm. Bull., 43, pp. 1827-1829, 1995). The action of this compound is thought to activate the RXR receptor, which forms the RXR-RAR heterodimer. Disclosure of the invention

An object of the present invention is to provide a compound having an action of regulating the action of retinoid such as retinoic acid. More specifically, it is capable of enhancing the action of retinoids such as retinoic acid, despite having no retinoide action or having a weak retinoide action, or It is an object of the present invention to provide a compound capable of suppressing the action of retinoid. The present inventor has made intensive efforts to solve the above-described problems, and as a result, is represented by the following general formula. These compounds have been found to have an effect of regulating the action of retinoids such as retinoic acid, and have completed the present invention.

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

Wherein, R ¹ represents a hydrogen atom or a _ ₆ alkyl group; R ^2, R ^d, and R ⁴ are each independently a hydrogen atom, an alkyl group, or either an alkoxy group, or a ^ and R ³ are adjacent 2 1 or on them, may form a 5- to 6-membered ring together with the carbon atoms on Fuweniru groups bonded together such connexion ^ and R ^u (above rings the ring in the case of X may be -C (R ⁵ ) (R ^D, which may have one of the above-mentioned alkyl groups or one condensed benzene ring which may have one or more substituents). )-Or -NR ^7- represents a divalent group (wherein IT represents a hydrogen atom or a hydroxyl group; ^RD represents a phenyl group which may have a substituent, or may have a substituent. It is 5 shows the saturated or heterocyclic group unsaturated nitrogen-containing 6-membered; R ⁷ is a hydrogen atom, on one or two or more non Also c ₂ alkyl group having a sum bond, (:. _Gamma cycloalkyl group, c ₄ _ ₁₂ cycloalkyl substituted alkyl groups, also Ararukiru group which may be substituted, c ₂ Arukanoiru group, which may be substituted Or a phenyl group which may have a substituent)) or a salt thereof. In another aspect, the present invention provides a compound represented by the formula And a pharmaceutically acceptable salt thereof, and a drug comprising as an active ingredient a substance selected from the group consisting of hydrates and solvates thereof. According to a preferred embodiment of the present invention, a nuclear receptor belonging to the nuclear receptor / superfamily type is used. The above medicament acting regulatory an action-enhancing or suppressing the activity; use are the aforementioned medicament as acting regulatory agent of a physiologically active substance to exert physiological effects by binding to the coater and the The above medicine wherein the physiologically active substance is a retinoid is provided.

 From a further aspect, according to the present invention, the above-mentioned compounds and physiologically acceptable salts thereof for the manufacture of the above-mentioned medicament, preferably for the manufacture of a medicament in the form of a pharmaceutical composition, and water thereof. And a method for regulating the action of retinoid in a living body of a mammal, including human, comprising the compound and a physiologically acceptable substance. A method comprising administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of a salt thereof, and hydrates and solvates thereof. This method includes, for example, vitamin A deficiency; keratosis of epithelial tissue and skin diseases such as psoriasis; allergic diseases; immunological diseases such as rheumatism; bone diseases such as osteoporosis and fractures; Alzheimer's disease; Or a method for preventing and / or treating a disease such as cancer, and preventing and / or treating a disease such as diabetes, arteriosclerosis, hyperlipidemia, hypercholesterolemia, bone disease, rheumatism, or immune disease. Available as a method. Further, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound selected from the group consisting of the above compound, a physiologically acceptable salt thereof, a hydrate thereof, and a solvate thereof, and a retinoid. Things are provided. BEST MODE FOR CARRYING OUT THE INVENTION

In the compound represented by the above formula (I), R ¹ is a hydrogen atom or an alkyl group (rc ^

— J means that the group contains from 1 to 6 carbon atoms in total, as well as other similar expressions used herein.) Indicate an alkyl group. The alkyl group may be straight-chain or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, etc. be able to. Preferably, a methyl group, an ethyl group, or the like can be used.

R ^2, R ^J s and R ⁴ each independently represent a hydrogen atom, - shows a ₆ alkoxy group - ₆ alkyl group, or. The alkyl group may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, A tert-butyl group or the like can be used. Among these, it is preferable to use a bulky alkyl group such as an isopropyl group and a tert-butyl group. The _6- alkoxy group may be straight-chain or branched, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, etc. Can be used. The substitution position of R ² and R ³ is not particularly limited, but can be substituted in any position independently, it is preferred that ^ Oyobi is substituted at adjacent positions with each other. For example, it is particularly preferred that R ² and R ³ are at the para and meta positions, respectively, with respect to X.

When R ² and R ³ are substituted at adjacent positions, they together form a 5- or 6-membered ring, preferably a 6-membered ring, with the carbon atom on the phenyl group to which R ² and R ³ are attached. May be. It thus 5 are formed in the 6-membered ring, the ring on the one or more (^ - ₄ alkyl groups may have, for example, 2-4-methylcarbamoyl group, preferably it may have 4 methyl groups. for example, by the R ² and R ³ and the benzene ring of Fuyuniru group you substituted R ² and R ^3, 5, 6,7,8-Tetorahi mud It is preferable that a naphthalene ring or a 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring or the like be formed.

Further, a 5- to 6-membered ring, preferably a 6-membered ring formed by combining R ² and R ³ may have one fused benzene ring. In such a case, one or more C ₁ _ _/ (alkyl groups may be present on the 5- or 6-membered ring formed by combining R ² and R ³ , for example, 2 Up to 4 methyl groups, preferably 4 methyl groups, may be present on each ring, and the condensed benzene ring may be unsubstituted, but may be an alkyl group or an alkoxy group. And may have one or more substituents such as a halogen atom, for example, depending on the benzene ring, R ² and R ^{3 of} the phenyl group substituted with and ^, and the benzene ring to be condensed. , 6, 7, 8 Tetorahi Doroanto Raseniru ring, 5, 5, 8, 8 - tetramethyl -. 5, 6, 7,8, etc. Te Torahi mud anthracenyl ring may be formed R ⁴ is It is preferably a hydrogen atom or an alkyl group.

X represents a divalent group represented by -C (R ⁵ ) (R ⁶ )-or -N (R ⁷ )-. R ⁵ represents a hydrogen atom or a water group, but is preferably a hydrogen atom. R ^D may have a substituent. It represents a benzyl group or a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group which may have a substituent. When ^RD represents a phenyl group having a substituent, the phenyl group may have one or more substituents. As the substituent, for example, it may be used an alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, a halogenated aralkyl kill group, a carboxyl group, _ ₆ alkoxycarbonyl group, an alkylcarbonyl group, and substituted or unsubstituted amino group force, ', of which ^ alkyl group, ^ _-6 alkoxy group, or a hydroxyl group are preferred. The number and substitution position of the substituents on the phenyl group are not particularly limited, but it is preferable that one substituent is present at the p-position.

The 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group represented by R ^Q may contain at least one nitrogen atom as a ring-constituting atom, for example, 1 pyrrolidinyl group, 1- Saturated nitrogen-containing heterocyclic groups such as piperidinyl group, morpholino group and 1-piperazinyl group; unsaturated nitrogen-containing heterocyclic groups such as 3-pyrroline-1-yl group; topirolyl group, trimidazolyl group, 1- Nitrogen-containing heteroaryl groups such as a bilazolyl group, a 1,2,4-triazol-1-yl group and a 1-tetrazolyl group can be used. These nitrogen-containing heterocyclic groups may contain one or more hetero atoms other than nitrogen, for example, an oxygen atom or a sulfur atom. Also, nitrogen-containing heterocyclic group may be unsubstituted, but for example, _alkyl group, ₆ alkoxy group, a hydroxyl group, a halogen atom, a halogenated alkyl group, a carboxyl group, ₆ alkoxycarbonyl group, - ₆ alkyl It may have one or two or more substituents such as a hydroxyl group or a substituted or unsubstituted amino group. The bonding mode between the nitrogen-containing heterocyclic group and the carbon atom to which R ⁵ and R ⁶ are bonded is not particularly limited, but the nitrogen atom constituting the nitrogen-containing hetero ring and the above carbon atom may be bonded. preferable.

R 'is a hydrogen atom, one or two or more are also ₁₂ alkyl Le group having an unsaturated bond, c ₃ - ₁₂ cycloalkyl group, - ^ cycloalkyl-substituted alkyl group, it may have a substituent Ararukiru And a c ₂ alkanol group, an optionally substituted aryloyl group, or an optionally substituted phenyl group. _{12 The} alkyl group may be linear or branched, and may have one or more unsaturated groups. May have a match. The unsaturated bond may have one or more double bonds and one or more triple bonds in combination. The double bond may be either Z- or E-type. The c ₃ one ₁₂ cycloalkyl group, for example, Shikuropuropi group, cyclobutyl group, cyclopentyl group, or the like can be used a cyclohexyl group, these cycloalkyl groups one or two more on the ring May have an alkyl group. c ₄ - The _C12 cycloalkyl substituted alkyl group, an alkyl group in which the cycloalkyl group is substituted, preferably a cycloalkyl substituent al Kill group, for example, can be used as the cyclopropylmethyl group.

Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a biphenylmethyl group, a phenethyl group and the like. The one or more substituent groups present on Ariru ring in substituent Ararukiru group, for example, (^ _-6 alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, a halogenated _alkyl group, a force Rupokishiru group, alkoxycarbonyl group, - ₆ alkylcarbonyl group, a substituted young properly may be used as the unsubstituted § Mi cyano group.

The c _{M 2} Arukanoiru group, for example, Asechiru group, Puropanoiru group, can be used as the pig Noiru group, the Aroiru group, for example, it can be used as Benzoiru group, naphthoyl group. The one or more substituent groups present on § Li Ichiru ring in substituent Aroiru group, e.g., p-alkyl group, (^ _ ₆ alkoxy group, a hydroxyl group, a halogen atom, a halogenated alkyl group, a carboxyl group , _ ₆ alkoxycarbonyl group, a (. alkylcarbonyl group, such as § Mi amino group substituted or Mu置conversion may be used. one or more substituents Fuweniru group having a substituent group of the substituents You can choose.

When R ⁷ represents a substituted phenyl group, two alkyl groups at adjacent positions

A fuunyl group having a group is preferable, and two adjacent alkyl groups may be bonded to each other to form a 5- to 6-membered ring, preferably a 6-membered ring. The ring thus formed has one or more ^ alkyl groups, preferably 2 to 4 methyl groups, more preferably 4 methyl groups on the ring. You may. For example, as 5,6,7,8-tetrahydronaphthalene-2-yl group, 5,5,8,8-tetramethyl A tyl-5,6,7,8-tetrahydronaphthalene-2-yl group or the like can be used. The compounds of the present invention include acid addition salts or base addition salts. Examples of the acid addition salt include a mineral acid salt such as hydrochloride or hydrobromide, or an organic acid salt such as p-toluenesulfonate, methanesulfonate, oxalate, or tartrate. it can. Examples of the base addition salt include metal salts such as sodium salt, potassium salt, magnesium salt or calcium salt, ammonium salts, and organic amine salts such as triethylamine or ethanolamine salts. Etc. can be used.

 The compound of the present invention may have one or more asymmetric carbons, and any optical isomer based on such asymmetric carbon, any mixture of optical isomers, racemate, two or more Any of the diastereoisomers, arbitrary mixtures of diastereoisomers, and the like based on the asymmetric carbon are included in the scope of the present invention. Also, any geometric isomer based on one or more double bonds is included in the scope of the present invention. Further, any hydrate or solvate of the compound in the form of a free compound or a salt is also included in the scope of the present invention.

Among the compounds of the present invention represented by the above general formula (I), specific examples of preferred compounds are shown, but the compounds of the present invention are not limited to the following compounds.

R ⁵ R 12

R ^J 3

DM010 H H H

DM011 H H OH

DM012 OH H H

DM013 HH OCH ₃ DM014 HHN (CH ₃ ) ₂

DM040

Y ¹

DM020 CH ₂

 DM021 O

DM022 NCH ₃

R ⁴ Y ² Y ³

 DM030 H C N DM031 (TLC low polarity isomer)

DM032 H C C DM036 (TLC highly polar isomer)

DM130 CH ₃ CN

DM033 (TLC low polarity isomer)

 R 4

R ¹ R ⁴ R ⁷

DA010 HH DA040 H Cfl ₂ then 6

_{DA011 H CH 3 DA041 H CH 2} C 6 H 4 - -CH 3 DA012 HC 2 H 5 DA042 H CH 2 C 6 H 4 - / 7-CF 3 DA013 H "-C 3 H 7 DA045 H CH 2 C 6 F _{4 -p-OC 2 H 5 DA014} H nC 4 H 9 DA046 H CH 2 C 6 H 4 -oC 6 H 5 DA015 H "C 5 H U DA048 H CH 2 -2-C 10 H 7 DA016 H" C 6 H ₁₃ DA112 CH ₃ C ₂ H ₅

DA017 H "C ₇ H ₁₅ DA113 CH ₃ nC ₃ H ₇

DA018 H "C ₈ H ₁₇ DA114 CH ₃ 2-C4H

DA020 H CH ₂ C≡CH DA120 CH ₃ CH ₂ C≡CH

DA021 H CH ₂ CH = CH ₂ DA121 CH ₃ CH ₂ CH = CH ₂ DA022 H 50-C ₃ H ₇ DA122 CH ₃ iso-C ^ H-;

DA023 H C-C3H5 DA123 CH ₃ cC ₃ H ₇

DA024 H CH ₂ (cC ₃ H ₅ ) DA124 CH ₃ CH ₂ (cC ₃ H ₅ ) DA025 H CH ₂ CH (CH ₃ ) ₂ DA125 CH ₃ CH ₂ CH (CH ₃ ) ₂ DA028 H CH ₂ CH = C ( CH ₃ ) ₂ DA130 CH ₃ CH ₂ (cC ₄ H ₇ ) DA030 H CH ₂ (cC ₄ H ₇ ) DA162 nC ₃ H ₇ C ₂ H ₅

_{DA036 H CH 2 (cC 6 H} u) DA163 "-C 3 H 7" -C 3 H 7

R ⁷ R ⁸丄 DA051

Then 2 ^tt 5 CH ₃

DA213 AZ-C3H7 DA055 C ₆ H ₅

_{DA222 DA058 C 6 H 4 - /} 7-COOH

DA223 C-C3H5

DA224 CH ₂ (cC ₃ H ₅ )

TA001 TA012 Examples in the present specification specifically describe methods for producing the above-mentioned preferred compounds included in the formula (i) of the present invention. Therefore, any compound 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, the reaction conditions, and the like. However, the production method of the compound of the present invention is not limited to those specifically described in Examples.

The compound of the present invention represented by the above formula (I) has an action of regulating the physiological action of retinoid. As used herein, the term "modulating effect" or its analogues It should be interpreted in the broadest sense, including any enhancement or suppression of use. Whether the compound of the present invention has an enhancing action or an inhibitory action can be easily assayed according to the method specifically shown in the test examples of the present specification.

 Among the compounds of the present invention represented by the above formula (I), the compound having potent retinoid action has no retinoid-like action itself, or has weak or moderate retinoid action. However, when the compound of the present invention is allowed to coexist with a retinoid such as retinoic acid, the physiological activity of the retinoid (typically, a cell differentiation action, a cell growth promoting action) , And life-sustaining effects). Without being bound by any particular theory, if the compound of the present invention itself has a retinoid effect, the effect is synergistic.

 Therefore, retinoic acid イ ン a compound having a retinoic acid-like biological activity (for example,

Retinoids containing 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-sir hthalenyl) carbamoyl "benzoic acid: Am80, etc., are used in vitamin A deficiency; epithelial tissue Skin diseases such as keratosis and psoriasis; allergic diseases; immune diseases such as rheumatism; bone diseases such as osteoporosis and fractures; Alzheimer's disease; Huntington's chorea; prevention of diseases such as leukemia or cancer; When administered as a therapeutic agent or a medicament for treatment, the compound of the present invention can be used as an enhancer of the action of the retinoid.

Further, even when retinoide is not administered for the treatment and / or prevention of the above-mentioned disease, the compound of the present invention enhances the action of retinoic acid already present in the living body, so It is also possible to administer the compound of the invention itself for Z or prophylactic purposes. Furthermore, the compound of the present invention has not only an effect of enhancing action on retinoids, but also a nuclear receptor superfamily (Evans, RM, Science, 240, p. 889, physiologically active substance to exert physiological effects by binding a ligand to a receptor (nuclear receptions terpolymer) belonging to 1988), for example, scan Teroi de compounds, vitamin D compounds such as vitamin!) _0, or potentiators, such as thyroxine Can also be used. For example, prevention and / or prevention of diseases such as diabetes, arteriosclerosis, hyperlipidemia, hypercholesterolemia, bone disease, rheumatism, or immune disease. Useful as a medicament for treatment. However, the use of the compound of the present invention is not limited to the use specifically described above.

In addition, among the compounds of the present invention represented by the above formula (I), compounds that inhibit retinoid action include physiological actions of retinoid (typically, cell differentiation action, cell proliferation action, life support action, etc.). ) Is significantly suppressed. Furthermore, compounds of the above SL is a substance exerting a physiological activity bound to the receptor that belongs to the nuclear receptor 'super one Hua Mi Li present in the nucleus of a cell, for example, steroids compounds, Vita Mi emissions 0 ₃ And the effects of vitamin D compounds such as thyroxine or unknown receptor receptors. Therefore, a compound having a retinoid action-suppressing property can be used, for example, for regulating the expression of the action of these physiologically active substances, and one of the nuclear receptors belonging to nuclear receptors and superfamily 1 or It can be used for prevention and / or treatment of diseases associated with abnormal biological effects involving 2 or more.

 When the compound of the present invention is used as a medicament, one or two selected from the compound of the above general formula (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof are used. More than one kind of substance may be administered as it is, but preferably, a pharmaceutical composition for oral or parenteral use containing one or more of the above substances as an active ingredient is available to those skilled in the art. It is preferable to administer and administer by using an additive for use. Further, one or more of the above-mentioned substances may be blended with a medicine containing retinoic acid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called combination drug.

Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups. Pharmaceutical compositions suitable for parenteral administration include Examples thereof include injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, and patches. Examples of pharmacologically and pharmaceutically acceptable additives for pharmaceuticals used in the production of the above pharmaceutical composition include excipients, disintegrants or disintegrants, binders, lubricants, —Tinting agents, pigments, diluents, bases, solubilizers or solubilizers, tonicity agents, pH regulators, stabilization And | J, a propellant, and an adhesive.

 The dosage of the medicament of the present invention is not particularly limited, and when the effect of retinoid is regulated by using a medicament of the present invention in combination with a medicament containing a retinoid such as retinoic acid as an active ingredient, or In the case of administering the medicament of the present invention to regulate the action of retinoic acid already existing in the living body without using the medicament containing the same, an appropriate dose can be easily selected in any administration method. For example, in the case of oral administration, it can be used in the range of about 0.01 to 1,000 mg per adult per day. When a medicament containing retinoid as an active ingredient is used in combination with the medicament of the present invention, the medicament of the present invention should be administered during the administration of retinoid and / or before or after the administration of retinoid. Is possible.

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 production methods employed in the following examples are shown in Schemes 1 to 8. The compound numbers in the scheme correspond to the compound numbers of the preferred compounds and the compound numbers in the examples.

Scheme 1

 1-1 1-2

1-3 R ⁵ = OH DM012 R ⁵ = OH 1-4 R ⁵ = H DM010 R ⁵ = H

Love

1-2 II-l R ⁵ = OH

Π-2 R ⁵ = H

HCl I MeOH I

Π-3 DM011 W

S

m-4 DM030

Scheme 4

tetrzole IH ₂ S0

 rv-i IV-2

 IV-3 DM033

Scheme 5

V-4 R ⁵ = OH, R ²¹ = OCH ₂ OCH ₃ DM040 V-5 R ⁵ = OH, R ²¹ = OH

V-6 R ⁵ = H, R ²¹ = OH

Scheme 6

 VI-1 VI-2 KOH aq / EtOH

(R ⁷ = H)

Scheme 7

 VII-4

Scheme 8

例 1 ： 4 - [(5， 6, 7， 8 -テ トラヒ ドロ- 5， 5， 8, 8- テ トラメチルナフタ レ、ノ- 2 - ィル） フエニルメチル] 安息香酸（DM010) の製造 （スキーム 1 )

Example 1: Production of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthaleyl, -2-yl) phenylmethyl] benzoic acid (DM010) Scheme 1)

 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene (1-1, 10.0 g) and monomethylterephthalic acid (10.0 g) in methylene chloride (10.0 g) Aluminum chloride (14.3 g) was slowly added to the solution (100 ml) at room temperature, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into an aqueous hydrochloric acid solution containing ice, and extracted with black hole form. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel gel chromatography (n-hexane: ethyl acetate = 4: 1) to give 4-[(5,6,7,8-tetrahydrofuran). Dro-5,5,8,8-Tetramethylnaphthalene-2-yl) carbonyl] benzoic acid methyl ester (Compound 1-2, 11.2 g) was obtained.

 ½-NMR (400 MHz, CDClg) 8.15 (2H, d, J = 8 Hz), 7.83 (2H, d, J = 8 Hz), 7.79 (1H, d, J = 2 Hz), 7.54 (1H, dd) , J = 8, 2 Hz), 7.41 (1H, d, J = 8 Hz), 3.95 (3H, s), 1.73 (4H, s), 1.32 (6H, s), 1.29 (6H, s).

 An anhydrous THF solution (30 ml) of compound 1-2 (4.99 g) was cooled to 0 ° C under a nitrogen atmosphere, and a Grignard solution of bromobenzene (1M THF solution, 14.3 ml) was slowly added dropwise. . The ice bath was removed, the mixture was stirred at room temperature for 40 minutes, the reaction solution was poured into ice water, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1), and 4- [phenyl- (5,6,7, 8-Tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) hydroxylmethyl] benzoic acid methyl ester (1-3, 4.45 g) was obtained.

 ½-NMR (90 MHz, CDC1J 7.96 (2H, d, J = 8 Hz), 7.42 (2H, d, J = 8 Hz), 7.37-6.81 (8H, m), 3.89 (3H, s), 2.85 ( 1H, s), 1.66 (4H, s), 1.27 (6H, s), 1.14 (6H, s).

Pd-C (0.5 g) was added to an ethanol solution (220 ml) of compound I-3 (4.0 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 46 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from petroleum ether to give 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) phenylmethyl] benzoic acid The acid methyl ester was obtained (4, 1.47 g). ½-NMR (90 MHz, CDClg) 7.94 (2H, d, J = 8 Hz), 7.44-6.69 (10H, m), 5.51 (1

H, s), 3.89 (3 H, s), 1.66 (4 H, s), 1.26 (6 H, s), 1.16 (6 H, s).

 To a solution of compound 1-4 (1.30 g) in ethanol (60 ml) was added a 3.5 sodium hydroxide aqueous solution (4.5 ml), and the mixture was stirred at 60 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 6 N hydrochloric acid while cooling to 0 ° C. The precipitated crystals were collected by filtration, dried, and washed with petroleum ether to obtain M010 (0.59 g).

½-wake (400 MHz, CDClg) 7.98 (2H, d, J = 8 Hz), 7.30-7.16 (6H, m), 7.09 (2H, d, J = 7 Hz), 7.01 (1H, d, J = 2 Hz), 6.79 (1H, dd, J = 8, 2 Hz), 5.50 (1H, s),

I.65 (4H, s), 1.25 (6H, s), 1.16 (6H, s). Example 2: 4- [4-hydroxyphenyl- (5, 6, 7, 8 tetrahydro-5,5 , 8,8-Tetramethylnaphthalene-2-yl) methyl] benzoic acid (M011) (Scheme 2)

 Under ice cooling, a separately prepared Grignard solution of 1-promo-4_ methoxymethoxybenzene (5.0 g) (THF, 20 ml) was added to an anhydrous THF solution (50 ml) of compound 1-2 (8.10 g). After the dropwise addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound II-1 (7.50 g). ½-丽 (90 MHz, CDClg) 7.97 (2H, d, J = 8 Hz), 7.40 (2H, d, J = 8 Hz), 7.3-6.8 (7H, ra), 5.18 (2H, s) , 3.90 (3H, s), 3.47 (3H, s), 2.75 (1H, s), 1.69 (4H, s 1.25 (6H, s), 1.15 (6H, s).

 Pd-C (0.45 g) was added to an ethanol solution (100 ml) of compound Π-1 (1.81), and the mixture was stirred at room temperature under a hydrogen atmosphere for 8.5 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure to obtain compound II-2 (0.76 g).

 ½-Picture (90 MHz, CDClg) 7.93 (2H, d, J = 8 Hz), 7.53-6.69 (7H, m), 7.18 (2H, d, J = 8 Hz), 5.46 (1H, s), 5.15 (2H, s), 3.89 (3H, s), 3.47 (3H, s), 1.66 (4H, s), 1.26 (6H, s), 1.16 (6H, s).

To a methanol solution (60 ml) of compound Π-2 (0.75 g) was added 2 drops of concentrated hydrochloric acid, and the mixture was heated to 40 to 50 ° C. and stirred for 9.5 hours. The reaction solution is concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a compound II-3 (0.63 g).

 ½-NMR (90 MHz, CDClg) 7.93 (2H, d, J = 8 Hz), 7.37-6.62 (9H, m), 5.44 (1H, s), 5.20 (1H , br s), 3.89 (3H, s), 1.65 (4H, s), 1.25 (6H, s), 1.16 (6H, s).

 To a solution of compound II-3 (0.60 g) in ethanol (10 ml) was added a 2.7 N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified by adding 6 N hydrochloric acid while cooling to 0 ° C. The precipitated crystals were separated by filtration, washed well with water, and dried under reduced pressure. The crystals were recrystallized from getyl ether-petroleum ether to give DM011 (0.40 g).

½-NMR (400 MHz, CDClg) 8.01 (2H, d, J = 8 Hz), 7.22 (2H, d, J = 8 Hz), 7.19

(1H, d, J = 8 Hz), 7.00 (1H, d, J = 2 Hz), 6.97 (2H, d, J = 8 Hz), 6.79 (1H, dd, J = 8 , 2 Hz), 6.76 (2H, d, J = 8 Hz), 5.46 (1H, s), 1.66 (4H, s), 1.23 (6H, s), 1.16 ( 6H, s). Example 3: 4- [Phenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) hydroxymethyl] benzoic acid ( M012) (Scheme 1)

 To an ethanol solution (30 ml) of compound 1-3 (2.0 g) was added an aqueous solution (5 ml) of sodium hydroxide (0.60 g), and the mixture was stirred at about 50 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with aqueous hydrochloric acid. The precipitated crystals were collected by filtration, dried, and washed with petroleum ether to obtain DM012 (1.2 g).

 ½-NMR (400 MHz, CDClg) 7.88 (2H, d, J = 8 Hz), 7.38-7.20 (8H, m), 7.15 (1H, d, J = 2 Hz), 6.89 (1H, d, J = 8, 2 Hz), 6.46 (1H, s), 1.65 (4H, s), 1.22 (6H, s), 1.10 (6H, s) Example 4: 4- [4-Methoxyphenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) methyl] benzoic acid (DM013) Manufacturing of

Starting from compound I-2 (see Example 1) and p-promoisole, the procedure described in Example 1 According to the method, M013 was obtained.

 ½-NMR (400 MHz, CDClg) 12.82 (1H, br s), 7.87 (2H, d, J = 8 Hz), 7.24-7.18

(3H, m), 7.07 (1H, s), 7.03 (2H, d, J = 8 Hz), 6.88 (2H, d, J = 8 Hz), 6.83

(1H, d, J = 8 Hz), 5.54 (1H, s), 3.72 (3H, s), 1.61 (4H, s), 1.21 (6H, s), 1.14 (3H, s), 1.13 (3H, s) s). Example 5: 4- [4-Dimethylaminophenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyltylnaphthalen-2-yl) methyl] Manufacture of benzoic acid (DM014)

 M014 was obtained according to the method described in Example 1 using compound 1-2 and 4-bromo-N, N-dimethylaniline as starting materials.

 ½-NMR (400 MHz, CDCl ^) 8.00 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz), 7.18 (1H, d, J = 8 Hz), 7.03 (1H, d, J-2 Hz), 6.97 (2H, d, J = 9 Hz), 6.81 (1H, dd, J = 8, 2 Hz), 6.68 (2H, d, J = 9 Hz), 5.43 (1H, s), 2.92 (6H, s), 1.65 (4H, s), 1.25 (6H, s), 1.17 (3H, s), 1.16 (3H, s). Example 6: 4- [3,4-methylenedi Preparation of oxyphenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) methyl] benzoic acid (M015)

 M015 was obtained according to the method described in Example 1 using Compound 2 and 4-bromo-1,2- (methylenedioxy) benzene as starting materials.

½-NMR (400 MHz, CDClg) 8.01 (2H, d, J = 8 Hz), 7.23 (2H, d, J = 8 Hz), 7.20 (1H, d, J = 8 Hz), 7.01 (1H, d , J = 2 Hz), 6.80 (1H, dd, J = 8, 2 Hz), 6.73 (1H, d, J = 8 Hz), 6.59 (1H, d, J = 2 Hz), 6.57 (1H, dd , J = 8, 2 Hz), 5.93 (2H, s), 5.44 (1H, s), 1.66 (4H, s), 1.26 (6H, s), 1.18 (3H, s), 1.17 (3H, s) Example 7: 4- [4- [2- (l-pyrrolidinyl) ethoxy] phenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2- Preparation of myl) benzoic acid (M016) DM016 was obtained according to the method described in Example 1 using compound 1-2 and 1- [2- (4-bromophenoxy) ethyl] pyrrolidine as starting materials. ½-NMR (400 MHz, CDClg + DMSO-d6) 12.28 (1H, br s), 7.94 (2H, d, J = 8 Hz), 7.18 (1H, d, J = 8 Hz), 7.17 (2H, d , J = 8 Hz), 7.03 (2H, d, J = 9 Hz), 7.01 (1H, d, J = 2 Hz), 6.85 (2H, d, J = 9 Hz), 6.78 (1H, dd, J = 8, 2 Hz), 5.45 (1H, s), 4.48 (2H, t, J = 5 Hz), 3.76 (2H, br s), 3.54 (1H, t, J = 5 Hz), 3.11 (2H, br s), 2.14 (4H, br s), 1.66 (4H, s), 1.25 (6H, s), 1.17 (3H, s), 1.16 (3H, s). Example 8: 4-[(5, 6 , 7, 8-Tetrahydro-5,5,8,8-tetramethylnaphthalene 2-yl) piridinomethyl] benzoic acid (M020) (Scheme 3)

 After sodium borohydride (0.60 g) was slowly added to a methanol solution (200 ml) of compound I-2 (5.0 g) at room temperature, the mixture was further stirred for 2 hours. The reaction mixture was poured into ice water, and the precipitated crystals were separated by filtration and sufficiently washed with water to obtain Compound II-1 (5.10 g).

 ½-NMR (400 MHz, CDCl ^) 7.90 (2H, d, J = 8 Hz), 7.47 (2H, d, J = 8 Hz), 7.29 (1H, d, J = 2 Hz), 7.25 (1H, d, J = 8 Hz), 7.04 (1H, dd, J = 8, 2 Hz), 5.82 (1H, d, J = 3 Hz), 3.89 (3H, s), 2.34 (1H, d, J = 3 Hz), 1.66 (4H, s), 1.23-1.26 (12H, m).

 Compound ΙΠ-1 (5.10 g), 2,4,6-trimethylpyridine (2.1 g) and lithium chloride (0.74 g) in anhydrous dimethylformamide (DMF) solution (30 ml) were added at room temperature. After methanesulfonyl chloride (2.0 g) was slowly added, the reaction mixture was gradually warmed and stirred at about 50 ° C for 3 hours. After the reaction mixture was poured into ice water and extracted with ethyl acetate, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel gel chromatography (n-hexane: ethyl acetate = 4: 1) to obtain Compound II-2 (2.4 g).

½ NMR (400 MHz, CDClg) 8.02 (2H, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 7.30 (1H, d, J = 2 Hz), 7.26 (1H, d, J = 8 Hz), 7.09 (1H, dd, J = 8, 2 Hz), 6.11 (1H, s), 3.91 (3H, s), 1.67 (4H, s), 1.26 (6H, s), 1.23 ( 6H, s).

An anhydrous DMF solution (10 ml) of compound II 1-2 (1.001), piperidine (0.691 g), and carbonated carbonate (1.175 g) was stirred at about 90 ° C. for 3 hours. Cool the reaction solution into ice water Poured and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate == 8: 1) to obtain compound III-3 (0.844 g).

 ½-NMR (400 MHz, CDClg) 7.93 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 8 Hz), 7.28 (1H, d, J = 2 Hz), 7.14 (1H, d , J = 8 Hz), 7.03 (1H, dd, J = 8, 2 Hz), 4.21 (1H, s), 3.87 (3H, s), 2.23 (4H, m), 1.62 (4H, s), 1.55 (4H, ra), 1.42 (2H, m), 1.23 (6H, s), 1.21 (6H, s).

 A 5 N aqueous sodium hydroxide solution (1.2 ml) was added to an ethanol solution (10 ml) of the above ester (0.844 g), and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was cooled to 0 ° C and neutralized with an aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the residue obtained by concentrating the organic phase under reduced pressure was reconstituted with petroleum ether to obtain M020 (0.756 g).

 ½-NMR (400 MHz, CDClg) 8.08 (2H, d, J = 8 Hz), 7.64 (2H, d, J = 8 Hz), 7.40 (1H, d, J2 Hz), 7.20 (1H, dd) , J = 8, 2 Hz), 7.17 (1H, d, J = 8 Hz), 4.47 (1H, s), 2.59 (4H, m), 1.70 (4H, m), 1.61 (4H, s), 1.48 (2H, m), 1.21 (6H, s), 1.19 (6H, s). Example 9: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene -2-yl) morpholinomethyl] benzoic acid (DM021)

 DM021 was obtained according to the method described in Example 8 using compound I-2 and morpholine as starting materials.

½-NMR (400 MHz, CDClg) 8.01 (2H, d, J = 8 Hz), 7.55 (2H, d, J = 8 Hz), 7.30 (1H, d, J = 2 Hz), 7.17 (1H, d , J = 8 Hz), 7.08 (1H, dd, J = 8, 2 Hz), 4.22 (1H, s), 3.72 (4H, m), 2.38 (4H, m), 1.62 (4H, s), 1.24 (3H, s), 1.23 (3H, s), 1.21 (6H, s). Example 10: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) (4-methylpiperazine-1-yl) methyl] benzo Production of acid (DM022)

 DM022 was obtained according to the method described in Example 8 using compound ΙΠ-2 and 1-methylbiperazine as starting materials.

 ½-NMR (400 MHz, CDClg) 7.92 (2H, d, J = 8 Hz), 7.37 (2H, d, J = 8 Hz), 7.27 (1H, d, J = 1.5 Hz), 7.15 (1H , d, J = 8 Hz), 7.08 (1H, dd, J = 8, 1.5 Hz), 4.

32 (1H, s), 2.87 (4H, br s), 2.55 (4H, br s), 2.52 (3H, s), 1.62 (4H, s), 1.21 (12H, s). Example 11: 4-[ (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)-(1,2,4-triazol-1-yl) methyl] Preparation of benzoic acid (M030) (Scheme 3) 1,2,4-Triazole (0.17 g) was added to a solution of sodium hydride (60% in oil, 0.11 g) in anhydrous MF (20 ml) under a dry nitrogen atmosphere. ) Was added at room temperature, and the mixture was stirred for about 1 hour, and then compound II 1-2 (1.0 g) was added. Heat the reaction slowly to about 80. The mixture was stirred at C for 5 hours. The reaction mixture was cooled, poured into ice water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound III-4 (0.81 g).

 ½-NMR (400 MHz, CDClg) 8.05 (2H, d, J = 8 Hz), 8.04 (1H, s), 7.92 (1H, s), 7.28 (1H, d, J = 8 Hz), 7.18 (2H , d, J = 8 Hz), 7.10 (1H, d, J = 2 Hz), 6.90

(1H, dd, J = 8, 2 Hz), 6.73 (1H, s), 3.92 (3H, s), 1.67 (4H, s), 1.26 (6H, s), 1.20 (3H, s), 1.17 ( 3H, s).

 An aqueous solution (3 ml) of sodium hydroxide (0.24 g) was added to an ethanol solution (10 ml) of compound ΠΙ-4 (0.80 g), and the mixture was stirred at about 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was adjusted to pH 6 with an aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was washed with petroleum ether to obtain DM030 (0.53 g).

½-NMR (400 MHz, CDClg) 8.09 (2H, d, J = 8 Hz), 8.07 (1H, s), 7.98 (1H, s), 7.30 (1H, d, J = 8 Hz), 7.19 (2H, d, J = 8 Hz), 7.12 (1H, d, J = 2 Hz), 6.89 (1H, d, J = 8 Hz) J = 8, 2 Hz), 6.75 (1H, s), 1.68 (4H, s), 1.27 (3H, s), 1.26 (3H, s), 1.21 (3H, s) s), 1.17 (3H, s). Example 12: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) -tetra Production of benzoyl acid (DM031 and M036)

 To a suspension of compound II-1 (3.0 g) in acetic acid (50 ml) was added 1H-tetrazol (1.87 g) and 5 drops of concentrated sulfuric acid, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into ice water, neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: chloroform = 1: 1, then 0: 1) to give 4-[(5 , 6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) -tetrazylmethyl] benzoic acid methyl ester (TLC low polar ester 0.810 g and TLC highly polar ester 1.50 g) were obtained.

Low polarity ester: ½-NMR (400 MHz, CDClg) 8.57 (1H, s), 8.03 (2H, d, J = 8 Hz),

7.31 (2H, d, J = 8 Hz), 7.31 (1H, s), 7.29 (1H, d, J = 8 Hz), 7.19 (1H, d, J = 2 Hz) , 7.01 (1H, dd, J = 8, 2 Hz), 3.91 (3H, s), 1.66 (4H, s), 1.25 (6H, s), 1.19 (3H, s) s), 1.18 (3H, s).

High polar ester:. ½- negation _{R (400 MHz, CDC1 3)} 8. 44 (1H, s), 8. 06 (2H, d, J = 8 5

Hz), 7.32 (1H, d, J = 8 Hz), 7.15 (2H, d, J = 8 Hz), 7.10 (1H, d, J = 2 Hz), 7.05 (1H , s), 6.87 (1H, dd, J = 8, 2 Hz), 3.93 (3H, s), 1.68 (4H, s), 1.27

(6H, s), 1.21 (3H, s), 1.16 (3H, s)

 A 5 N aqueous solution of sodium hydroxide (1 ml) was added to an ethanol solution (10 ml) of the above low-polar ester (0.622 g), and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was cooled to 0 ° C, and then acidified by adding aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and the obtained residue was recrystallized from petroleum ether to obtain DM031 (0.226 g).

½-NMR (400 MHz, CDClg) 8.59 (1H, s), 8.10 (2H, d, J = 8 Hz), 7.35 (2H, d, J = 8 Hz), 7.33 ( 1H, s), 7.30 (1H, d, J = 8 Hz), 7.21 (1H, d, J = 2 Hz), 7.03 (1H, dd, J = 8, 2 Hz), 1.66 (4H, s), 1.26 (6H, s), 1.20 (3H, s), 1.19 (3H, s).

 M036 (1.10 g) was obtained by hydrolyzing the highly polar ester (1.40 g) in the same manner.

 ½-NMR (400 MHz, CDClg + DMSO-dg) 8.57 (1H, s), 8.07 (2H, d, J = 8 Hz), 7.32 (1H, d, J = 8 Hz), 7.17 (2H, d, J = 8 Hz), 7.11 (1H, d, J = 2 Hz), 7.09 (1H, s), 6.89 (1H, dd, J = 8, 2 Hz), 1.68 (4H, s), 1.27 ( 6H, s), 1.21 (3H, s),

1.17 (3H, s). Example 13: 4-[(5,6,7,8 tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) (imidazole- 1-yl) Methyl] benzoic acid (DM032)

 According to the method described in Example 11 using compound III-2 and imidazole as starting materials, M032 was obtained.

 ½-MR (400 MHz, CDClg) 7.95 (2H, d, J = 8 Hz), 7.66 (1H, s), 7.33 (1H, d, J = 8 Hz), 7.22 (2H, d, J = 8 Hz) ), 7.12 (2H, br s), 6.97 (1H, s), 6.90 (1H, dd, J = 8, 2 Hz), 6.87 (1H, s), 1.63 (4H, s), 1.22 (6H, s) ), 1.16 (3H, s), 1.14 (3H, s). Example 14: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracene-2-yl) ) -Tetrazyl) methyl] Benzoic acid (DM033) (Scheme 4)

 To a solution of p-formylbenzoic acid methyl ester (6.2 g) in anhydrous THF (30 ml) was separately prepared 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracene A Grignard solution (THF, 30 ml) of (IV-1, 10 g) was added dropwise over about 1 hour under ice cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was poured into ice water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain compound IV-2 (6.5 g).

½- MR (400 MHz, CDCl) 7.98 (2H, d, J = 8 Hz), 7.75 (2H, d, J = 8 Hz), 7.73

(1H, d, J = 2 Hz), 7.68 (1H, d, J = 8 Hz), 7.48 (2H, d, J = 8 Hz), 7.26 (1H, dd, J = 8, 2 Hz), 5.98 (1H, d, J = 3 Hz), 3.88 (3H, s), 2.42 (1H, d, J = 3 Hz), 1.76 (4H, s), 1.38 ( 6H, s), 1.37 (6H, s).

 To a solution of compound IV-2 (0.502 g) in acetic acid (2 ml) was added 1H-tetrazole (0.131 g) and one drop of concentrated sulfuric acid, and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into ice water, the precipitated solid was filtered and dried, then purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give compound IV-3 (TLC low polar isomer Body, 0.212 g).

 ½-NMR (400 MHz, CDCl ^) 8.60 (1H, s), 8.04 (2H, d, J = 8 Hz), 7.77 (1H, s), 7.74 (1H, d, J = 8 Hz), 7.71 ( 1H, s), 7.56 (1H, d, J = 2 Hz), 7.50 (1H, s), 7.33 (2H, d, J = 8 Hz), 7.26 (1H, dd, J = 8, 2 Hz), 3.91 (3H, s), 1.75 (4H, s), 1.37 (6H, s), 1.36 (6H, br s).

 To a solution of compound IV-3 (0.197 g) in ethanol (5 ml) was added a 5 N aqueous solution of sodium hydroxide (0.5 ml), and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and an aqueous solution of hydrochloric acid was added while cooling to 0 ° C to make the residue acidic. The mixture was extracted with ethyl acetate, and the obtained residue was recrystallized from petroleum ether to obtain M033 (0.190 g). ½-NMR (400 MHz, CDClg) 8.60 (1H, s), 8.06 (2H, d, J-8 Hz), 7.77 (1H, s), 7.74 (1H, d, J = 8 Hz), 7.71 (1H , s), 7.56 (1H, d, J = 2 Hz), 7.51 (1H, s), 7.31 (2H, d, J = 8 Hz), 7.26 (1H, dd, J = 8, 2 Hz), 1.75 (4H, s), 1.37 (6H, s), 1.36 (6H, br s). Example 15: 4- [4-Hydroxyphenyl- (3-isopropyl-4-methoxyphenyl) methyl] benzoic acid (DM040) Manufacturing (Scheme 5)

 Under an argon atmosphere, 0-isopropylphenol (V-1, 25.67 g), lithium carbonate

To a solution of (77.32 g) in anhydrous 2-butanone (300 ml) was slowly added dimethyl sulfate (27 ml), and the mixture was stirred at about 70 ° C for 10 hours. The reaction solution was cooled and then filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue was added a 1N aqueous sodium hydroxide solution (150 ml). After the mixture was stirred at room temperature for 12 hours, it was extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the resulting residue was subjected to silylation gel column chromatography (n-hexane: ethyl acetate = Purification by 7: 1) afforded compound V-2 (25.94 g) as an oil.

½-NMR (400 MHz, CDClg) 7.21 (1H, dd, J = 7.5, 1.7 Hz), 7.15 (1H, ddd, J = 8, 7,5, 1.7 Hz), 6.92 (1H, ddd, J = 7.5 , 7.5, 1 Hz), 6.84 (1H, dd, J = 8, 1 Hz), 3.82 (3H, s), 3.32 (1H, m, J = 7 Hz), 1.21 (6H, d, J-7 Hz) ).

 To a solution of compound V-2 (17.23 g) and monomethyl terephthalic acid chloride (25.44 g) in anhydrous dichloromethane (300 ml) was slowly added aluminum chloride (23.61 g) under water cooling, and the mixture was added at room temperature. Stir for 18 hours. The reaction mixture was poured into an aqueous hydrochloric acid solution containing ice and extracted with dichloromethane. The solvent was distilled off under reduced pressure, and the residue was recrystallized from n-hexane to obtain compound V-3 (23.31).

 ½-MR (400 MHz, CDClo) 8.14 (2H, d, J = 8.6 Hz), 7.80-7.78 (3H, ra), 7.63 (1H, dd, J = 8.5, 2.5 Hz), 6.88 (1H, d, J = 8.5 Hz), 3.96 (3H, s), 3.91 (3H, s), 3.34 (1H, m, J = 7 Hz), 1.21 (6H, d, J = 7 Hz).

 To a solution of compound V-3 (2.0 g) in anhydrous THF (25 ml), separately add a separately prepared solution of topromo 4-methoxyethoxybenzene (1.52 g) in Grignard (THF, 6 ml) under ice-cooling. After dripping dropwise, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (n-hexane: ethyl acetate = 5: 1 to 3: Purification in 1) gave compound V-4 (0.88 g).

 ½-band R (400 MHz, CDClo) 7.96 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.13 (1H, d, J-2.4 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.91 (1H, dd, J = 8.8, 2.4 Hz), 6.73 (1H, d, J = 8.8 Hz), 5.15 (2H, s), 3.89

(3H, s), 3.80 (3H, s), 3.46 (3H, s), 3.26 (1H, m, J = 7 Hz), 2.85 (1H, s),

1.11 (6H, d, J = 7 Hz).

 Concentrated hydrochloric acid (3 drops) was added to a THF solution (10 ml) of compound V-4 (0.80 g), and the mixture was stirred at about 50 ° C for 5 hours. The reaction solution was cooled, water was added and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain compound V-5 (0.49 g).

½-NMR (400 MHz, CDC1) 7.95 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz), 7.79 (1H, d, J = 2.5 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.90 (1H, dd, J = 8.5, 2.5 Hz) ), 6.76 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 8.5 Hz), 5.68 (1H, s), 3.90 (3H, s ), 3.80 (3H, s), 3.25 (1H, m, J = 7 Hz), 2.85 (1H, s), 1.10 (6H, d, J = 7 Hz).

 PdC (0.05 g) was added to an ethanol solution (13 ml) of compound V-5 (0.14 g), and the mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through activated carbon, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain compound V-6 (0.1 g).

 ½-NMR (400 MHz, CDClg) 7.94 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 6.94 (3H, m), 6.72 (1H, dd, J = 8.3, 2.4 Hz), 6.75 (2H, d, J = 8.5 Hz), 6.74 (1H, d, J = 8.5 Hz) ), 5.46 (1H, s), 5.25 (1H, s), 3.89 (3H, s), 3.76 (3H, s), 3.25 (1H, m, J = 7 Hz) ), 1.12 (6H, d, J = 7 Hz).

 To a solution of compound V-6 (0.06 g) in ethanol (7 ml) was added a 1 N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at about 50 ° C for 6 hours, and then the reaction mixture was concentrated under reduced pressure. did. Water was added to the residue, an aqueous solution of hydrochloric acid was added while cooling to 0 ° C to make the residue acidic, and the mixture was extracted with ethyl acetate. The obtained residue was recrystallized from getyl ether-petroleum ether to obtain M040 (0.04 g).

 ½-NMR (400 MHz, CDClg) 7.94 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz), 6.95 (1H, d, J -2.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.81 (1H, dd, J = 8.5, 2.5)

Hz), 6.76 (2H, d, J = 8.5 Hz), 6.73 (1H, d, J = 8.5 Hz), 5.43 (1H, s), 3.79

(3H, s), 3.24 (1H, m, J = 7 Hz), 1.12 (6H, d, J = 7 Hz). Ex. 16: 4-[(5, 6, 7, 8-tetrahi Production of Dro-3,5,5,8,8-Pentamethylnaphthalene-2-yl)-(1,2,4-triazol-1-yl) methyl] benzoic acid (DM130)

4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene 2-yl) -force rubonyl] Benzoic acid methyl ester (5.0 g) is added to tetrahydrofuran ( Dissolve in a mixed solution of 250 ml) and methanol (100 ml) and add sodium borohydride at room temperature until the raw materials disappear. After the disappearance of the raw materials, the reaction mixture is poured into ice water and extracted with ether. Issued. The reduced phase was quantitatively obtained by concentrating the organic phase under reduced pressure. This was dissolved in tetrahydrofuran (250 ml) and stirred for 24 hours while blowing hydrochloric acid gas under water cooling. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane to give 4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl Naphthalene 2-yl) chloromethyl] benzoic acid methyl ester (4.0 g) was obtained as crystals.

½ - testimony _{(400 MHz, CDC1 3) 8.02} (2H, d, J = 8 Hz), 7.47 (2H, d, J = 8 Hz), 7.30 (1H, s), 7.07 (1H, s), 6.30 ( 1H, s), 3.91 (3H, s), 2.27 (3H, s), 1.65 (4H, s), 1.27 (3H, s), 1.26 (3H, s), 1.25 (3H, s), 1.15 (3H , s).

 4-[(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl) octamethyl] benzoic acid methyl ester and 1,2,4- DM130 was obtained according to the method described in Example 11 using triazole as a starting material.

 ½-NMR (400 MHz, CDC1) 8.11 (2H, d, J = 8 Hz), 8.08 (1H, s), 7.84 (1H, s), 7.14 (1H, s), 7.12 (2H, d, J = 8 Hz), 6.93 (1H, s), 6.67 (1H, s), 2.17 (3H, s), 1.62 (4H, br s), 1.27 (3H, s), 1.27 (3H, s), 1.08 (3H , s), 1.01 (3H, s). Example 17: 4- [N- (5,6,7,8-tetrahydro-5,5,8,8_tetramethylnaphthalene-2-yl) a Production of benzoic acid (DA010) (Scheme 6)

 6-amino-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (VI-1, 1.214 g, 5.97 mmol), 4-ethyl benzoate (1.622 g, 5.87 mmol) and tert-BuONa (600 mg) were dissolved in 60 ml of anhydrous toluene, and 97.0 mg of tris (dibenzylideneacetone) dipalladium (0) and 158 mg of (R) -BINAP were replaced with argon. And heated at 80 ° C. One hour later, the mixture was cooled to room temperature, poured into 200 ml of water, and extracted with ether. The organic layer was dried over magnesium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 19: 1) to give 4- [N- (5,6,7,8-te) Trahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid ethyl ester (VI-2) (1.0 g, 48%) was obtained.

½-Picture (400 MHz, CDC1) 7.91 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.10 (1H, d, 1 = 2.6 Hz), 6.96 (1H, dd, J = 2.6, 8.8 Hz), 6.94 (2H, d, J = 9.2 Hz), 4.33 (2H, q, J = 7.0 Hz), 1.69 (4H, s), 1.37 (3H, t, J = 7.3 Hz), 1.28 (6H, s), 1.27 (6H, s).

 Compound VI-2 (118 mg) was dissolved in ethanol (4 ml), a 20% aqueous KOH solution (0.5 ml) was added, and the mixture was refluxed. After the disappearance of the raw materials, the reaction solution was poured into 30 ml of 1N hydrochloric acid and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain DA010 as white crystals (109 mg, quant.).

pale colored prisms (Echinoleic acid n hexane :); mp 277. C

½-NMR (400 MHz, CDClg + DMSO-dg) 7.89 (2H, dt, J = l.0, 8.8 Hz), 7.25 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 2.2 Hz), 6.98 (1H, dd, J = 2.6, 8.4 Hz), 6.97 (2H, dt, J = 1.8, 8.8 Hz), 6.78 (1H, br s), 1.69 (4H, s), 1.28 (6H, s), 1.27 (6H, s)

Anal. Calcd for C ₂₁ H ₂₅ N0 _2> C: 77.98%, H: 7.79%, N: 4.33%; Found C: 78.02%, H: 8.01%, N: 4.29%. Example 18: 4- [N-methyl Production of -N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA011) (Scheme 6)

 4- [N- (5,6,7,8 tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) 242 mg NaH (145 mg) dissolved in 2 ml of MF and suspended in 2 ml of DMF was added. Thereafter, methyl iodide (1.5 ml) was added, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction solution was poured into water (50 ml) and extracted with methylene chloride. The organic layer was dehydrated with magnesium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 4- [N-methyl-N- (5, 6, 7, 269 mg (quantitative) of 8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid ester were obtained.

Colorless needles (n-hexane); m 131 ° C

½-MR (400 MHz, CDClg) 7.86 (2H, dd, J = 2.2, 9.16 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 2.6 Hz), 6.95 (1H, dd, J = 2.2, 8.4 Hz), 6.74 (2H, dd, J = 2.2, 9.2 Hz), 4.32 (2H, q, J = 7.0 Hz), 3.34 (3H, s), 1.70 (4H, s), 1.36

(3H, t, J = 7.3 Hz), 1.30 (6H, s), 1.25 (6H, s)

_{. Anal Calcd for 4 Η 31 Ν0} 2, C: 78.86%, H: 8.55%, N: 3.83%; Found C: 78.88%, H: 8.68%, N: 3.78%

 The above ester derivative (367 rag) was dissolved in ethanol (5 ml), and the mixture was refluxed by adding a 20% K0H aqueous solution (1 ml). After the disappearance of the raw materials, the reaction solution was poured into 50 ml of 1N hydrochloric acid and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated to give DA011 as 334.5 mg (quantitative) of white crystals.

colorless powders (n-hexane; mp 252. C

 ½ -Certificate (400 MHz, CDClg) 7.92 (2H, dd, Jl.8, 9.2 Hz), 7.35 (1H, d, J = 8.4 Hz), 7.17 (1H, d, J = 2.2 Hz), 6.98 (1H , dd, J = 2.6, 8.4 Hz), 6.76 (2H, dd, J = 2.2, 9.2 Hz), 3.38 (3H, s), 1.73 (4H, s), 1.33 (6H, s), 1.28 (6H, s). Anal. Calcd for C ^ H ^ NO ^ C: 78.30%, H: 8.07%, N: 4.15%; Found C: 78.16

%, H: 8.14%, N: 4.16%. Example 19: 4— [N-ethyl-N- (5, 6,7, 8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2 -) Amino] Production of benzoic acid (DA012)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene 2-yl) amino] ethyl benzoate (VI-2) 249 mg NaH (134 mg) dissolved in DMF (5 ml) and suspended in DMF (5 ml) was added. Thereafter, iodo chill (3 ml) was added, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction mixture was poured into water (50 ml) and extracted with methylene chloride. The organic layer was dehydrated with magnesium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 4- [N-ethyl-N- (5,6, There was obtained 269 mg (quantitative) of 7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid ethyl ester.

Colorlrss needles (n-hexane); mp 88.5 ° C

½-NMR (400 MHz, CDClg) 7.83 (2H, dd, J = 1.8, 9.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J-2.2 Hz), 6.93 (1H, dd, J = 2.2, 8.1 Hz), 6.65 (2H, dd, J = 2.2, 9.2 Hz), 4.31 (2H, q, J = 7.3 Hz), 3.76 (2H, q, J = 7.0 Hz), 1.70 (4H, s), 1.35 (3H, t, J = 7.0 Hz) , 1.30 (6H, s), 1.24 (6H, s), 1.24 (3H, t, J = 7.3 Hz)

Anal.Calcd for C: 79.11%, H: 8.76%, N: 3.69%; Found C: 78.84

%, H: 8.86%, N: 3.40%

 The above ester (270 tng) was dissolved in ethanol (8 ml), and 2 ml of a 20% K0H aqueous solution was added thereto, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1 N hydrochloric acid (40 ml) and extracted with methylene chloride. The organic layer is dehydrated with magnesium sulfate and concentrated to a white crystal 251 mg

DA012 was obtained as (quantitative).

colorless powders n-hexane methylene salt; mp 256. C

½-band R (400 MHz, CDCl) 7.88 (2H, d, J = 9.2 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.11 (1H, s), 6.93 (1H, d, J = 8.4 Hz), 6.65 (2H, d, J = 9.2 Hz), 3.77 (2H, q, J = 7.3 Hz), 1.70 (4H, s), 1.31 (6H, s), 1.25 (6H, s), 1.25 ( (3H, t, J = 7.0 Hz)

_{. Anal Calcd for 3 Η 29 Ν0} 2, C: 78.59%, H: 8.32%, N:. 3.99%; Found C: 78.81% H: 8.23%, N: 4.09% Example 20: 4 - [Nn-propyl - Production of N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA013)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) 252 mg NaH (135 mg) dissolved in DMF (5 ml) and suspended in MF (5 ml) was added. Thereafter, n-propyl iodide (3 ml) was added, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction solution was poured into water (30 ml) and extracted with methylene chloride. The organic layer was dehydrated with magnesium sulfate and concentrated, and then purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to obtain 282 mg (99.6 mg) of white crystals.

Colorless powder n-hexane); m 114 ° C

½-NMR (400 MHz, CDC1J 7.83 (2H, dd, J = 1.8, 8.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 2.2 Hz), 6.93 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.64 (2H, dd, J = 2.2, 9.2 Hz), 4.31 (2H, q, J = 7.0 Hz), 3.63 (2H, t, J = 7.7 Hz), 1.71 (2H, hex, J = 7.3 Hz), 1.70 (4H, s), 1.35 (3H, t, J-7.3 Hz), 1.31 (6H, s), 1.25 (6H, s), 0.94 (3H, t, J = 7.3 Hz)

Anal.Calcd for C: 79.34%, H: 8.96%, N: 3.56%; Found C: 79.21

 %, H: 8.75%, N: 3.48%.

 The above ester (282 mg) was dissolved in ethanol (8 ml), and a 20% aqueous K0H solution (2 ml) was added thereto, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1 N hydrochloric acid (50 ml) and extracted with methylene chloride. The organic layer is dehydrated with magnesium sulfate and concentrated to give white crystals 262 mg

DA013 was obtained as (quantitative).

 Colorless powder (n-hexane); mp 235.5 ° C

 ½-image (400 MHz, CDCl) 7.87 (2H, d, J = 9.2 Hz), 7.33 (1H, d, J = 8.1 Hz), 7.11 (1H, d, 1 = 2.2 Hz), 6.93 (1H, dd , J = 2.6 Hz, 8.4 Hz), 6.63 (2H, d, J = 9.2 Hz), 3.63 (2H, t, 1 = 1.1 Hz), 1.67-1.76 (2H, m), 1.70 (4H, s), 1.31 (6H, s), 1.25 (6H, s), 0.94 (3H, t, J = 7.7 Hz)

Anal. Calcd for C ^ H ^ NO ^ C: 78.86%, H: 8.55¾, N: 3.83%; Found C: 78.64%, H: 8.46%, N: 3.84%. Example 21: 4-[Nn-butyl -N- (5,6,7,8-Tetrahydro-5,5,8,8 tetramethylnaphthalene-2-yl) amino] Production of benzoic acid (DA014)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid ethyl ester (VI-2) and iodide DA014 was synthesized according to the method of Example 20 using n-butyl.

 Colorless powder (n-hexane methylene chloride); mp 216 ° C

½-NMR (400 MHz, CDC1) 7.87 (2H, d, J = 8.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.10 (1H, s), 6.93 (1H, d, J = 6.6 Hz) ), 6.63 (2H, d, J = 9.2 Hz), 3.67 (2H, t, J = 7.7 Hz), 1.70 (4H, s), 1.64-1.74 (2H, m), 1.37 (2H, hex,] = 7.7 Hz), 1.31 (6H, s), 1.25 (6H, s), 0.94 (3H, t, J = 7.3 Hz) Anal.Calcd for C ₂₅ H ₃ N0 _o> C: 79.11%, H: 8.76%, N: 3.69%; Found C: 79.23%, H: 8.68%, N: 3.71% .Example 22: 4- [Nn- Production of pentyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA015)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid ethyl ester (VI-2) and iodine DA015 was synthesized according to the method of Example 20 using n-pentyl compound.

 Colorless powder (n-hexane-methylene chloride); mp 219 221. C

 ½-NMR (400 MHz, CDClg) 7.88 (2H, dd, J = l.8, 8.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.11 (1H, d, J = 2.6 Hz), 6.93 (1H, dd, J = 2.6, 8.4 Hz), 6.63 (2H, dd, J = 1.83, 9.2 Hz), 3.66 (2H, t, J = 7.7 Hz), 1.70 (4H, s), 1.66-1.70 ( 2H, m), 1.31 (6H, s), 1.25 (6H, s), 1.22-1.37 (4H, m), 0.89 (3H, t, J = 7.0 Hz)

. Anal Calcd for C ₂₆ H _{3 "N0 9, C: 79.34%,} H: 8.97%, N: 3.56%; Found C: 79.05

%, H: 8.95%, N: 3.44%. Example 23: 4 [Nn-hexyl-N- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethylnaphthalene-2 -) Amino] Production of benzoic acid (DA016)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and iodine DA016 was synthesized according to the method of Example 20 using n-hexyl chloride.

 Colorless powder (n-hexane-methylene chloride); mp 199-200.5 ° C

 ½-NMR (400 MHz, CDC1) 7.87 (2H, dd, J = 2.2, 9.2 Hz), 7.32 (1H, d, J-8.1 Hz), 7.10 (1H, d, J = 2.6 Hz), 6.93 (1H , dd, J = 2.6, 8.4 Hz), 6.63 (2H, dd, J = 1.8, 8.8 Hz), 3.67 (2H, t, J = 7.7 Hz), 1.70 (4H, s), 1.65-1.70 (2H, m), 1.31 (6H, s), 1.25 (6H, s), 1.29-1.46 (6H, m), 0.88 (3H, t, J = 7.0 Hz).

Anal.Calcd for C ^ H ^ NO ^ C: 79.56%, H: 9.15%, N: 3.44%; Found C: 79.53

%, H: 8.94%, N: 3.14%. Example 24: 4- [Nn-heptyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA017)

 4-[N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)]-mino] Ethyl benzoate (VI-2) and iodine DA017 was synthesized according to the method of Example 20 using the compound n-heptyl.

 Colorless powder (n-hexane-methylene chloride); mp 168. C

½-NMR (400 MHz, CDClg) 7.86 (2H, d, J = 9.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 1.8 Hz), 6.93 (1H , dd, J = 2.2, 8.4 Hz), 6.63 (2H, d, J = 8.8 Hz), 3.66 (2H, t, J = 7.7 Hz), 1.70 (4H, s), 1.70 (2H, br m), 1.31 (6H, s), 1.25-1.31 (8H, br m), 1.25 (6H, s), 0.87 (3H, t, J-6.6 Hz)

Anal. Calcd for CggHggNOg, C: 79.76%, H: 9.32%, N: 3.32%; Found C: 79.80%, H: 9.62%, N: 3.06%. Example 25: 4-[Nn (5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] Production of benzoic acid (DA018)

 4-[N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) Rino] ethyl benzoate (VI-2) and iodide DA018 was synthesized according to the method of Example 20 using n-octyl.

 Colorless cotton (n-hexane-methylene chloride); m 160 ° C

 NMR-NMR (400 MHz, CDCl ^) 7.87 (2H, dd, J = 2.2, 9.2 Hz), 7.32 (1H, d, J-8.4 Hz), 7.10 (1H, d,} = 2.2 Hz), 6.92 ( 1H, dd, 1 = 2.2, 8.4 Hz), 6.63 (2H, d, J = 9.2 Hz), 3.66 (2H, t, J = 8.1 Hz), 1.70 (4H, s), 1.70 (2H, m), 1.31 (6H, s), 1.26 (10H, m), 1.25 (6H, s), 0.87 (3H, t, J = 6.6 Hz)

Anal.Calcd for C _2g H ₄₁ N0 _2> C: 79.95%, H: 9.49%, N: 3.22%; Found C: 79.92

%, H: 9.54%, N: 3.18%. Example 26: 4- [N- (propyne-3-yl) -N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) ami Production of benzoic acid (DA020)

 4 [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and bromide DA020 was synthesized according to the method of Example 20 using acetylenylmethyl.

 Colorless prisms (n-hexane methylene chloride); mp 269-270 ° C (dec.)

 ½-NMR (400 MHz, CDClg) 7.93 (2H, dd, J = 2.2, 9.2 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J = 2.2 Hz), 7.03 (1H , Dd, J = 2.2, 8.4 Hz), 6.80 (2H, dd, J = 2.2, 9.2 Hz), 4.41 (2H, d, J = 2.6 Hz), 2.29 (1H, t, J = 2.2 Hz), 1.71 (4H, s), 1.31 (6H, s), 1.25 (6H, s) Example 27: 4 [N- (propene-3-yl) -N (5,6,7,8-tetrahydro-5, 5,8,8-Tetramethylnaphthalene-2-yl) amino] Production of benzoic acid (DA021)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthale, 2--2-yl) amino] Ethyl benzoate (VI-2) Was synthesized according to the method of Example 20 by using and aryl bromide.

 Colorless powder (n-hexane-methylene chloride); rap 247-248 ° C

 ½-NMR (400 MHz, CDCl ^) 7.87 (2H, dd, J = l.8, 9.2 Hz), 7.32 (1H, d, J = 8.1 Hz), 7.16 (1H, d, J = 2.2 Hz), 6.98 (1H, dd, J = 2.2, 8.1 Hz), 6.71 (2H, dd, J = l.8, 9.2 Hz), 5.94 (1H, ddt, J = 5.2, 10.3, 17.2 Hz), 5.28 (1H, dd,] = l.

5, 17.2 Hz), 5.22 (1H, dd, J = l.5, 10.3 Hz), 4.35 (1H, dd, J = l.8, 4.8 Hz), 1.70 (4H, s), 1.30 (6H, s ), 1.24 (6H, s)

 Anal.Calcd for C ^ H ^ NO ^ C: 79.30%, H: 8.04%, N: 3.85%; Found C: 79.08

%, H: 8.18¾, N: 4.15%. Example 28: 4- [N-Isopropyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtalen-2-yl) amino] benzoic acid (DA022) Manufacturing of

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) 113 mg, And potassium carbonate (89 mg) were dissolved in isopropyl iodide and refluxed for 48 hours. The reaction solution was poured into water (30 ml) and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by flash gel chromatography (n-hexane: ethyl acetate = 20: 1) to obtain 13 mg (10%). .

Colorless prisms (n hexane); rap 81 ° C

 ½-MR (400 MHz, CDClg) 7.80 (2H, dd, J = 2.2, 9.2 Hz), 7.33 (1H, d, J = 8.4 Hz), 6.99 (1H , d, J = 2.2 Hz), 6.82 (1H, dd, J = 2.2, 8.4 Hz), 6.50 (2H, dd, J = 2.6, 9.2 Hz) , 4.35 (1H, hep, J = 6.6 Hz), 4.29 (2H, q, J = 7.0 Hz), 1.71 (4H, s), 1.33 (3H, t, J = 7.0 Hz), 1.31 (6H, s), 1.24 (611, s), 1.14 (6H, d, J = 6.6 Hz).

 The above ester (45 mg) was dissolved in ethanol (4 ml), and a 20% aqueous K0H solution (1 ml) was added thereto, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 40 mg (98%) of DA022.

 Colorless powder (n-hexane-methylene chloride); rap 259 ° C

½ NMR (400 MHz, CDClg) 7.85 (2H, dd, J = 2.2, 9.2 Hz), 7.34 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J = 2.2 Hz), 6.82 (1H, dd, J = 2.2, 8.1 Hz), 6.51 (2H, d, J = 9.2 Hz), 4.37 ( 1H, hep, J = 6.6 Hz, 1.71 (4H, s), 1.32 ₍ 6H ₍ s), 1.24 (6H, s), 1.15 (6H, d, J = 6 6 Hz) Example 29: 4- [N-cyclopropyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzo Production of acid (DA023)

Cyclopropylamine (1 ml), 4-ethyl benzoate (407 mg) and tert-BuONa (180 mg) were dissolved in anhydrous toluene (10 ml), and the solution was dissolved in tris (with argon). Dibenzylideneacetone) Dipalladium (0) (54 mg) and (R) -BINAP (102 mg) were added, and the mixture was heated at 80 ° C. Four hours later, the mixture was cooled to room temperature, poured into 30 ml of water, and extracted with ether. The organic layer is dehydrated with anhydrous sodium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 4- (cyclopropylamino) benzoic acid. 150 mg (56%) of ethyl ester was obtained.

Colorless needles (n-hexane); mp 69 ° C

 ½-NMR (400 MHz, CDC1) 7.88 (2H, dd, J = 2.2, 8.8 Hz), 6.74 (2H, dd, J = 2.2, 8.8 Hz), 4.53 (1H, brs), 4.32 (2H, q, J-7.0 Hz), 2.48 (1H, dtt, J = l.5,

2.6, 6.2 Hz), 1.36 (3H, t, J-7.0 Hz), 0.79 (2H, ddd, J = 4.4, 6.6, 7.0 Hz),

0.54 (2H, ddd, J = 3.7, 4.8, 6.6 Hz)

Anal.Calcd for C ₁₂ H ₁₅ N0 _o , C: 70.22%, H: 7.37%, N: 6.83%; Found C: 70.20%, H: 7.23%, N: 6.68%.

 4- (cyclopropylamino) ethyl benzoate (97 rag), 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (121.5 mg) and tert BuONa

(67 mg) in anhydrous toluene (5 ml), add tris (dibenzylideneacetone) dipalladium (0) (24 mg) and (R) -BINAP (40.5 mg) under argon and add 80 ° C. And heated. After 1.5 hours, the mixture was cooled to room temperature, poured into 30 ml of water, and extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 4- [N-cyclopropyl- N- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] 42 mg (20%) of ethyl benzoate were obtained.

 ½-picture (400 MHz, CDClo) 7.86 (2H, dd, J = 2.2, 9.2 Hz), 7.29 (1H, d, J = 8.1 Hz), 7.02 (1H, d, J = 2.6 Hz), 6.93 (2H , dd, J = l.8, 8.8 Hz), 6.87 (dd, J-

2.2, 8.1 Hz), 4.31 (2H, q, J = 7.3 Hz), 2.80 (1H, tt, J = 3.7, 6.6 Hz), 1.70 (4H, s), 1.35 (3H, t, J = 7.3 Hz) , 1.30 (6H, s), 1.24 (6H, s), 0.89 (2H, ddd, J = 4.8, 6.2, 7.0 Hz), 0.63 (2H, ddd, J = 3.7, 5.1, 7.0 Hz).

Dissolve the above ester (42 mg) in ethanol (2 ml), and add a 20% K0H aqueous solution (0. 5 ml) and refluxed. Two hours later, the reaction solution was poured into an aqueous IN NaOH solution (30 ml), washed with ether, the aqueous layer was made strongly acidic with concentrated hydrochloric acid, and extracted with methylene chloride. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated to obtain 14 mg (35%) of yellowish white crystals. The obtained crystals were treated with activated carbon and then recrystallized to obtain DA023 as white crystals.

Colorless prisms (n-hexane-methylene chloride); mp 260-261 ° C (dec.)

½-NMR (400 MHz, CDClg) 7.89 (2H, dd, J = 2.2, 9.2 Hz), 7.30 (1H, d, J = 8.43 Hz), 7.02 (1H , D, J = 2.2 Hz), 6.94 (1H, dd, J = 2.2, 9.2 Hz), 6.87 (2H, dd, J = 2.2, 8.4 Hz) , 2.82 (1H, tt, J = 4.0, 7.0 Hz), 1.70 (4H, s), 1.31 (6H, s), 1.25 (6H, s), 0. 90 (2H, ddd, J = 5.1, 6.6, 7.0 Hz), 0.64 (2H, ddd, J = 5.1, 5.5, 7.3 Hz) Example 30: 4- Production of [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyylnaphthalen-2-yl) amino] benzoic acid (DA024)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and odor DA024 was synthesized according to the method of Example 20 using cyclopropylmethyl fluoride.

 Colorless prisms (n-hexane-methylene chloride); mp 245. C

 ½-Hidden (400 MHz, CDClg) 7.88 (2H, dd, J = l, 8, 9, 2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.16 (1H , d, J = 2.6 Hz), 6.95 (1H, dd, J = 2.2, 8.1 Hz), 6.68 (2H, dd, J = 1.8, 9.2 Hz) , 3.56 (2H, d, J = 6.6 Hz), 1.70 (4H, s), 1.31 (6H, s), 1.25 (6H, s), 1.15-1. 22 (1H, m), 0.50 (2H, ddd, J = 4.4, 5.9, 8.1 Hz), 0.14 (2H, q, J = 4.8 Hz)

Anal.Calcd for C ^ H ^ NO ^ C: 79.53%, H: 8.28%, N: 3.71%; Found C: 79.33%, H: 8.36%, N: 3. 82¾. Example 31: 4- [N-isobutyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA025)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and iodine DA025 was synthesized according to the method of Example 20 using isobutyl fluoride.

 Colorless prisms (n-hexane-methylene chloride); mp 232 ° C

½-NMR (400 MHz, CDC1 0) 7.85 (2H, dd, J = l.8, 9.2 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.12 (1H, d, J = 2.6 Hz), 6.93 (1H, dd, J = 2.2, 8.4 Hz), 6.67 (2H, d, J = 9.2 Hz), 3.52 (2H, d, J = 7.3 Hz), 2.08 (1H, 7th, J = 7.0 Hz), 1.70 (4H, s), 1.30 (6H, s), 1.24 (6H, s), 0.96 (6H, d, J = 6.6 Hz)

Anal.Calcd for C: 79.11%, H: 8.76%, N: 3.69%; Found C: 79.10

 %, H: 8.81%, N: 3.65%. Example 32: 4- [N-isopentenyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-y Production of benzoic acid (DA028)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and prenyl bromide Was used to synthesize DA028 according to the method of Example 20.

 Colorless prisms (n-hexane-methylene chloride); mp 215 ° C

½-NMR (400 MHz, CDClg) 7.87 (2H, dd, J = 2.2, 9.2 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.11 (1H, d, 1 = 2.2 Hz), 6.94 (1H , dd, J = 2.2, 8.4 Hz), 6.67 (2H, dd, J = 2.2, 9.2 Hz), 5.33 (1H, t, J = 5.86 Hz), 4.29 (2H, d, J = 5.49 Hz), 1.72 (3H, s), 1.70 (4H, s), 1.61 (3H, s), 1.30 (6H, s), 1.24 (6H, s) Example 33: 4-[N-cyclobutylmethyl-N- (5, Production of 6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA030)

4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)] mino] Ethyl benzoate (VI-2) and odor Example 20 using cyclobutylmethyl bromide DA030 was synthesized according to the method described above.

 Colorless needles (n-hexane-methylene chloride); mp 232 ° C

½-NMR (400 MHz, CDClg) 7.85 (2H, dd, J = 2.2, 9.2 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 2.2 Hz), 6.89 (1H , dd, J = 2.2, 8.4 Hz), 6.60 (2H, dd, J = 1.8, 8.8 Hz), 3.70 (2H, d, J = 7.0 Hz), 2.74 (1H, 5th, J = 7.7 Hz), 2.01 (2H, m), 1.82 (2H, m), 1.70 (4H, s), 1.66 (2H, m), 1.30 (6H, s), 1.24 (6H, s)

Anal.Calcd for C: 79.75%, H: 8.50%, N: 3.58%; Found C: 79.82

%, H: 8.53%, N: 3.61%. Example 34: 4-[N-cyclohexylmethyl-N- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl) Production of tylnaphthalene 2-yl) amino] benzoic acid (DA036)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) Ύmino] ethyl benzoate (VI-2) and odor DA036 was synthesized according to the method of Example 20 using cyclohexylmethyl fluoride.

 Colorless cubes (n-hexane-methylene chloride); mp 230-231 ° C

½-NMR (400 MHz, CDC1 _Q ) 7.86 (2H, d, J = 9.2 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 2.2 Hz), 6.92 (1H, dd, J = 2.2, 8.4 Hz), 6.65 (2H, dd, J = 9.2 Hz), 3.59 (2H, d, J = 7.0 Hz), 1.75 (6H, m), 1.70 (4H, s), 1.31 (6H, s),

1.24 (6H, s), 1.16 (3H, m), 0.95 (2H, m)

_{.. Anal Calcd for C 28 H} 37 N0 2, C: 80.15%, H: 8.89%, N: 3.34%; Found C: 79.86%, H: 8.89%, N: 3.33% Example 35: 4 - [N- Production of benzyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) amino] benzoic acid (DA040)

4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and bromide DA040 was synthesized according to the method of Example 20 using benzyl. Colorless powder (n-hexane-methylene chloride); mp 272-273 ° C

½-NMR (400 MHz, CDC1) 7.84 (2H, dd, J = 2.2, 9.2 Hz), 7.32 (4H, d, J = 4.8

Hz), 7.30 (1H, d, J = 7.3 Hz), 7.23-7.25 (1H, m), 7.21 (1H, d, J = 2.2 Hz),

7.04 (1H, dd, J = 2.2, 8.4 Hz), 6.73 (2H, dd, J = 1.8, 9.2 Hz), 5.00 (2H, s), 1.69 (4H, s), 1.29 (6H, s), 1.22 (6H, s)

_{. Anal Calcd for C 28 H 31} N0> C: 81.32%, H: 7.56%, N:. 3.39%; Found C: 81.05%, H: 7.49%, N: 3.57% Example 36: 4 [N- (4 -Methylbenzyl) -N-(5,6,7,8-Tetrahydro 5,5,8,8 Tetramethylnaphthalene-2-yl) amino] Production of benzoic acid (DA041)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) Ύmino] ethyl benzoate (VI-2) and bromide DA041 was synthesized according to the method of Example 20 using (4-methylbenzyl).

 Colorless powder (n-hexane-methylene chloride); mp 246-248 ° C

 ½-NMR (400 MHz, CDClg) 7.83 (2H, dd, J = 2.2, 9.2 Hz), 7.30 (1H, d, J-8.4 Hz), 7.21 (1H, d, J = 2.2 Hz), 7.20 (2H , d, J = 6.6 Hz), 7.12 (2H, d, J-8.1 Hz), 7.03 (1H, dd, J = 2.2, 8.4 Hz), 6.73 (2H, dd, J-2.9, 9.2 Hz), 4.96 (2H, s), 2.32 (3H, s), 1.68 (4H, s), 1.29 (6H, s), 1.22 (6H, s)

Anal.Calcd for C: 81.46%, H: 7.78%, N: 3.28%; Found C: 81.28

 %, H: 7.82%, N: 3.44%. Example 37: 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) ) -N- (4-Trifluoromethylbenzyl) amino] Production of Benzoic Acid (DA042)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and bromide DA042 was synthesized according to the method of Example 20 using (4-trifluoromethylbenzyl).

Colorless powder (n-hexane); mp 209-210. C

½-NMR (400 MHz, CDClg) 7.86 (2H, dd, J = 2.2, 9.2 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.19 (1H, d, J = 2.2 Hz), 7.02 (1H, dd, J = 2.2, 8.4) Hz), 6.70 (2H, d, J = 8.8 Hz), 5.04 (2H, s), 1.69 (4H, s), 1.29 (6H, s), 1.22 (6H, s)

Anal.Calcd for C _2g H _{3 ()} N0 ₂ F _3> C: 72.33%, H: 6.28%, N: 2.91%; Found C: 72.

15%, H: 6.41%, N: 2.94%. Example 38: 4-[N- (4-ethoxy-2,3,5,6-tetrafluorobenzyl) -N (5,6,7,8 Production of tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA045)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthale-yl) amino] ethyl benzoate (VI-2) and odor The DA045 was synthesized according to the method of Example 20 using fluorinated benzene (fluorobenzene).

Colorless powder (n-hexane-methylene chloride); mp 227-229 ° C

^ -NM (400 MHz, CDClg) 7.90 (2H, dd, J = l.8, 8.8 Hz), 7.26 (1H, d, J = 8.4 Hz), 6.98 (1H, d, J = 2.2 Hz), 6.87 (1H, dd, J = 2.2, 8.4 Hz), 6.75 (2H, dd, J = 1.8, 8.8 Hz), 4.92 (2H, s), 4.22 (q, J = 7.0 Hz), 1.66 (4H, s) , 1.36 (3H, t, J = 7.0 Hz), 1.25 (6H, s), 1.16 (6H, s)

Anal. Calcd for C _{3 ()} H ₃₁ F ₄ N0 _o> C: 68.04%, H: 5.90%, N: 2.65%; Found C: 67. 78%, H: 5.89%, N: 2.61¾. Example 39 : 4-[N- (2-biphenylmethyl) -N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA046)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and odor DA046 was synthesized according to the method of Example 20 using biphenylmethyl chloride.

 Colorless prisms (n-hexane-methylene chloride); mp 237-239. C

^{L E-MR (400 MHz,} CDCl) 7.80 (2H, d, J = 8.8 Hz), 7.79-7.48 (1H, m), 7.35-7.

44 (4H, m), 7.23-7, 31 (6H, m), 7.15 (1H, d, J = 2.6 Hz), 6.98 (1H, dd, J = 2. 2, 8.8 Hz), 6.64 (2H, d, J = 9.2 Hz), 4.87 (2H, s), 1.68 (4H, s), 1.28 (6H, s), 1.19 (6H, s)

_{. Anal Calcd for 4 H 35 N0} 2, C: 83.40% H: 7.21%, N:. 2.86%; Found C: 83.11%, H: 7.50%, N: 2.75% Example 40: 4- [N- (2 -Naphthylmethyl) -N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] Production of benzoic acid (DA048)

4-[N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) and bromide- DA048 was synthesized according to the method of Example 20 using 2-naphthylmethyl.

 Colorless powder (n-hexane-methylene chloride); mp 233 ° C

丄 H-NMR (400 MHz, CDCl ^) 7.84 (2H, dd, J = 2.2, 9.2 Hz), 7.78 (4H, m), 7.44

(3H, in), 7.31 (1H, d, J = 8.4 Hz), 7.27 (1H, d, J = 2.6 Hz), 7.09 (1H, dd, J = 2.2, 8.4 Hz), 6.79 (2H, dd, J = 2.2, 9.2 Hz), 5.15 (2H, s), 1.68 (4H, s),

1.28 (6H, s), 1.22 (6H, s)

Anal. Calcd for C ₃₂ H _{3 <1} NO, C: 82.90%, H: 7.18¾, N: 3.02%; Found C: 82.66%, H: 7.48%, N: 2.73%. Example 41: 4- [ Production of N-acetyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalenyl-1-yl) amino] benzoic acid (DA051)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) 605 mg Was dissolved in anhydrous toluene (15 ml), acetyl chloride (1 ml) was added, and the mixture was refluxed overnight under argon. The solvent was distilled off under reduced pressure, and the residue was purified by flash gel gel chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 677 mg (quantitative) of white crude crystals.

Colorless cubes (n-hexane); mp 102 ° C

½- 丽 R (400 MHz, CDClg) 8.00 (2H, d, J = 8.4 Hz), 7.33 (2H, dd, J = l.8, 8.8 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.15 (1H, d, J = 2.6 Hz), 6.95 (1H, dd, J = 2. 2, 8.4 Hz), 4.36 (2H, q, J = 7.0 Hz), 2.05 (3H, s), 1.69 (4H, s), 1.37 (3H, t, J-7.0 Hz), 1.28 (6H, s) , 1.24 (6H, s)

Anal.Calcd for C: 76.30%, H: 7.94%, N: 3.56%; Found C: 76.26

%, H: 7.93¾, N: 3.51%.

 The above ester (404 mg) was dissolved in ethanol (10 ml), a 5% aqueous NaOH solution (0.9 ml) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water (0.5 ml) and concentrated hydrochloric acid (5 ml) were added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 342 mg of white crystals (DA051 as 91).

Colorless powder (n-hexane); mp 222 ° C

½— NMR (400 MHz, CDC1) 8.04 (2H, d, J = 8.4 Hz), 7.36 (2H, dd, J = 2.2, 8.8 Hz), 7.33 (1H, d, J = 8.1 Hz), 7.16 (1H , d, J = 2.2 Hz), 6.96 (1H, dd, J-2. 6, 8.4 Hz), 2.06 (3H, s), 1.70 (4H, s), 1.29 (6H, s), 1.25 (6H, s) Anal.Calcd for C: 75.59%, H: 7.45%, N: 3.83%; Found C: 75.29

%, H: 7.54%, N: 3.65%. Example 42: 4- [N-benzoyl-N- (5, 6, 7, 8 tetrahydro-5, 5, 8, 8-tetramethylnaphthalene-2 -Yl) Amino] Production of benzoic acid (DA055)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] ethyl benzoate (VI-2) 104 mg Was dissolved in anhydrous benzene (5 ml), benzoyl chloride (1 ml) and pyridine (1 ml) were added, and the mixture was stirred. After the disappearance of the raw materials, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was washed with 1 N hydrochloric acid (30 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Flash residue gel gel ram chromatography (n-hexane: ethyl acetate = 20: 1

) To give 130 mg (96.5%) of white crude crystals.

Colorless powder (n-hexane-methylene chloride); mp 149 ° C

½-NMR (400 MHz, CDCl ^) 7.97 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.18-7.30 (6H, m), 6.91 (1H, d, 1 = 2.2 Hz), 6.84 (1H, dd, J = 2.6, 8.4 Hz),

4.36 (2H, q, J = 7.0 Hz), 1.61 (4H, s), 1.38 (3H, t, J = 6.96 Hz), 1.23 (6H, s), 1.02 (6H, s)

_{. Anal Calcd for C 3Q H 33} N0 3, C: 79.09%, H: 7.30%, N: 3.08%; Found C: 78.94%, H: 7.29%, N: 3.08%.

 The ester (79 mg) was dissolved in ethanol (4 ml), a 5% aqueous NaOH solution (1 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 77 mg (quantitative) of DA055.

 Colorless cotton (n-hexane-methylene chloride); mp 228-229.5 ° C

½- negation _{R (400 MHz, CDC1 3)} 8.03 (2H, dd, J = l.8, 8.8 Hz), 7.42 (2H, dd, J = l.

5 Hz, 8.4 Hz), 7.19-7.30 (6H, m), 6.91 (1H, d, 1 = 2.6 Hz), 6.85 (1H, dd,

J = 2.6 Hz, 8.4 Hz), 1.61 (4H, s), 1.23 (6H, s), 1.02 (6H, s)

_{. Anal Calcd for 8 Η 29 Ν0} 3, C: 78.66%, H: 6.84%, N: 3.28%; Found C: 78.77

%, H: 6.95%, N: 3.19%. Example 43: 4- [N- (4-carboxybenzoyl) -N- (5,6,7,8-tetrahydro-5,5,8 8 Preparation of tetramethylnaphthalene-2-yl) amino] benzoic acid (DA058)

 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthaleno, -2-yl)] mino] Ethyl benzoate (VI-2) 153.0 mg was dissolved in anhydrous benzene (5 ml), terephthalic acid monomethyl ester chloride (210 mg) and 2 drops of pyridine were added, and the mixture was stirred. After the disappearance of the raw materials, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was washed with 1 N hydrochloric acid (30 ml), dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was flash silica gel column chromatography (n-hexane: ethyl acetate = 10: 1). To give 191 rag (quantitative) of white crude crystals.

Colorless powder n); mp 135. I

½-NMR (400 MHz, CDClg) 7.98 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.24 (2H, d , J = 8.4 Hz), 7.21 (1H, d, J = 8.4 Hz), 6.92 (1H, s), 6.84 (1H, dd, J = 2.2, 8.4 Hz), 4.36 (2H, q, J-7.3 Hz) ), 3.89 (3H, s), 1.61 (4H, s), 1.38 (3H, t, J = 7.0 Hz), 1.23 (6H, s), 1.03 (6H, S)

_{. Anal Calcd for C 32 H 35} N0 5, C: 74.83%, H: 6.87¾, N: 2.73%; Found C: 74.75%, H: 7.00%, N: 2.44%.

 The above ester (86.3 mg) was dissolved in ethanol (50 ml), a 5% aqueous NaOH solution (2 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 1 N hydrochloric acid and extracted with methylene chloride and ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain DA058 as 78.2 mg (98%) of white crystals.

Colorless powder (n-hexane); mp> 300 ° C

 ½-NMR (400 MHz, CDClg) 7.90 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.1 Hz), 7.43 (1H, s ), 7.35 (2H, d, J = 8.4 Hz), 7.29 (1H, d, J = 8.4 Hz), 6.92 (1H, d, J = 8.4 Hz), 1.56 (4H, s), 1.18 (6H, s ), 1.02 (6H, s) Example 44: 4- [N-ethyl-N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2- Production of benzoic acid (DA112) (Scheme 7)

 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylnaphthalene (VII, 21.888 g) is dissolved in acetic acid (80 ml) and mixed with hydrochloric acid and sulfuric acid under ice-cooling. Add slowly and stir at room temperature. After 3 hours, the reaction solution was poured into water (200 ml), and the precipitated crystals were collected by filtration, washed with water, and dissolved in methylene chloride. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude crystals were recrystallized from methanol to give 7-2-to-1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (VI 1- 2)

14.59 g (54.5%) were obtained as white crystals.

½-NMR (400 MHz, CDClg) 7.96 (1H, s), 7.21 (1H, s), 2.56 (3H, s), 1.72 (4H, s), 1.30 (6H, s), 1.29 (6H, s) .

14.59 g of the above nitro compound (VII-2) was dissolved in ethyl acetate (200 ml) and ethanol (100 ml), and catalytic reduction was performed by adding 10% Pd / C (1.74 g). The reaction solution was filtered through celite, and the filtrate was distilled off. The crude crystals obtained were purified by flash gel chromatography (n-hexane: ethyl acetate = 25: 1) to give 7- Amino-1, 2, 12.14 g (94.6%) of 3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (VI 1-3) was obtained as yellowish white crystals.

 ½-NMR (400 MHz, CDClg) 6.98 (1H, s), 6.63 (1H, s), 3.61 (2H, br s), 2.14 (3H, s), 1.64 (4H, s), 1.24 (12H, s) ).

 The above amino compound (VII-3) (1.085 g), 4-ethyl benzoate (1.676 g) and tert-BuONa (616 mg) were dissolved in anhydrous toluene (20 ml), and tris (dibenzylideneacetate) was dissolved under argon. Ton) Dipalladium (0) (101.5 mg) and (R) -BINAP (163.8 mg) were added, and the mixture was refluxed. After 3 hours, the reaction solution was cooled to room temperature, poured into 100 ml of water, and extracted with ether. After dehydrating the organic layer with anhydrous sodium sulfate and concentrating the residue, the residue was purified by flash chromatography and gel chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 4- [N- ( 5,6,7,8 Tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl) amino] 1.095 g (60%) of ethyl benzoate (VII 4) was obtained. .

Colorless needles (n-hexane); m 173-175 ° C

 ½-NMR (400 MHz, CDClg) 7.89 (2H, dd, J = l.83 Hz, 8.8 Hz), 7.21 (1H, s), 7.16 (1H, s), 6.77 (2H, dd, J = l. 8 Hz, 8.8 Hz), 4.33 (2H, q, J = 7.0 Hz), 2.19 (3H, s), 1.68 (4H, s), 1.37 (3H, t, J = 7.0 Hz), 1.29 (6H , s), 1.24 (6H, s)

 Anal.Calcd for C ^ H ^ NO ^ C: 78.86%, H: 8.55%, N: 3.83%; Found C: 79.05%, H: 8.80%, N: 3.58%.

 The above amino compound (VII-4, 92 mg) was dissolved in DMF (2 ml), and NaH (61.5 mg) suspended in MF (2 ml) was added. Thereafter, iodo chill (1 ml) was added, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction solution was poured into water (30 ml) and extracted with methylene chloride. The organic layer was dehydrated with magnesium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 4- [N-ethyl-N- (5, 6,7,8-Tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl) amino] 98 mg (99%) of ethyl benzoate was obtained.

Colorlrss powder (n-hexane); mp 94 ° C

½-NMR (400 MHz, CDC1) 7.83 (2H, d, J-8.8 Hz), 7.20 (1H, s), 7.00 (1H, s), 6.43 (2H, d, J = 9.2 Hz), 4.30 (2H, q, J = 7.3 Hz), 3.66 (2H, d, J = 6.6 Hz), 2.03 (3H, s), 1.69 (4H, s), 1.34 (3H, t, 1 = 1.0 Hz), 1.31 (6H, s), 1.25 (3H, t, J = 7.3 Hz), 1.23 (6H, s)

Anal.Calcd for C: 79.34%, H: 8.96%, N: 3.56¾; Found C: 79.12

%, H: 8.93%, N: 3.57%.

 The above ester (83 mg) was dissolved in ethanol (4 ml), and 1 ml of a 20% aqueous KOH solution was added thereto, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1 N hydrochloric acid (40 ml), and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain 77 mg (quantitative) of DA112.

Colorless powder (n-hexane methylene chloride); mp 266. C

½-NMR (400 MHz, CDClg) 7.87 (2H, d, J = 9.2 Hz), 7.20 (1H, s), 7.00 (1H, s), 6.45 (2H, d, J = 8.8 Hz), 3.67 (2H , br), 2.04 (1H, s), 1.69 (4H, s), 1.31 (6H, s), 1.26 (3H, t, J = 7.0 Hz), 1.23 (6H, s)

Anal Calcd for C ₂₄ H ₃₁ N0 _o , C: 78.86%, H: 8.55%, N: 3.83%; Found C: 78.56%, H: 8.71%, N: 3.82%. Example 45: 4- [N-n -Propyl-N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl) amino] Production of benzoic acid (DA113)

 DA113 was synthesized according to the method of Example 44 using compound VII-4 and n-propyl iodide.

 Colorless powder (n-hexane); mp 245. C

^X H-NMR (400 MHz, CDClg) 7.86 (2H, d, J = 9.2 Hz), 7.20 (1H, s), 7.00 (1H, s), 6.42 (2H, d, J = 8.8 Hz), 3.52 ( 2H, br s), 2.02 (3H, s), 1.72 (2H, hep,

J = 7.7 Hz), 1.69 (4H, s), 1.31 (6H, s), 1.23 (6H, s), 0.95 (3H, t, J = 7.7

Hz)

Anal. Calcd for C ₂₅ H ₃ . NO, C: 79.11%, H: 8.76%, N: 3.69%; Found C: 79.17%, H: 8.89%, N: 3.64%. Example 46: 4- [N-isopropylmethyl-N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl) amino ] Manufacture of benzoic acid (DA122)

 Compound VI I-4 (299 mg) and potassium carbonate (499 mg) were dissolved in isopropyl iodide and heated at 150 ° C for 7 days in a sealed tube. The reaction solution was filtered, and the filtrate was dehydrated with anhydrous sodium sulfate and concentrated. The obtained residue was purified by flash column chromatography (n-hexane: ethyl acetate = 20: 1) to obtain 7 mg (2%) of a colorless transparent oily substance. ½-NMR (400 MHz, CDClg) 7.82 (2H, d, J = 9.2 Hz), 7.18 (1H, s), 6.91 (1H, s), 6.41 (2H, d , J = 8.8 Hz), 4.34 (1H, hept, J = 7.0 Hz), 4.29 (2H, q, J = 7.3 Hz), 2.01 (3H, s), 1.69 (4H, s), 1.33 (3H, t, J = 7.3 Hz), 1.30 (6H, s), 1.22 (6H, s), 1.15 (6H, s) ).

 The above ester (12 mg) was dissolved in ethanol (3 ml), and 0.5 ml of a 20% K0H aqueous solution was added, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1N hydrochloric acid (20 ml) and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain DA122.

 Colorless cubes (n-hexane-methylene chloride); mp 257 ° C

½-NMR (400 MHz, CDClg) 7.85 (2H, d, J = 9.2 Hz), 7.19 (1H, s), 6.91 (1H, s), 6.43 (2H, d , J = 9.2 Hz), 4.36 (1H, pent, J = 7.0 Hz), 2.01 (3H, s), 1.69 (4H, s), 1.31 (6H, s ), 1.23 (6H, s), 1.16 (6H, brs). Example 47: 4- [N-cyclopropylmethyl-N- (5, 6, 7, 8-tetrahydro-3, 5, 5,8,8-Penyl methylnaphthalene-2-yl) amino] Production of benzoic acid (DA124)

 DA124 was synthesized according to the method of Example 44 using compound VI I-4 and cyclopropylmethyl bromide.

 Colorless plates (n-hexane-methylene chloride); mp 213 ° C

½-NMR (400 MHz, CDClg) 7.88 (2H, d, J = 9.2 Hz), 7.17 (1H, s), 6.50 (2H, d, J = 8.8 Hz), 3.50 (2H, brs), 2.03 (3H, s), 1.69 (4H, s), 1.30 (6H, s), 1.24 (6H, s), 1.22 (1H , ra), 0.51 (2H, ddd, J = 4.8, 5.5, 8.1 Hz), 0.13 (2H, q, J = 4.8 Hz). Example 48: 4- [N-isobutyl-N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl) amino] benzoic acid (DA125) production

 DA125 was synthesized according to the method of Example 44 using compound VII-4 and isobutyl iodide.

 Colorless cotton (n-hexane-methylene chloride); mp 245 ° C

½-NMR (400 MHz, CDC1) 7.85 (2H, d, J = 9.2 Hz), 7.18 (1H, s), 7.07 (1H, s), 6.44 (2H, d, J = 9.2 Hz), 3.40 (2H , brs), 1.67 (1H, hept, J = 7.0 Hz), 1.98 (3H, s), 1.69 (4H, s), 1.31 (6H, s), 1.24 (6H, s), 0.99 (6H, d, J = 6.6 Hz). Example 49: Preparation of 4- [N-ethyl-N- (3,5-di-tert-butylphenyl) amino] benzoic acid (DA212) (Scheme 8)

 Dissolve 1.087 g of 3,5-di-tert-butylaniline (VIII-1), ethyl 4-ethylbenzoate (1817 g) and tert-BuONa (667.5 mg) in anhydrous toluene (20 ml), and replace with argon. Tris (dibenzylideneacetone) 106 mg of dipalladium (0) and (R) -BINAP (176 mg) were added, and the mixture was refluxed. Two hours later, the reaction solution was cooled to room temperature, poured into water (100 ml), and extracted with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 4- [N- (3, 5-Di-tert-butylphenyl) amino] benzoic acid ethyl ester (VIII-2) was obtained in an amount of 1.28 g (68%).

Colorless needles (n-hexane); mp 123 ° C

 ½-Hidden (400 MHz, CDClg) 7.92 (2H, dd, J = l.8, 8.8 Hz), 7.14 (1H, t, J = l.8 Hz), 7.03 (2H, d, J = l.5 Hz), 6.96 (2H, dd, J = l.8, 8.8 Hz), 6.01 (1H, br s), 4.33 (2H, q, J = 7.3 Hz), 1.37 (3H, t, J = 7.0 Hz) , 1.32 (18H, s)

_{. Anal Calcd for C 23 H 31} N0 2> C: 78.14%, H: 8.84%, N: 3.96%; Found C: 78.33

%, H: 8.94%, N: 3.69%.

101 mg of the above amino compound (VIII-2) was dissolved in MF (2 ml), and 90 mg of NaH suspended in MF (2 ml) was added. Thereafter, iodo chill (1 ml) was added, and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction solution was poured into water (30 ml) and extracted with methylene chloride. The organic layer was dehydrated with magnesium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 4- [N-ethyl-N- (3,5-di- -tert-Butylphenyl) amino] Ethyl benzoate (99%) was obtained. Colorless powder π-hexane); mp 90. C

 ½-NMR (400 MHz, CDC1J 7.83 (2H, dd, 1 = 2.2, 9.2 Hz), 7.31 (1H, t, J = l.8 Hz), 7.02 (2H, d, J = l.5 Hz), 6.64 (2H, dd, J = 2.2, 9.2 Hz), 4.31 (2H, q, J = 7.0 Hz), 3.79 (2H, q, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.32 (18H, s), 1.26 (3H, t, J = 7.0 Hz)

 Anal.Calcd for C ^ H ^ NO ^ C: 78.69%, H: 9.25%, N: 3.67%; Found C: 78.77%, H: 9.09%, N: 3.69%.

 The above ester (89 mg) was dissolved in ethanol (4 ml), and a 20% aqueous K0H solution (1 ml) was added thereto, followed by reflux. After the disappearance of the raw materials, the reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain 80 mg (97%) of DA212.

Colorless prisms (n-hexane-methylene chloride); mp 225 ° C

½-NMR (400 MHz, CDC1) 7.88 (2H, dd, 1 = 2.2, 9.2 Hz), 7.33 (1H ₍ t, J = l.8

Hz), 7.02 (2H, d, J = 1.8 Hz), 6.63 (2H, dd, J-1.8, 8.8 Hz), 3.80 (2H, q,

J = 7.0 Hz), 1.32 (18H, s), 1.27 (3H, t, J = 7.0 Hz)

Anal Calcd for C ₂₃ H ₃₁ N0 _o , C: 78.14%, H: 8.84%, N: 3.96%; Found C: 78.20%,

H: 8.91%, N: 3.92%. Example 50: Production of 4- [N-n-propyl-N- (3,5-di-tert-butylphenyl) amino] ethyl benzoate (DA213)

 DA213 was synthesized according to the method of Example 49 using compound VIII-2 and n-propyl iodide.

 Colorless prisms (n-hexane-methylene chloride); mp 247-248. C

½-Marauder R (400 MHz, CDClg) 7.87 (2H, dd, J = 2.2, 9.2 Hz), 7.33 (1H, t, J = l.8 Hz), 7.03 (2H, d, J = 1.8 Hz), 6.61 (2H, dd, J = 1.8, 9.2 Hz), 3.66 (2H, t, J = 7.7 Hz), 1.74 (2H, hex , J = 7.7 Hz), 1.32 (18 H, s), 0.95 (3H, t, J = 7.7 Hz)

_{. Anal Calcd for 4 Η 33 Ν0} 2, C: 78.43%, H: 9.05¾, N:. 3.81¾; Found C: 78.55%, H: 8.94%, N: 3.59% Example 51: 4 - [N- Fuweniru -N- [2- (5,6,7,8-Tetrahydro 5,5,8,8-tetramethylnaphthyl)] amino] Production of benzoic acid (TA001)

 4-[N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) Ύmino] ethyl benzoate (VI-2) 107 mg, Dissolve 0.1 ml of phenyl iodide and 33.5 m of tert-BuONa in 5 ml of anhydrous toluene, and add 21 mg of tris (dibenzylideneaceton) dipalladium (0) and 43 rag of BINAP (registered trademark) under argon atmosphere. Heated at 80 ° C. One hour and 40 minutes later, 33 mg of tert-BuONa was added. After an additional 1 hour and 50 minutes, the mixture was cooled to room temperature, poured into 30 ml of water, and extracted with methylene chloride. The organic layer was dehydrated with sodium sulfate, concentrated, and purified by flash silica gel column chromatography (n-hexane: ethyl acetate = 40: 1) to give 4- [N-phenyl-N- [2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthyl)] amino] Ethyl benzoate 28 mg (y.22%) was obtained.

 ½-NMR (400 MHz, CDClg) 7.84 (2H, dd, J = 1.8, 8.8 Hz), 7.29 (2H, t, J = 7.3 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.08 -7.16 (4H, m), 6.97 (2H, dd, Jl.8, 8.8 Hz), 6.82 (1H, dd, J = 2.6, 8.4 Hz), 4.33 (2H, q, J = 7.3 Hz), 1.67 (4H, s), 1.36 (3H, t, J2 7.3 Hz), 1.28 (6H, s), 1.17 (6H, s).

 23 mg of the above ester was dissolved in 3 ml of ethanol, 0.5 ml of a 20% K0H aqueous solution was added, and the mixture was refluxed for 1 hour. The reaction solution was poured into 1N hydrochloric acid and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 21 mg (quantitative) of yellowish white crystals. After the obtained crystals were treated with activated carbon, white crystals were obtained by recrystallization.

TA001: colorless prism (n-hexane-methylene chloride); mp 239 ° C

½-NMR (400 MHz, CDClg) 7.88 (2H, dd, J = 1.8, 8.8 Hz), 7.31 (2H, t, J = 8.4 Hz), 7.22 (1H, d, J = 8.4 Hz), 7.17 (2H, dd, J = l. 5, 8.8 Hz), 7.12 (1H, t, J = 7 3 Hz), 7.10 (1H, d, J = 2.6 Hz), 6.97 (2H, dd, J = 2.2, 9.2 Hz), 6.84 (2H, dd, J = 2. 6, 8.4 Hz), 1.68 (4H, s), 1.28 (6H, s), 1.18 (6H, s). Example 52: 4- [N, N-bis [ Production of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl)] amino] benzoic acid (TA012)

 In a nitrogen atmosphere, P-aminobenzoic acid ethyl ester (7.42 g), 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (10 g), A mixture of carbon dioxide (10.4 g), copper oxide (0.5 g), and nitrobenzene (5 ml) was stirred at about 220 ° C for 5 hours. After cooling the reaction mixture, ether was added and the mixture was filtered. The ether phase was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 5) to give compound VI-2 ( 3.5 g) and 4- [N, N-bis [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl)] amino] benzoic acid ethyl ester (3 1 g) was obtained.

Bis form: ½-NMR (400 MHz, CDClg) 7.82 (2H, d, J = 9 Hz), 7.19 (2H, d, J = 8 Hz), 7.08 (2H, d, J = 2 Hz), 6.94 (2H, d, J = 9 Hz), 6.84 (2H, dd, J = 8, 2 Hz), 4.

32 (2H, q), 1.67 (8H, s), 1.35 (3H, t), 1.27 (12H, s), 1.17 (12H, s). 4-[N, N- Bis [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthyl)] amino] Ethyl benzoate (3 g) in ethanol (20 ml) solution An aqueous solution (3 ml) of sodium hydroxide (0.67 g) was added, and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and an aqueous hydrochloric acid solution was added while cooling to 0 ° C. for neutralization. The mixture was extracted with ethyl acetate, and the obtained residue was purified by column chromatography (ethyl acetate) to obtain TA012 (1.5 g).

½-NMR (400 MHz, CDClg) 7.87 (2H, d, J-9 Hz), 7.21 (2H, d, J = 8 Hz), 7.10 (2H, d, J = 2 Hz) , 6.93 (2H, d, J = 9 Hz), 6.86 (2H, dd, J = 8, 2 Hz), 1.67 (8H, s), 1.27 (12H, s), 1 . 18 (12H, s). Test example: Cell differentiation induction assay in HL-60 cells

The effects of each compound on cell differentiation induction by itself and the effect of coexisting retinoid on cell differentiation were examined. Retinoic acid or Am80 [4 [(5678-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) potassium] 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 carried out using the promyelocytic leukemia cell line HL-60, and the morphological changes and the conversion of nitroble-tetrazolium (NBT) were performed. Judgment was made by measuring the reducing ability. Table 1, concentration dependent differentiation inducing ability of each compound alone, and showed a concentration-dependent effects on Rechinoi phosphate (RA) or inducing the differentiation of Am80 the ^{lxl (T 9 M, 1 x} 10 Table 2 Table 3 shows the concentration-dependent effects of each compound on the differentiation-inducing ability of ¹⁰ Am80. Table 3 shows the concentration-dependent differentiation-inducing ability of each compound alone and the concentration of 1 x 10-1 ⁽⁾ M Am80 on the differentiation-inducing ability. The percentage (%) of the differentiated cells shown in the following tables was calculated from the NBT reducing ability, the concentration was shown as a logarithmic value, and 1 means not measured. Table 1 compound 1 x 10- ⁹ M Am80 coexistence lxl (T ^a 9M induced to differentiate at _¾ RA and coexistence differentiation induction were derived differentiated during cell cells alone

 (%) Percentage of cells (%) Percentage of cells (%) Compound concentration 1

 -8 7 -6 None -8-7 -6 None -8 -7 stroke 10 1 0 66 76 89 14 26 66

DM012 0 1 1 66 73 85 94 14 57 69 Drawing 30 1 1 4 66 68 94 90 14 58 73

DM032 1 1 17 66 58 90 88 14 Table 2

The proportion of differentiated induced cells in the case of coexisting with 1x10 one ¹⁰ M Ara80 (%) Compound of

 None 10-9 -8-7 -6 stroke 21 4.5 6 12 43 83 Leg 30 15.5 38 41 43 81 90 stroke 31 4.5 8 14 41 81 86

DM032 15.5 36 39 46 81 87

Table 3 Induction of differentiation by compound alone When coexisting with 1x10 to ¹⁰ M Am80 Percentage of cells induced (%) Percentage of cells induced differentiation (%) Compound concentration Concentration

 -9 -8-7-6 None -10 -9 8 -7-6

DA010 1.7 2.7 3.2 61 12 34 38 46 89

DA011 2.4 3.6 5 81 12 43 49 85 91

DA012 1.3 6.7 15.2 4.5 10 21 80 89

 DA013-1 4 3.3 4.5 18 28 87 90

 DA014 2.1 4.5 3.2 14 36 69 92 57

DA015 2.3 2.6 2.3 14 28 50 65 47

DA021-3.4 2.5 8.2 4.5 8.1 9.6 42 90 One

DA022 2.8 3.8 5.5 5.5 42 55 89

 DA023 2 3.9 6.8 5.5 39 67 95

 DA024 4.3 8.3 6.6 5.5 24 48 87

Leg 30 0.9 2.7 1.6 4 12 55 87 86 47

DA051 2.5 3.3 3 14 31 32 46 74

DA112 3.5 5 4 5.5 40 71 90

 DA113 2.1 2.2 4.3 5.5 37 80 94

 DA212 1.5 1.8 2.5 4.5 4.8 8.5 8 45 66

DA213 1.3 0.6 0.9 4.5 8 17 74 88 66 Test Example 2: Blood glucose lowering effect on diabetes model mouse

Blood was collected from the tail vein of KK mice that developed diabetes at the age of 4 to 5 months, and their blood glucose levels were measured. Next, the mice were divided into groups so that the average of the blood glucose levels of the mice in each group was the same (one group, four mice), and a mouse powder prepared so as to contain the test substance at 0.01% to 0.03%. The diet (F-1, Funabashi Farm) was given to each group of mice for 3 days. As a control, a powder diet containing no drug was administered to control mice. Three days later, blood was collected from the tail vein of the mouse, and the glucose concentration in the plasma obtained by centrifugation was measured using a glucose analyzer-1 and Glucoda-F (A & T). The hypoglycemic rate of the test substance was determined by the following formula. Hypoglycemic rate (%) = (blood glucose level of control mouse-blood glucose level of drug-administered mouse) / blood glucose level of control mouse

Table 4 Compound Concentration in feed <<) Blood glucose level (mean) Hypoglycemic rate (¾) Control 455 ± 10

Image 11 0.03 383 ± 38 15.9

 DA051 0.03 462 ± 38 1.4

 DM010 0.03 431 ± 14 5.4

 DM011 0.03 396 ± 44 13.1

 DM030 0.03 416 ± 17 8.7

 DM031 0.03 326 ± 30 28.3 Control 452 ± 38

 DA012 0.01 282 ± 47 37.6

 DA012 0.03 352 ± 61 22.2

 DA013 0.01 426 ± 53 5.9

 DA013 0.03 430 ± 25 4.9 Control 374 ± 51

DA012 0.03 255 ± 26 31.7

Industrial applicability

 The compound of the present invention has an action of regulating the expression of physiological activities of retinoids such as retinoic acid, and thus is useful as an active ingredient of a drug such as a retinoid action regulator.

Claims

1. The following general formula (0: Contract

Wherein, R ¹ represents a hydrogen atom or a - ₆ represents an alkyl group; or shows a R ^2, R ^J, and R ⁴ are each independently a hydrogen atom, _alkyl group, or (^ alkoxy group, or R ² and ^ Chapter Are together, and they are joined together and the carbon surrounding the phenyl group to which ^ is attached. It may form a 5- or 6-membered ring with the atoms (the above-mentioned ring may have one or two or more _4- alkyl groups on the ring, or may have one or more substituents). X may represent a divalent group represented by -C (R ⁵ ) (R ⁰ )-or -NR, wherein R ⁵ represents a condensed benzene ring. R ^D represents a phenyl group which may have a substituent, or a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic group which may have a substituent; R ′ represents a hydrogen atom or a hydroxyl group; hydrogen atom, may also have an unsaturated bond on one or two or more - ^ alkyl group, c ₃ _ ₁₀ cycloalkyl group, c ₄ _ ₁₂ cycloalkyl substituted alkyl groups, it may have a substituent Ararukiru group, c _{{_ l2} Arukanoiru group, also Aroiru group which may be substituted, or Rukoto which have a substituent Or a salt thereof that Hue illustrates a two Le group)].  2. A medicament comprising as an active ingredient a compound selected from the group consisting of the compound according to claim 1 and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.  3. The medicament according to claim 2, which is a retinoid action regulator. 4. The nuclear receptor according to claim 2 or 3, which is used as an action enhancer or action inhibitor of a physiologically active substance which exerts a physiological action by binding to a nuclear receptor belonging to the superfamily. The medicament according to claim. 5. The medicament according to claim 4, wherein the physiologically active substance is a retinoid.  6. A pharmaceutical composition comprising the compound according to claim 1 and a physiologically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof, and a retinoid. object.  7. The compound according to claim 1 and a physiologically acceptable salt thereof, and a hydrate thereof for the manufacture of a medicament according to any one of claims 2 to 5. And a substance selected from the group consisting of solvates thereof.  8. A method for regulating the action of retinoid in a living body of a mammal, comprising the compound according to claim 1, a physiologically acceptable salt thereof, a hydrate thereof, and a solvent thereof. Administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of Japanese citrates.  9. Claim 8 which is a method of preventing and / or treating vitamin A deficiency, skin disease, allergic disease, immune disease, bone disease, Alzheimer's disease, Huntington's disease, or malignant tumor. The described method.  10. The method according to claim 8, which is a method for preventing and / or treating diabetes, arteriosclerosis, hyperlipidemia, or hypercholesterolemia.