WO1997032837A1 - Nonsteroidal estrogen derivatives - Google Patents

Abstract

Compounds of general formula (I) exhibiting an estrogenic activity and/or anti-estrogenic activity, geometrical isomers of them, and pharmaceutically acceptable salts thereof, wherein R0 is hydrogen or a hydroxyl-protecting group; R1 is hydrogen, halogeno, C¿1?-C6 alkyl, hydroxyl or protected hydroxyl; R?2¿ is hydrogen or -(CH¿2?)k-X-R?3¿; the solid lines with short dashes are each a single bond or a double bond; A is (1) methylene, oxygen or a single bond, or (2) methyne; E is (1) -GR7- or -CO-, or (2) =CR7- or nitrogen; and Z is carboxyl, carbamoyl, hydroxyaminocarbonyl, hydroxymethyl or a protected functional group derived therefrom.

Description

 Description Non-speroidal estrogen derivative Technical field to which the invention pertains

 The present invention relates to a novel non-speroidal compound having estrogenic activity and Z or antiestrogenic activity, and a pharmaceutically acceptable salt thereof.

Conventional technology

Estrogen is a steroidal or non-speroidal estrus hormone, and many substances are known not only in nature but also synthetically (Envίro nmental Health Therapeutics, Nos. 61, 97). ~ 110 pages (1 985)). Naturally occurring estrogen in humans is 17-estradiol, mainly produced by the ovaries, which develops female secondary sexual characteristics, endometrial growth, regulates sexual function, regulates bone metabolism, It plays an important role in regulating lipid metabolism. Therefore, as women age and their ovarian function declines, estrogen deficiency in the body can lead to certain medical conditions, such as menopause-related autonomic imbalance, lipid metabolism disorders and vasomotor disorders, menopause, Atrophic vaginitis, sexual dysfunction, osteoporosis, etc. are caused, and estrogen replacement therapy is administered for these. Recently, estrogen has been shown to prevent coronary heart disease and osteoporotic fractures in postmenopausal women (Anna Isofinternal Medicine, Vol. 117, 1038- 1041 (1992)). Estrogens have also been used in combination with other female hormones, such as progesterone, which promote gonadotropin suppression and are used as oral contraceptives. You. However, long-term administration of estrogen can cause side effects such as breast pain, irregular genital bleeding, obesity, endometrial hyperplasia, endometrial and breast cancer, myocardial infarction, thromboembolism, and cerebrovascular disease. As a therapeutic drug, a drug showing a more selective estrogenic effect is desired. Previous studies have shown that antiestrogen, an estrogen receptor antagonist, has a high therapeutic effect on estrogen-dependent breast cancer and has few side effects. Tamoxifen, a Lloyd antiestrogen, has widespread clinical application. Further, it has become known that such antiestrogen includes a compound which expresses an estrogen action (agonist action) in a tissue-specific manner. For example, raloxifene, like estrogen, suppresses postmenopausal bone loss, but has a very low uterine stimulatory effect (Internal Medicine, Vol. 76, pp. 939-942 (1959)). . On the other hand, most of the estrogen and antiestrogen known so far have a phenolic or alcoholic hydroxyl group at a position similar to 17 estradiol in terms of chemical structure, but slightly It has been described that certain types of ribonucleic acid conductors have estrogenic activity, such as doisynolicacid and methanolic acid (meSteroid Biochem. Vol. 31, 393-404 (1 988) and Bui in Soc. Chim. Fr., 71 1-718 (1 960)).

The present invention relates to a therapeutically useful and novel non-speroidal peptide having an estrogen activity and / or an anti-estrogen activity and exhibiting a tissue-selective agonist or antagonist action against various estrogen-dependent diseases. It is an object to provide a trogen derivative. Means for solving the problem

 The present inventors have conducted intensive studies to find a novel carboxylic acid derivative having estrogenic activity in order to solve the above-mentioned problems. As a result, surprisingly, the present inventors have found that a novel carboxylic acid derivative represented by the following general formula (I) The present inventors have found that a group of compounds exhibit not only strong estrogenic activity but also strong anti-estrogenic activity and remarkably restore bone mineral density in ovariectomized rats, thereby completing the present invention. That is, the present invention

[1]. General formula

 [Wherein, R ° represents a hydrogen atom or a hydroxyl-protecting group.

R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a protected hydroxyl group.

R ² is a hydrogen atom or a formula (CH ₂ ) _k — X—R ³ (where k is an integer of 0 to “! 0, X is a single bond, formula 1 O—, 1 S—, 1 SO —, One S0 ₂ —

, One CO— or a formula CON R ⁴ — (wherein, R ⁴ represents a hydrogen atom or an alkyl group having from 6 to 6 carbon atoms), and R ³ represents the number of carbon atoms which may have a substituent. Represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or an aryl group which may have a substituent. )

Represents

A solid line with a dashed line indicates a single bond or a double bond, and R ^{1 Q} is absent when the bond between carbon and carbon in each of R ² and R ^1Q is a double bond.

 A and E are

(1) When A-E is a single bond, A is a methylene group, an oxygen atom or Represents a single bond, E is wherein one GR ⁷ - (wherein, G represents a methine group or a nitrogen atom, the R ⁷ represent the same meaning as R ² above), the formula one CR ⁸ R ⁹ i (wherein, R ⁸ and R ⁹ represent an alkyl group having 1 to 6 carbon atoms which may be the same or different) or one CO—, but when A is a single bond and R ² is not a hydrogen atom, , E may represent an oxygen atom or a sulfur atom,

 (2) When A-E is a double bond, A represents a methine group;

CR ⁷ — (wherein, R ⁷ has the same meaning as described above) or a nitrogen atom.

R ¹ °, R ¹ 'and R ¹² each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms, but R''and R ¹² are simultaneously hydrogen atoms It cannot be an atom.

 Z is a carboxyl group, carbamoyl group, hydroxyamino carbonyl group

Represents a hydroxymethyl group or a protected functional group thereof. However, (E) — 3- (6-Methoxynaphthalene-1-yl) -12-methyl-12-hexenoic acid and its carboxyl-protected derivatives are excluded. Or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof,

[2]. The compound according to [1], wherein R ² and R ⁷ are not simultaneously hydrogen atoms, or a geometric isomer thereof with respect to a double bond, or a pharmaceutically acceptable salt thereof,

 [3]. The description of [2], wherein A-E is a single bond and A is a methylene group or an oxygen atom, or A-E is a double bond and A is a methine group and R ° is a hydrogen atom. Or a geometric isomer of the double bond, or a pharmaceutically acceptable salt thereof,

 [4]. —General formula (Ia)

(la) [Wherein, R ′, R ² , R ⁷ , R ¹ °, R ″, R ′ ² and Z have the same meaning as in claim 1], or the compound or double bond according to [3]. Or a pharmaceutically acceptable salt thereof,

 [5]. The compound according to any one of [2] to [4], wherein Z is a carboxyl group or an alkoxycarbonyl group having 2 to 2 carbon atoms, or a geometric isomer relating to a double bond, or a pharmaceutical thereof. Acceptable salts,

[6]. General formula

[Wherein, R ² , R ⁷ , R "and R ¹² represent the same meaning as in [1], and R ¹³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.]

 [5] The compound according to any one of the above, or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof,

[F]. X is a single bond, one O— or one CO—, and R ³ is an alkyl group having 10 to 10 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, and a cycle having 3 to 7 carbon atoms. Mouth alkyl group or formula

(In the formula, m is 0 or 1, n is an integer of 1 to 10, Y is a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms or a formula NR ⁵ R ⁶ (wherein, R ⁵ and R ⁶ represents an alkyl group having 1 to 6 carbon atoms which may be the same or different, and R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group. Which can be formed)

The compound according to any one of [2] to [6] or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof, [8]. Y is a group represented by the formula NR ^5a R ^6a (wherein, R ^5a and represents an alkyl group having 1 to 6 carbon atoms which may be the same or different), a pyrrolidino group, a pyridino group or a morpholino group [7] The compound according to [7] or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof,

 [9]. General formula (I c)

[Wherein, R ′, R ² , R ″, R ¹² , E and Z have the same meanings as in claim 1] or a geometrical isomer relating to a double bond. Or a pharmaceutically acceptable salt thereof,

[10]. E is a group represented by the formula: NR ⁷ — (wherein R ⁷ has the same meaning as [1]). The body, or a pharmaceutically acceptable salt thereof,

[1 1]. E is -O- or 1S-, and R ² is a group represented by the formula (CH ₂ ) _k- XR ³ (where k, X, and R ³ have the same meanings as [1]. The compound according to [9], which is a group represented by the following formula: <> is a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof;

 [12] A pharmaceutical comprising the compound according to [1] or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof,

 [1 3]. The medicament according to [1 2], which is a therapeutic agent for a disease caused by estrogen deficiency.

 [14] The medicament according to [12], which is a therapeutic agent for estrogen-dependent diseases, and

[15] The pharmaceutical according to [12], which is a therapeutic agent for postmenopausal osteoporosis. Hereinafter, the contents of the present invention will be described in detail.

 In the present invention, examples of the alkyl group having 1 to 6 carbon atoms include a linear or branched alkyl group, and specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, Monomethylpropyl, 2-methylpropyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl pill, 1-methylbutyl, 3-methylbutyl, 2-ethylbutyl, hexyl, 2-methylpentyl, 4-methylpentyl And the like.

 Specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the alkyl group having 1 to 10 carbon atoms for R ³ include a linear or branched alkyl group.Specifically, in addition to the specific examples of the alkyl group having 1 to 6 carbon atoms, heptyl, Examples include 1-ethylpentyl, 1-methylheptyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, and decyl.

Examples of the alkenyl group having 3 to 10 carbon atoms for R ³ include a straight-chain or branched-chain alkenyl group, specifically, 2-probenyl, 2-butenyl, 3-butenyl, and 2-methyl- 2-Propenyl, 2-pentenyl, 4-dipenyl, 3-methyl-1-butenyl, 2-hexenyl, 3-heptenyl, 1-ethyl-3-pentenyl, 1-methyl-2-d And p-thenyl, 4-octenyl, 1,5-dimethylhexenyl, 2-ethylhexenyl, 7-nonenyl, 5-decenyl and the like.

Specific examples of the cycloalkyl group having 3 to 7 carbon atoms for R ³ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Examples of the haloalkyl group having 1 to 6 carbon atoms include a linear or branched alkyl group substituted with 1 to 5 halogen atoms which may be the same or different (specific examples are the same as described above). , Specifically, fluoromethyl, 2- Loroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3 , 3,3-pentafluoropropyl, 3-bromopropyl, 4-chlorobutyl, 4,4,5,5,5-pentafluoropentyl and the like.

Examples of the aryl group for R ³ include aryl groups having 10 or less carbon atoms, such as phenyl and naphthyl.

When the alkyl group or aryl group in R ³ has an S substituent, examples of the substituent include halogens such as fluorine, chlorine, bromine, and iodine; alkylamino having 1 to 6 carbon atoms such as amino, methylamino, and ethylamino; and acetylamino. JSft such as dialkylamino having 2 to 12 carbon atoms such as ethylmethylamino, aminoalkyl having 1 to 6 carbon atoms such as aminomethyl and aminoethyl, JSft having 3 to 18 carbon atoms such as dimethylaminoethyl and dimethylaminoethyl Dialkylaminoalkoxy having 3 to 18 carbon atoms such as aminoalkyl and dimethylaminoethoxy, hydroxyl group, alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy and propoxy, and alkoxy having 1 to 6 carbon atoms such as acetoxy and methyl. C2-C7 alkoxycarbonyloxy, such as toxiccarbonyloxy, Alkoxycarbonyl having 2 to 7 carbon atoms, such as moyloxy, carboxy, methoxycarbonyl, etc.Alkoxycarbonyl having 1 to 6 carbon atoms, such as alkamoyl, acetyl, oxo, formyl, cyano, nitro, methyl, ethyl, propyl, butyl, etc. Alkenyl having 2 to 6 carbon atoms such as alkenyl, ethynyl, alkynyl having 2 to 6 carbon atoms such as ethynyl, aryl having 6 to 10 carbon atoms such as phenyl, heterocyclic group such as pyridyl, furyl, phenyl and aryl. Aralkyl having 7 to 11 carbon atoms, such as benzyl, benzyl and phenyl, among which one or more arbitrary groups are selected.

Examples of the substituted alkyl group and aryl group include, for example, those represented by the general formula

(In the formula, m is 0 or 1, n is an integer of 1 to 10, Y is a carboxyl group, an alkoxycarbonyl group having 2 to 2 carbon atoms or a formula NR ⁵ R ⁶ (wherein, R ⁵ and R ⁶ represents an alkyl group having 1 to 6 carbon atoms which may be the same or different, but R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group. Which can be formed).

 Examples of the alkoxycarbonyl group having 2 to 7 carbon atoms in Y include a straight-chain or branched-chain alkoxycarbonyl group. Specifically, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n —Butoxycarbonyl, t-butoxycarbonyl, 2-methylpropoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

 When R ° represents a hydroxyl-protecting group, examples of the hydroxyl-protecting group include ether-type protecting groups such as methyl, t-butyl, aryl, 3-methyl-2-butenyl, benzyl, and triphenylmethyl; , Acetal-type protecting groups such as pentahydrobiranil, etc .; silyl ether-type protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc .; Ester-type protecting groups such as t-butoxycarbonyl, 2,2,2-dichloroethoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxy Carbonate-type protecting groups such as xyloxycarbonyl;

Examples of the protecting group in the case where 1 is a protected hydroxyl group include the same examples as described above. R ⁵ and R ⁶ forces When combined with the nitrogen atom to which they are bonded to form a 6-membered saturated heterocyclic group, the 5- to 6-membered heterocyclic group has a total number of atoms of 5 to 6 And a heterocyclic group in which one or more nitrogen atoms, in addition to one or more nitrogen atoms, oxygen atoms and sulfur atoms, constitute a ring, and specifically, a pyrrolidino , Piperidino, morpholino, thiomorpholino, piperazino and the like. The heterocyclic group may be substituted with lower alkyl such as methyl and ethyl, and may be, for example, 4-methylpiperazino.

 When Z represents a protected carboxyl group, the protecting group may be any of various commonly used protecting groups, and is preferably, for example, methyl or ethyl.

Linear or branched such as isopropyl, t-butyl, and 1 carbon

Alkyl groups of up to 6 such as haloalkyl groups having 1 to 6 carbon atoms such as 2-iodyl thiol and 2,2,2-trichloroethyl, such as 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl and isobutoxymethyl. 6-alkoxymethyl group, for example, an aliphatic acyloxymethyl group having 3 to 7 carbon atoms such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, and bivaloyloxymethyl, for example, 1-ethoxycarbonyloxyxetyl 1 - (C, ~C ₆₎ alkoxycarbonyl O key Chez butyl group, for example benzyl, 4-main Tokishibenjiru, 2 two Torobenjiru, 4-nitro base Ararukiru groups such as Njiru, e.g. Ariru, 2- Mechiruariru, C3-C7 alkenyl, such as 3-methylaryl, benzhydryl, or phthalidyl Groups.

When Z represents a protected hydroxyaminocarbonyl group or hydroxymethyl group, the protecting group for the hydroxyl group may be any of various protecting groups which are usually used, and preferably, for example, methyl, t-butyl, aryl Ether-type protecting groups such as, 3-methyl-1-butenyl, benzyl and triphenylmethyl, acetal-type protection such as methoxymethyl and tetrahydroviranyl Groups, silyl ether-type protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc .; , 2,2-dichloromouth ethoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 412-trobenzoyloxycarbonyl, etc. And the like.

In the general formula (I), preferably, when A to E is a single bond, A is a methylene group or a single bond, and when A to E is a double bond, A is a methine group. When A is a methylene group (a single bond between A and E) or a methine group (a double bond between A and E), E is preferably a compound of the formula GR ⁷ — (where G and R ⁷ are Which represents the same meaning as described above). X in R ² or R ⁷ is preferably a single bond, one O— or one CO—, and R ³ in R ² or R ⁷ is preferably an alkyl group having 1 to 10 carbon atoms. An alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a formula

(Wherein, m, n and Y represent the same meaning as described above). Further, Y is preferably a group represented by the formula: NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ have the same meanings as described above), and particularly preferably a pyrrolidino group, a piperidino group or a morpholino group. Group. Pharmaceutically acceptable salts of the compound (I) of the present invention include, for example, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like, triethylammonium salt, triethanol Ammonium And organic base salts such as salts, pyridinium salts and diisopropylammonium salts. In addition, when an amino group is present in the molecule, for example, inorganic salts such as hydrochloric acid, hydrobromide, nitrate and sulfate, and acetate, propionate, trifluoroacetate, and Organic acid salts such as acid, maleate, tartrate, methanesulfonate and benzenesulfonate are also included. The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be a solvate such as a hydrate.

The compound of the present invention represented by the general formula (I) can be produced, for example, according to the following method.

 1 0 1 1

[Wherein, R (RA, E, RRR ' ² and Z are

 , 2 0

R has the same meaning, and R represents a phosphorus substituent such as dimethylphosphono, getylphosphono, or triphenylphosphonium bromide, or a silicon substituent such as trimethylsilyl. ]

 Process A

A known compound represented by the general formula (VI) or a compound which can be prepared by a known method is dissolved in a suitable solvent in a strong base (eg, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium). , Lithium diisopropylamide, potassium hexamethyldisilazide, dimsyl sodium, etc.) to form a carbanion, which is then reacted with a carbonyl compound represented by the formula (V) to obtain a compound of the formula (I) The olefin compound represented by the following formula can be obtained. Suitable solvents may be those that do not adversely affect the reaction, but are preferably tetrahydrofuran or dimethylformamide. And dimethyl sulfoxide and a mixed solvent thereof. One equivalent or a slight excess of a strong base relative to the compound represented by the formula (VI) is added at a reaction temperature of usually not less than 1 78 ° C to 80 ° C, to give a corresponding carbanion. 0.5 to 1 equivalent of the carbonyl compound represented by the formula (V) is added, and the reaction temperature is not particularly limited, but the reaction is usually desirably performed at a temperature of 1 78 ° C to 80 ° C. The isomers around the newly formed double bond ((E) -isomer and (Z) -isomer) generally depend on the type of surrounding substituents, but generally R ² ° is phosphorus In the case of a substituent, the isomer represented by the above formula (I) is usually selectively obtained. In general, when R ² ° is a gay substituent, the formation of an isomer represented by the formula ( ^II ) described below is advantageous, and in some cases, the isomer (Ni) force << selectively can get. If desired, the content of the isomer (I ′) can be increased by performing a photoisomerization reaction using a high-pressure mercury lamp or the like. These can be separated into the (E)-and (Z) isomers by a usual method, for example, chromatography or the like, if necessary.

 In the compound represented by the formula (I) and the compound represented by the formula (V),

When R ° is a protecting group for a hydroxyl group or when R ¹ is a protected hydroxyl group, deprotection or conversion of the protecting group is carried out as required. This deprotection and conversion of the protecting group can be performed according to a general method, for example, the method described in Protective 'Groups' Inorganic Synthesis Second Edition (

Protective Groups in Organic Synthesis 2nd Edition, TW Greene and PG. Wuts, John Wiley and Sons, Inc.) 145-162 (1991). Thereafter, when a compound of the formula (I) wherein Z is a protected propyloxyl group is obtained, deprotection is carried out. This de-rubber can be carried out according to a general method. For example, the above-mentioned Protective Groups in Organic Synthesis 2nd Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc.) 227-276 (1991).

The starting carbonyl compound represented by the formula (V) is known or can be produced by a known method. For example, in the case of a formyl form in which R ¹¹ is a hydrogen atom in the formula (V), it is produced by a method similar to a known technique. (1) Naphthalene, dihydronaphthalene, indene, and the like according to the method described in European Patent No. 298466 or Journal of Chemistry, Vol. 33, 2856-2864 (1990). Preparation of compounds having a benzofuran, benzothiophene and indole skeleton, (2) reduction of the corresponding carboxylic acid or its derivative (optionally protected) using a suitable reducing agent, for example, diisobutylaluminum hydride Formyl form, or (3) the corresponding substituted methanol (for example, the above carboxylic acid can be produced using lithium aluminum hydride or the like) by a suitable oxidation method, for example, pyridinium chloride Formyl form by oxidation using a mart method or Swern Oxidation It can be produced by a method of. In equation (V)

When R ¹¹ is an acyl group representing an alkyl group having 1 to 6 carbon atoms, for example, an organometallic agent suitable for the formyl body produced by the above-mentioned technology, for example, ethylmagnesium bromide, methyllithium, pentafluore It is produced by the reaction of tyllithium or the like to form an alcohol, followed by a usual oxidation reaction of alcohol to ketone, for example, a method using a ruthenium catalyst and N-oxide, a method using a chromate salt, or the like. Alternatively, the compound can be produced by introducing an acyl group into the corresponding aryl compound by a Friedel-Crafff reaction, and the compound represented by the formula (V) has a naphthalene skeleton and R ² Is a 2-phenylethyl group which may be substituted, according to known techniques [for example, the method described in JP-A-7-82205]. Ri is expressed by the corresponding compounds wherein R ² is a hydrogen atom (also formula (V) (Corresponding to a compound) with a styrene compound. In addition, the corresponding aryl compound or aryl halide is led to aryl anion, and then, for example, dimethylformamide is introduced into the formyl compound by introducing an R ¹ 'CO group by a reaction with an acyl halide or the like. And an acyl form can also be produced.

In the formulas (V) and (I), when R ² contains one or more reactive groups such as a halogen, a hydroxyl group, a carbonyl group, a carboxyl group, a primary or secondary amine, a mercapto group, etc. In accordance with known methods, if necessary or necessary, for example, protection and deprotection of functional groups, oxidation and reduction reactions, amination, alkylation using alkyl halides, etc., introduction of substituents, main chain One or more of the conversions of the reactive group, such as extension of the reaction, can be performed in any order. In the conversion reaction, portions other than R ² , for example, R °, R ¹ , a carbonyl group in the formula (V), and a free carboxyl group Z in the formula (I) are protected by an appropriate protecting group. You may. Also, when E represents the formula GR ⁷ and R ⁷ contains one or more reactive groups as described above, it can optionally carry out the same conversion reaction as described above.

Other methods for synthesizing compound (I) from compound (V) in the same manner as in step A include a method in which an Aldol reaction is performed using a compound in which R ² ° is a hydrogen atom in formula (VI); )), A method of performing a Reformatsky reaction using a compound in which R ² ° is a halogen atom such as bromine or the like may be mentioned.

(Where RR and Z are Represent the same meaning. )

 Process a

The geometrical isomer represented by the formula (II) (may be a mixture containing up to about 30% of the isomer represented by the formula (I)) is dissolved in a suitable solvent, for example, acetone, and nitrogen gas is dissolved. Is irradiated with light from a high-pressure mercury lamp at room temperature for 1 to 3 hours while stirring, whereby an isomer mixture containing 40 to 60% or more of isomer (I) can be obtained. The resulting geometric isomer mixture can be subjected to a usual method, for example, silica gel column chromatography to separate the isomer (I) and the isomer (ni). If the separated isomer is re-irradiated with light to be isomerized, further isomer (I) can be obtained. Conversely, it is also possible to irradiate the isomer (I) with light to cause isomerization ₍

Wherein, R ", R ', A , E, R' °, R '', k and FT represents the same meaning as above, R _P represents a protecting group of a hydroxyl group. Q and Q 'are each Represents an alkoxy group and represents a chain acetal structure, or together represents a 5- to 6-membered cyclic acetal, or Q represents a hydrogen atom and Q ′ represents a methoxymethyl group, t-butyl Represents a hydroxyl group protected by a protecting group such as a dimethylsilyl group, or when Q and Q 'are taken together, the formula = C (R ^{, Z} ) Z (R ¹² and Z represent the same meaning as described above.) ] Process B

General methods of protecting group R _P of the hydroxyl groups of the compound represented by the formula (VI la)

, For example, in the same manner as in R ° and R ′.

 Process C

In a general manner for the hydroxyl group of a compound of the formula (VI lb), for example, represented by the formula H aI—R ³ (H aI represents a halogen and R ³ has the same meaning as described above) The halide is reacted in the presence of a suitable base, for example, triethylamine or sodium hydride, in a suitable solvent, for example, dimethylformamide at a reaction temperature of 0 ° C to 1oo ° c.

 In the compound represented by the formula (VI Ic), the protecting group at R ° is removed, if desired. When the compound (VI Ic) corresponds to the compound of the formula (I), the protecting group for Z is removed as required. When Q and Q ′ represent a cyclic or linear acetal structure, they are treated in a dilute mineral acid, preferably dilute hydrochloric acid, at a temperature of from 140 ° C. to room temperature, or Q represents a hydrogen atom and Q When 'represents a hydroxyl group protected by a methoxymethyl group, a t-butyldimethylsilyl group, etc., deprotection is carried out by a usual method, followed by a method using pyridinium chloromouth mart or Swern oxidation (Swern Oxidation). The oxidation reaction of the alcohol is carried out to convert the alcohol into a liponyl compound corresponding to the compound represented by the formula (V).

 In the above formulas (V I Ia) and (V I lb).

When P corresponds to the aforementioned R ³ and Q and Q ′ together represent the above formula = C (R ′ ² ) —Z, these compounds are the same as the compounds of the present invention of the above formula (I). Equivalent to. The following formulas (VIIb '), (VIId). (VIIe), (VIIf). (VIIg), (VIIla). (VIIlb), (VIIIc), (X), (X The same applies to (a), (XII), (XI la). (XIII) and (XMia). R 11

R ° 0 ', (CH ₂ ) _k OR _P R ° 0 (CH ₂ ) _k OH

(Vnd) (Vile)

 (Vllf)

(In the formula, R °, R ¹ , R ² , R ′ ¹ , k, R ³ , _RP , Q and Q ′ have the same meanings as described above.)

 Process B '

Removing the protecting group R _P of the hydroxyl groups of the compound represented by the formula (VII d) in a general way.

 Process C '

 A substituent is introduced into the hydroxyl group of the compound represented by the formula (VIIe) in the same manner as in Step C described above.

In the compound represented by the formula (VIIf), the protecting group at R ° is removed, if desired. When the compound (VIIf) corresponds to the compound of the formula (I), the protecting group for Z is removed as required. When Q and Q ′ represent a cyclic or chain acetal structure, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above formula (V) can be obtained by the same method as described in the step C. To a carbonyl compound corresponding to the compound represented by

( n and R _p have the same meanings as above, G is a single bond, formula (CH ₂ ) _e one (g is an integer of 1 to 10), formula — (CH ₂ ) _h- 1 O— (CH ₂ ) _{g represents} one (h is 0 or an integer of 1 to 10, g represents the same meaning as described above), or represents one CO—. )

 Process D

The protecting group R _p for the hydroxyl group of the compound represented by the formula (VII la) is removed by a general method.

 Process E

The compound represented by the formula (IX) is added to the compound represented by the formula (IX) in a suitable solvent such as dimethylformamide in the presence of a suitable base such as sodium hydride. React at 0 ° C to 80 ° C. In the compound represented by the formula (VIIIc), if necessary, the protecting group at R ° is removed. Further, when the compound (VIIIc) corresponds to the compound of the formula (I), the protecting group of Z is optionally removed. Q and Q 'are cyclic or chain In the case where it represents an acetal structure in the form of a chain, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above-described formula can be used in the same manner as described in Step C above.

The compound is converted to a carbonyl compound corresponding to the compound represented by (V).

(Vllb ') (X) (XI): R ³ -X- (CH ₂ ) `` CH ₂ -R 20

And Q ′ have the same meanings as above, and i and ″ each represent 0 or an integer of 1 to 8, provided that ί + j + 2 = k. )

Process F

 The hydroxyl group of the compound represented by the formula (VIIb ′) (which can be obtained in the same manner as the compound of the formula (VI lb)) can be obtained by a usual method, for example, a method using pyridinium chlorochromate, (Swern

Oxidation), etc., to oxidize the hydroxyl group to convert to the formyl form (X).

 Process G

A compound represented by the general formula (XI) is dissolved in a suitable solvent, for example, dimethylformamide in a strong base (for example, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium, lithium diisopropylamide, potassium). Hexamethyldisilazide, Jimsil sodium, etc.) To form a carbanion and react with a formyl compound represented by the formula (X) to obtain an olefin compound represented by the formula (XII).

 Process H

 The compound represented by the formula (XII) is hydrogenated and reduced in an inert solvent such as methanol in the presence of a suitable catalyst such as a palladium carbon catalyst under a hydrogen atmosphere of 1 to 5 atm, preferably at room temperature. A compound represented by the formula (XIII) can be obtained.

 In the compound represented by the formula (XIII), the protecting group at R ° is removed, if desired. Further, when the compound (XIII) corresponds to the compound of the formula (I), the protecting group of Z is optionally removed. When Q and Q ′ represent a cyclic or chain acetal structure, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above formula (V) can be obtained by the same method as described in the step C. To a carbonyl compound corresponding to the compound represented by

(XI): R ³ -X- (CH ₂ ) rCH ₂ -R ²⁰ 'Has the same meaning as described above. )

Process F ' The hydroxyl group of the compound represented by the formula (VIIg) is converted to a formyl compound (Xa) in the same manner as in the above step F.

 Process G '

 The compound represented by the general formula (Xa) is reacted with the compound represented by the general formula (XI) in the same manner as in the step G to convert the compound into the polyolefin compound (XIIa).

 Process H '

 The compound represented by the formula (XIla) is hydrogenated and reduced in the same manner as in the above step H to obtain a compound (XIla).

 In the compound represented by the formula (XIIla), if necessary, the protecting group at R ° is removed. Further, when (XIIIA) corresponds to the compound of the formula (I), the protecting group of Z is optionally removed. When Q and Q ′ represent a cyclic or chain acetal structure, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above-mentioned formula (V) can be obtained in the same manner as described in Step C above. To a carbonyl compound corresponding to the compound represented by

(Va) (XIV)

[Wherein, R °, R ′, R ² , A, E, R ′ °, and R ¹¹ represent the same meaning as described above (however, R is not a hydrogen atom). ]

Process I A compound represented by the formula (Va) and an organometallic reagent, such as methyllithium, ethylmagnesium bromide, and pentafluoroethyllithium, are mixed in a suitable solvent, such as tetrahydrofuran, at a reaction temperature of about 78 ° C. React at C-80 ° C.

 Process J

 The compound represented by the formula (XIV) is converted to a ketone compound of the formula (Vb) by an oxidation reaction of an alcohol to a ketone, for example, a method using a ruthenium catalyst and N-oxide, a method using a chromate salt, or the like.

 (XV) (XVI)

(R ^u , R ″, R ′ ¹ , Q and Q ′ have the same meanings as above, provided that Q

 12

And Q 'together unless they together represent the formula = C (R ¹² ) -Z (R "and Z are as defined above).

 Process

 One equivalent of an organolithium reagent such as methyllithium, phenyllithium, p-methoxymethoxyphenyllithium (P-methoxymethoxybromobenzene and n-butyllithium in a conventional manner) is added to the compound represented by the formula (XV). Is reacted in a suitable solvent, for example, tetrahydrofuran at a reaction temperature of 78 to 80 ° C to obtain a compound of the formula (XVI).

The compound represented by the formula (XVI) is converted to a carbonyl compound corresponding to the compound represented by the formula (V) by the same method as described in the above step C.

 (XV) (XVII)

 (XVIII)

(R °, R ″, Q and Q ′ have the same meanings as above, provided that Q and Q ′ are taken together to form the formula = C (R ¹² ) 1 Z (R ¹² and Z are the same as above.

) Is excluded. R ′ ⁴ represents a protecting group for a hydroxyl group, or has the same meaning as in the above formula R ³ . )

 Process

 The compound represented by the formula (XV) is reacted with a suitable reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a suitable solvent such as tetrahydrofuran at a reaction temperature of 78 ° C. React at ~ 80 ° C. Process M

Or protecting a hydroxyl group of the compound represented by the formula (XV II) in the usual manner by appropriate coercive Mamorumoto, or a suitable base, for example Toryechiruamin, the presence of sodium hydride, the formula _{H a} I - R ³ (R ³ and HaI have the same meanings as described above), for example, propyl bromide, ethyl bromoacetate, ethyl ethyl 6-bromohexanoate and a suitable solvent, for example, The compound of formula (XVIII) is obtained by reacting in dimethylformamide at a reaction temperature of 0 ° C to 1 oo ° c.

The compounds of the formula (XV III), is converted to carbonyl body corresponding to the compound represented by step C to the description and the formula by the same method (V) _lambda

 (XIX) (XV)

(Wherein, R 1, R 2, Q and Q ′ represent the same meaning as described above, and T f represents a trifluoromethanesulfonyl group.)

 Process N

 The triflate represented by the formula (XIX) is converted to methanol and triethylamine in the presence of a phosphine, for example, triphenylphosphine or 1,3-bis (diphenylphosphino) propane and a palladium complex catalyst formed in the system from palladium acetate. By reacting at a reaction temperature of 50 to 120 ° C. in a suitable solvent containing, for example, dimethylformamide under a carbon monoxide atmosphere, a compound of the formula (XV) is obtained.

The compound represented by the formula (XIX) can be produced, for example, by using 6-methoxytetralone as a starting material. 1-hydroxy-6-methoxy-2-carbaldehyde J. Med. Chem.), Vol. 22, 363-365 (1987)], and the 1-position hydroxy group is protected with triflate by a usual method, and if desired, the formyl group is protected as an acetal under general conditions. Or by reducing the formyl group of the above triflate by an ordinary method, for example, using sodium borohydride or the like to obtain an alcohol form, and then protecting the hydroxyl group under general conditions. Or by converting the formyl group of the above carbaldehyde (the hydroxyl group may be protected if necessary) to the ketone form by carrying out the above-mentioned step and the same reaction as in step J to give a ketone body. The 1-position hydroxyl group and triflate after that, and a method of manufacturing provides protection of if desired carboxy group.

(And T f represents the same meaning as described above, and R _P , and R _P2 represent a hydroxyl-protecting group.)

 Process O

 The compound represented by the formula (XX) is reacted with a suitable reducing agent such as diisobutylaluminum hydride in a suitable solvent such as methylene chloride at a reaction temperature of 78 ° C to 80 ° C.

 The compound represented by the formula (XX) protects the carboxyl group of, for example, 3-hydroxy-7-methoxy-2-naphthoic acid with a usual protecting group, for example, an ester, and then the 3-position hydroxyl group is formed by a usual method. It can be obtained by, for example, a method of manufacturing with protection by triflate.

 Process P

 The hydroxyl group of the compound represented by the formula (XXI) is protected with a suitable protecting group by an ordinary method.

Process Q A compound represented by the formula (XXII) is reacted with a phosphine, for example, trif; a suitable solvent containing methanol and triethylamine in the presence of a palladium complex catalyst formed in a system from Lnyl phosphine or diphenylphosphinopropane and palladium acetate. For example, the reaction is carried out in dimethylformamide under a carbon monoxide atmosphere at a reaction temperature of 50 to 120 ° C.

 Process R

 The compound represented by the formula (XXIII) is reacted with a suitable reducing agent such as diisobutylaluminum hydride in a suitable solvent such as methylene chloride at a reaction temperature of 178 ° C to 80 ° C. Let it.

 Process S

The compound represented by the formula (XXIV) is subjected to a real alcohol oxidation reaction by a method using pyridinum chromatography or Swane oxidation (Swern Oxidation) to formyl represented by the formula (Vc). Convert to body. The production method described above exemplifies and describes in detail the production steps of the compound represented by the general formula (I) in the present invention, whereby the starting material, the production process, the reaction conditions, or the treatment The manufacturing method such as conditions is not limited. Some of the compounds (I) of the present invention may have optical isomers based on asymmetric carbon, and these isomers are all represented by a single formula for convenience. The scope of the invention is not limited, and the present invention includes all of these isomers and isomer mixtures. When the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used for therapy, it may be administered orally or parenterally (for example, intravenously, subcutaneously or intramuscularly, topically) as a pharmaceutical composition. , Rectal, transdermal, or nasal). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like. Examples of compositions for parenteral administration include injections Aqueous or oily agent, Ointments, creams, lotions, aerosols, suppositories, patches and the like. These preparations can be prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of preparations.

 The dose varies depending on the patient's condition such as age and weight, symptoms, and the administration route, but it is usually 0.05 to 500 mg, preferably 5 to 500 mg, per day for an adult as the amount of the active ingredient of the present invention. The dose can be administered once to three times daily, continuously, or intermittently or intermittently. Specific examples of the compounds included in the present invention include the following compounds. However, these compounds are for illustration only, and the present invention is not limited to these.

 (E) 1-3- (1-ethyl-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 (E) 1-3-(6-Hydroxy-1 -propyl naphthalene-1-2-yl)-

2-Methyl-2-pentenoic acid

 (E) -3--(6-Hydroxy-1-isopropylnaphthalene-1-yl) -2-methyl-2-pentanoic acid

 (E) -3--(1 -Butyl-6-hydroxynaphthalene-l-^-t-l) -1-methyl-2-pentenoic acid

 (E) — 3- (1-butyl-1-fluoro-6-hydroxynaphthalene-1-yl) 1,2-methyl-1-pentenoic acid

 (E) 1-3- (1-butyl-1-6-hydroxy-18-methylnaphthalene-1-yl) 1-2-methyl-2-pentanoic acid

 (E) 1-3- (1-butyl-5-fluoro-6-hydroxynaphthalene-12-yl) 1,2-methyl-1-pentenoic acid

(E) — 3— (1 —Butyl-6,7-dihydroxynaphthalene-1-yl) ) —2-Methyl-1-pentenoic acid

 (E) 1-3- (6-Hydroxy-1-isobutylnaphthalene-12-yl) 1-2-Methyl-1-pentenoic acid

 (E) — 3— [6-hydroxy-1- (3-methylbutyl) naphthalene-2-yl] -12-methyl-12-pentenoic acid

 (E) — 3— (6-Hydroxy-1 ”! Pentylnaphthalene-1-yl) 1-Methyl-2-pentenic acid

 (E) — 3— [6-Hydroxy-11- (4-methylpentyl) naphthalene-2-yl) -1-Methyl-2-pentenoic acid

 (E) — 3— (1-butyl-6-methoxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— (“I-hexyl-16-hydroxynaphthalene-12-yl) -1-methyl-1-pentenoic acid

 (E) — 3— (1-heptyl-6-hydroxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— (6-hydroxy 1-octylnaphthalene-1-2-tol) 1-2-methyl-1-pentenoic acid

 (E) —3— (6-Hydroxy-1-nonylnaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) —3— (1-decyl-1-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentanoic acid

 (E) — 3— (6-Hydroxy-1-opendecylnaphthalen-2-yl) 1-2-methyl-2-pentenoic acid

 (E) —3— (1-dodecyl-6-hydroxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

(E) —3— (6-Hydroxy-11-tridecylnaphthalene-12-yl) -1-Methyl-2-pentenoic acid (E) 1-3- (6-Hydroxy-1 "! 10-tradecylnaphthalene-2-T) 1-2-Methyl-2-pentenoic acid

 (E) —3— (6-Hydroxy-11-pentadecylnaphthalene-12-yl) —2-Methyl-2-pentenoic acid

 (E) -3--(1-Hexadecyl-6-hydroxynaphthalene-1--2- ^) -2-methyl-2-pentenoic acid

 (E) —3— (1 1-heptadecyl-6-hydroxynaphthalene-1-yl) —2-methyl-1-pentenoic acid

 (E) —3— (6-Hydroxy-1-octadecylnaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) 1-3- (6-hydroxy-1-nonadecylnaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— (1-eicosanyl-6-hydroxynaphthalene-12-yl) -1-methyl-2-pentenoic acid

 (E) —3— (11- (6-hydroxyhexyl) -1-6-hydroxynaphthalene-1-yl) -2-methyl-2-pentenoic acid

 (E) 1-[-(1- (1-vinyl) -1-6-hydroxynaphthalene-12-yl] -12-methyl-2-pentanoic acid

 (E) 1- (6-Hydroxy-11- (1-pentenyl) naphthalene-1-yl) -2-methyl-2-pentanoic acid

 (E) —3— C 1-(1-hexenyl) 1-6-hydroxynaphthalene 1 2 1 ^^) 1 2-methyl-12-pentenoic acid

 (E) —3— [6-Hydroxy-11- (3-methyl-2-butynyl) naphthalen-1-yl] 1-2-Methyl-2-pentenoic acid

 (E) — 3— [1 — (1 heptenyl) 1-6-hydroxynaphthalene 1 2 —yl] 1-2-methyl-12-pentenoic acid

(E) — 3— [6-hydroxy-1-11 (5, 5, 6, 6, 6-pentaflu Orol 1-hexenyl) naphthalene-1-yl] 1-2-methyl-2-pentic acid

 (E) — 3— (1-cyclopentyl-6-hydroxynaphthalene-1-yl)

 (E) 1-3- (1-cyclohexyl-6-hydroxynaphthalene-12-yl) 1-2-methyl-1-pentenoic acid

 (E) 1-3- (1-cyclopropylmethyl-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3 -— (1- (2-cyclopropylethyl) -1-6-hydroxynaphthalene-12-yl) 1-2-methyl-12-pentenoic acid

 (E) — 3— (1-cyclohexylmethyl-1-6-hydroxynaphthalene-1-yl) 1,2-methyl-2-pentenoic acid

 (E) —3— (6-Hydroxy-11-trifluoromethylnaphthalene-12-yl) 1,2-methyl-1-pentenoic acid

 (E) — 3— [6-Hydroxy-11- (2,2,2-trifluoroethyl) naphthalene-1-yl] -2-methyl-12-pentanoic acid

 (E) —3— (11- (2-furloethyl) -1-6-hydroxynaphthalene —2-yl) -12-methyl-2-pentenoic acid

 (E) — 3— [11- (2-chloroethyl) -1-6-hydroxinaphthalene-12-yl] 1-2-methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-1- (4,4,5,5,5-pentafluoropentyl) naphthalene-1-yl] 1-2-methyl-1-pentenoic acid (E) — 3— (1 1-hexyl-6-hydroxynaphthalene-1-yl-1-2-hexenoic acid

 (E) -3- (1-hexyl-6-hydroxynaphthalene-12-yl) -12-methyl-2-hexenoic acid

(E) —3— (1-pentyl-6-hydroxynaphthalene-2-yl) 2-Methyl-1-heptenoic acid

 (E) —3— (1-butyl-1-hydroxynaphthalene-1-yl) 2-methyl-2-octenoic acid

 (E) —3— (1-Hexyl-6-hydroxynaphthalene-1-yl) 1-2-Methyl-2-butyric acid

 (E) —3— (1-hexyl-1-hydroxynaphthalene-1-yl) -1-ethyl-2-butanoic acid

 (E) 1-3- (1-hexyl-6-hydroxynaphthalene-12-yl) 1-2-propyl-12-propenoic acid

 (E) —3— (6-hydroxy-11-phenylnaphthalene-1-yl)

2-Methyl-1-pentenoic acid

 (E) 1-3-(1-benzyl-6-hydroxynaphthalene-2-^ T) 1-2-methyl-1-2-pentenoic acid

 (E) — 3— [6-Hydroxy-11- (4-methoxyphenyl) naphthalene-12-yl] 1-2-Methyl-12-pentanoic acid

 (E) I-3- (1- (4-dimethylaminophenyl) -1-hydroxynaphthalene-12-yl) -1-methyl-2-pentenoic acid

 (E) 1-3- (1-1 (4- (2-dimethylaminoethoxy) phenyl) -6-hydroxynaphthalene-12-yl) 1-2-methyl-12-pentenoic acid (E) — 3 -— [6— Hydroxy-11 (4- (2-pyrrolidinoethoxy) phenyl) naphthalene-12-yl] 1-2-methyl-2-pentenoic acid (E) 1-3- [6-hydroxy-11- (4- (2-pi Beridinoethoxy) phenyl) naphthalene-1-yl] -1-methyl-2-pentanoic acid

 (E) I-3- (6-hydroxy-11- (4-1- (2-piberidinoethoxy) phenyl) naphthalene-12-yl) -12-methyl-2-propenoic acid

(E) I-3- (1- (4-chlorobenzyl) -1-6-hydroxynaphthalene-21-)-2-methyl-2-pentanoic acid (E) -3--[1- (4-Fluorobenzyl) -1 6-hydroxynaphthalene-12-Tl] -12-Methyl-12-pentenoic acid

 (E) —3— 6-Hydroxy-11- (4- (2-pyrrolidinoethoxy) benzyl) naphthalene-12-yl] 1-2-Methyl-2-pentenoic acid

 (E) -3--[6-Hydroxy-1- (4- (2-piberidinoethoxy) benzyl) naphthalene-1-yl] -12-methyl-2-propenoic acid

(E) —3— (6-Hydroxy-1-phenethylnaphthalene-1-yl) 1-2-Methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-11- (3-phenylpropyl) naphthalene-12-yl] 1-2-Methyl-2-pentanoic acid

 (E) 1-3- [6-Hydroxy-11- (4-phenylbutyl) naphthalene-2Tl] 1-2-methyl-12-pentenoic acid

 (E) — 3— [6-Hydroxy-1- (5-phenylpentyl) naphthalene-2-yl] -1-2-Methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-1- (6-phenylhexyl) naphthalene-2-yl] -12-methyl-2-pentanoic acid

 (E) -3- [6-Hydroxy-1- (4-hydroxyphenethyl) naphthalene-1--2-^-2-yl] -2-methyl-12-pentanoic acid

 (E) —3— [6-Hydroxy-11- (4-methylphenethyl) naphthalene-2-yl] -1-2-Methyl-2-pentenoic acid

 (E) — 3— [6-hydroxy-11- (4-methoxyphenethyl) naphthalene-1-yl] 1-2-methyl-12-pentenoic acid

 (E) 1-[-(1- (4-ethoxyphenethyl) -1-6-hydroxynaphthalene-2-yl] -1-2-methyl-2-pentenoic acid

 (E) -3- [1- (4-carboxymethoxyphenethyl) 16-hydroxynaphthalene-12-yl] 1-2-methyl-2-pentanoic acid

(E) — 3— [6-hydroxy-1- 1- (4— (2-piberidinoethoxy) Phenethyl) naphthalene-1-yl] 1-methyl-2-pentenoic acid

(E) —3— [6-hydroxy-11- (4- (2-piberidinoethoxy) phenethyl) naphthalene-1-yl] 1-2-methyl-2-hexenoic acid

(E) —3— [6-Hydroxy-1 — (4- (2-pyrrolidinoethoxy) phenethyl) naphthalene-1-yl] 1-2-methyl-1-pentenoic acid

(E) -3- [1- (4- (2-dimethylaminoethoxy) phenethyl) -6-hydroxynaphthalene-1-yl] -12-methyl-2-pentenoic acid

(E) — 3— [1 — (4- (2-Jetylaminoethoxy) phenethyl) 1-6-hydroxynaphthalene-12-yl] 1-2-Methyl-2-pentenoic acid (E) —3 — [6-Hydroxy-1— (4- (4- (4,4,5,5,5-pentafluoropentylsulfonyl) butoxy) phenethyl) naphthalen-2-yl] -12-methyl-2-pent ーAcid

 (E) -3--[6-Hydroxy-11 (4-1 (5- (4,4,5,5,5-pentapentafluoropentylsulfonyl) pentyloxy) benzyl) naphthalene-2-yl] 1-2 —Methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-1- (5-pyrrolidinopentyl) naphthalene-1-yl] -2-methyl-2-pentenoic acid

 (E) 1-3- [6-Hydroxy-11- (6-pyrrolidinohexyl) naphthalene 1-> T-l] -2-methyl-2-pentenoic acid

 (E) — 3— [6-Hydroxy-11- (6-piperidinohexyl) naphthalene-12-yl] -1-Methyl-2-pentenoic acid

 (E) -3--[6-hydroxy-11- (7-piperidinoheptyl) naphthalene-2-yl] -12-methyl-2-pentanoic acid

 (E) —3— [6-Hydroxy-1 "! 1- (8-piperidinooctyl) naphthalene-1-yl] 1-2-Methyl-2-pentenoic acid

(E) -3- [6-Hydroxy-11- (9-piperidinonyl) naphthalen-2-yl] -12-Methyl-2-pentanoic acid (E) 1-3- [6-hydroxy-1- 1- (10-piperidinodecyl) naphthalene-1-yl] 1-2-methyl-12-pentanoic acid

 (E) -3- [6-Hydroxy-1-((11-piperidin-n-decyl) naphthalene-1-yl] -12-methyl-12-pentanoic acid

 (E) —3— [1- (N-butylcarbamoyl) -1-6-hydroxynaphthalene-1-yl] 1,2-methyl-2-pentenoic acid

 (E) -3--[1- (N-pentylcarbamoyl) -1-6-hydroxynaphthalene-2-yl] -12-methyl-2-pentenoic acid

 (E) —3— [1- (N- (5-carboxypentyl) pothambamoyl) -1-6-hydroxynaphthalene-12-yl] -12-methyl-2-pentenoic acid

(E) 13- [6-Hydroxy-1- (N-butyl-1-N-methylcarbamoyl) naphthalene-1-yl] -12-methyl-2-pentenoic acid

 (E) — 3— [6-Hydroxy-11- (N-methyl-N-pentylcarbamoyl) naphthalene-1-yl] 1,2-methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-1 — (N-hexyl-N-methylcarbamoyl) naphthalene-1-yl] -12-methyl-2-pentenoic acid

 (E) 1-3- [6-Hydroxy-11- (N-heptyl-N-methylcarbamoyl) naphthalene-1-yl] -12-methyl-2-pentenoic acid

 (E) 13- [6-Hydroxy-1- (6- (N, N-dimethylcarbamoyl) hexyl) naphthalene-1-yl] -12-methyl-2-pentenoic acid

(E) -3--[6-Hydroxy-1- (7- (NrN-dimethylcarbamoyl) heptyl) naphthalene- _l - _l -]-l- 2-methyl-2-pentenoic acid

(E) 13- [6-Hydroxy-1— (10-N, N-getylcarbamoyl) decyl) naphthalene-12-yl] -12-methyl-2-pentenoic acid (E) — 3 -— [6— Hydroxy-1 — (10— (N-butyl-N-methylcaprolbumoyl) decyl) naphthalene-2-yl] -12-methyl-2-pentenoic acid (E) 13- [6-Hydroxy-1- 1- (7- (N-heptyl-1-N-methylpyruvamoyl) heptyl) naphthalene-1-yl] 1-2-methyl-12-pentenoic acid

 (E) —3— [6-hydroxy-11- (4- (7- (N-butyl-1-N-methylcarbamoyl) heptyloxy) benzyl) naphthalen-1-yl] —2-methyl-12-pentenoic acid

 (E) — 3— [6-Hydroxy-1- 1 — (4- (6- (methyl-butylcarbamoyl) hexyloxy) phenethyl) naphthalene-12-yl] 1-2-methyl-12-pentanoic acid

 (E) —3— [6-Hydroxy-11 (9-1 (4,4,5,5,5-pentaforolopentylsulfinyl) nonyl) naphthalene-1--2-yl] Acid

 (E) —3— [6-Hydroxy-1— (9— (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl) naphthalene-1-yl] 1-2—methyl-2-propenoic acid

 (E) 13- [6-Hydroxy-1— (9— (4,4,5,5,5-pentafluoropentylsulfonyl) nonyl) naphthalene-1-yl] 1-2-methyl-12-pentene Acid

 (E) 1-3-(1-1 (4-(2-dimethylaminoethoxy) benzoyl)-6-hydroxynaphthalene-1-2-yl] 1-2-methyl-2-pentanoic acid (E) -3- [6 —Hydroxy-1 — (4- (2-pyrrolidinoethoxy) benzoyl) naphthalene-1-yl] 1-Methyl-2-pentenoic acid

(E) 1-3-[6-Hydroxy-11 (4- (2-piberidinoethoxy) benzoyl) naphthalene-1 T] 1-2-methyl-1-pentanoic acid (E)-3-[6 —Hydroxy-1— (4- (2-piberidinoethoxy) benzoyl) naphthalene-1--2-yl] 1-2-Methyl-2-propenoic acid (E) — 3— [6-Hydroxy-1— (4— (2 —Piberdinoethoxy) Benzyl) naphthalene-1-yl] -1-ethyl-2-propenoic acid

(E) -3--[6-Hydroxy-11- (4- (2-piberidinoethoxy) benzoyl) naphthalene-12-] 1-2-propyl-2-propenoic acid

(E) — 3— [6-hydroxy-1- (4- (2-pyrrolidinoethoxy) benzoyl) naphthalene-1-yl] 1-2-butyl-2-propenoic acid

(E) 1-3- [6-Hydroxy-1— (4-1 (2-piberidinoethoxy) benzoyl) naphthalene-1-yl] 1-2-pentenoic acid

 (E) — 3— (1-ethoxy-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 (E) 1-3- (6-Hydroxy-1-propoxynaphthalene-2T) -2-methyl-2-pentanoic acid

 (E) — 3— (1-butoxy-6-hydroxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) -3- (6-Hydroxy-1-isobutoxynaphthalene-1-yl) -2-methyl-2-pentenoic acid

 (E) —3— (6-Hydroxy-11-pentyloxynaphthalene-12-yl) -1-2-Methyl-2-pentenoic acid

 (E) —3— (6-Methoxy-1-pentyloxynaphthalene-1-yl) 1-2-Methyl-2-pentenoic acid

 (E) —3— (6-Hydroxy-11- (3-methylbutoxy) naphthalene-12-yl) 1-2-Methyl-2-pentenoic acid

 (E) — 3— (1—Hexyloxy-6-hydroxynaphthalene-2-yl) -1-Methyl-2-pentanoic acid

 (E) — 3— (1-heptyloxy-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentanoic acid

(E) -3- (6-Hydroxy-1 octyloxynaphthalene 1-2-yl) 1-2-Methyl-2-pentenoic acid (E) -3- (6-Hydroxy-1-nonyloxynaphthalene-1-yl) -2-methyl-1-pentenoic acid

 (E) — 3— (1-decyloxy 6-hydroxynaphthalene 1-2-yl) 1-2-methyl-2-pentenoic acid

 (E) —3— (6-Hydroxy-1-onedecyloxynaphthalene-1-yl) 1,2-methyl-2-pentenoic acid

 (E) 1-3- (1-Dodecyloxy-6-hydroxynaphthalene-12-yl) 1-2-Methyl-1-pentenoic acid

 (E) 1-3- (6-Hydroxy-11-pentylquinaphthalene-1-yl) -2-hexenoic acid

 (E) -3- (6-Hydroxy-11-hexyloxynaphthalene-12-yl) 1-2-methyl-12-hexenoic acid

 (E) — 3— (6-Hydroxy-11-phenoxynaphthalene-12-yl) 1-2-Methyl-2-pentenoic acid

 (E) 1-3- (1-benzyloxy-6-hydroxynaphthalene-12-yl) 1-2-methyl-1-pentenoic acid

 (E) —3— (6-hydroxy-11-phenethyloxynaphthalene-12-yl) 1-2-methyl-12-pentenoic acid

 (E) -3- [6-Hydroxy-11- (3-phenylpropoxy) naphthalene-1-yl] 1-2-methyl-2-pentenoic acid

 (E) —3— 6-Hydroxy-11- (4,4,5,5,5-pentafluoropentyl) naphthalene-1-yl] 1-2-Methyl-2-pentanoic acid

 (E) 13- [6-Hydroxy-11- (8- (4,4,5,5,5-pentapentafluoropentylsulfinyl) octyloxy) naphthalene 1-2r] 1-2-Methyl-2-pentenoic acid

(E) — 3— [1— (2-butenyloxy) -1-6-hydroxynaphthalene —2-yl] mono 2-methyl-2-pentanoic acid

 (E) -3-[6-Hydroxy-1- (3-methyl-1--2-vinyloxy) naphthalene-1--2-]]-2-methyl-2-pentenoic acid

 (E) —3— (1-cyclopropylmethoxy-1-6-hydroxynaphthalene-12-yl) 1-2-methyl-12-pentenoic acid

 (E) 1-3- (11- (2-cyclopropylethoxy) -1 6-hydroxylphthalene-1-yl) 1-2-methyl-2-pentenoic acid

 (E) -3- (1-Cyclopentylmethoxy 6-hydroxynaphthalene-2-yl) -1-methyl-2-pentenoic acid

 (E) -3- (1-Cyclohexylmethoxy 6-hydroxynaphthalene 12-peryl) 1-2-methyl-12-pentenoic acid

 (E) 1-3- (1— (9- (N-butyl-N-methylcarbamoyl) nonyloxy) 1-6-hydroxynaphthalene-12-yl) 1-2-Methyl-12-pentanoic acid

 (E) — 3 -— (1- (3-dimethylaminopropoxy) methyl-6-hydroxynaphthalene-1-yl) -12-methyl-12-pentenoic acid

 (E) — 3— [6-Hydroxy 1 — (2-piberidinoethoxy) ethyl naphthalene-1-yl] 1-2-methyl-12-pentanoic acid

 (E) —3— [6-hydroxy-1- (3- (2-pyrrolidinoethoxy) propyl) naphthalene-1-yl] -1-methyl-2-pentenoic acid

 (E) I-3- (6-Hydroxy-1- (4- (2-piperidinoethoxy) butyl) naphthalene-1-yl) -1-Methyl-2-pentenoic acid

 (E) 1-3-[6-Hydroxy- 1 "!-1 (5- (2-piberidinoethoxy) pentyl) naphthalene-1-2-yl] 1-2-methyl-2-pentenoic acid (E) —Hydroxy-11- (4- (2-pyrrolidinoethoxy) phenoxy) naphthalene-1-2-^-2-yl-1--2-methyl-2-pentanoic acid

(E) One 3— [6-hydroxy-1 — (4-1 (2-piberidinoethoxy) Phenoxy) naphthalene-1-yl] 1-2-methyl-12-pentanoic acid

 (E) —3— [6-Hydroxy-1 — (4- (2-Dimethylaminoethoxy) phenoxy) naphthalene-1-yl] -12-methyl-2-pentenoic acid (E) — 3 -— [6 —Hydroxy 1- (4- (2-diisopropylaminoethoxy) phenoxy) naphthalene-1-yl] -1-methyl-2-pentenoic acid

 (E) — 3— [6-hydroxy-1- (4- (3- (1-piperidino) propoxy) phenoxy) naphthalene-2-yl] -2-methyl-2-pentenoic acid

 (E) -3- [6-Hydroxy-1— (4- (3- (1-morpholino) propoxy) phenoxy) naphthalene-1 2T] 1-2-Methyl-2-pentinic acid

 (E) -3- [6-Hydroxy-11- (4- (2-pyrrolidinoethoxy) benzyloxy) naphthalene-1-yl] -12-methyl-2-pentenoic acid (E) -3- [6-hydroxy- 1-1 (4- (2-piberidinoethoxy) benzyloxy) naphthalene-1-yl] 1-2-methyl-2-pentenoic acid (E) 1 3- (6-hydroxy-11- (4- (2- Dimethylaminoethoxy) benzyloxy) naphthalene-1-yl] -1-methyl-2-pentenoic acid

 (E) — 3 -— (1- (3-carboxypropoxy) -1-6-hydroxyhydroxyphthalene-2-yl) -2-methyl-12-pentanoic acid

 (E) 1-3- (1-1 (4-carboxybutoxy) -1-6-hydroxynaphthalene-2-yl) -2-methyl-2-pentenoic acid

 (E) —3— [6-Hydroxy-1- (2-picolyloxy) naphthalene-12-yl] 1-2-methyl-12-pentanoic acid

(E) 1- (6-hydroxy-11- (3-picoloxy) naphthalene —2-yl] 2-Methyl-1-pentanoic acid

 (E) -3--[6-Hydroxy-1- (4-picolyloxy) naphthalene-2T] 2-Methyl-2-pentanoic acid

 (E) — 3— [1 1-furfuryloxy-6-hydroxynaphthalene-1-yl] 1-methyl-2-pentenoic acid

 (E) 1-3- (6-hydroxy-1-propylthionaphthalene-12-yl) 1-2-methyl-12-pentanoic acid

 (E) —3— (1-butylthio-6-hydroxynaphthalene-12-yl) 1-2-methyl-12-pentanoic acid

 (E) —3— (6-Hydroxy-1-pentylthionaphthalene-1-yl) —2-Methyl-2-pentenoic acid

 (E) — 3— (1-hexylthio-1-6-hydroxynaphthalene-12-yl) 1-2-methyl-1-pentenoic acid

 (E) —3— [6-Hydroxy-11- (4,4,5,5,5-pentafluoropentylthio) naphthalene-1-yl] -12-methyl-2-pentanoic acid

 (E) — 3— (1-hexylsulfinyl 6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— [6-Hydroxy-11- (4,4,5,5,5-pentapentyl-lopentylsulfinyl) naphthalene-12-propyl] 1-2-Methyl-2-pentanoic acid

 (E) — 3— [6-Hydroxy-11- (4,4,5,5,5-pentafluoropentylsulfonyl) naphthalene-1-yl] -12-Methyl-2-dinoic acid

 (E) — 3- (3-butyl-1-hydroxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid

(E) -3- (1 butyl-6-hydroxy-3-methylnaphthalene-1 —Yl) 1-Methyl-12-pentanoic acid

 (E) I-3- (1-hexyl-6-hydroxy-3-methylnaphthalene-12-yl) 1,2-methyl-2-pentanoic acid

 (E) —3— (1-Butoxy-1-6-hydroxy-3-methylnaphthalene-1-yl) 1-2-Methyl-2-pentanoic acid

 (E) —3— (1-Pentyloxy-6-hydroxy-13-methylnaphthalene-1-2- ^ T) 2-Methyl-2-pentenoic acid

 (E) — 3- (1-hexyloxy-16-hydroxy-3-methylnaphthalene-1-yl) mono-2-methyl-2-pentanoate

 (E) -3- (3-Ethyl-6-hydroxy-1-1-phenethylnaphthalene-2-yl) -1-methyl-2-pentenoic acid

 (E) —3— [1— (4-Dimethylaminophenethyl) -1-3-ethyl-6-hydroxynaphthalene-12-per] -12-Methyl-2-pentanoic acid

 (E) —3— [3-Ethyl-6-hydroxy-11- (5-piperidinopentyloxy) naphthalene-1-yl] 1,2-methyl-2-pentenoic acid

 (E) —3— (1-butoxy-3-ethyl-6-hydroxynaphthalene-1-yl) -1-methyl-2-pentenoic acid

 (E) — 3— (3-ethyl-6-hydroxy-1-pentyloxynaphthalene-1-yl) 2-methyl-2-pentenoic acid

 (E) —3— [3- (2-Fluoroethyl) -1-6-hydroxy-1-pentyloxynaphthalene-1-yl] -1-methyl-2-pentanoic acid

 (E) 13- [3- (10-N-butyl-N-methylcarbamoyl) decyl) 16-hydroxy-11-methoxynaphthalene-12-yl] 1-2-methyl-2-pentenoic acid

 (E) 1-3- (1-Butyl-6-hydroxynaphthalene-12-yl) 1-2-Methyl-2-ethyl ether

(E) —3— (6-hydroxy-1-pentylnaphthalene-1-yl) 2-Methyl-1-tert-butyl pentanate

 (E) 1-N-ethyl-3- (1-hexyl-6-hydroxynaphthalene-12-yl) -1-methyl-2-pentenoic acid amide

 (E) 1-N-hydroxy-3- (6-hydroxy-1-octylnaphthalene-12-yl) 1-2-methyl-12-pentenoic acid amide

 (E) — 1-acetoxy 3— (6-acetoxy 1-pentyloxynaphthalene 1-2-yl) 1-2-methyl-12-pentene

 (E) — 1-acetoxy-1 3— (1-hexyl-6-methoxynaphthalene 1-2-yl) 1-2-methyl-12-pentene

 (E) —3— (1-butyl-6-hydroxy-3,4-dihydronaphthalene-12-yl) -12-methyl-2-pentenoic acid

 (E) — 3— (6-hydroxy-1-pentyl-3,4-dihydronaphthalene-1-yl) 1,2-methyl-2-pentenoic acid

 (E) I-3- (1-Hexyl-6-hydroxy-3,4-dihydronaphthalene-1-yl) I-2-Methyl-2-pentenoic acid

 (E) —3— (6-hydroxy-1-octyl-1,3,4-dihydrodronaphthalene-1-yl) -1-methyl-2-pentenoic acid

 (E) 1-3- [6-Hydroxy-11- (4- (2-pyrrolidinoethoxy) phenyl) -13,4-dihydronaphthalene-12-yl] 1-2-Methyl-12-pentenoic acid

 (E) I-3- (6-Hydroxy-11- (4- (2-piberidinoethoxy) benzoyl-3,4-dihydronaphthalene-12-yl) -12-Methyl-2-pentanoic acid

 (E) —3— (6-Hydroxy-1-pentyloxy-3,4-dihydronaphthalene-12-yl) -1-2-Methyl-2-pentenoic acid

(E) — 3- (1-hexyloxy-6-hydroxy-3,4-dihydronaphthalene-12-yl) -1-methyl-2-pentenoic acid (E) — 3— [6-Hydroxy-1 1 — (4,4,5,5,5-pentafluoropentyloxy) -1,3,4-dihydronaphthalene-1-2-yl] 1-2-Methyl 1-2-pentenoic acid

 (E) — 3- (1-butyl-6-hydroxy-1-, 2,3,4-tetrahydrodronaphthalene-1-yl) 1-2-methyl-1-pentanoic acid

 (E) —3— (1—Hexyl-6—Hydroxy 1,2,3,4-tetrahydronaphthalene-1-T-l) 1-2-Methyl-1-pentenoic acid

 (E) — 3— (1-octyl-6-hydroxy-1,2,3,4-ditrahydronaphthalene-1-yl) 1,2-methyl-1-pentenoic acid

 (E) —3— (6-Hydroxy-1-octyl-1,2,3,4-tetrahydronaphthalene-1-yl) 1-2-methyl-1-pentinoic acid

 (E) — 3— [6-Hydroxy-11- (4- (2-piberidinoethoxy) phenyl) 1-1,2,3,4-tetrahydronaphthalene-1-yl] -1-methyl-2-pentene Acid

 (E) —3— 6-Hydroxy-11- (4- (2-piberidinoethoxy) benzyl) 1-1,2,3,4-tetrahydrodronaphthalene-1-yl 1-2-Methyl-2- Penic acid

 (E) -3--[11- (10- (N-butyl-1-N-methylcarbamoyl) decyl) -1-6-hydroxy-1,2,3,4-trihydronaphthalene-1-yl] 1-2 —Methyl-2-pentenoic acid

 (E) 1-3- (1— (9- (N-butyl-1-N-methylcarbamoyl) nonyloxy) -1-6-hydroxy-1,2,3,4-tetrahydronaphthalene-12-yl] 1-2-methyl-1 2-pentenoic acid

(E) 1-3- (6-Hydroxy-3-methyl-11- (9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl) 1-1,2,3,4-dihydro Naphthalene-12-yl] -12-methyl-12-pentenoic acid (E) -13- [6-hydroxy-1— (9-1-1 (4,4,5,5,5-pentene Tafluolopentylsulfinyl) nonyl) 1, 1,2,3,4— 亍 trahidronaphthalene-12-yl] -12-methyl-12-pentenoic acid

 (Ε) — 3- (4-hexyl-7-hydroxy-12-methyl-1,1,2-dihydroisoquinolin-3-yl) -12-methyl-12-pentanoic acid

 (Ε) — 3— (2-ethyl-1-7-hydroxy-1-octyl-1,2-dihydroisoquinoline-13-yl) -1-methyl-2-pentenoic acid

 (Ε) 1- 3-[7-hydroxyl 4- (4- (2-piberidinoethoxy) phenyl) 1-2-methyl-1, 2- dihydroisoquinoline-1-3-yl] 1-2-methyl-2- pen Acid

 (Ε) — 3— [7-Hydroxy-1- (4- (2-piberidinoethoxy) benzyl) -1-methyl-1--1,2-dihydroisoquinoline-1-yl]-

2-Methyl-2-pentenoic acid

 (Ε) 13- [2- (10- (Ν-butyl-Ν-methylcarbamoyl) decyl) -1 7-hydroxy-11,2-dihydroisoquinoline-13-yl] -12-methyl-2-pentenoic acid

 (Ε) — 3— (4-Hexyl-1-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-13-yl) -12-methyl-2-pentanoic acid

 (Ε) -3--[2-Ethyl-7-hydroxy-4-1 (4-1- (2-piberidinoethoxy) phenyl) -1,1,2,3,4-tetrahydroisoquinoline-1

3-yl] mono 2-methyl-2-pentenoic acid

 (Ε) -3-(4-Ethyl-7-hydroxy-2-methyl-2 Η-chromen-3-yl) -1-methyl-2-pentenoic acid

 (Ε) — 3— (4-butyl-7-hydroxy-2-methyl-2Η-chromen-3-yl) mono-2-methyl-2-pentenoic acid

(Ε) 1-3- (4-Hexyl-7-hydroxy-2-methyl-2 ク ロ -chromen-3-yl) 1-2-Methyl-2-pentenoic acid (E) —3— (7-Hydroxy-12-methyl-4-octyl-2H—chromen-3-yl) -1-2-Methyl-2-pentenoic acid

 (E) —3— (7-hydroxy-14-phenyl-2H—chromene-3-yl) 1-2-methyl-2-pentenoic acid

 (E) -3- (7-Hydroxy-12-methyl-4-1 (4- (2-pyrrolidinoethoxy) phenyl) -12H-chromen-3-yl) 1-2-Methyl-1-pentene

 (E) — 3— (7-hydroxy-4-pentyloxy-1 2 H—chromen-3-yl) 1-2-methyl-1-pentenoic acid

 (E) —3— (4-butyl-7-hydroxycoumarin-1-yl) -1-methyl-2-pentenoic acid

 (E) —3— (4-Hexyl 7-hydroxycoumarin 13-T) 2-Methyl-2-pentenoic acid

 (E) 1- (4-Hexyloxy 7-hydroxycoumarin-13-yl) -2-methyl-1-pentenoic acid

 (E) 1-3- [7-hydroxy-1 41- (4- (2-piberidinoethoxy) phenyl) chroman-3-yl] 1-2-methyl-1-pentenoic acid

 (E) 1-3- [2,2-dimethyl-1-hydroxy-4-1 (4-1 (2-pyrrolidinoethoxy) phenyl) chroman-13-Tl] 1-2-methyl-2-pentenoic acid

 (E) —3— [2,2-Dimethyl-7-methoxy-1 4- (4- (2-pyridinoethoxy) phenyl) chroman-3-yl] 1-2-Methyl-2-dinoic acid

 (E) -3- (2,2-Dimethyl-17-hydroxy-14-octylchroman-3-yl) 1-2-Methyl-2-pentanoic acid

(E) 1-3- (3-butyl-6-hydroxy-1-methyl-1H-indene-12- ^ T) 1-2-methyl-12-pentenoic acid (E) -3--(3-Hexyl-6-hydroxy-1-methyl-1H-indene-1-yl) -1-methyl-2-pentenoic acid

 (E) — 3— [6-Hydroxy-3- (4- (2-piberidinoethoxy) phenyl) -1H-indene-2-yl] 1-2-methyl-12-pentanoic acid (E) — 3 — (3-Hexyl-6-hydroxy-1 monomethylindan 1-2 —yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— [6-Hydroxy-3- (4-1 (2-dimethylaminoethoxy) benzyl) indan-1-yl] 1-2-methyl-12-pentenoic acid

(E) -3--(3-Butyl-l-ethyl-l-6-hydroxyindole-l-yl) -l-Methyl-2-pentenoic acid

 (E) —3— (1-ethyl-3-hexylyl-6-hydroxyindole-1-yl) -1-methyl-2-pentenoic acid

 (E) — 3— (1-Ethyl-6-hydroxy-3—Cutylindogen I—2-yl) 2-Methyl-1-pentenoic acid

 (E) — 3— (3-decyl-6-hydroxy-1-methylindole-2-yl) 1,2-methyl-1-pentenoic acid

 (E) — 3— (3-ethyl-1-hexyl-6-hydroxyindole-2 perl) 1-methyl-2-pentenoic acid

 (E) — 3— [3-Ethyl-1-hydroxy-11- (6-piperidinohexyl) indole-1-yl] -12-methyl-12-pentanoic acid

 (E) —3— (1-ethyl-6-hydroxy-1-3- (4-1- (2-pyrrolidinoethoxy) phenyl) indole-2-yl) 1-2-methyl-2-pentenoic acid

 (E) — 3— (1-Ethyl-6-hydroxy-3— (4- (2-Piberidinoethoxy) phenyl) Indole-2-yl) 2-Methyl-2-pentenoic acid

(E) One 3— (6-Hydroxy-11) (4— (2-Piperidinoethoxy) Benzyl) 1-3-phenylindole 1-2-yl) 2-methyl-12- 一

 (E) —3— (1-ethyl-6-hydroxy-1-3- (4-1- (2-piberidinoethoxy) benzoyl) indole-1-2-yl) 1-2-methyl-1-benzoic acid

 (E) —3— (1-ethyl-6-hydroxy-13-pentyloxyindole-12-yl) 1-2-methyl-2-pentanoic acid

 (E) 13- [6-acetoxy-3-propoxy-11- (10- (N-butyl-1-N-methylcarbamoyl) decyl) indole-2-yl] 1-2-methyl-2-pentene Acid

 (E) —3— [3-ethyl-6-hydroxy-11- (9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl) indole-2

T]] 2-Methyl-2-pentenoic acid

 (E) 13- [6-Hydroxy-11 (9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl) -13-phenylindole-12-yl] 1-2 Methyl-2-pentanoic acid

 (E) 1-3- (3-hexyl-6-hydroxybenzo [b] thiophene 12-mol) 1-2-methyl-2-pentenoic acid

 (E) -3--[6-Hydroxy-3- (6-piperidinohexyl) benzo [b] thiophen-2-yl] -12-methyl-2-pentenoic acid

 (E) — 3— [6-hydroxy-3- (4- (2-piberidinoethoxy) benzoyl) benzo [b] thiophen-1-Tl] -2-methyl-2-dinoic acid

 (E) — 3— [6-Hydroxy-3- (4- (2-piberidinoethoxy) benzoyl) benzo [b] thiophen-1-yl] 1-2-methyl-1-hexanoic acid

(E) One 3— [6-hydroxy-3- (4- (2-piperidineethoxy) Benzyl) benzofuran-2-yl] 2-methyl-2-hexenoic acid Furthermore, the Z-isomer corresponding to each of the above compounds can be exemplified.

Example

 Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1

(E) —3— (6-Methoxynaphthalene 1-2-yl) 1-2-Methyl-12-ethyl pentenoate

 Under nitrogen, triethyl phosphonoacetate (2.2 g) was added to a solution of 60% sodium hydride (0.36 g) in dimethylformamide (1 OmL), and the mixture was stirred. A suspension of ketone (2. Og) obtained in Reference Example 1 in dimethylformamide was added thereto, and the mixture was stirred at 80 to 90 ° C for 7.5 hours. After cooling on ice, water was added, and the mixture was extracted three times with ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate 50: 1) to obtain the desired compound (0.47 g) as an oil.

1 H-NMR (CDC I ₃ ) <5: ppm

0.97 (3H, t, J = 7.4Hz), 1.36 (3Η, t, J = 7.1Hz), 1.76 (3H, s), 2.68 (2H , Q, J = 7.4 Hz), 3.93 (3 H, s), 4.28 (2 H, q, J = 7.2 Hz), 7.14 to 7.26 (3 H, m), 7.51 (1H, d, J = 1.3 Hz), 7.70 to 7.74 (2H, m). Example 2

 (E) — 3- (6-Hydroxynaphthalene-1-yl) -1-2-Methyl-2-ethylpentenoate

 Under ice-cooling, a dichloromethane (1 mL) solution of the ester (0.34 g) obtained in Example 1 was added dropwise to a dichloromethane (1 OmL) solution of aluminum chloride (0.30 g) and octanethiol (0.33 g). The mixture was stirred at the same temperature for 2 hours and then at room temperature overnight. The reaction solution was poured into 3N hydrochloric acid containing ice chips and extracted twice with dichloromethane. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by preparative thin-layer chromatography (hexane Z ethyl acetate 50: 1) to obtain the desired compound (0.079 g) as an oil.

 H-NMR (CDCI3) <5: ppm

0.97 (3 H, t, J = 7.4 Hz), 1.37 (3 H, t, J = 7.1 Hz), 1.76 (3 H, s), 2.68 (2 H, q, J = 7.3 Hz), 4.29 (2 H, q, J = 7.3 Hz), 7.08 to 7.25 (3 H, m), 7.49 (1H, s), 7.62 to 7.74 (2H, m).

Example 3

 (E) -3-(6-Hydroxynaphthalene-1-yl) 1-2-Methyl-2 monopentanoic acid

Under a nitrogen atmosphere, a 10 ° / o potassium carbonate solution (5 mL) was added to a methanol (5 mL) solution of the ester (0.079 _g ) obtained in Example 2 and the mixture was refluxed for 14 hours. After cooling on ice, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by preparative thin-layer chromatography to obtain the desired product (0.039 g). Mp 114-116. C.

'H -NR (dimethyl sulfoxide one d ₆₎ δ ppm

 0.87 (3 H, t, J = 7.3 Hz), 1.68 (3 H, s), 2.67 (2 H, q, J = 7.3 Hz), 05—7.15 (2H, m), 7.19 (1H, dd, J = 1.6 and 8.3Hz), 7.55 (1H, s), 7. 6 9 (1H, d, J = 8.6Hz), 7.77 (1H, d, J = 8.6Hz), 9.76 (1H, br.), 12 Example 4 8 (1 H, br.)

(E) —and (Z) —2-Ethyl-3- (6-Methoxymethoxy-naphthalene-1-yl) t-Butyl-1-pentenoate

 At 70 ° C, diisopropylamine (9.4 mL) in tetrahydrofuran

To the (10 OmL) solution was added 1.63 N n-butyllithium hexane solution (33.2 mL) to prepare lithium diisopropylamide. A solution of the ester (10.6 g) obtained in Reference Example 5 in tetrahydrofuran (20 mL) was added dropwise thereto, and the mixture was stirred for 1 hour. Further, at the same temperature, a solution of the ketone (10. Og) obtained in Reference Example 3 in tetrahydrofuran (5 OmL) was slowly dropped, and the mixture was stirred for 7.5 hours after completion of the dropping. Saturated saline (30 OmL) was added, and the mixture was extracted with ethyl acetate (80 mLx3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained mixture was treated with silica gel column chromatography (ethyl hexane acetate 30: 1) to isolate the (E) form (0.39 g) and the (Z) form (2.41 g). . (E) body: 'HNR (CD CI ₃ ) δ ppm

0.95 (3H, t, J = 7.2Hz), 1.47 (3H, t, J = 7.2Hz), 1.57 (9H, s), 2. 1 0 (2 H, q, J = 7.2 Hz), 2.56 (2 H, q, J = 7.2 Hz), 3.52 (3 H, s), 5.30 ( 2H, s), 7.21-7.25 (2H, m), 7.41 (1H, d, J = 2.6Hz), 7.51 (1H, br) ), 7.73 (1H, d, J = 8.2Hz), 7.74 (1H, d, J = 8.5Hz).

 (Z) form: 'H— NMR (C D C I 3) 5: ppm

0.91 (3H, t, J = 7.2Hz), 1.00 (9H, s), 1.13 (3H, t, J = 7.2Hz), 2. 42 -2.5.5 (4H, m), 3.53 (3H, s), 5.30 (2H, s), 7.19 (1H, dd, J = 2.3 and 8 9 Hz), 7.27 (1 H, dd, J = 1.9 and 8.2 Hz), 7.37 (1 H, d, J = 2.6 Hz), 7.50 (1 H, br.), 7.66-7.70 (2 H, m).

Example 5

 (E) 1-Ethyl 3- (6-Methoxy methoxy naphthalene 1-yl) 1-butyl 2-pentenoate

'. .COOBu-t

 MOMO AAJ

 A solution of (Z) -naphthyl ester (1.7 g) obtained in Example 4 in acetone (25 OmL) was irradiated with light from a high-pressure mercury lamp at 20 ° C. for 1 hour in a nitrogen stream. After removing the solvent, the mixture was purified by silica gel column chromatography (hexane Z: ethyl acetate 30: 1) to obtain the desired product (0.38 g).

 (The NMR spectrum is described in Example 4.)

Example 6

(E) — 2-Ethyl- 3 — (6-Hydroxynaphthalene-1-yl) 1 _2 -T-butyl pentenoate

Under ice-cooling, acetyl chloride (0.3 mL) was added dropwise to a solution of the ester (0.38 _g ) obtained in Example 5 in methanol (5 mL), and the mixture was stirred for 30 minutes. Further, acetyl chloride (1.5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Saturated saline (1 OOmL) was added, and the mixture was extracted with ethyl acetate (30mLx3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained mixture was purified by silica gel column chromatography (hexane / ethyl acetate 2: 1) to obtain the desired product (0.30 g).

 '' H-NMR (CDC I 3) δ: ppm

 0.90-0.99 (6H, m), 1.57 (9H, s), 2.12 (2H, q, J = 7.2Hz), 2.55 (2H, q, J = 7.2 Hz), 7.12 (1 H, dd, J = 2.3 and 8.9 Hz), 7.16 (1 H, d, J = 2.6 H z), 7.20 (1 H, dd, J = 1.6 and 8.6 Hz), 7.49 (1 H, b), 7.65 (1 H, d, J = 8.6 H z), 7.71 (1H, d, J = 8.9Hz).

Example 7

 (E) — 2-Ethyl-3 — (6-Hydroxynaphthalene-1-2-yl)

Formic acid (5 mL) was added to the ester (0.3 g) obtained in Example 6, and the mixture was stirred at 20 ° C for 3 days. To the reaction mixture were added methanol (5 mL) and 2N sodium hydroxide solution (5 mL), and the mixture was stirred for 5 minutes. ) And extracted with ether (20 mL × 3). The aqueous layer was adjusted to pH 4 with 2M-HGI and extracted with ether (20 mL x 3). The organic layer was collected, washed with saturated saline (30 mL), dried over magnesium sulfate, and the solvent was removed. The obtained mixture was recrystallized from hexane / dichloromethane to obtain the desired product (0.15 g) as a white powder.

'H-NMR (acetone-1 d ₆ ) 6: ppm

 0.95 (3 H, t, J = 7.2 Hz), 0.96 (3 H, t, J = 7.2 Hz), 2.15 (2 H, q, J = 7. 2 Hz), 2.68 (2 H, q, J = 7.2 Hz), 7.17 (1 H, dd, J = 2.3 and 8.6 Hz), 7.20- 7.24 (2H, m), 7.57 (1H, br.), 7.73 (1H, d, J = 8.6Hz), 7.81 (1H, d, J = 8.6 Hz).

Example 8

(E) — and (Z) — 3- (6-Methoxy methoxy naphthalene 1-2-yl) 1-Methyl-2-butenoic acid t-butyl

Using the ketone (2.57 g) obtained in Reference Example 8 as the starting material, the silyl ester (2.82 g) obtained in Reference Example 4 was used instead of t-butyl ² -trimethylsilylbutanoate. Obtained by a method similar to the method described in Example 4. (E) the body 2. 04g, (Z) the body 1. 38 _g.

(E) isomer: 'Η—NMR (CDCI ₃ ) δ: ppm

1.56 (9 H, s), 1.76 (3 H, q, J = 1.5 Hz), 2.28 (3 H, q, J = 1.5 Hz), 3.52 (3H, s), 5.30 (2H, s), f. 23 (1H, dd, J = 2.6 and 8.9Hz), 7.26 (1H, dd, J = 2 .0 and 8.6Hz), 7.39 (1H, d, J = 2 6 Hz), 7.54 (1 H, d, J = 2.0 Hz), 7.73 (1 H, d, J = 8.6 Hz), f. 74 (1 H, d , J = 8.9 Hz).

 (Z) isomer: 'Η—NMR (CDC I 3) δ: ppm

 1.03 (9H, s), 2.04 (3H, q, J = 0.9 Hz), 2.12 (3H, q, J = 0.9 Hz), 3.53 (3 H, s), 5.29 (2 H, s), 7.19 (1 H, dd, J = 2.6 and 8.9 Hz), 7.28 (1 H, dd, J = 1 9 and 8.6 Hz), 7.36 (1 H, d, J = 2.6 H 2), 7.51 (1 H, d, J = 1.9 Hz), 7.68 ( 1 H, d, J = 8.6 Hz), 7.68 (1 H, d, J = 8.9 Hz).

Example 9

(E) —3— (6-Hydroxynaphthalene-1-yl) t-butyl-1-methyl-1-monobutyrate

 Using the (E) -ester (2.04 g) obtained in Example 8 as the starting material, a method similar to that described in Example 6 (1.82 g) was obtained.

 1 H-NMR (CDC I 3) δ: ppm

 1.57 (9H, s), 1.77 (3H, q, J = 1.7 Hz), 2.27 (3H, q, J = 1.7 Hz), 7.12 (1 H, dd, J = 2.4 and 8.9 Hz), 7.15 (1 H, d, J = 2.4 Hz), 7.24 (1 H, dd, J = .7 And 8.6 Hz), 7.52 (1 H, d, J = 1.7 Hz), 7.65 (1 H, d, J = 8.6 Hz), and 70 (1 H , d, J = 8.9 Hz).

Example 10

(E) — 3— (6-Hydroxynaphthalene-1-yl) 1-2-Methyl-12-butanoic acid

 Using the ester obtained in Example 9 (1.82 g) as the starting material, a method similar to that described in Example 7 was used (0.90 g).

 1 H-NMR (CDC I a) δ: ppm

 1.83 (3 H, q, J = 1.4 Hz), 2.39 (3 H, q, J = 1.4 Hz), 7.13 (1 H, dd, J = 2 .6 and 8.6 Hz), 7.14 (1H, d, J = 2.6H2), 7.22 (1H, dd, J = 1.7 and 8.6Hz) , 7.52 (1H, d, J = 1.7Hz), 7.67 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.6 Hz).

Example 1 1

(E) mono- and (Z) — 2-ethyl-3- (6-methoxyethoxynaphthalene-1-yl) t-butyl mono-2-butyrate

Using the ketone (3.41 g) obtained in Reference Example 8 as a starting material, it was obtained in the same manner as described in Example 4. (E) 0.53 g body, (Z) 0.61 g ₀

(E) form: 'H-NMR (CDC I ₃ ) 5: ppm

0.94 (3 H, t, J = 7.6 Hz), 1.57 (9 H, s), 2.15 (2 H, q, J = 7.6 Hz), 2. 2 1 (3 H, s), 3.52 (3 H, s), 5.30 (2 H, s), 7.22 (1 H, dd, J = 2.3 and 8.9 Hz) , 7.26 (1H, dd, J = 1.7 and 8.6Hz), 7.40 (1H, d, J = 2.3Hz), 7.54 (1H, d, J = 1. f Hz), 7.72 (1H, d, J = 8.6Hz), f. 7 4 (1H, d, J = 8.9 Hz).

(Z) form: ¹ H-NMR (CDC I 3) δ: ppm

 1.04 (9 H, s), 1.1 (3 H, t, J = 7.6 Hz), 2.1

2 (3 H, s), 2.48 (2 H, q, J = 7.6 Hz), 3.53 (3 H, s), 5.29 (2 H, s), 7.19 (1H, dd, J = 2.3 and 8.9Hz), 7.29 (1H, dd, J = 1.7 and 8.6Hz), 7.29

36 (1H, d, J = 2.3Hz), 7.54 (1H, d, J = 1.7Hz), 7.68 (1H, d, J = 8.6Hz) ), F. 68 (1 H, d, J = 8.9 Hz).

Example 1 2

(E) —2-Ethyl-1- (6-hydroxy-2-phthalene-2- ^ T) t-Butyl monobutyrate

 Using the (E) -ester (0.53 g) obtained in Example 11 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.45 g).

-NMR (CDC I ₃ ) 5: ppm

0.95 (3H, t, J = 7.6Hz), 1.58 (9H, s), 2.16 (2H, q, J = 7.6Hz), 2.21 (3H , S), 7.12 (1 H, dd, J = 2.6 and 8.6 Hz), 7.16 (1 H, d, J = 2.6 Hz), 7.22 ( 1 H, dd, J = 1.7 and 8.2 Hz), 7.52 (1 H, d, J = 1.6 Hz), 7.64 (1 H, d, J = 8.2 Hz), f. 70 (1H, d, J = 8.6Hz).

Example 13

(E) — 2-Ethyl-1- (6-hydroxy-2-phthalene-2-yl) —2 monobutyric acid

 Using the ester (0.45 g) obtained in Example 12 as the starting material, it was obtained in a similar manner to that described in Example 7 (0.35 g).

H-NMR (CD CI ₃ ) δ: ppm

 0.99 (3H, t, J = 7.6Hz), 2.25 (2H, q, J = 7.6Hz), 2.37 (3H, s), 7.1 3 (1 H, dd, J = 2.6 and 8.9 Hz), 7.16 (1 H, d, J = 2.6 Hz), 7.24 (1 H 'dd, J = 1.7 and 8.6 Hz), 7.54 (1 H, d, J = 1.7 Hz), 7.69 (1 H, d, J = 8.6 Hz), 7.74 (1 H, d, J = 8.9 Hz).

Example 14

 (Z) — 4,4,5,5,5-pentafluoro-3- (6-methoxymethoxynaphthalene-1-yl) 1-2-methyl-2-pentenoic acid t-butyl

 The ketone (1. Og) obtained in Reference Example 11 was used as a starting material, and the silyl ester obtained in Reference Example 4 (0.72 g) was used instead of t-butyl 2-trimethylsilylbutanoate. And obtained in the same manner as described in Example 4 (1.15 g).

 '' H-NMR (CD C I 3) δ ppm

0.94 (9H, s), 2.23 (3H, t, _JH - _F = 2.8Hz), 3.52 (3H, s), 5.29 (2H, s) , 7.22 (1H, dd, J = 2.6 and 9.1Hz), 7.30 (1H, br.dd), 7.37 (1H, d, J = 2. 6 Hz), 7.59 (1H, br.), 7.67-7. 7 3 (2 H, m).

Example 15

(E) -4,4,5,5,5-pentafluorene 3- (6-methoxyquinone 7-n-2-yl) -t-butyl-1-2-methyl-2-pentenoate

 Using the ester (1. Og) obtained in Example 14 as the starting material, it was obtained in a similar manner to that described in Example 5 (0.24 g).

 '' H-NR (CDC I 3) 6: ppm

1.55 (9 H, s), 1.78 (3 H, t, J _H — _F = 2.4 Hz), 3.5 1 (3 H, s), 5.30 (2 H , s), 7.25 (1H, dd, J = 2.6 and 8.9Hz), 7.26 (1H, br.dd), 7.42 (1H, d, J = 2 .6 Hz), 7.66 (1 H, br.), 7.76 (1 H, d, J = 8.6 Hz), 7.77 (1 H, d, J = 8.9) H z).

Example 16

 (E) — 4,4,5,5,5-Pentafluoro-3- (6-hydroxynaphthalene-1-2-^-propyl) tert-butyl mono-2-methyl-2-penteneate

 Using the ester obtained in Example 15 (0.48 g) as the starting material, a method similar to that described in Example 6 was used (0.2 g).

1 H-NMR (CD CI ₃ ) <5: ppm

1.55 (9 H, s), 1.79 (3 H, t, _JH - _F = 2.5 Hz), 7.12-7.17 (2 H, m), 7. 23 (1H, br.d), 7.62 (1H, br.), F.68 (1H, d, J = 8.3Hz), 7.74 ( 1 H, d, J = 8.6 Hz).

Example 17

 (E) — 4,4,5,5,5-pentafluoro-3- (6-hydroxynaphthalene-1-yl) mono-2-methyl-2-pentanoate

 Using the ester (0.2 g) obtained in Example 16 as the starting material, a method similar to that described in Example 7 (0.15 g) was obtained.

 1 H-NMR (CDCI3) δ: ppm

1.90 (3H, t, _JH- F = 2.3 Hz), 7.11-7.18 (2H, m), 7.26 (1H, br.d), 7 66 (1H, br.), 7.72 (1H, d, J = 8.6Hz), 7.77 (1H, d, J = 8.3Hz).

Example 18

 3— (6-Methoxymethoxy 3,4-dihydronaphthalene-1-yl) — 2-Methyl-1-pentenedioic acid t-butyl

 Example 1 The ketone (3. Og) obtained in Reference Example 17 was used as a starting material, and the silyl ester obtained in Reference Example 4 was used instead of t-butyl 2-trimethylsilylbutanoate. It was obtained in a similar manner to that described in 4. (4.69 g). This is a 2:98 mixture of (E) and (Z) bodies.

 (Z) isomer: 'Η—NMR (CDCI3) <5: ppm

0.97 (3 H, t, J = 7.6 Hz), 1.3 1 (9 H, s), 1.90 (3 H, s), 2.23 (2 H, q, J = 7.6 Hz), 2.34 (2 T for H, b), 2.83 (2 H, br. T), 3.48 (3 H, s), 5.15 (2 H, s), 6.15 (1 H, s) , 6.65-6.81 (2 H, m), 6.89 (1 H, d, J = 8.6 Hz).

Example 19

 (E) 3- (6-Methoxymethoxy-3,4-dihydronaphthalene-12T) t-butyl-1-methyl-1--2-pentanoate

 Using the ester (4.69 g) obtained in Example 18 as the starting material, a compound was obtained in a similar manner to that described in Example 5 (1.83 g).

 1 H-NMR (CDC I a) δ: ppm

 1.01 (3H, t, J = 7.2Hz), 1.52 (9H, s), 1.89 (3H, s), 2.27-2.35 (2H, m ), 2.39 (2 H, q, J = 7.2 Hz), 2.83 (2 H, br.t), 347 (3 H, s), 5.16 (2 H, s) , 6.19 (1 H, s), 680-6.89 (2 H, m), 6.97 (1 H, d, J = 8.9 Hz).

Example 20

 (E) 3- (6-Hydroxy-3,4-dihydronaphthalene-1-yl) tert-butyl 2-methyl-2-penteneate

 Using the ester (0.5 g) obtained in Example 19 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.42 g).

 '' H-NMR (CD C I a) 5: ppm

1.01 (3 H, t, J = 7.2 Hz), 1.54 (9 H, s), 1.9 0 (3H, s), 2.26 (2H, br.t), 2.38 (2H, q, J = 7.2Hz), 2.78 (2H, br.t), 6.16 (1H, s), 6.24 (1H, br.), 6.61—6.68 (2H, m), 6.89 (1H, d, J = 8. 9 Hz).

Example 21

 (E) — 3-— (6-hydroxy-3,4-dihydronaphthalene-1-yl) —2-methyl-2-pentenoic acid

 Using the ester obtained in Example 20 as the starting material, it was obtained in the same manner as described in Example 7 (0.1 Og).

 1 H-NMR (CDC I a) δ: ppm

 1.05 (3 H, t, J = 7.2 Hz), 1.97 (3 H, s), 2.30 (2 H, b r.t), 2.58 (2 H, q , J = 7.2 Hz), 2.83 (2 H, b r.t), 6.18 (1 H, s), 6.61 -6. 66 (2 H, m), 6 93 (1 H, d, J = 8.9 Hz).

Example 22

 (Z) 12-Ethyl-13- (6-Methoxymethoxy-1,3,4-dihydronaphthalene-12-yl) 1-2-Pentenoic acid t-butyl

 Using the ketone (4.47 g) obtained in Reference Example 1 as the starting material, a compound was obtained in the same manner as described in Example 4 (1.49 g).

 (Z) form: 'H-NMR (C D C I 3) 5: ppm

0.97 (3 H, t, J = 7.6 Η ζ), 1.05 (3 ，, t, J = 7. 6 Hz), 1.32 (9 H, s), 2.22 (2 H, q, J = 7.6 Hz), 2.33 (2 H, q, J = 7.6 Hz) , 2.35 (2H, br.t), 2.83 (2H, br.t), 3.48 (3H, s), 5.16 (2H, s), 6.18 (1H, s), 6.70-6.81 (2H, m), 6.90 (1H, d, J = 7, 6Hz).

Example 23

 (E) —2—Ethyl-3- (6-Methoxymethoxy-1,3,4-dihydronaphthalene-1—2-O) 1-2-T-butyl pentanoate

 Using the ester obtained in Example 22 (1.19 g) as starting material, it was obtained in a similar manner to that described in Example 5 (0.45 g).

¹ H-NMR (CDC I 3) δ: ppm

0.99 (3 H, t, J = 7.6 Hz), 01 (3 H, J =

6 Hz), 1.53 (9 H, s), 229 (2 H, br.t), 2.31 (2 H, q, J = 7.6 Hz), 233 (2 H , q, J = 7.6 Hz), 2.83 (2 H, br.t), 348 (3 H, s), 5.17 (2 H, s), 6.19 (1 H, s), 680-6.86 (2H, m), 6.97 (1H, d, J = 9.2Hz).

Example 24

 (E) — 2-Ethyl-3- (6-hydroxy-3,4-dihydrodronaphthalene-2-yl) -1-tert-butyl 2-pentenoate

The starting material used was the (E) -ester (0.45 g) obtained in Example 23. It was obtained in the same manner as described in Example 6 (0.40 g).

Η NMR— NMR (CDC I ₃ ) 5: ppm

 0.98 (3 H, t, J = 7.6 Hz), 1.01 (3 H, t, J = 7.6 Hz), 1.53 (9 H, s), 2.28 2.34 (6 H, m), 2.80 (2 H, brt), 6.17 (1 H, s), 6.62-6.65

(2 H, m), 6.92 (1 H, d, J = 8.9 Hz).

Example 25

(E) —2-Ethyl-3— (6-Hydroxy-1,3,4-dihydronaphthalene-2-—T) 2-Pentenoic acid

To a solution of the ester (0.40 g) obtained in Example 24 in dichloromethane (10 mL) was added titanium tetrachloride (0.13 mL) at 0 ° C, and the mixture was stirred for 3 minutes. The reaction solution was poured into ice water and extracted with ether. The organic layer was extracted with saturated aqueous sodium bicarbonate and an aqueous solution of lithium carbonate. The aqueous layer was acidified with 6N hydrochloric acid and extracted with ether. The organic layer was dried over magnesium sulfate to remove the solvent. The residue was recrystallized from hexane to the dichloro port methane Z to obtain the title compound (0. 1 O _g).

¹ H-NMR (CDC I ₃ ) <5: ppm

 1.04 (3 H, t, J = 7.6 H 2), 1.05 (3 H, t, J = 7.6 H z), 2.28-2.53 (6 H, m), 2.83 (2 H, b r.t), 6.18 (1 H, s), 6.60-6.67 (2 H, m), 6.94 (1 H, d, J = 8 9 Hz).

Example 26

(E) 1- (6-Methoxy-methoxy-naphthalene-1-2- ^ T) 1-2-Methyl 2-ethyl hexenoate

To a solution of potassium hexamethyldisilazide (0.22 g) in dimethylformamide (22.1 mL) was added a solution of triethyl 2-phosphonopropanoate (12.2 g) in dimethylformamide (22.1 mL). In addition, the mixture was stirred at 180 degrees for 30 minutes. A solution of the ketone (8.82 g) obtained in Reference Example 20 in dimethylformamide (35 mL) was added, and the mixture was stirred at 180 ° C for 6 hours. After cooling, the reaction mixture was poured into saturated saline (500 mL) and extracted with ether (150 mL × 3). The organic layer was collected, washed with saturated saline (100 mL × 3), and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane ethyl acetate 50: 1) to obtain the desired product (2.14 g).

¹ H-NMR (CD CI 3) δ ppm

 0.85 (3 H, t, J = 7.4 Hz), 1.33-1.39 (2 H, m), 1.36 (3 H, t, J = 7.1 Hz), 1.75 (3 H, s), 2.64 (2 H, t, J = 7.7 Hz), 3.53 (3 H, s), 4.28 (2 H, q, J = 7 1 Hz), 5.31 (2 H, s), f. 23 (1 H, dd, J = 1.6 and 8.0 Hz), 7.25 (1 H, dd, J = 2 3 and 8.9 Hz), f. 41 (1 H, d, J = 2.3 Hz), f. 51 (1 H, d, J = 1.6 Hz), 7.74 (1 H, d, J = 8.0 Hz), 7.74 (1 H, d, J = 8.9 Hz).

Example 27

 (E) —3— (6-Hydroxynaphthalene-1-2-^-per) -1-Methyl-2—ethyl hexenoate

Using the ester obtained in Example 26 (2.14 g) as the starting material, it was obtained in a similar manner to that described in Example 6 (1.59 g).

 1 H-NMR (CDC I 3) δ: ppm

 0.86 (3 H, t, J = 7.3 Hz), 1.26-1.43 (2 H, m), 1.37 (3 H, t, J = 7.1 Hz), 1.76 (3 H, s), 2 • 64 (2 H, t, J = 7.6 Hz), 4.29 (2 H, q, J = 7.1 Hz), 5.15 (1 H, s), f. 1 2 (1 H, dd, J = 2.6 and 8.6 Hz), 7.16 (1 H, d, J = 2.6 Hz), 7 . 21 (1H, dd, J = 1.8 and 8.3Hz), 7.50 (1H, d, J = 1.8Hz), 7.67 (1H, d, J = 8.3 Hz), 7.73 (1 H, d, J = 8.6 Hz).

Example 28

 (E) — 3— (6-Hydroxynaphthalene-1-yl) 1-2-Methyl-1-hexenoic acid

 Using the ester (1.59 g) obtained in Example 27 as the starting material, a compound was obtained in a similar manner to that described in Example 3 (1.04 g).

 1 H-NMR (CDC I 3) δ: ppm

 0.85 (3 H, t, J = 7.3 Hz), 1.20-1.43 (2 H, m), 1.77 (3 H, s), 2.75 (2 H, t , J = 8.3 Hz), 7.1 1-off. 25 (3 H, m), 58. (1 H, br.), 7.72 (

1H, d, J = 8.3Hz), 7.80 (1H, d, J = 8.6Hz) .Example 29

(E) —and (Z) -3- (1-Phthyl-6-methoxymethoxynaphthalene-1-yl) 1-Methyl-2-pentenoate t "^ tyl

 The ketone (2.4 g) obtained in Reference Example 27 was used as a starting material, and the silyl ester (2.1 g) obtained in Reference Example 4 was used instead of t-butyl 2-trimethylsilylbutanoate. Then, it was obtained in the same manner as described in Example 4. (E) 0.25g body, (Z) 0.79g body.

(E) Form: 'H-NMR (CDCI ₃ ) δ: ppm

0.97 (3H, t, J = 7.3Hz), 1.01 (3H, t, J = 7.3Hz), 1.43-1.62 (4H, m), 1.56 (9H, s), 1.57 (3H, s), 2.21-2.34 (1H, m), 2.78-3.01 (3H, m), 3.53 (3 H, s), 5.30 (2 H, s), 7.06 (1 H, d, J = 8.6 Hz), 7.25 (1 H, dd, J = 2.6 and 9.2 Hz), 7.40 (1 H, d, J = 2.6 Hz), 7.58 (1 H, d, J = 8.6 Hz), 7.97 (1 H, d, J = 9.2Hz).

 (Z) form: 'Η— NMR (CDC I 3) (5: ppm

0.92 (9H, s), 0.97 (3H, t, J = 7.2Hz), 0.9

8 (3 H, t, J = 7.6 H 2), 1.42-1.76 (4 H, m), 2

.05 (3 H, s), 2.1 1 -2.25 (1 H, m), 2.64-3.

00 (3 H, m), 3.53 (3 H, s), 5.27-5. 32 (2H, m), 7.06 (1 H, d, J = 8.6 Hz), 7 22 (1 H, dd, J = 2.6 and 9.2 Hz), 7.35 (1 H, d, J = 2.6 Hz), 7

. 51 (1 H, d, J = 8.6 Hz), 7.92 (1 H, d, J = 9.2

H z).

Example 30

(E) 3- (1-butyl-6-hydroxynaphthalene-12-yl) -methyl-2-tert-butyl pentanate .COOBu-t

HO People J

 Using the (E) -ester (0.50 g) obtained in Example 29 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.43 g).

 '' H-NMR (CDC I 3) δ: ppm

 0.97 (3 H, t, J = 7.3 Hz), 1.01 (3 H, t, J = 7.3 Hz), 1.47-1.64 (4H, m), 1 56 (3 H, s), 1.57 (9 H, s), 2.21-2.34 (1 H, m), 2.78—3.00 (3 H, m), 5.1 2 (1H, s), 7.04 (1H, d, J = 8 • 3Hz), 7.13 (1H, dd, J = 2.3 and 8.6Hz), 7 .1 5 (1 H, d, J = 2.3 Hz), 7.52 (1 H, d, J = 8.3 Hz), 7.95 (1 H, d, J = 8.6 H z).

Example 31

 (E) —3— (1-butyl-1-hydroxynaphthalene)

At 0 ° C, titanium tetrachloride (0.13 mL) was added to a solution of the (E) -ester (0.43 g) obtained in Example 30 in dichloromethane (1 OmL), and the mixture was stirred for 10 minutes. Water (1 OOmL) was added and extracted with ether (30mL x 4). The organic layer was collected, the solvent was removed, 6N sodium hydroxide solution (3 OmL) was added, and the mixture was stirred for 3 minutes. The mixture was extracted with ether (30 mL × 4), the aqueous layer was made into a solution having a pH of 4 with 6 N hydrochloric acid, and extracted with ether (3 OmL × 4). The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent was removed. The obtained residue was recrystallized (hexane / dichloromethane) to obtain the desired product (0.30 g). H-NMR (CDCI ₃ ) δ: ppm

0.97 (3 H, t, J = 7.1 Hz), 1.05 (3 H, t, J = 7.4 Hz), 1.42-1.67 (4 H, m ), 1.67 (3H, s) 2.33-2.46 (1H, m), 2.77—3.01 (2H, m), 3.18-3. 3 2 (1 H, m), 7.02 (1 H, d, J = 8.6 Hz), 7.14 (1 H, dd, J = 2.6 and 9.9 Hz), 7.15 (1H, d, J = 2.6Hz), 7.52 (1H, d, J = 8.6Hz), 7.96 (1H, d, J = 9 9 Hz).

Example 3 2

 (E) -3-(1-ethyl-6-methoxynaphthalene-1-yl) 1-2-ethyl ethyl butane

 Using the ketone (3.05 g) obtained in Reference Example 29 and triethyl phosphonoacetate instead of triethyl 2-phosphonopropanoate, the desired product (0.8 g) was obtained by the method described in Example 26. Obtained.

 1 H-NMR (CD C I 3) δ: ppm

 1.28 (3 H, t, J = 7.6 Hz), 1.32 (3 H, t, J = 7.2 H 2), 2.52 (3 H, d, J = 1. 5 Hz), 3.02 (2 H, q, J = 7.6 Hz), 3.92 (3 H, s), 4.23 (2 H, q, J = 7.2 Hz) , 5.82 (1H, q, J = 1.5Hz), 7.13 (1H, d, J = 2.6Hz), 7.13 (1H, d, J = 8.6 Hz), 7.19 (1 H, dd, J = 2.6 and 9.2 Hz), 7.57 (1 H, d, J = 8.6 Hz), 7 96 (1H, d, J = 9.2Hz).

Example 3 3

(E) -3-(1 ethyl-1-6-hydroxynaphthalene-1 2 ^^)-2 —Ethyl butyrate

 At 78 ° C, boron tribromide (2.17 g) was added dropwise to a solution of the ester obtained in Example 32 (1.73 g) in dichloromethane (17 mL) at 20 ° C. The mixture was stirred at C for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Organics were collected, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate: 10: 1) to obtain the desired product (1.18 g).

 '' H-NMR (CDC I 3) δ: ppm

1.28 (3 H, t, J = 7.6 Hz), 1.33 (3 H, t, J = 7.3 Hz), 2.53 (3 H, d, J = 1.2 Hz), 3.01 (2H, q, J = 7.6Hz), 4.25 (2H, q, J = 7.3Hz), 5.75 (1H, b) , 5.84 (1H, q, J = 1.2Hz), 7.11 (1H, d, J = 8.5Hz), 7.16 (1H, d, J = 2.6 Hz), 7.17 (1 H, dd, J = 2.6 and 6.9 Hz), 7.50 (1 H, d, J = 8.5 Hz), f. 97 (1H, d, J = 6.9Hz).

Example 34

 (E) —3— (1-ethyl-6-hydroxynaphthalene-1-yl)

Using the ester obtained in Example 33 (1.18 g) as a starting material, the same procedure as described in Example 3 was carried out to obtain a crude product. Recrystallization from 2-propanol Z hexane gave the desired product (0.71 g). ¹ H-NMR (CD CI a) <5: ppm

 1.28 (3 H, t, J = 7.5 Hz), 2.47 (3 H, d, J = 1.3 Hz), 3.02 (2 H, q, J = 7. 5Hz), 5.77 (1H, q, J = 1.3Hz), 7.08 (1H, d, J = 8.3Hz), 7.10 (1H, d, J = 2.6 Hz), 7.11 (1 H, dd, J = 2.6 and 8.6 Hz), 7.49 (1 H, d, J = 8.3 Hz) ), 7.96 (1H, d, J = 8.6Hz).

Example 35

 (E) — and (Z) -3--(1-Ethyl-16-methoxy-1-methoxynaphthalene-1-yl) 2-tert-butyl 2-methyl-2-pentenoate

Using the ketone (6.25 g) obtained in Reference Example 30 and the method described in Reference Example 2, 1- (1-ethyl-1-6-hydroxynaphthalene-1-yl) propan-1-one (3.55 g) ) was gotten. To a solution of naphthol (3.5 Og) and imidazole (2.6 Og) thus obtained in tetrahydrofuran (50 mL), t-butyldimethylsilyl chloride (5.76 g) was added. Stirred for hours. Saturated saline (500 mL) was added, and the mixture was extracted with ether (150 mL × 3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (ethyl hexanoacetate 10: 1), and purified by elution with 1- (1-ethyl-1-6-t-butyldimethylsilyloxynaphthalene-1-yl) propane-1 1-one (5 .2 Og) was obtained. Using the ketone (5.20 g) thus obtained, the silyl ester (3.7 Og) obtained in Reference Example 4 was used instead of t-butyl 2-trimethylsilylbutanoate. In the same manner as described in Example 4, 3- (1-ethyl-6-tert-butyldimethylsilyloxynaphthalene-1-2-) Yl) t-Butyl-1-methyl-2-pentenoate was obtained. This is a 6: 4 mixture of (E) body and (Z) body. To a solution of the ester thus obtained in tetrahydrofuran (1 OmL) was added a 1 N solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3.9 mL), and the mixture was stirred for 10 minutes. Saturated saline (1 O OmL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was collected and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl hexanoacetate 10: 1) to give 3- (1-ethyl-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-pentenoic acid t-Butyl (1.3 Og) was obtained. Using the ester (1.30 g) thus obtained, a method similar to that described in Reference Example 3 was carried out to give 3- (1-ethyl-1-6-methoxymethoxynaphthalene-12-yl) -1 T-Butyl 2-methyl-2-pentenoate was obtained and purified by silica gel column chromatography (50: 1) to separate the (E) form (0.40 g) and the (Z) form (0.53 g).

(E) body: ¹ HNR (CD CI ₃ ) <5: ppm

 1.01 (3H, t, J = 7.6Hz), 1.26 (3H, t, J = 7.6Hz), 1.56 (3H, s), 1.5 7 (9 H, s), 2.25—2.40 (1 H, m), 2.83 -3.11 (3 H, m), 3.52 (3 H, s), 5. 30 (2H, s), 7.06 (1H, d, J = 8.3Hz), 7.25 (1H, dd, J = 2.6 and 9.2Hz), 7. 4 1 (1 H, d, J = 2.6 Hz), 7.59 (1 H, d, J = 8.3 Hz), 7.99 (1 H, d, J = 9. 2 Hz).

 (Z) form: 'H-NMR (CDCI3) <5: ppm

0.91 (9H, s), 0.98 (3H, t, J = 7.6Hz), 1.27 (3H, t, J = 7.6Hz), 2. 06 (3 H, s), 2.1 1-2.28 (1 H, m), 2.64—2.75 (1 H, m), 2.80-3.1 1 1 (2 H, s) m), 3.53 (3 H, s), 5.30 (2 H, s), 7. 06 (1 H, d, J = 8.3 Hz), 7.22 (1 H, dd, J = 2.6 and 9.2 Hz), 7.37 (1 H, d, J = 2. 6 Hz), 7.52 (1 H, d, J = 8.3 Hz), 7.95 (1 H, d, J = 9.2 Hz).

(E) 1-3- (1-ethyl-6-hydroxynaphthalene-2-propyl) 2-methyl-2-pentenoic acid t-butyl

 Using the (E) -ester (0.4 g) obtained in Example 35 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.28 g).

'Η— NMR (CDC I ₃ ) <5: ppm

 1.01 (3 H, t, J = 7.6 Hz), 1.27 (3 H, t, J = 7.6 Hz), 1.57 (9 H, s), 1.60 ( 3H, s), 2.23—2.40 (1H, m), 2.83-3.05 (3H, m), 5.15 (1H, s), 7.03 (1 H, d, J = 8.6 Hz), 7.1 1 -7. 15 (2 H, m), 52. (1 H, d, J = 8.2 Hz), 7.98 (1 H, d, J = 8.6 Hz).

Example 37

 (E) —3— (1-ethyl-1-6-hydroxy-2-phthalene-2-yl) -2-methyl-2-pentenoic acid

 Using the (E) -ester (0.25 g) obtained in Example 36 as the starting material, it was obtained in a similar manner to that described in Example 31 (0.20 g).

'' H-NMR (CD ₃ OD) <5: ppm 1.00 (3H, t, J = 7.2Hz), 1.24 (3H, t, J = 7.2Hz), 1.59 (3-H, s), 2.32 -2.40 (1H, m), 2.85-3.07 (3H, m), 6,97 (1H, d, J = 8.3Hz), 7.11 (1H , dd, J = 2.6 and 10.0 Hz), 7.11 (1H, d, J = 2.6 Hz), 7.51 (1H, d, J = 8.6 Hz), 7.95 (1 H, d, J = 10.0 Hz).

Example 38

 (E) — 3— (1-Propyl-1-6-methoxy-methoxynaphthalene-1-yl) 1,2-Methyl-2-pentenoic acid t-butyl

 Example 4 was repeated using the ketone (3.1 g) obtained in Reference Example 33 and the silyl ester (2.83 g) obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate. (0.3 Og) o obtained in the same manner as described in

¹ H-NMR (CD CI a) δ: ppm

 1.01 (3 H, t, J = 7.6 Hz), 1.07 (3 H, t, J = 7.2 Hz), 1.57 (3 H, s), 1.59 ( 9 H, s), 2.23—2.38 (2 H, m), 2.76-3. 03 (4H, m), 3.52 (3 H, s), 5.30 (2 H, m) s), 7.06 (1H, d, J = 8.6Hz), 7.24 (1H, dd, J = 2.6 and 9.2Hz), 7.40 (1H, d, J = 2.6 Hz), 7.58 (1 H, d, J = 8.6 Hz), 7.95 (1 H, d, J = 9.2 Hz).

Example 39

(E) 1- (1-Propyl-6-hydroxynaphthalene-12- · ^ Γ) 1-Methyl-2-pentenoic acid t-butyl ester

 Using the (E) -ester (0.30 g) obtained in Example 38 as the starting material, it was obtained in the same manner as described in Example 6 (0.17 g).

 'H-N R (C DC I a) δ: ppm

 1.01 (3 H, t, J = 7.2 Hz), 1.05 (3 H, t, J = 7.2 Hz), 1.50- 1.69 (2 H, m), 1.58 (3 H, s), 1.59 (9 H, s), 2.20-2.40 (1 H, m), 2.77-2.98 (3 H, m), 7. 02 (1 H, d, J = 8.5 Hz), f. 15 (1 H, dd, J = 2.6 and 9.6 Hz), 7.17 (1 H, d, J = 2. 6 Hz), 7.49 (1 H, d, J = 8.5 Hz), 7.92 (1 H, d, J = 9.6 Hz).

Example 40

 (E) — 3- (1-Propyl-6-hydroxynaphthalene-12-yl) -1-Methyl-2-pentenoic acid

 Using the ester (0.16 g) obtained in Example 39, it was obtained in the same manner as described in Example 31 (0.13 g).

¹ H-NMR (CDC I 3, 1% DMSO-d 6) <5: ppm

1.00 (3H, t, J = 7.2Hz), 1.05 (3H, t, J = 7.2Hz), 1.51-1.72 (2H, m), 1 64 (3 H, s), 2.27-2.45 (1 H, m), 2.76-2.91 (2 H, m), 3.08-3.22 (1 H, m) , 6.98 (1H, d, J = 8.2Hz), 7.13-7. 17 (2H, m), 7.49 (1H, d, J = 8.2Hz) ), 7.88 (1 H, d, J = 9.9 Hz).

Example 41

 (E) -3- (1-Ethyl-1-6-methoxy-2-naphthalene-2-yl) -1-tert-butyl 2-methyl-1-butenoate

 The method described in Example 4 was repeated using the ketone (3.36 g) obtained in Reference Example 34 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate. Obtained in a similar manner (0.50 g).

1 H-NMR (CDC I ₃ ) 5: ppm

1.25 (3 H, t, J = 7.6 Hz), 1.56 (3 H, s), 1.57 (9 H, s), 2.25-2.26 (3 H, s) m), 2.93—2.99 (2 H, m), 3.53 (3 H, s), 5.30 (2 H, s), 7.07 (1 H, d, J = 8. 4 H z), 7.26 (1 H, dd, J = 2.6 and 9.2 H 2), 7.40 (1 H, d, J = 2.6 H z), 7.61 (1 H, d, J = 8.4 Hz), 7.99 (1 H, d, J = 9.2 Hz).

Example 42

 (E) -3- (1-Ethyl-6-hydroxynaphthalene-1-yl) -1-methyl-2-butenoate t-butyl

 Using (E) -espile (0.5 Og) obtained in Example 41 as a starting material, it was obtained in the same manner as described in Example 6 (0.45 g).

 1 H-NMR (CDC I a) δ: ppm

1.25 (3H, t, J = 7.6Hz), 1.57 (9H, s), 1.5 7 (3 H, s), 2. 24-2.2.26 (3 H, m), 2.92. 2.98 (2 H, m), 7.05 (1 H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 2.0 and 8.3Hz), 7.16 (1H, d, J = 2.OHz), 7.54 (1 H, d, J = 8.3 Hz), f. 97 (1 H, d, J = 8.6 Hz).

Example 43

(E) —3— (1-Ethyl-6-hydroxynaphthalene-1-yl) 1-2-Methyl-2-butenoic acid

 The ester obtained in Example 42 (0.45 g) was used in a similar manner to that described in Example 31 (0.31 g).

'' H-NMR (CDC Ia + CD ₃ OD) δ: ppm

 1.26 (3H, t, J = 7.6Hz), 1.67 (3H, s), 2.40 (3H, s), 2.87-3.03 (2H, m ), 7.03 (1H, d, J = 8.3H2), 7.14 (1H, d, J = 2.0Hz), 7.16 (1H, dd, J = 2.0 and 8.6 Hz), 7.56 (1 H, d, J = 8.3 Hz), 7.98 (1 H, d, J = 8.6 Hz).

Example 44

(Z) -3- (1-Ethyl-6-hydroxy-naphthalene-1-yl) -1-2-Methyl-1-tert-butylpentanoate

Using the (Z) -ester (1.80 g) obtained in Example 35 as the starting material, a compound was obtained in the same manner as described in Example 6 (1.09 g). H-NMR (CDC I 3) δ: ppm

0.93 (9H, s), 0.98 (3H, t, J = 7.6Hz), 1.26 (3H, t, J = 7.2Hz), 2.07 ( 3 H, s), 2.1 3-2. 26 (1 H, m), 2.63—2.76 (1 H, m), 2.78-3.1 1 1 (2 H, m), F. 03 (1 H, d, J = 8.2 Hz), 7.10— 7.18 (2 H, m), 7.41 (1 H, d, J = 8.2 Hz) ), 7.90 (1 H, d, J = 10.2 Hz).

Example 45

 (Z) —3— (1-ethyl-6-hydroxynaphthalene-1-T) —2— —methyl-2-pentenoic acid

 Using the ester (1.09 g) obtained in Example 44, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.1 3g) was obtained.

 '' H-NMR (CDC I 3) δ: ppm

 0.98 (3 H, t, J = 7.6 Hz), 1.20 (3 H, t, J = 7.6 Hz), 2. 16-2.34 (1 H, m) , 2.66-2.91 (2H, m), 2.92-3.09 (1H, m), 7.00 (1H, d, J = 8.2Hz), 7.09 (1 H, d, J = 2.6 Hz) 7.13 (1 H, dd, J = 2.6 and 9.6 Hz), 7.44 (1 H, d, J = 8. 2 H z), 7.91 (1 H, d, J = 9.6 H z).

Example 46

(E) —3— (Ethyl-6-Methoxy methoxy naphthalene-1-yl) —2-Butyl pentenoate

Described in Example 4 using the ketone (1.5 _g ) obtained in Reference Example 35 and using t-butyl trimethylsilylacetate (1.35 g) instead of t-butyl 2-trimethylsilylbutanoate (0.52g) o obtained in the same manner as

'H—NMR (CDC I ₃ ) <5: ppm

 1.01 (3 H, t, J = 7.6 Hz), 1.29 (3 H, t, J = 7.6 Hz), 1.53 (9H, s), 2.98 (2H , Q, J = 7.6 Hz), 3.03 (2 H, q, J = 7.6 Hz), 3.52 (3 H, s), 5.30 (2 H, s), 5.67 (1H, s), 7.11 (1H, d, J = 8.4Hz), 7.26 (1H, dd, J = 2.6 and 9.2Hz) , 7.39 (1 H, d, J = 2.6 Hz), 7.56 (1 H, d, J = 8.4 Hz), 7.99 (1 H, d, J = 9. 2 Hz).

Example 47

(E) —3— (1-Ethyl-6-hydroxynaphthalene-1--2-T-l) t-Butyl monopentenoate

 Using the (で) -ester (0.52 g) obtained in Example 46 as the starting material, a method similar to that described in Example 6 was used (0.44 g).

'' H-NMR (CDC I ₃ ) δ: ppm

1.02 (3 H, t, J = 7.6 Hz), 1.27 (3 H, t, J = 7.6 Hz), 1.53 (9 H, s), 2.98 ( 2 H, q, J = 7.6 Hz), 3.02 (2 H, q, J = 7.6 Hz), 5.08 (1 H, s), 5 68 (1H, s), 7.11 (1H, d, J = 8.6Hz), 7.15 (1H, dd, J = 2.-6 and 9.2Hz ), 7.15 (1 H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz), 7.98 (1 H, d, J = 9.2 Hz).

Example 48

 (E) —3— (1-Ethyl-6-hydroxynaphthalene-1-yl) -monopentanoic acid

 Using the ester (0.44 g) obtained in Example 47, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.4%). 32g) was obtained.

 1 H-NMR (CDCI 3) 5: ppm

 1.05 (3 H, t, J = 7.6 Hz), 1.31 (3 H, t, J = 7.6 Hz), 3.03 (2 H, q, J = 7.6 Hz), 3.06 (2H, q, J = 7.6Hz), 5.83 (1H, s), 7.12 (1H, d, J = 8.3Hz) 16 (1H, dd, J = 2.6 and 9.9Hz), 7.16 (1H, d, J = 2.6Hz), 7.53 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 9.9 Hz).

Example 49

3- [6-Methoxymethoxyl- (3-phenylpropyl) -naphthalene-2-yl] -t-butyl 2-methyl-2-penteneate

.COOBu-t

MO O A method described in Example 4 using the ketone (10.7 g) obtained in Reference Example 39 and using the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate Was obtained in the same manner as in (2.33 g). This is a 1: 2 mixture of (E) and (Z) bodies.

Example 50

 (E) — 3 -— [6-Methoxy methoxy 1- (3-phenylpropyl) -naphthalene-2-yl] —2-Methyl-2-pentenoic acid t-butyl

 Using the ester obtained in Example 49 (2.83 g) as the starting material, it was obtained in a similar manner to that described in Example 5 (0.71 g).

'' H-NMR (CDC I ₃ ) δ: ppm

0.99 (3H, t, J = 7.2Hz), 1.55 (3H, s), 1.58 (9H, s), 1.86-2.02 (2H, m ), 2.2 1 -2.34 (1 H, m), 2.78 (2 H, t, J = 7.2 H 2), 2.8 1 —3.05 (3 H, m), 3.5 1 (3 H, s), 5.28 (2 H, s), 7.05 (1 H, d, J = 8.6 H 2) _T 7.18 (1 H, dd, J = 2.6 and 9.2Hz), 7.19—7.35 (5H, m), 7.38 (1H, d, J = 2.6H2), 7.58 (1H , D, J = 8.6 Hz), 7.78 (1H, d, J = 9.2 Hz).

Example 51

(E) — 3- [6-Hydroxy-11- (3-phenylpropyl) -naphthalene-l- 2-yl] -l-Methyl-2-pentenoic acid t-butyl

 Using the (E) -ester (0.70 g) obtained in Example 50 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.59 g).

1 HNR (CDC I ₃ ) 5: ppm

 1.01 (3 H, t, J = 7.2 Hz), 1.57 (3 H, s), 1.59 (9H, s), 1.85-2.02 (2 H, m ), 2. 1 7-2. 32 (1 H, m), 2.78 (2 H, t, J = 7.2 Hz), 2.80—3.04 (3 H, m), 7 02 (1 H, d, J = 8.6 Hz), 7.09 (1 H, dd, J = 2.8 and 9.1 Hz), 7.15 (1 H, d, J = 2.6 Hz), 7.17-7.33 (5 H, m), 7.50 (1 H, d, J = 8.3 Hz), 7.75 (1 H, d, J = 9.2 Hz).

Example 52

 (E) —3— [6-Hydroxy-11- (3-phenylpropyl) -naphthalene-1-yl] -1-Methyl-2-pentenoic acid

 Using the ester (0.59 g) obtained in Example 51, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.46 g). ).

 H-NR (CDC I 3) δ: ppm

0.97 (3 H, t, J = 7.2 Hz), 1.59 (3 H, s), 1.8 2-2.01 (2 H, m), 2.18—2 34 (1 H, m), 2.65 -2.84 (3H, m), 2.85-2.98 (1H, m), 3.03—3.17 (1H, m), 6.94 (1H, d, J = 8.6 Hz), 7.04 (1 H, dd, J = 2.6 and 8.9 Hz), 7.10 (1 H, d, J = 2.3 Hz), 7.11-7.27 (5H, m), 7.47 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 9.2H z).

Example 5 3

 3- [6-Methoxymethoxy 1- (3-methylbutyl) naphthalene "^-yl] — 2-Methyl-2-butyl pentanoate

 The method described in Example 4 using the ketone (1 4. Og) obtained in Reference Example 40 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate (4.0 g). This is a 1: 3 mixture of (E) and (Z) bodies.

Example 54

 (E) -3-[6-Methoxymethoxy-1- (3-methylbutyl) naphthalene-1-yl] -12-methyl-2-pentenoic acid t-butyl ester

 Using the ester (1. Og) obtained in Example 53 as the starting material, a method similar to the method described in Example 5 was carried out, and the obtained crude product was subjected to silica gel column chromatography (hexane). Purification with Z ethyl acetate 20: 1) gave the desired product (0.1 Og).

 1 H-NM (CD C I 3) δ: ppm

1.03 (3 H, d, J = 6.6 Hz), 1.04 (3 H, d, J = 6. 6 Hz), 1.06 (3 H, t, J = 7.6 Hz), 1.45-1.70 (2 H, m), 1.60 (3 H, s), 1.60 (9 H, s), 1.7 1-1.86 (1 H, m), 2.23-2.38 (1 H, m), 2.70-3.07 (3 H, m), 3.56 (3 H, s), 5.34 (2 H, s), 7.11 (1 H, d, J = 8.6 H 2), 7.30 (1 H, dd, J = 2.6 and 9.2 Hz), 7.44 (1 H, d, J = 2.3 Hz), F. 63 (1 H, d, J = 8.6 Hz), 8.01 (1 H, d, J = 9.2 Hz) Example 55

 (E) — 3 -— [6-hydroxy-1- (3-methylbutyl) naphthalene-2-yl] -12-methyl-2-pentenoic acid t-butyl

Using the (E) -ester (0.25 g) obtained in Example 54 as the starting material, it was obtained in the same manner as described in Example 6 (0.22 _g ).

H-NMR (CDC I ₃ ) δ: ppm

 0.98 (6 H, d, J = 6.2 Hz), 1.02 (3 H, t, J = 7.

3 H 2), 1.2-1.78 (3 H, m), 1.57 (3 H, s), 1

57 (9 H, s), 2.1 7-2. 36 (1 H, m), 2. 82-2.

99 (3 H, m), 5.70 (1 H, b r.s), 7.03 (1 H, d, J = 8.6 Hz), 7.14 (1 H, dd, J = 2.5 and 7.8 Hz),

7. 1 6 (1 H, d , J = 2. 3 H z), 7. 49 (1 H r d, J = 8.

3 Hz), 7.94 (1 H, d, J = 10.2 Hz).

Example 56

(E) — 3— [6-Hydroxy 1- (3-methylbutyl) naphthalene 1—2 ^^] -— 2-Methyl-2-pentanoic acid

 Using the ester (0.22 g) obtained in Example 55, the desired product (0.15 g) was obtained in the same manner as described in Example 31.

'' H-NMR (CD CI ₃ ) δ: ppm

 1.00 (3 H, d, J = 6.5 Hz), 1.01 (3 H, d, J = 6.8 Hz), 1.06 (3 H, t, J = 6. 9 Hz, 1.42-1.60 (1H, m), 1.62-1.83 (1H, m), 1.67 (3H, s), 2.31-2 50 (1H, m), 2.70—3.13 (3H, m), 3.14-3. 33 (1H, m), 7.03 (1H, d, J = 8.3 Hz), 7.16 (1 H, dd, J = 2.3 and 7.9 Hz), 7.17 (1 H, d, J = 2.0 Hz), 7.56 (1 H, d, J = 8.3 H 2), 7.9 f (1 H, d, J = 9.9 Hz).

Example 57

 (E) —3— (6-Methoxymethoxy 1-n-dodecylnaphthalene 1-yl) 1-Methyl-2-pentenoic acid t-butyl

 Reference Example 41 The procedure described in Example 4 was repeated using the ketone (10.0 g) obtained in 1 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate. Obtained in a similar manner (0.85 g).

'' H-NMR (CDC I ₃ ) δ: ppm

0.88 (3 H, t, J = 6.8 Hz), 1.0 1 (3 H, t, J = 7.6 Hz), 1.2 1-1.37 (16 H , m), 1.40—1.62 (4 H, m), 1.55 (3 H, s), 1.57 (9 H, s), 2.2 1 -2 32 (1 H, m), 2.77-3.00 (3 H, m), 3.52 (3 H, s), 5.30 (2 H, s), 7.05 (1 H, m) d, J = 8.6 Hz), 7.25 (1 H, dd, J = 2.5 and 9.4 H2), 7.39 (1 H, d, J = 2.6 Hz) , 7.58 (1 H, d, J = 8.3 Hz), 7.96 (1 H, d, J = 9.2 Hz).

Example 58

 (E) 1-3- (6-Hydroxy-1-n-dodecylnaphthalene-1-yl) t-butyl 2-methyl-2-pentenoate

 Using the (E) -ester (0.85 g) obtained in Example 57 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.75 g).

 1 H-NMR (CDC I a) δ: ppm

 0.87 (3 H, d, J = 6.8 Hz), 1.01 (3 H, t, J = 7.3 Hz), 1. 24-1.31 (16 H, m) , 1.44-1.65 (4 H, m), 1.56 (3 H, s), 1.57 (9H, s), 2.24—2.34 (1 H, m), 2. 77—3.01 (3H, m), 7.04 (1H, d, J = 8.3Hz), 7.10-7.16 (2H, m), 7.51 (1 H, d, J = 8.6 Hz), 7.94 (1 H, d, J = 8.9 Hz).

 (E) 1-3- (6-Hydroxy-11-π-dodecylnaphthalene-1-2- ^ T

) —2-Methyl-2-pentenoic acid

The ester obtained in Example 58 (0.85 _g ) was used and described in Example 31. The desired product (0.18 g) was obtained in the same manner as described above.

 '' H-NMR (C D C I 3) δ ppm

 0.88 (3 H, d, J = 7.1 Hz), 1.04 (3 H, t, J = 7.4 Hz), 1.20- 1.39 (16 H, m) , 1.1-1.52 (2 H, m), 1.55-1.66 (2 H, m), 1.66 (3 H, s), 2.3-2.45 (1 H, m) m), 2.73—2.99 (2 H, m), 3.17-3.30 (1 H, m), 7.02 (1 H, d, J = 8.6 Hz), 7.1 2-7. 18 (2 H, m), 7.54 (1 H, d, J = 8.2 Hz), 7.95 (1 H, d, J = 9.9 Hz) ).

Example 60

 (Z) —3— (1-butyl-6-hydroxynaphthalene 12-perl)

 As starting material, (Z) -ester [1.13 g, obtained by the method described in Example 29, which is 1- (1-butyl-6-methoxymethoxyxinaphthalene-1-yl) propane-one-one (Z) -3- (1-Phtyl-6-hydroxysinaphthalene-12T) 1-2-Methyl-2- in a manner similar to that described in Example 6 using There was obtained t-butyl pentenoate [1.07 g, which is an approximately 40% mixture with 1- (1-1-butyl-6-hydroxynaphthalene-1-yl) propan-1-one]. Performed using (Z) -ester [0.82 g, which is an approximately 40% mixture with 1- (1-butyl-6-hydroxynaphthalen-2-yl) propan-1-one] The same procedure as described in Example 31 was carried out to obtain the desired product (0.23 g).

¹ H-NMR (CDC I 3) δ: ppm 0.92 (3 H, t, J = 7.1 Hz), 0.98 (3 H, t, J = 7.6 Hz), 1.37—1.61 (4 H, m), 2.08 (3 H, s), 2 • 1 4-2.30 (1 H, m), 2.66-2.80 (2 H, m), 2.87-2.98 (1 H, m) m), 6.98 (1 H, d, J = 8.6 Hz), 7.03-7.10 (2 H, m), 7.39 (1 H, d, J = 8.2 Hz), 7.87 (1 H, d, J = 8.9 Hz).

Example 61

 (E) — 3— (6-Methoxymethoxy 1-n-butylnaphthalene 1-2-yl) t-butyl mono-2-pentanoate

 The ketone obtained in Reference Example 27 (2.16 g) was used as a starting material, and t-butyl trimethylsilyl acetate was used in place of t-butyl 2-trimethylsilylbutanoate. Obtained in a similar manner (0.42 g) o

'' HNR (CDC I ₃ ) δ ppm

 0.97 (3 H, d, J = 7.3 Hz), 1.01 (3 H, t, J = 7.

4 Hz), 1.42-1.69 (4 H, m), 1.53 (9H, s), 2

90-3. 02 (4 H, m), 3.52 (3 H, s), 5.30 (2 H

's), 5.67 (1H, s), 7.12 (1H, d, J = 8.6Hz), 7.26 (1H, dd, J = 2.6 and 9. 2 H z), 7.38 (1 H, d, J = 2.6 Hz), 7.56 (1 H, d, J = 8.3 Hz), 7. 9

7 (1H, d, J = 9.2Hz).

Example 62

(E) —3— (6-Hydroxy-1-n-butylnaphthalene-1-yl) —2-butyl t-butylpentanate

 Using the (E) -ester (0.42 g) obtained in Example 61 as the starting material, it was obtained in the same manner as described in Example 6 (0.37 g). 1 H-NMR (CD C I 3) δ: ppm

 0.97 (3 H, d, J = 7.3 Hz), 1.02 (3 H, t, J = 7.3 Hz), 1.41-1.56 (2H, m), 1 52 (9H, s), 1.57-1.72 (2H, m), 2.88-3.03 (2H, m), 5.67 (1H, s), 7.11 (1H, d, J = 8.3Hz), 7.12—7.16 (2H, m), 7.49 (1H, d, J = 8.6Hz), 7 . 9 4 (1 H, d, J = 9.2 H z).

Example 63

 (E) —3— (6-hydroxy-11-n-butylnaphthalene-12-per) -1-pentenoic acid

 Using the ester (0.37 g) obtained in Example 62, the desired product (0.23 g) was obtained in the same manner as described in Example 31.

 'H-NMR (C D C I 3) δ: ppm

0.98 (3 H, d, J = 7.3 H 2), 1.04 (3 H, t, J = 7.3 H z), 1.41-1.56 (2 H, m), 1.57-1.72 (2H, m), 2.88-3.10 (2H, m), 5.82 (1H, s), 7.11 (1H, d, J = 8.6 Hz), f. 13-7.19 (2 H, m), 7.52 (1 H, d, J = 8.6 Hz), 7.96 (1 H, d) , J = 9.6 Hz). Example 64

 (E) — 3— (6-Methoxymethoxy 1-n-octylnaphthalene 1 2 1 ^ T) 1-Methyl-2-pentenoic acid t-butyl

 The method described in Example 4 using the ketone (15.Og) obtained in Reference Example 42 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate (0.50 g). '' H-NMR (CDC I 3) δ: ppm

 0.89 (3 H, d, J = 7.OHz), 1.01 (3 H, t, J = 7.4 Hz), 1.23-1.37 (8H, m), 1. 38- 1.67 (4 H, m), 1.55 (3 H, s), 1.57 (9 H, s), 2.23-2.37 (1 H, m), 2.78- 3.04 (3 H, m), 3.51 (3 H, s), 5.30 (2 H, s), 7.06 (1 H, d, J = 8.3 Hz), 7. 25 (1 H, dd, J = 2.6 and 9.6 Hz), 7.39 (1 H, d, J = 2.3 Hz), 7.58 (1 H, d, J = 8 .3 Hz), 7.96

(1 H, d, J = 9.6 Hz).

Example 65

 (E) —3— (6-hydroxy-1-n-octylnaphthalene-1-yl) —2-methyl-2-pentenoic acid t-butyl

Using the (E) -ester (0.50 g) obtained in Example 64 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.32 g). 1 H-NMR (CDC I 3) δ ppm 0.88 (3 H, d, J = 6.9 H 2), 1.01 (3 H, t, J = 7.4 Hz), 1.18-1.37 (8H, m), 1.40- 1.67 (4H, m), 1.57 (3H, s), 1.58 (9H, s), 2. 18-2.36 (1H, m), 2 75-3. 01 (3 H, m), F. 02 (1 H, d, J = 8.6 Hz), 7.1 -7. 18 (2 H, m), 7.50 ( 1 H, d, J = 8.6 Hz), 7.93 (1 H, d, J = 10.2 Hz) .Example 66

 (E) — 3— (6-hydroxy-1-n-octylnaphthalene-12-yl) 1-2-methyl-2-pentenoic acid

 Using the ester (0.31 g) obtained in Example 65, the desired product (0.20 g) was obtained in the same manner as described in Example 31.

'' H-NMR (CDC I ₃ ) δ: ppm

0.89 (3H, d, J = 6.8H2), 1.05 (3H, t, J = 7.4Hz), 1.18 to 1.37 (8H, m) , 1.38-1.72 (4H, m), 1.66 (3H, s), 2.29—2.47 (1H, m), 2.73-3.02 (2H, m) m), 3.1 5-3. 32 (1 H, m), 7.0 2 (1 H, d, J = 8.3 Hz), 7.1 1 -7. 18 (2 H, m m) ₍ 7.55 (1 H, d, J = 8.6 Hz), 7.95 (1 H, d, J = 9.9 Hz).

Example 67

(E) — and (Z) — 3 -— (1- (2-p-benzyloxyphenylethyl) -1-6-methoxyethoxy-naphthalene-1-yl] -12-methyl-2-pentenoic acid t Buchirile

 Using the ketone (16.4 g) obtained in Reference Example 45 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate, the method described in Example 4 Was obtained in the same manner as described above. (E) 0.88g, (Z) 3.88g.

(E) form: ¹ H-NMR (CDCI ₃ ) δ: ppm

1.05 (3 H, t, J = 7.4Η ζ), 1.58 (9Η, s), 1.62 (3Η, s), 2.20-2.37 (1Η, m ), 2.71 -3.47 (5 mm, m), 3.51 (3 mm, s), 5.05 (2 mm, s), 5.29 (2 mm, s), 6.92-7 02 (2 Η, m), 7.1 1 (1 Η, d, J = 8.6 Η), 7.21 -7.28 (2 Η, m), 7.28-7.48 (7Η, m), 7.63 (1Η, d, J = 8.3Η), 8.08 (1Η, d, J = 9.2Η).

Example 68

 (Ε) — 3— [1- (2-ρ-hydroxyphenylethyl) 1-6-methoxymethoxy-2-naphthalene-1-yl] —2-Methyl-2-pentenoic acid t-butyl

An ethanol solution (30 mL) of the (E) -ester (1.0 g) obtained in Example 67 and 10% palladium carbon (0.10 g) was stirred under a hydrogen atmosphere for 4 hours. The catalyst was purified with celite, and the solvent was distilled off under reduced pressure. g) was obtained.

 1 H-N R (CDC I 3) 6 ppm

 1.03 (3 H, t, J = 7. Hz), 1.59 (9 H, s), 1.60 (3 H, s), 2.1 5-2.36 (1 H, m), 2.7 1 -3.47 (5 H, m), 3.54 (3 H, s), 5.32 (2 H, s), 6.78 to 6.88 (2 H, m ), 7.10 (1 H, d, J = 8.6 Hz), 7.15-7.23 (2 H, m), 7.23-7.35 (1 H, m), 7.4 1 -7. 47 (1 H, m), f. 63 (1 H, d, J = 8.9 Hz), 8.08 (1 H, d, J = 8.9 H 2) .

Example 69

 (E) — 3— {6—Methoxymethoxy 1-1-1 [2-p— (piperidine-1 1-ylethoxy) phenylethyl] naphthalene-12-yl I 1-2-methyl-12-pentenoic acid t-butyl

At 0 ° C, 60% sodium hydride (0.26 g) was added to a solution of N- (2-chloroethyl) piperidine hydrochloride (0.81 g) in dimethylformamide (2 mL), and the mixture was stirred for 1 hour. . In a separate container, 60% sodium hydride (0.11 g) was added to a solution of the phenol (0.86 g) obtained in Example 68 in dimethylformamide (3 mL), and the mixture was stirred for 1 hour. The N- (2-chloroethyl) piperidine solution prepared above was added thereto, and the mixture was stirred at room temperature for 1 hour and then at 80 ° C for 1 hour. Saturated saline (1 O OmL) was added, and the mixture was extracted with dichloromethane (20 mL × 5). The organic layer was collected, dried over sodium sulfate, and the solvent was removed. The obtained reaction mixture was purified by silica gel column chromatography (chloroformomethanol 95: 5) to obtain the desired product (1. Og). HNR (CDCI 3) δ: ppm

1.04 (3 H, t, J = 7.6 Hz), 1.3 9-1.5 2 (3 H, m), 1.59 (9 H, s), 1.6 1 ( 3 H, s), 1.5 2-1.6 9 (3 H, m), 2.20-2.37 (1 H, m), 2.46-2.5 7 (4 H, m ), 2.79 (2 H, t, J = 6.1 Hz), 2.79 -3.33 (5 H, m), 3.53 (3 H, s), 4.1 2 (2 H, t, J = 6.1 Hz), 5.31 (2 H, s), 6.85-6.95 (2 H, m), 7.1 1 (1 H, d , J = 8.3 Hz), 7.20—7.27 (2 H, m), 7.3 1 (1 H, dd, J = 2.6 and 9.2 Hz), 7. 44 (1H, d, J = 2.6Hz), 7.63 (1H, d, J = 8.3Hz), 8.09 (1H, d, J = 9.2H z).

Example 70

 (E) —3— {6-Hydroxy-1- 1- [2-p— (piperidin-1-ylethoxy) phenylenyl] naphthalene-1-yl} -1-methyl-1--2-t-butyl pentanate

 Example 6 Using the ester obtained in 9 (0.23 g), a method similar to that described in Example 6 (0.21 g) was obtained.

Example 7 1

(E) 1-3- {6-hydroxy-1— [2-p— (piperidine-1—ylethoxy) phenylethyl] naphthalene-1-yl} —2-methyl-2-pentene?

Using the ester obtained in Example 70 (0.45 _g ), a crude product was obtained in the same manner as described in Example 31 and obtained by preparative high performance liquid chromatography.

(Column, YMC—Pack R—355—20 (50, 0.1% aqueous solution of trifluoroacetic acid ΖΟ. 1% solution of acetonitrile in trifluoroacetic acid) to obtain the desired product (0.20 _g ).

¹ H-NMR (CD ₃ OD) δ: ppm

 1.01 (3H, t, J = 7.4Hz), 1.61 (3H, s), 1.75-2.00 (5H, m), 2.25-2.34 ( 1 H, m), 2.65 -2.92 (2 H, m), 2.94-3.25 (5 H, m), 3.51 (2 H, t, J = 4.8 Hz ), 3.45-3.69 (2H, m), 4.33 (2H, t, J = 4.8Hz), 6.89-6.96 (2H, m), 7 00 (1H, d, J = 8.3Hz), 7.12-7.25 (4H, m), 7.55 (1H, d, J = 8.6Hz), 8.01 (1 H, d, J = 9.9 Hz).

Example 72

 3- [6-Methoxymethyxoxy 1- (2-phenylethyl) naphthalene-1-yl] 1-Methyl-2-pentenoate t-butyl

Using the ketone (3.5 g) obtained in Reference Example 46, the silyl ester obtained in Reference Example 4 was used instead of t-butyl 2-trimethylsilylbutanoate. In the same manner as described in Example 4. (E) Body 0. 37 g, (Z) the body 1. 1 1 _g.

(E) form: ¹ H-NMR (CDC I ₃ ) δ: ppm

1.04 (3 H, t, J = 7.6 Hz), 1.59 (9 H, s), 1.6

1 (3 H, s), 2.20-2.36 (1 H, m), 2.77—3.37 (5 H, m), 3.53 (3 H, s), 5.32 ( 2 H, s), 7.1 2

(1H, d, J = 8.3Hz), 7.22-7.40 (6H, m), 7.

44 (1 H, d, J = 2.6 Hz), 7.64 (1 H, d, J = 8.3 Hz), 8.10 (1 H, d, J = 92 Hz) ).

Example 73

 (E) —3— [6-Hydroxy 1 (2-phenylethyl) naphthalene

2-yl] mono 2-methyl-2-tert-butyl pentanate

 Using the ester (0.64 g) obtained by the method described in Example 72, it was obtained in the same manner as described in Example 6 (0.58 g).

 '' H-NMR (CDC I 3) δ: ppm

 1.05 (3H, t, J = 7.4Hz), 1.62 (9H, s), 1.65 (3H, s), 2.22-2.40 (1H, m) , 2.75-3.05 (3 H, m), 3.05-3.21 (1 H, m), 3.21 -3.37 (1 H, m), 6.67 (1 H, m) s), 7.06 (1 H, d, J = 8.6 Hz), 7.15-7. 38 (7 H, m), 7.52 (1 H, d, J = 8) 6 Hz), 8.06 (1 H, d, J = 8.9 Hz).

Example 74

(E) —3— [6-hydroxy-1- (2-phenylethyl) naphthalene —2-yl] mono 2-methyl-2-pentenoic acid

 Using the ester (0.58 g) obtained in Example 73, the desired product (0.52 g) was obtained in the same manner as described in Example 31.

 1 H-NMR (CDC I 3) δ: ppm

 0.99 (3 H, t, J = 7.4 Hz), 1.63 (3 H, s), 2.2 2-2.46 (1 H, m), 2.69-2.91 (2 H, m), 2.96-3.38 (3 H, m), 6.94 (1 H, d, J = 8.6 Hz), 7.05-7.25 (7 H, m m), 7.45 (1 H, d, J = 8.6 Hz), 7.97 (1 H, d, J = 8.9 Hz), 8.76 (1 H, b r.s Example 75

 (E) -3— [1- (2-p-benzyloxyphenylethyl) -1-6-hydroxy-droxynaphthalene-12-yl] -1-methyl-2-pentenoic acid t-butyl Le

 Using the (E) -ester (0.88 g) obtained in Example 67, it was obtained in the same manner as described in Example 6 (0.60 g).

 1 H-NMR (CDC I a) 5: ppm

1.04 (3H, t, J = 7.3Hz), 1.61 (9H, s), 1.64 (3H, s), 2.21-2.38 (1H, m ), 2.71 -3. 33 (5 H, m), 5.05 (2 H, s), 6.53 (1 H, s), 6.91 I 6.98 (2 H, m), 7.06 (1 H, d, J = 8.3 H z), 7.16--7.46 (9 H, m), 7.52 (1 H , d, J = 8.6 Hz), 8.04 (1 H, d, J = 8.6 Hz).

Example 76

 (E) —3— [1-(2-p-benzyloxyphenylethyl) -6-2-droxynaphthalene-1-yl] — 2-methyl-2-pentanoic acid

 To the ester (0.60 g) obtained in Example 75, trifluoroacetic acid was added at room temperature and stirred for 10 minutes. Dichloromethane (30 mL) was added, the mixture was vigorously reduced under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane Z methanol 20: 1) to obtain the desired product (0.30 g).

 'H-NMR (CDC I a) <5: ppm

 1.09 (3 H, t, J = 7.4 Hz), 1.72 (3 H, s), 2.43 (1 H, qd, J = 7.0 and 14.4 Hz ), 2.76-2.95 (2 H, m), 3.04-3.37 (3 H, m), 5.05 (2 H, s), 6.97 (2 H, d, J = 8.6 Hz), 7.05 (1 H, d, J = 8.6 Hz), 7.16—7.45 (9 H, m), 7.56 (1 H, d, J = 8.6 Hz), 8.55 (1 H, d, J = 8.9 Hz).

Example 77

(E) —3— [6-Hydroxy-1 — (2-p-Hydroxyphenyl) naphthalene-1-yl] —2-Methyl-2-pentenoic acid

A solution of the acid (0.18 g) obtained in Example 76 and 10% palladium carbon (0.02 g) in methanol (3 mL) was stirred under a hydrogen atmosphere for 7 hours. The palladium carbon was filtered off and the solvent was removed under reduced pressure to obtain the desired product (0.15 g). 1 H-NMR (CD ₃ OD) <5: ppm

 1.03 (3 H, t, J = 7.6 Hz), 1.64 (3 H, s), 2.24—2.40 (1 H, m), 2.66-2.87 (2 H, m), 2.99 -3.28 (3 H, m), 4.96 (3 H, bs), 6.74-6.81 (2 H, m), 7.00 (1 H, d, J = 8.3 Hz), 7.07—7.14 (2 H, m), 7.1 6-7.23 (2H, m), 7.54 (1 H, d , J = 8.2 Hz), 8.03 (1 H, d, J = 9.6 Hz).

 3- [6-Methoxymethoxy 1-phenylnaphthalene 1-2-yl] —2-methyl-2-methoxymethyl propenoate

Using the aldehyde (1.69 g) obtained in Reference Example 49 and using the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate, the method described in Example 4 In the same manner as described above, t-butyl 3- [6-benzyloxy-11-phenylnaphthalene-12-yl] -12-methyl-2-propenoate (1.71 g) was obtained. This is a mixture of (E) and (Z) bodies. Described in Reference Example 26 using the ester thus obtained 3- [6-benzyloxy-1-phenylnaphthalene-12-yl] -12-methyl-1-propenoic acid was obtained by the method described above. The acid (1.37 g) thus obtained was suspended in thioanisole, and meta-cresol (1 OmL) and trifluoroacetic acid (1 O OmL) were added at room temperature, followed by stirring for 2 hours. The reaction solution was added to water (60 OmL) and extracted with dichloromethane (200 mL × 3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate 4: 1 to dichloromethane-methanol 10: 1) to give 3- [6-hydroxy-11-phenylnaphthalene-12-yl] -12-methyl. There was obtained 2-propenoic acid (0.79 g). The desired product (0.79 g) was obtained by the method described in Reference Example 39 using the acid (0.79 g) thus obtained. This is a mixture of (E) and (Z) bodies.

Example 79

 (E) — and (Z) — 3 -— [6-hydroxy-1-phenylnaphthalene —2-yl] -12-methyl-12-propenoic acid

 Using the ester (0.78 g) obtained in Example 78, the crude product obtained in the same manner as described in Example 6 was subjected to silica gel column chromatography (dichloromethane Zmethanol 50: 1). Purification yielded (E) -isomer (0.52 g) and (Z) -isomer (0.1 Og).

(E) isomer: 'H— NMR (CDC I ₃ ) <5: ppm

2.05 (3 H, d, J = 1.7 Hz), 6.97 (1 H, dd, J = 2.5 and 9.1 Hz), 7.17 (1 H, d, J = 2.6 Hz, 7.19-7.25 (2 H, m), 7.37-7.55 (6 H, m), 7.67 ( 1 H, d, J = 8.9 Hz)

 (Z) form: H—NMR (C DC I a) δ ppm

1.93 (3 H, d, J = 1.3 Hz), 6.44 (1 H, d, J = 1.3 Hz), 6.96 (1 H, dd, J = 2.6 And 9.2 Hz), 7.15 (1 H, d, J = 2.3 Hz), f. 28—7.35 (2 H, m), 7.36-7.42 ( 5H, m), 7.57 (1H, d, J = 8.6Hz).

 (E) -3-(6-Methoxy-1 -p-Methoxymethoxyphenylnaphthalene-1-yl) -1-Methyl-2-ethyl ethyl propenoate

 The target product (3.03 g) was obtained in the same manner as described in Example 1 using the aldehyde (2.86 g) obtained in Reference Example 51.

1 H-NMR (CD CI ₃ ) 5: ppm

 1.23 (3H, t, J = 7.1 Hz), 2.07 (3Η, d, J = 1.3Η), 3.55 (3Η, s), 3.93 (3 Η, s), 4.16 (2 Η, q, J = 7.0 ζ ζ), 5.25 (2 Η, s), 7.04 (1 Η, dd, J = 2.6 And 9.2 Hz), 7.09—7.21 (5 H, m), 7.45 (1 H, d, J = 1.3 Hz), 7.49 (1 H, d, J = 8.6 Hz), 7.55 (1 H, d, J = 9.2 Hz), 7.73 (1 H, d, J = 8.6 Hz).

Example 8 1

(E) — 3— (11-p-hydroxyphenyl 6-methoxynaphthalene-1-yl) 1-methyl-2-ethyl ethyl propenoate

 The desired product (2.83 g) was obtained by the method described in Example 6 using the ester (2.96 g) obtained in Example 80.

1 H-NMR (CDC I ₃ ) δ ppm

 1.28 (3H, t, J = 7.3Hz), 2.11 (3H, d, J = 1.3H2), 3.96 (3H, s), 4.22 (2H, q, J = 7.OHz), 6.52 (1H, br.s), 6.91-7.00 (2H, m), 7.06 (1H, dd, J = 2.6 and 9.2 Hz), 7.10—7.17 (2H, m), 7.19 (1H, d, J = 2.6 Hz), 7.52 (1 H, d, J = 8.9 Hz), 7.55 (1 H, d, J = 1.3 Hz), 7.60 (1 H, d, J = 9.2 Hz) , 7.75 (1 H, d, J = 8.9 Hz)-Example 82

 (E) — 3— {6-Methoxy-11- [p— (piperidine-11-ylethoxy) phenyl] naphthalene-1-yl} -12-methyl-12-ethyl propenoate

Using the phenol obtained in Example 81 (2.65 g), The desired product (3.12 g) was obtained by the method described.

 1 H-NMR (CD C I 3) δ: ppm

 1.23 (3 H, t, J = 7.1 Hz), 1.38-1.53 (2 H, m), 1.53-1.69 (4 H, m), 2.06 ( 3 H, d, J = 1.6 Hz), 2.55 (4 H, t, J = 5.0 Hz), 2.83 (2 H, t, J = 5.9 Hz), 3.93 (3 H, s), 4.16 (2 H, q, J = 7.3 Hz), 4.18 (2 H, t, J = 5.9 Hz), 6. 96—F. 0 2 (2 H, m), 7.04 (1 H, dd, J = 2. '6 and 9.2 H z), 7.1 1 -7. 19 (3 H, m ), 7.45 (1 H, d, J = 1.7 Hz), 7.49 (1 H, d, J = 8.6 Hz), f. 55 (1 H, d, J = 9 2 H z), 7.73 (1 H, d, J = 8.6 H z).

Example 83

 (E) —3— {6-Hydroxy-11- [p— (piperidine-1-ylethoxy) phenyl] naphthalene-12- ^}} 2-Methyl-2-ethyl ethyl propenoate hydrochloride

At 0 ° C, n-octanethiol (10.4 mL) was added to a suspension of aluminum chloride (5.63 g) in 1,2-dichloroethane (67 mL) and stirred for 15 minutes to dissolve the aluminum chloride. . A solution of the ester (2.77 g) obtained in Reference Example 107 in 1,2-dichloroethane (3 mL) was added, and the mixture was stirred for 1 hour. (4) Trahydrofuran (60 mL) was added, and water (300 mL) containing glaucoma hydrochloride (6 mL) was added. Separate the organic layer and add dichloromethane (1 O OmL x 2) and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol 9: 1) to obtain the desired product (2.83 g).

1 H-NMR (CDC I ₃ ) 5: ppm

 1.21 (3 H, t, J = 7.1 Hz), 1.61 (2 H, br.s), 1.94 (4 H, br.s), 1.98 (3 H, d , J = 1.3 Hz), 3.05 (4H, b to s), 3.23 (2 H, t, J = 4.5 Hz), 4.13 (2 H, q, J = 7.2 Hz), 4.33 (2H, t, J = 4.8Hz), 6.61-6.70 (2H, m), 6.86-6.95 (2H, m), 7.04 (1 H, dd, J = 2.5 and 9.4 Hz), 7.32 (1 H, br.s), 7.36-7.4 (2 H, m ), 7.65 (1 H, d, J = 8.6 Hz).

Example 84

 (E) — 3-—6-Hydroxy-1— [p— (piperidine-11-ylethoxy) phenyl] naphthalene-1-yl} —2-methyl-2-propenoic acid hydrochloric acid

To a solution of the ester (2.69 g) obtained in Example 83 in methanol (6 mL) was added a 5N aqueous sodium hydroxide solution (5.5 mL), and the mixture was heated with stirring at 50 ° C for 3 hours. After cooling, the solvent was removed under reduced pressure, 2N hydrochloric acid (50 mL) was added to the residue, and the insoluble matter was collected by filtration and dried to obtain the desired product (2.48 g) as a white solid. 1 H-NMR (CD ₃ OD) δ: ppm 1.50-2.10 (6H, br.m), 2.01 (3H, d, J = 1.3Hz), 2.95-3.40 (6H, m), 3 50— 3.80 (2 H, m), 3.62 (2 H, t, J = 5.0 Hz), 4.46 (2 H, t, J = 5.0 H 2), 6 96 (1 H, dd, J = 2.5 and 9.1 Hz), 7.09-7.23 (5 H, m), 7.35-7.43 (2 H, m), 7 46 (1H, d, J = 8.6Hz), 7.69 (1H, d, J = 8.6Hz).

Example 85

 — (E) — _3— (6-hydroxy-1- 1-p-hydroxyphenylnaphthalene

 Using the phenol (1. Og) obtained in Example 81, the desired product (0.60 g) was obtained by the method described in Example 83.

H-NMR (CD ₃ OD) δ ppm

 1.17 (3 H, t, J = 7.1 Hz), 2.01 (3 H, d, J = 1.3 Hz), 4.09 (2 H, q, J = 7. 2Hz), 6.86-7.06 (7H, m), 7.19 (1H, d, J = 2.3Hz), 7.35 (1H, d, J = 1. 7 Hz), 7.42 (1 H, d, J = 8.9 Hz), 7.47 (1 H, d, J = 8.6 Hz), 7.71 (1 H, d, J = 8.9 Hz).

Example 86

(E) —3— (6-Hydroxy-1-p-hydroxyphenylnaphthalene-2-yl) -1-Methyl-2-propenoic acid

Using the ester (0.89 g) obtained in Example 85, the desired product (0.78 _g ) was obtained by the method described in Example 84.

¹ H-NMR (CD ₃ SOCD ₃ ) δ: ppm

1.96, 3H, d, J = 1.3Hz), 684-7.05 (5H, m), 7.17 (1H, d, J = 2.6Hz) 7 .33 (1 H, d, J = 1.3 Hz), 7.39 (1 H, d, J = 92 Hz), 7.45 (1 H, d, J = 8.6 Hz) ), 7.69 (1 H, d, J = 8.6 Hz).

Example 87

(Z) —3— (6-Methoxy 1-Methoxymethoxynaphthalene 1-2-yl) 1-Methyl-2-pentenoate

A method similar to that described in Example 4 using the ketone (8.29 g) obtained in Reference Example 53 and substituting methyl 2-trimethylsilylpropanoate for t-butyl 2-trimethylsilylbutanoate. (9.27g) H-NMR (CDC I ₃ ) (5: ppm

0.92 (3H, t, J = 7.6Hz), 2.09 (3H, s), 2.46-2.75 (2H, m), 3.38 (3H, s), 3.56 (3 H, s) 3.92 (3 H, s), 5.07-5.20 (2H, m), 7.04 (1 H, d, J = 8.6 Hz), 7.10 (1 H, d, J = 2.3 Hz), 7.16 (1H, dd, J = 2.6 and 9.2Hz), 7.43 (1H, d, J = 8.3Hz), 8.13 (1H, d , J = 8.9 Hz).

Example 88

 (E) —3— (6-Methoxy 1-methoxy methoxynaphthalene 1-2-yl) 1-Methyl 2-pentenoate

 Using the (Z) -ester (3.14 g) obtained in Example 87, a mixture of the (E) -isomer and the (Z) -isomer was obtained by the method described in Example 5 and subjected to silica gel column chromatography (He Purification was performed using xanthine ethyl acetate 50: 1) to separate the desired product (0.93 g).

¹ H-NMR (CDC I ₃ ) 6: ppm

 0.95 (3 H, t, J = 7.6 Hz), 1.78 (3 H, s), 2.46-2.64 (1 H, m), 2.87—3.05 (1 H, m), 3.56 (3 H, s), 3.81 (3 H, s), 3.92 (3 H, s), 5.07 (2 H, s), 7.1 0 (1H, d, J = 8.6Hz), 7.13 (1H, d, J = 2.3Hz), 7.18 (1H, dd, J = 2.6 And 9.2 Hz), 7.51 (1 H, d, J = 8.6 Hz), 8.10 (1 H, d, J = 8.9 Hz).

Example 89

 (E) — 3— (1-hydroxy-6-methoxynaphthalene-1-yl)

2-Methyl-2-methyl pentenoate

Described in Example 6 using the ester (0.90 g) obtained in Example 88 Thus, the desired product (0.76 g) was obtained.

 '' H-NMR (CDC I 3) δ: ppm

 0.99 (3 H, t, J = 7.4 Hz), 1.77 (3 H, s), 2.39 -2.56 (1 H, m), 2.75-2. 93 (1H, m), 3.83 (3H, s), 3.90 (3H, s), 5.71 (1H, s), 7.06 (1H, d, J = 8.6 Hz, 7.9 (1 H, d, J = 2.3 Hz), 7.15 (1 H, dd, J = 2.6 and 9.2 Hz), 7. 3 2 (1H, d, J = 8.3Hz), 8.17 (1H, d, J = 9.2Hz).

Example 90

 (E)-3-(6-Methoxy-1-propoxynaphthalene-1-yl)-2-Methyl-1- 2-methylpentanoate

 To a solution of naphthol (0.50 g) obtained in Example 89 in dimethylformamide (4.5 mL) was added 60% sodium hydride (0.083 g), and the mixture was stirred for 5 minutes. To this was added 1-propyl bromide (0.23 mL), and the mixture was stirred for 1.5 hours. Saturated saline (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3) and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (methylene chloride 1: 1) to obtain the desired product (0.44 g).

1 H-NMR (CDC I ₃ ) δ: ppm

0.95 (3 H, t, J = 7.4 Hz), 1.06 (3 H, t, J = 7.4 Hz), 1.73-1.90 (2 H, m), 1.77 (3 H, s), 2.5 1-2.73 (1 H, m), 2.84-3.03 (1 H, m), 3.82 (3 H, s) , 3.88 (2 H, t, J = 6.4 Hz), 3.92 (3 H, s), 7.08 (1 H, d, J = 8.2 Hz), 7. 1 0- 7.1 9 (2 H, m), 7.47 (1 H, d, J = 8.3 Hz), 8.08 (1 H, d, J = 8.9 Hz).

Example 91

 (E) -3- (6-Hydroxy-1-propoxynaphthalene-1-yl) -2-methyl-2-pentanoate

 Using the ester (0.44 g) obtained in Example 90, the desired product (0.15 g) was obtained by the method described in Example 83.

'' H-NMR (CDC I ₃ ) <5: ppm

 0.96 (3 H, t, J = 7.4 Η ζ), 1.06 (3 Η, t, J = 7.4 ζ), 1. 74-1.90 (2 Η, m), 1 78 (3Η, s), 2.52-2.71 (1Η, m), 2.84-3.04 (1Η, m), 3.84 (3Η, s), 3.88 (2 Η, t, J = 6.4 Η ζ), 6.42 (

S), 705 (1 Η, d, J = 8.3 Η), 7.12—7.19 (2H, m) 7.38 (1Η, d, J = 8.6 Η), 8.08 (1 H, d, J = 86 Η).

Example 92

 (E) 1-3- (6-hydroxy-11-propoxynaphthalene-12-yl) -2-methyl-12-pentenoic acid

 The desired product (0.1 Og) was obtained by the method described in Example 84 using the ester (0.15 g) obtained in Example 91.

H-NMR (CDC I) δ: ppm 0.99 (3 H, t, J = 7.4 Hz), 1.08 (3 H, t, J = 7.3 Hz), 1.74-1.93 (2 H, m), 1.83 (3H, s), 2.5-2.7 (1H, m), 3.07-3.27 (1H, m), 3.90 (2H, t, J = 6.4 Hz.), 7.07 (1 H, d, J = 8.6 Hz), 7.1 1-7. 19 (2 H, m), f. 4 1 (1 H, d, J = 8.6 Hz), 8.10 (1 H, d, J = 8.6 Hz).

Example 93

 (E) —3— (6-Methoxy-11-p-Methoxymethoxybenzoylnaphthalene-1-2-Tel) -1-Methyl-2-ethyl ethyl propenoate

 The desired product (1.01 g) was obtained in the same manner as described in Example 1 using the aldehyde (1.0 Og) obtained in Reference Example 57.

 1 H-N R (CD C I 3) <5: ppm

 1.21 (3H, t, J = 7.1Hz), 2.01 (3H, d, J = 1.3Hz), 3.47 (3H, s), 3. 93 (3 H, s), 4.13 (2

H, q, J = 7.1 Hz), 5.21 (2H, s), 6.97—7.20 (2H, m), 7.08 (1H, dd, J = 2 6 and 9.2 Hz), 7.

1 8 (1 H, d, J = 2.6 Hz), 7.47 (1 H, d, J = 8.6 Hz), 7.5 1 (1 H, d, J = 9.2 Hz), 7.56 (1H, d, J = 1.7Hz), 7.68-7.76 (2H, m), 7.83 (1H, d

, J = 8.6 Hz).

Example 94

(E) —3— (1 p-Hydroxybenzoyl-6-methoxynaphthalene —2-yl) 1-Methyl-12-ethyl propeneate

The desired product (0.81 g) was obtained by the method described in Example 6 using the ester (0.91 _g ) obtained in Example 93.

 1 H-NMR (CD C I 3) S: ppm

 1.19 (3H, t, J = 7.H2), 1.99 (3H, d, J = 1.7Hz), 3.89 (3H, s), 4.1 2 (2 H, q, J = 7.2 Hz), 6.68-6.78 (2 H, m), 7.05 (1 H, dd, J = 2.5 and 9.1 Hz) ), 7.16 (1H, d, J = 2.6Hz), 7.44 (1H, d, J = 8.6Hz), 7.48 (1H, d, J = 9.2 Hz), 7.56-7.67 (3 H, m), 7.79 (1 H, d, J = 8.6 Hz), 8.32 (1 H, b S).

Example 95

 (E) -3-[6-Methoxy-1-p- (2-piperidine-111-perethoxy) benzoylnaphthalene-1-yl] -1-methyl-2-propenoate

 The desired product (2.40 g) was obtained in the same manner as in Example 69 using phenol (2.49 g) obtained by the method described in Example 94. 'H-NMR (CD C I 3) δ: ppm

1.26 (3H, t, J = 6.9Hz), 1.38-1.49 (2H, m), 1.52-1.65 (4H, m), 2. 00 (3 H, d, J = 1.3 Hz), 2.49 (2H, t, J = 5.OHz), 2.76 (2H, t, J = 6.1Hz), 3.92 (3H, s), 4 07-4. 17 (4 H, m), 6.86 (2 H, d, J = 8.9 Hz), 7.07 (1 H, dd, J = 2.5 and 9.1 Hz), 7.18 (1 H, d, J = 2.6 Hz), 7.46 (1 H, d, J = 8.6 Hz), 7.51 (1 H, d, J = 9.2 Hz, 7.56 (1 H, d, J = 1.7 Hz), 7.71 (2 H, d, J = 8.6 Hz), 7.82 (1 H, d, J = 8.6 Hz).

Example 96

 (E) 1- [6-Hydroxy-l-p- (2-piperidine-l-l-ethoxy) benzoylnaphthalene-l- 2-yl] l-Methyl-l- 2-ethyl propene hydrochloride

 Using the ester (2.35 g) obtained in Example 95, the desired product (2.40 g) was obtained by the method described in Example 83.

1 H-NMR (CDC I ₃ ) δ: ppm

1.21 (3 H, t, J = 7.1 Hz), 1.41-1.56 (2 H, bs), 1.68-1.82 (4 H, br.m), 197 (3 H, d 'J = 1.3 Hz), 2.78 (4 H, br.s), 300 (2 H, bt), 4.12 (2 H, q, J = 7. 1Hz), 425 (2H, br.t), 6.71 (2H, d, J = 8.9Hz), 697 (1H, dd, J = 2.3 and 9. 2 Hz), 7.16 (1 H, d, J = 2.3 Hz), 7.35 (1 H, d, J = 9.2 Hz), 7.36 (1 H, d , J = 8.6 Hz), 7.51 (1 H, d, J = 1.3 Hz), 7.55-7.67 (3 H, m). Example 97

 (E) —3— [6-Hydroxy-1 (2-piperidine-11-ylethoxy) benzoylnaphthalene-12-yl] -12-Methyl-2-propene hydrochloride

 The target product (2.22 g) was obtained by the method described in Example 84 using the ester (2.35 g) obtained in Example 96.

_{'HN R (CD 3 0 D} ) δ: ppm

 1.43- 1.63 (1 H, m), 1.72-2.05 (5 H, m), 1.96 (3 H, d, J = 1.3 Hz), 3.06 ( 2 H, b r. T), 3.50-3. 68 (4H, m), 4.37-4.51 (2 H, m), 6.88-7.10 (3 H, m) , 7.22 (1H, d, J = 2.3 Hz), 7.37 (1H, d, J = 8.9H2), 7.48 (1H, d, J = 8. 6 Hz), 7.51 (1 H, d, J = 1.3 Hz), 7.69-7.78 (2 H, m), 7.82 (1 H, d, J = 8. 9 Hz).

Example 98

 (E) — 3— (3-formyl-6-methoxynaphthalene-12-yl) 1-methyl-2-methyl-2-pentenoate

Using the ketone (1 g) obtained in Reference Example 58, methyl 2-trimethylsilylpropanoate was used instead of t-butyl 2-trimethylsilylbutanoate. And using the same method as described in Example 4 and using (Z) —3- (6-methoxy-3-methoxyethoxymethylnaphthalene-12-yl) -12-methyl-12-pentene Then, a mixture of the (E) -isomer and the (Z) -isomer was prepared in the same manner as in Example 5 to give a mixture of the (E) -isomer (0.44 g) by silica gel column chromatography (ethyl hexanoate 50: 1). And (Z) body (0.70 g) were separated. The (E) -ester (0.44 g) thus obtained was used and the method described in Example 6 was used to prepare (E) -3- (3-hydroxymethyl-6-methoxynaphthalene-1-yl). ) 1-Methyl-1-methyl 2-pentenoate

(0.28 g), of which 0.23 g was oxidized with pyridinium bromide to obtain the desired product (0.1 at all).

'H-NMR (CDC I ₃ ) δ: PPm

 1.01 (3 H, t, J = 7.4 Hz), 1.64 (3 H, s), 2.5 2-2.68 (1 H, m), 2.79-2.97 (1H, m), 3.84 (3H, s), 3.95 (3H, s), 7.26-7.33 (2H, m), 7.52 (1H, s) , 7.77 (1 H, d, J = 8.6 Hz), 8.41 (1 H, s), 10.17 (1 H, s).

Example 99

 (E) 1-3- (3-butyl-6-hydroxynaphthalene-12-yl) 1-2-methyl-2-methyl pentenoate

At 0 ° C, a 1.69N n-butyllithium hexane solution (1 mL) was added to a solution of n-propyltriphenylphosphonium bromide (0.93 g) azeotropically dried with benzene (0.93 g) in tetrahydrofuran (8 mL). 30 mL) solution and stirred for 10 minutes. Here, the aldehyde (0.17 g) obtained in Example 98 was extracted. A solution of trahydrofuran (1 mL) was added, and the mixture was stirred for 10 minutes. A saturated ammonium chloride solution (1 OmL) was added, and the mixture was extracted with dichloromethane (1 OmL × 3) and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate 10: 1). (E) — 3 -— (3- (1-butenyl) -16-methoxynaphthalene-12-yl 1) 2-methyl-

Methyl 2-pentanoate (0.19 g), followed by a hydrogenation reaction using a catalyst containing palladium on coal (E) — 3— (3-butyl-6-methoxynaphthalene) M) 1-2-Methyl-2-pentenoate methyl (0.18 g) was obtained. The desired product (0.08 g) was obtained by the method described in Example 83 using the ester (0.18 g) thus obtained.

¹ HNR (CD CI 3) δ: ppm

 0.93 (3 H, t, J = 7.3 Hz), 1.03 (3 H, t, J = 7.4 Hz), 1.30-1.46 (2 H, m), 1.57-1.71 (2H, m), 1.64 (3H, s), 2.22-2.39 (1H, m), 2.59 (2H, t, J = 7.9 Hz, 2.9 1 -3.08 (1 H, m), 7.04-7.15 (2 H, m), 7.31 (1 H, s), 7.54 (1 H, s), 7.66 (1 H, d, J = 8.9 Hz).

Example 100

 (E) -3--(3-butyl-6-hydroxynaphthalene-1-yl) 1-2-methyl-12-pentenoic acid

 The desired product (0.08 g) was obtained by the method described in Example 84 using the ester (0.08 g) obtained in Example 99.

1 H-NMR (C DC I 3) <5: ppm 0.95 (3H, t, J = 7.3Hz), 1.06 (3H, t, J = 7.Hz), 1.33-1.48 (2H, m), 1.59-1.73 (2H, m), 1.68 (3H, s), 2.29-2.46 (1H, m), 2.61 (2H, t, J = 7.9 Hz, 3.12-3.26 (1 H, m), 7.06 (1 H, dd, J = 2.5 and 8.7 Hz), 7.12 (1H, d, J = 2.3Hz), 7.33 (1H, s), 7.57 (1H, s), 7.69 (1H, d, J = 8 . 6 H z). Reference Example 1

1 1 (6—Methoxynaphthalene 1—2 ^^) Propane 1 1 1

 Under a nitrogen atmosphere, propionyl chloride (7.5 g) was added dropwise to a solution of aluminum trichloride (10.78 g) and 2-methoxynaphthalene (1 Og) in nitrobenzene (50 mL) under ice cooling over 20 minutes. . After stirring at the same temperature for 30 minutes, the reaction solution was added to concentrated hydrochloric acid (50 mL) to which ice chips had been added, and extracted three times with dichloroethane. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline, and the solvent was removed under reduced pressure. The residue is purified by silica gel column chromatography (hexane to ethyl hexanenoacetate 50: 1), followed by repulping and washing with hexane to give the desired product (4.26 g) as a colorless crystal having a melting point of 104 to 105 ° C. As obtained.

 1 H-NMR (CDCI3) δ: ppm

1.28 (3 H, t, J = 7.3 Hz), 3.12 (2 H, q, J = 7.3 Hz), 3.95 (3 H, s), 7.1 5 (1H, d, J = 2.3Hz), 7.20 (1H, dd, J = 2.6 and 8.9Hz), 7.77 (1H, d, J = 8 6 H z), 7.85 (1 H, d, J = 8.9 H z), 8.02 (1 H, dd, J = 1.6 and 8.6 H z), 8.40 ( 1 H, br. s).

Reference example 2

1 (6 droxynaphthalene-2-yl) propane-1 1-on

 A mixture of the ketone (4.3 Og) obtained in Reference Example 1 and pyridine hydrochloride (23.2 g) was stirred at 180 ° C for 4 hours. After cooling, saturated saline (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate 5: 1 to 1: 1) to give the desired compound (

2.2 g) was obtained.

¹ HN R (Aseton one d ₆₎ δ: ppm

 1.19 (3 H, t, J = 7.2 Hz), 3.13 (2 H, q, J = 7.2 Hz), 7.21 -7.27 (2 H, m ), 7.75 (1H, d, J = 8.7Hz), 7.94-7.98 (2H, m), 8.52 (1H, br.), 9.04 (1 H, s).

Reference example 3

1-one (6-Methoxymex-methoxynaphthalene-1-yl) Propane 1-one-one

To a solution of ketone (2.2 g) obtained in Reference Example 2 and potassium carbonate (7.6 Og) in acetone (15 OmL) was added a solution of octamethyl methyl ether (1.77 g) in acetone (1 OmL). Was added and refluxed for 2 hours. After cooling, the insolubles were filtered off, saturated saline (50 OmL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2), and the organic layer was dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is silica gel. Purification by column chromatography (ethyl hexanodiate 5: 1) gave the desired product (2.1 Og).

 1 H-NMR (CD C I 3) δ: ppm

 1.2 f (3 H, t, J = 7.2 Hz), 3.10 (2 H, q, J = 7.2 Hz), 3.53 (3 H, s), 5. 32 (2 H, s), f. 27 (1 H, dd, J = 2.5 and 8.9 Hz), 7.41 (1 H, d, J = 2.5 Hz), 7 . 7 7 (1H, d, J = 8.6Hz), 7.87 (1H, d, J = 8.9Hz), 8.00 (1H, dd, J = 1.7) And 8.6 Hz), 8.40 (1 H, d, J = 1.6 Hz).

Reference example 4

T-butyl 2-trimethylsilylpropanoate At 70 ° C, a 1.6 N n-butyllithium hexane solution (40 OmL) was added to a solution of diisopropylamine (113 mL) in tetrahydrofuran (800 mL) to prepare lithium diisopropylamide. To this was added dropwise t-butyl acetate (72.1 g), and the mixture was stirred for 20 minutes. At the same temperature, chlorotrimethylsilane (83 mL) was slowly added dropwise, and the mixture was stirred for 30 minutes after the addition was completed. After the temperature was raised to 0 ° C, 1N hydrochloric acid and water ("I.5L) were added, and the mixture was extracted with n-hexane (50 OmLx3). The organic layer was collected, and 1N hydrochloric acid (1.0L) and water were added. (500 mL x 3), dried over magnesium sulfate, and the solvent was removed, and the obtained mixture was distilled to obtain t-butyl trimethylsilylacetate (8.5.56 g, boiling point: 174 to 175 ° C). A solution of the silyl acetate (20.0 g) thus obtained in tetrahydrofuran (2 OmL) was added to a solution of lithium diisopropylamide at 170 ° C. (diisopropylamine (20.3 mL) at 170 ° C.). In water (1.6 mL) and 1.6N η-butyllithium hexane solution (73 mL) And stirred for 1 hour. Further, methyl iodide (6.57 mL) was slowly added dropwise at the same temperature, and the mixture was stirred for 1 hour after completion of the addition. After heating to 20 ° C and stirring for 1 hour, saturated aqueous ammonium chloride (300 mL) was added, and the mixture was extracted with n-hexane (1O Orrlx 3). The organic layer was collected, washed with water (100 mL × 3), dried over magnesium sulfate, and the solvent was removed. The obtained mixture was subjected to reduced pressure distillation to obtain a desired product (16 _g , boiling point: 69 to 1 ° CZ1 OmmHg).

1 HNR (CDC I ₃ ) 5: ppm

 0.06 (9 H, s), 1.10 (3 H, d, J = 7.2 Hz), 1.42 (9H, s), 1.92 (1 H, q, J = 7 2 Hz).

Reference example 5

2-tert-butyl trimethylsilylbutanoate

 The compound was obtained by the same method as that described in Reference Example 4 except that methyl iodide (8.46 mL) was used instead of methyl iodide reacted with t-butyl trimethylsilylacetate (20.0 g). 1 5.19 g, boiling point 80 ~ 81 1. CZ1 OnmHgo

 'H-NMR (CDC I a) δ: ppm

 0.05 (9 H, s), 0.93 (3 H, t, J = 7.1 Hz), 1.3 3—1.48 (2 H, m), 1.43 (9 H, s), 1.73-1.75 (1 H, m).

Reference example 6

 One-one (6-Methoxynaphthalene one-two-one)

Use 2-methoxynaphthalene (100 g) instead of propionyl chloride It was obtained in the same manner as described in Reference Example 1 (20.5 g), except that acetyl chloride (59.5 g) was used and dichloromethane was used instead of nitrobenzene as a solvent.

1 H-NMR (CD Cl ₃ ) (5: ppm

 2.69 (3 H, s), 3.94 (3 H, s), f. 15 (1 H, d, J = 2.6 Hz), 7.20 (1 H, dd, J = 2.6 and 8.9 Hz), 7 • 76 (1 H, d, J = 8.6 Hz), 7.85 (1 H, d, J = 8.9 Hz), 8:00 (1H, dd, J = 1.8 and 8.7Hz), 8.38 (1H, d, J = 1.1z.).

Reference Example 7

1 — _ (6—Hydroxynaphthalene-2-yl) Ethan-1

This was obtained in the same manner as described in Reference Example 2 using the ketone (20.5 g) obtained in Reference Example 6 as a starting material. 5. 82g.

1 H-NMR (acetone-1 d ₆ ) δ ppm

 2.65 (3 H, s), 7.2 1 -7. 26 (2 H, m), 7.74 (1 H, d, J = 8.6 Hz), 7.92-8. 00 (2 H, m), 8.52 (1 H, br.s).

Reference Example 8

1 — (6-Methoxy methoxy naphthalene 1-yl) Ethane 1 1-one

Using the ketone (5.82 g) obtained in Reference Example 7 as a starting material, it was obtained in the same manner as described in Reference Example 3. 5.5 7 _g . ¹ H-NMR (CD CI 3) δ: ppm

 2.71 (3 H, s), 3.54 (3 H, s), 5.33 (2 H, s), 7.28 (1 H, dd, J = 2.1 and 8.7 Hz ), 7.42 (1 H, d, J = 2.6 Hz), 7.78 (1 H, d, J = 8.9 Hz), 7.89 (1 H, d, J = 8. 9 Hz), 8.01 (1 H, dd, J = 2.0 and 8.6 Hz), 8.41 (1 H, br.s).

Reference Example 9

6-Methoxymethoxynaphthalene-1 2-carbaldehyde

 Using 6-hydroxynaphthalene-12-carbaldehyde (2.6 g) as a starting material, it was obtained in the same manner as described in Reference Example 3. 3.1 g.

 1 H-NMR (CDC I 3) δ: ppm

 3.54 (3 H, s), 5.33 (2 H, s), 7.37 (1 H, dd, J = 2.6 and 8.9 Hz), 7.44 (1 H, d , J = 2.3 Hz, 7 • 81 (1 H, d, J = 8.6 Hz), 7.90-7.94 (2 H, m), 8.26 (1 H, br) ), 1 0.10 (1 H, s).

Reference example 10

 2,2,3,3,3-Pentafluoro-1- (6-methoxime ethoxynaphthalene-1-yl) Propane-1-ol

1. At 70 ° C, add a 1.15N methyl lithium ether solution (38 mL) to a solution of pentafluoroethyl iodide and the aldehyde (3. Og) obtained in Reference Example 9 in tetrahydrofuran (3 OmL). ) Was added dropwise and stirred for 30 minutes. Saturated saline (30 OmL) was added, and the sleeve was made with ether (50 mL x 3). Organic The layers were collected, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (1.65 g).

 1 H-NMR (CDC I 3) δ: ppm

 2.79 (1H, d, J = 4.6Hz), 3.51 (3H, s), 5.29 (2H, s), 5.18-5.29 (1H , m), 7.24 (1H, dd, J = 2.6 and 8.9Hz), 7.39 (1H, d, J = 2.3Hz), 7.50 (1H D), 7.76 (1 H, d, J = 8.6 Hz), 7.77 (1 H, d, J = 8.9 Hz), 7.83 (1 H, br Reference example 1 1

 2,2,3,3,3-Pentafluoro-1- (1-methoxy-2-methoxy-naphthalene-2-yl) Propane-1-one

 The alcohol obtained in Reference Example 10 (1.65 g), molecular sieve 4A (2 g), N-methylmorpholine N-oxide (0,86 g), tetra-n-propylammonium perruthenate (0.1 A solution of 8 g) in dichloromethane (30 mL) was stirred at 20 ° C. for 30 minutes. The insoluble material was separated by filtration and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate 2: 1) to obtain the desired product (1.38 g).

1 H-NMR (CDC I ₃ ) 5: ppm

 3.53 (3 H, s), 5.34 (2 H, s), 7.31 (1 H, dd, J = 2.6 and 8.9 Hz), 7.42 (1 H, d , J = 2.3 Hz), f. 79 (1 H, d, J = 8.9 Hz), 7.90 (1 H, d, J = 8.9 Hz), 8.02 (1 H, br. D), 8.57 (1 H, br.). Reference Example 1 2

6-Hydroxy-one-latralone

 A solution of anhydrous aluminum chloride (236 g) in dichloromethane (50 OmL) was cooled to 5 ° C, n-octanethiol (307 mL) was added, and 6-methoxy-11-tetralone (125 g) in dichloromethane (200 ml_) was added. ) The solution was added dropwise. After completion of the dropwise addition, the mixture was further stirred for 5 hours. Ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was subjected to silica gel column chromatography (hexane Z: ethyl acetate 3: 1) to obtain the desired product (75 g).

¹ H-NMR (CD CI 3) δ: ppm

2.06-2. 19 (2 H, m), 2.60-2.65 (2 H, m), 2.88—2.93 (2 H, m), 6.70 (1 H, m) d, J = 2.0 Hz), 6.78 (-H, dd, J = 2.6 and 8.6 Hz), 7.98 (1 H, d, J = 8.6 Hz) .

Reference Example 1 3

2-Jetoxymethyl-6-hydroxy-3,4-dihydro-2H-naphthalene 1 1-one

Triethyl orthoformate (19 OmL) was cooled to 130 ° C, a solution of borane trifluoride ether complex (168 mL) in dichloromethane (20 OmL) was added dropwise, and after the addition was completed, the temperature was raised to 0 ° C. Stir for 15 minutes. After cooling to 30 ° C, a solution of petrolone (75 g) obtained in Reference Example 12 in dichloromethane (20 OmL) was added, and ethyldiisopropylamine (300 mL) was slowly dropped. Stir for 1 hour. Add saturated saline and add dichloromethane Extracted. The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture was subjected to silica gel column chromatography (hexane ethyl acetate 3: 1 to 2 _: 1) to obtain the desired product (95 g).

1 H-NMR (CDCI ₃ ) δ: ppm

 1.13 (3 H, t, J = 7.1 H 2), 1.26 (3 H, t, J = 7.1 H z), 2.02-2.33 (2 H, m) , 2.73 (1H, ddd, J = 3.1, 5.3, and 8.5Hz), 2.80—3.05 (2H, m) '3.51-3. 64 (2 H, m), 3.7 2 -3.84 (2 H, m), 5.18 (1 H, d, J = 3.1 Hz), 5.59 (1 H, s), 6.65 (1 H, d, J = 2.3 Hz), 6.74 (1 H, dd, J = 2.3 and 8.6 Hz), 7.96 (1 H , d, J = 8.6 Hz).

Reference example 1 4

2-Jetoxymethyl-6-Methoxymethoxy 3,4 dihydro-2H-naphthalene-one-one

 Using the ketone (90 g) obtained in Reference Example 13 as a starting material, it was obtained in the same manner as described in Reference Example 3.

 1 H-NMR (CD C I 3) δ ppm

1.13 (3 H, t, J = 7.2 Hz), 1.26 (3 H, t, J = 7.2 Hz), 2.13-2.38 (2 H, m), 2.68—2.77 (1H, m), 2.82-3.10 (2H, m), 3.48 (3H, s), 3.52-3. 62 (2 H, m), 3.73—3.8 1 (2 H, m), 5.18 (1 H, d, J = 3.3 Hz), 5.22 (2 H, s ), 6.85 (1H, d, J = 2.3Hz), 6.93 (1H, dd, J = 2.5 and 8.7Hz), 7.99 (1H, d _f J = 8.6 Hz). Reference example 1 5

 6-Methoxy methoxy 3,4-dihydronaphthalene 2-carbaldehyde

 At 5 ° C, lithium aluminum hydride (6.45g) ether (20

OmL), a solution of the ketone (105 g) obtained in Reference Example 14 in ether (30 mL) was added, and the mixture was stirred for 12 hours. Saturated saline was added, and the mixture was extracted with ether. The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture is subjected to silica gel column chromatography (hexane Z: ethyl acetate 10: 1) to give 2-ethoxymethoxy-6-methoxymethoxy 1,2,3,4-tetrahydronaphthalen-1-ol (8 Og ). Pyridinium p-toluenesulfonate (6.05 g) was added to a solution of the alcohol (75 g) thus obtained in benzene (50 OmL), and the mixture was stirred at 50 ° C. for 30 minutes. Saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was dissolved in acetonitrile (100 mL), alumina (3 g) was added, and the mixture was stirred for 30 minutes. After removing the alumina, the solvent was concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate 10: 1) to obtain the desired product (19.5 g).

1 H-NMR (CD CI ₃ ) <5: ppm

 2.55 (2 H, t, J = 7.3 Hz), 2.86 (2 H, t, J = 7.3 Hz), 3.49 (3 H, s), 5.21 ( 2 H, s), 6.89—6.93 (2 H, m), 7.21-7.24 (2 H, m), 9.62 (1 H, s)

Reference Example 1 6

1- (6-Methoxymethoxy 3,4-dihydronaphthalene-1-yl) Propane 1—all

 At 78 ° C, add 1.04N ethylmagnesium bromide tetrahydrofuran (89mL) to a solution of the aldehyde (17.Og) obtained in Reference Example 15 in tetrahydrofuran (80mL), and add it for 30 minutes. I searched. Saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture was subjected to silica gel column chromatography (hexane ethyl acetate: 10: 1) to obtain the desired product (17.1 g).

¹ H-NMR (CDC I 3) δ: ppm

 0.91 (3 H, t, J = 7.4 Hz), 1.59-1.71 (2H, m), 2.1 1 -2.41 (2 H, m), 2.78 ( 2 H, t, J = 8.1 Hz), 3.47 (3 H, s), 4.10-4. 16 (1 H, m), 5.15 (2 H, s) , 6.36 (1 H, s), 6.80-6.83 (2H, m), 6.95 (1 H, d, J = 8.9 Hz).

Reference Example 1 7

 1- (6-Methoxymethoxy-1,3,4-dihydronaphthalene-1-yl) propane-1-one

 Using the alcohol (17 Og) obtained in Reference Example 16 as the starting material, it was obtained in the same manner as described in Reference Example 11 (9.52 g).

 1 H-NMR (CDC I a) δ: ppm

1.16 (3 H, t, J = 7.3 Hz), 2.57 (2H, t, J = 7. 9H z), 2.76-2.84 (4 H, m), 3.48 (3 H, s), 5.19 (2 H, s), 6.8 fu 6.90 (2 H, m), 7.16 (1H, d, J = 8.9Hz), 7.3f (1H, s).

Reference Example 1 8

 1-(6-Methoxynaphthalene-1-yl)

 The method described in Reference Example 1 except that 2-methoxynaphthalene (31.6 g) was used, butyryl chloride (25.6 g) was used instead of propionyl chloride, and nitromethane was used instead of nitrobenzene as the solvent. It was obtained in the same way as (15.3 g).

 1 H-NMR (CDC I 3) S: ppm

 1.04 (3 H, t, J = 7.4 Hz), 1.76-2.00 (2 H, m), 3.06 (2 H, t, J = 7.3 Hz), 3 95 (3 H, s), 7.16 (1 H, d, J = 2.6 H 2), 7.20 (1 H, dd, J = 2.6 and 8.9 Hz), 7 77 (1H, d, J = 8.9Hz), 7.85 (1H, d, J = 9.2Hz), 8.01 (H, dd, J = 1.8 and 8 7 Hz), 8.40 (1 H, d, J = 1.7 Hz).

Reference Example 1 9

 1 1 _ (6—Hydroxynaphthalene 1 2—> Pel) Butane 1 1 ON

 Using the ketone (1 Og) obtained in Reference Example 18 as a starting material, it was obtained in the same manner as described in Reference Example 2I (9.5 g).

1 H-NMR (CDC I ₃ ) <5: ppm 1.04 (3 H, t, J = 7.4 Hz), 1. F 5—1.88 (2 H, m), 3.06 (2 H, t, J = 7.4 Hz) , 3.80 (1H, br.s), 7.17-7.21 (2H, m), 7.69 (1H, d, J = 8.9Hz), 7.85 ( 1H, d, J = 9.6Hz), 7.92-7.96 (1H, m), 8.40 (1H, br. S,).

Reference Example 20

 1-(6-Methoxy methoxy naphthalene-1-yl) Butane 1-one

 Using the naphthol (9.5 g) obtained in Reference Example 19 as a starting material, it was obtained in the same manner as described in Reference Example 3 (10.2 g).

 1 H-N R (CD C I 3) δ: ppm

 1.04 (3 H, t, J = 7.4 Hz), 1.76-1.87 (2H, m), 3.06 (2 H, t, J = 7.4 Hz), 3 53 (3 H, s), 5.32 (2 H, s), 7.27 (1 H, dd, J = 2.6 and 8.9 Hz), 7.41 (1 H, d, J = 2.3 Hz), F.77 (1 H, d, J = 8.6 Hz), 7.88 (1 H, d, J = 8.9 Hz), 8.01 (1 H , dd, J = 1.8 and 8.7 Hz), 8.41 (1 H, br. s).

Reference Example 21

 4-butyl-7-methoxy 1._2-dihydronaphthalene

To a solution of 6-methoxy-1-tetralone (60 g) in tetrahydrofuran (1.2 L) at 40 ° C. was added a 1.63 N n-butyllithium hexane solution (23 OmL), and the mixture was stirred for 30 minutes. Borane trifluoride complex (1 65 mL) and stirred for another 30 minutes. Saturated aqueous ammonium chloride (1.OL) was added, and the mixture was extracted with ethyl acetate (500 mL × 2). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was purified by silica gel column chromatography (hexane ethyl acetate 5: 1) to obtain the desired product (36.05 g).

 1 H-NMR (CDCI3) δ: ppm

 0.92 (3 H, t, J = 7.3 Hz), 1.3 1-1.53 (m, 4 H), 2. 18-2.25 (2 H, m), 2 40 (2 H, t, J = 6.9 Hz), 2.71 (2 H, t, J = 7.9 Hz), 3.80 (3 H, s), 5.71 (1H, t, J = 4.6Hz), 6.70-6.74 (2H, m), 7.17 (1H, d, J = 9.2Hz).

Reference Example 22

 1-butyl-1-6-methoxy-3,4-dihydronaphthalene-1-2-carbaldehyde

 Phosphorus oxychloride (40 g) was added to dimethylformamide (92.9 g) at 0 ° C, and the mixture was stirred for 20 minutes. A solution of naphthalene (50 g) obtained in Reference Example 21 in dimethylformamide (25 mL) was slowly added dropwise, and the mixture was stirred for 16 hours after completion of the addition. The reaction mixture was poured on ice and extracted with ether (500 mL x 3). The organic layer was collected, washed with water and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was purified by silica gel column chromatography (ethyl hexanoacetate 20: 1) to obtain the desired product (31.3 g).

 '' H-NMR (CDC I 3) δ: ppm

0.94 (3 H, t, J = 7.3 Hz), 1.3 7-1.50 (2 H, m ), 1.53-1.65 (2 H, m), 2.46—2.52 (2 H, m), 2.68-2.74 (2 H, m), 3.00 (2 H, m) , T, J = 7.3 Hz, 3.85 (3 H, s), 6.76 (1 H, d, J = 2.6 Hz), 6.81 (1 H, dd, J = 2.6 and 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 10.28 (1H, s).

Reference Example 23

1-butyl 6-methoxy-naphthalene 1 2-carbaldehyde

 To a solution of the aldehyde (31.3 g) obtained in Reference Example 22 in benzene (50 OmL) was added dichlorodicyanobenzoquinone (33.4 g), and the mixture was stirred under heating and reflux for 7 hours. The insolubles were filtered through celite to remove the solvent. The resulting reaction mixture was purified by silica gel column chromatography (hexane Z ethyl acetate 5: 1) to obtain the desired product (25.83 g).

'HNR (CDC I ₃ ) 6: ppm

0.99 (3 H, t, J = 7.3 Hz), 1.46- 1.60 (2 H, m), 1.67- 1.78 (2 H, m), 3.48 ( 2 H, t, J = 8.1 Hz), 3.96 (3 H, s), 7.14 (1 H, d, J = 2.6 Hz), 7.23 (1 H, dd, J = 2.6 and 9.2 Hz), 7.65 (1 H, d, J = 8.6 Hz), 7.90 (1 H, d, J = 8.6 Hz) , 8.13 (1 H, d, J = 9.2 Hz).

Reference Example 24

1- (1-butyl-6-methoxynaphthalene-2-yl) propane-1-11 all

 The aldehyde (1 3. Og) obtained in Reference Example 23 was used as a starting material, and it was obtained in the same manner as described in Reference Example 16 (1. 46 g).

 1 H-NMR (CDC I a) δ: ppm

 0.99 (3H, t, J = 7.4Hz), 1.00 (3H, t, J = 7.1Hz), 1.4-1.70 (4H, m), 1.77- 1.98 (2H, m), 2.97-3.16 (2H, m), 3.92 (3H, s), 5.04-5.15 (1H , m), 7.12 (1 H, d, J = 2.6 Hz), 7.17 (1 H, dd, J = 2.6 and 9.2 Hz), 7.58 ( 1H, d, J = 8.6Hz), 7.64 (1H, d, J = 8.6Hz), 7.96

(1 H, d, J = 9.2 Hz).

Reference Example 25

1- (1-butyl-6-methoxynaphthalene-2-yl) propane-1-one

Using the alcohol obtained in Reference Example 24 (1. 4.46 g) as the starting material, it was obtained in the same manner as described in Reference Example 11 (1. 3.87 g). 1 H-NMR (CDC I ₃ ) 5: ppm

0.98 (3 H, t, J = 7.7 Hz), 1.23 (3 H, t, J = 7.3 Hz), 1.44-1.57 (2 H, m), 1.63-1.74 (2H, m), 2.95 (2H, q, J = 7.3Hz), 3.09-3.15 (2H, m), 3.94 ( 3 H, s), 7.13 (1 H, d, J = 2.6 Hz), f. 21 (1 H, dd, J = 2.6 and 9.2 Hz), 7.51 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d, J = 8.6 Hz), 8.06 (1 H, d, J = 9.2 Hz).

Reference Example 26

 1- (1-butyl-6-hydroxynaphthalene 2--2- ^) propane

 Sodium iodide (23.8) was added to a solution of ketone (1.87 g) obtained in Reference Example 25 in acetonitrile (10 OmL), and trimethylsilane (20 mL) was added dropwise thereto. The mixture was heated under reflux for 8 hours. Was done. Ice water (1.5 L) was added, and the mixture was extracted with dichloromethane (200 mL × 3). The organic was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture was purified by silica gel column chromatography (ethyl hexanoacetate 3: 1) to obtain the desired product (4.66 g).

'H—NMR (CDC I ₃ ) <5: ppm

 0.97 (3 H, t, J = 7.3 Hz), 1.23 (3 H, t, J = 7.3 Hz), 1.43- 1.57 (2 H, m), 1.65- 1.74 (2 H, m), 2.95 (2 H, q, J = 7.4 Hz), 3.09-3.15 (2 H, m), 5.90 ( 1 H, b r. S), 7.14 (1 H, d, J = 2.3 Hz), 7.18 (1 H, dd, J = 2.6 and 9.2 Hz) , 7.48 (1 H, d, J = 8.6 Hz), 7.53 (1 H, d, J = 8.6 Hz), 8.06 (1 H, d, J = 9 . 2 Hz).

Reference Example 27

1- (1-butyl-6-methoxy-2-methoxynaphthalene-2-yl) propane 1-year-old

 To a solution of 60% sodium hydride (0.73 g) in tetrahydrofuran (3 OmL) was added dropwise a solution of ketone (4.66 g) obtained in Reference Example 26 in tetrahydrofuran (24 mL), and the mixture was stirred for 20 minutes. . Chloromethyl methyl ether (1.4 mL) was added, and the mixture was stirred for 1 hour. Saturated saline (200 mL) was added, and the mixture was extracted with ether (50 mL x 3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was purified by silica gel column chromatography (hexane Z: ethyl acetate 10: 1) to obtain the desired product (2.4 g).

¹ H-NMR (CDC I 3) δ: ppm

 0.98 (3 H, t, J = 7.1 Hz), 1.23 (3 H, t, J = 7.3 Hz), 1.43-1.57 (2 H, m), 1.63-1.74 (2H, m), 2.94 (2H, q, J = 7.3Hz), 3.09-3.15 (2H, m), 3.53 (3H, s), 5.32 (2H, s), 7.29 (1H, dd, J = 2.6 and 9.2Hz), 7.39 (1H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz), f. 62 (1 H, d, J = 8.6 Hz), 8.08 (1 H, d, J = 9.2 Hz).

Reference Example 28

 1-Ethyru 6-Methoxy-naphthalene 2-Carbaldehyde

6-Methoxy 1-petralone (0.88 g) was used as the starting material, and ethyl methyl bromide was used in place of butyl lithium, in the same manner as described in Reference Example 21. 7-Methoxy 1 and 2- Hydronaphthalene (0.66 g) was obtained. The thus obtained naphthalene (31. Og) was used to prepare 1-ethyl-6-methoxy-1,3,4-dihydronaphthalene-12-carbaldehyde (15.31 g) according to the method described in Reference Example 22. ) was gotten. The desired product (6.64 g) was obtained by the method described in Reference Example 23 using the aldehyde (1 Og) thus obtained.

¹ H-NMR (CDC I ₃ ) <5: ppm

 1.40 (3 H, t, J = 7.6 Hz), 3.52 (2 H, q, J = 7.6 Hz), 3.95 (3 H, s), 7.15 (1 H, d, J = 2.6 Hz), 7.23 (1 H, dd, J = 2.6 and 9.2 Hz), 7.65 (1 H, d, J = 8. 6 Hz), 7.90 (1 H, d, J = 8.6 Hz), 8.15 (1 H, d, J = 9.6 Hz), 10.55 (1 H, s).

Reference Example 29

 1-(1-ethyl-6-methoxynaphthalene 1-2-yl) ethane-1-

 The aldehyde (5.25 g) obtained in Reference Example 28 was used, and methylmagnesium bromide was used instead of ethylmagnesium bromide. The method described in Reference Example 16 was followed by the method described in Reference Example 16 (1-ethyl-6-methoxy). (Naphthalene-1-yl) ethane-1-ol (5.93 g) was obtained. The desired product (5.07 g) was obtained by the method described in Reference Example 11 using the alcohol (5.64 g) thus obtained.

 1 H-N R (CDC I 3) δ ppm

1.35 (3 H, t, J = 7.6 Η ζ), 2.64 (3 Η, s), 3.23 (2 q, q, J = 7.5 Η ζ), 3.94 ( 3 Η, s), 7.13 (1 Η, d, J = 2.6 Η ζ), 7.22 (1 Η, dd, J = 2.8 and 9.4 Hz), f. 59 (1H, d, J = 8.7Hz), 7.63 (1H, dJ = 8.7Hz), 8.10 (1H, d, J = 9.6 Hz).

Reference Example 30

 1-(1-ethyl-6-methoxy-2-phthalene-2-yl) propane-1 on

 Reference Example 28 The aldehyde (2.58 g) obtained in Example 8 was used and the method described in Reference Example 16 was used to obtain 1- (1-ethyl-6-methoxynaphthalene-1-yl) propane-11-ol ( 2. 83 g) was obtained. The desired product (2.39 g) was obtained by the method described in Reference Example 11 using the alcohol (2.83 g) thus obtained.

1 H-NMR (CDC I ₃ ) δ ppm

 1.23 (3 H, t, J = 7.3 Η), 1.36 (3 t, t, J = 7.4 Η), 2.95 (2 Η, q, J = 7.3) Η ζ), 3.16 (2 Η, q 'J = 7.5 Hz), 3.94 (3 Η, s), 7.14 (1 Η, d, J = 2.6 Hz) ), 7, 22 (1 H, dd, J = 2.8 and 9.4 Hz), f. 52 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d , J = 8.6 Hz), 8.09 (1 H, d, J = 9.2 Hz).

Reference example 3 1

 1-Propyl-6-Methoxynaphthalene-1 2-Carbaldehyde

Reference example using 6-methoxy 1-tratralone (180 g) as the starting material and using sodium instead of lithium. In a similar manner as described in 21 above, 4-propyl-17-methoxy-1,2-dihydronaphthalene (97.5 g) was obtained. Using naphthalene (95 _g ) obtained in this manner, 1-propyl-16-methoxy-13,4-dihydronaphthalene-12-carbaldehyde (49.4 _g ) was prepared according to the method described in Reference Example 22. ) was gotten. The desired product (37.4 g) was obtained by the method described in Reference Example 23 using the aldehyde (49 g) thus obtained.

 1 H-NMR (CDC I 3) δ: ppm

1.08 (3 H, t, J = 7.2 Hz), 1.7 1-1.82 (2 H, m), 3.42-3.48 (2 H, m), 3.95 (3 H, s), 7.14 (1 H, d, J = 2.6 Hz), 7.22 (1 H _T dd, J = 2.8 and 9.4 Hz), 7. 64 (1 H, d, J = 8.6 H z), 7.90 (1 H, d, J = 8.6 H z), 8.12 (1 H, d, J = 9.6 H z).

Reference Example 32

 1 1 (1 propyl 1 6—Methoxynaphthalene 1 2—yl) Propane 1 1 1 on

Reference Example 31 Using the aldehyde (15 _g ) obtained in 1 and using the method described in Reference Example 16 to obtain 1- (1-propyl-16-methoxynaphthalene-12-yl) propane-1-ol (16.8 g) was obtained. The desired product (15.8 g) was obtained by the method described in Reference Example 11 using alcohol (18.Og) thus obtained. 'Η— NMR (CD CI ₃ ) δ: ppm

1.07 (3 H, t, J = 7.4 Hz), 1.22 (3 H, t, J = 7.3 Hz), 1.65-1.80 (2 H, m), 2.93 (2 H, q, J = 7.3 Hz), 3.07—3.13 (2 H, m), 3.91 (3 H, s), 7.11 ( 1 H, d, J = 2.6 Hz), 7.20 (1 H, dd, J = 2.8 and 9.4 Hz), f. 50 (1 H, d, J = 8.6 Hz), 7.60 (1 H, d, J = 8.6 Hz), 8. 04 (1 H, d, J = 9.2 Hz).

Reference Example 33

 1-(1-propyl-6-methoxy methoxy naphthalene-2-^）)

 Using the ketone (15.9 g) obtained in Reference Example 32 and the method described in Reference Example 26, 1- (1-propyl-16-hydroxynaphthalene-1-yl) 1 1.75 g) was obtained. Using the naphthol (11 g) thus obtained, the desired product (3.1 g) was obtained by the method described in Reference Example 3.

¹ HNR (CDC I a) <5: ppm

 1.07 (3 H, t, J = 7.3 Hz), 1.23 (3 H, t, J = 7.3 Hz), 1.67-1.80 (2 H, m), 2.94 (2 H, q, J = 7.3 Hz), 3.07-3.13 (2 H, m), 3.52 (3 H, s), 5.31 (2 H, s), f. 28 (1 H, dd, J = 2.6 and 9.2 Hz), 7.38 (1 H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d, J = 8.6 Hz), 8.08 (1 H, d, J = 9.2 Hz).

Reference example 34

1-(1-Ethyl-6-Methoxyoxime Toxinaphthalene-1-yl)

 Using the ketone (28.1 g) obtained in Reference Example 29 and the method described in Reference Example 26, 1-1 (1-ethyl-6-hydroxynaphthalene-1-yl) ethane-one (19.4 g) ) was gotten. The desired product (1 g, 1 g) was obtained by the method described in Reference Example 27 using the naphthol (19.4 g) thus obtained.

 1 H-NMR (CDC I 3) δ: ppm

 1.35 (3 H, t, J = 7.4 Hz), 2.64 (3 H, s), 3.23 (2 H, q, J = 7.5 Hz), 3.53 (3H, s), 5.31 (2H, s), 7.29 (1H, dd, J = 2.6 and 9.2Hz), 7.39 (1H, d, J = 2.6 Hz), 7.58 (1 H, d, J = 8.6 Hz), 7.63 (1 H, d, J = 8.6 Hz), 8.13 (1 H , d, J = 9.2 Hz).

Reference Example 35

1-(1-ethyl-6-methoxy-2-methoxyphthalene 2-yl) propane 1-year-old

 Using the ketone (45. Og) obtained in Reference Example 30 and the method described in Reference Example 26, 1-1 (1-ethyl-6-hydroxynaphthalene-1-yl) propane-1-one (35. Og) ) was gotten. The desired product (40.5 g) was obtained by the method described in Reference Example 27 using the naphthol (35. Og) thus obtained.

¹ H-NMR (CDCI 3) δ: ppm 1.23 (3 H, t, J = 7.2 Hz), 1.36 (3 H, t, J = 6 Hz), 2.94 (2 H, q, J = 7.6 Hz), 3.15 (2H, q, J = 7.2Hz), 3.53 (3H, s), 5.31 (2H, s), 7.29 (1H, dd, J = 2.6 and 9.2 Hz), 7.39 (1 H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz) , F. 63 (1H, d, J = 8.6Hz), 8.11 (1H, d, J = 9.6Hz). Reference Example 36

 6-Methoxy 1- (3-phenylpropyl) naphthalene-1 2-carbaldehyde

 Using 6-Methoxy-1-tetralone (200 g) as the starting material, 3-butylpropylmagnesium bromide [magnesium (31 g), 3-phenylpropylpromide (225 g) was used instead of butyryl lithium. 7-Methoxy-4- (3-phenylpropyl) -11,2-dihydronaphthalene in a similar manner to that described in Reference Example 21 using {prepared in trahydrofuran (1.0 L)]. (1 89. Og) was obtained. Using the naphthalene (180.Og) obtained in this manner, 6-methoxy-11- (3-phenylpropyl) -13,4-dihydronaphthalene-12-carbaldehyde was obtained according to the method described in Reference Example 22. 126 g) was obtained. The desired product (94. Og) was obtained by the method described in Reference Example 23 using the aldehyde (126 g) thus obtained.

'H—NMR (CDC I ₃ ) <5: ppm

1.98-2.07 (2 H, m), 2.82 (2 H, t, J = 7.2 Hz), 3.43-3.49 (2 H, m), 3.92 ( 3 H, s), 7.1 1 (1 H, d, J = 2.3 Hz), 7.15 (1 H, dd, J = 2.6 and 9.2 Hz), 7.1 9-7.34 (5 H, m), 7.63 (1H, d, J = 8.6Hz), 7.87 (1H, d, J = 8.6Hz), 7.91 (1H, d, J = 9.2 Hz), 10.42 (1 H, s).

Reference Example 37

 1- [6-Methoxy-1- (3-phenylpropyl) naphthalene-2-yl] propane-J-one

 Using the aldehyde (94. Og) obtained in Reference Example 36 and the method described in Reference Example 16-1-1 [6-methoxy-11- (3-phenylpropyl) naphthalene-1-yl] propane One-one-ol (94. Og) was obtained. The desired product (33. Og) was obtained by the method described in Reference Example 11 using the alcohol (35. Og) thus obtained.

¹ HNR (CDC I ₃ ) δ: ppm

 1.21 (3H, t, J = 7.2Hz), 1.93-2.12 (2H, m), 2.82 (2H, t, J = 7.6Hz) , 2.93 (2 H, q, J = 7.2 Hz), 3.1 1 -3. 17 (2H, m), 3.92 (3 H, s), 7.09-7. 1 5 (2 H, m), 7.18-7.33 (5 H, m), 7.52 (1 H, d, J = 8.6 H 2), 7.60 (1 H, d , J = 8.6 Hz), 7.82 (1 H, d, J = 9.2 Hz).

Reference Example 38

1- [6-hydroxy-11- (3-phenylpropyl) naphthalene-2-yl] propane-11-one

 The desired product (19.5 g) was obtained by the method described in Reference Example 26 using the ketone (33. Og) obtained in Reference Example 37.

 1 H-N R (CDC I 3) δ ppm

 1.21 (3 H, t, J = 7.2 Hz), 1.97-2.09 (2 H, m), 2.80 (2 H, t, J = 7.6 Hz), 2.93 (2 H, q, J = 7.2 Hz), 3.10-3. 16 (2 H, m), 6.02 (1 H, br.s), 7.09 ( 1 H, dd, J = 2.6 and 8.6 Hz), 7.12 (1 H, d, J = 2.6 Hz), 7.15-7.31 (5 H, m ) 7.47 (1 H, d, J = 8.7 Hz), 7.52 (1 H, d, J = 87 Hz), 7.81 (1 H, d, J = 8. 9 Hz).

Reference example 39

 1- [6-Methoxymethoxy 1- (3-phenylpropyl) 1-naphthalene 1- 2-yl] propane 1-one

Nuff obtained in Reference Example 38! Chloromethyl methyl ether (11.6 mL) was added dropwise to a solution of ethanol (13.0 Og) and diisopropylethylamine (44 mL) in chloroform (13 OmL), and the mixture was heated under reflux for 1 hour. Saturated saline (1.0 L) was added, and the mixture was extracted with ether (300 mL × 2). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture was purified by silica gel column chromatography (ethyl hexanenoacetate 5: 1). The desired product (21.4 g) was obtained.

 1 H-NMR (CD C I 3) 5: ppm

 1.21 (3H, t, J = 7.2Hz), 2.81 (2H, t, J = 7.6Hz), 2.91 (2H, q, J = 7.2H) z), 3.1 0-3.16 (2 H, m), 3.51 (3 H, s), 5.29 (2 H, s), 7.16-7.33 (6 H , m), 7.36 (1 H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz), 7.61 (1 H, d, J = 8.6 Hz), 7.85 (1 H, d, J = 9.2 Hz).

Reference example 40

-[6-Methoxy methoxy 11- (3-methylbutyl) naphthalene 1-yl] Propane 1-one

Using 6-methoxy 1-petralone (200 _g ) as the starting material, 3-methylbutylmagnesium bromide [magnesium (27.4 g), 3-methylbutyl bromide (170.6 _g ) was used instead of lithium. 7-Methoxy-41- (3-methylbutyl) -11,2-dihydronaphthalene (prepared in the presence of hydrogen chloride in tetrahydrofuran (30 OmL)) in the same manner as described in Reference Example 21. 102. Og) was obtained. The naphthalene (102.Og) obtained in this manner was used to prepare 6-methoxy-11- (3-methylbutyl) -1,3,4-dihydronaphthalene-12-carbaldehyde (57 07g) was obtained. Using the aldehyde (57.Og) thus obtained, 6-methoxy-11- (3-methylbutyl) naphthalene-12-carbaldehyde (49.7 g) was obtained by the method described in Reference Example 23. Was done. ¹ one [6- menu Tokishi 1- (3-methylcarbamoyl In thus obtained aldehyde (49. Og) method described in Reference Example 1 6 using (L-butyl) naphthalene-1-yl] propane-1-ol (50.1 g) was obtained. Using the alcohol (50. Og) obtained in this way, the method described in Reference Example 11 was used to prepare 1-1 [6-methoxy-11- (3-methylbutyl) naphthalene-1-yl] propane-1. —On (45.5g) was obtained. Using the ketone (45. Og) thus obtained, 1- [6-hydroxy-111- (3-methylbutyl) naphthalene-12-yl] propane is obtained by the method described in Reference Example 26. ON (13.8 g) was obtained. The desired product (14.2 g) was obtained by the method described in Reference Example 39 using the naphthol (13.8 g) thus obtained.

'H—NMR (CDC I ₃ ) <5: ppm

 1.02 (6 H, d, J = 6.6 Hz), 1.23 (3 H, t, J = 7.2 Hz), 1.56-1.64 (2 H, m), 1.70-1.85 (1 H, m), 2.93 (2 H, t, J = 7.2 Hz), 3.08-3.15 (2 H, m), 3.52 (3H, s), 5.31 (2H, s), 7.29 (1H, dd, J = 2.6 and 9.2Hz), 7.38 (1H, d, J = 2.6 Hz), 7.49 (1 H, d, J = 8.4 Hz), 7.61 (1 H, d, J = 8.4 Hz), 8.07 (1 H, d, J = 9.2 Hz).

Reference Example 41

 1-one (6-Methoxy-methoxy-1-1-n-Dodecylnaphthalene-1-yl) Propane-1-1one

6-Methoxy-1-tetralone (200 g) was used as the starting material, and n-dodecylmagnesium bromide (magnesium (27.4 g), n-dodecyl bromide (283 g) was used instead of butyryl lithium to form tetrahydrofuran ( 650 mL) in the same manner as described in Reference Example 21. In a similar manner, 7-methoxy-4-n-dodecyl-11,2-dihydronaphthalene (106 g) was obtained. Using naphthalene (106 g) thus obtained, 6-methoxy-1-n-dodecyl-13,4-dihydronaphthalene-12-carbaldehyde (68.5 g) was obtained by the method described in Reference Example 22. was gotten. Using the aldehyde (68.5 g) thus obtained, 6-methoxy-111-n-dodecylnaphthalene-12-carbaldehyde (50.) was obtained by the method described in Reference Example 23. Using the aldehyde (50.7 g) obtained in this way, the method described in Reference Example 16 was followed by the method described in Reference Example 16 (6-Methoxy 1-n-dodecylnaphthalene-1-yl) propane-1-1 All (60.4 g) was obtained. Using the alcohol (60.4 g) obtained in this manner, 1- (6-methoxy-1-n-dodecylnaphthalene-1-yl) propane-1-11 was obtained by the method described in Reference Example 11-11. On (51.8 g) was obtained. Using the ketone (51.8 g) obtained in this way, according to the method described in Reference Example 26, 1- (6-hydroxy-1-n-dodecylnaphthalene-l-l-Tl) propane-l-one (17 6 g) was obtained. Using the naphthol (17.6 g) thus obtained, the target product (1.82 g) was obtained by the method described in Reference Example 39.

 1 H-NMR (CDC I 3) δ: ppm

 0.88 (3 H, d, J = 6.6 Hz), 1.23 (3 H, t, J = 7.3 Hz), 1.20-1.40 (16 H, m) , 1.43- 1.55 (2 H, m), 1.63- 1.69 (2 H, m), 2.94 (2 H, q, J = 7.3 Hz), 3.08 -3. 14 (1H, m), 3.53 (3H, s) '5.31 (2H, s), 7.28 (1H, dd, J = 2.6 and 9. 2 Hz), 7.38 (1 H, d, J = 2.6 Hz), 7.50 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d, J = 8.6 Hz), 8.07 (1 H, d, J = 9.2 Hz).

Reference Example 42 1- (6-Methoxyoxime 1-n-octylnaphthalene 2-yl) Propane 1-on

Using 6-methoxy 1-petralone (200 g) as a starting material, n-octylmagnesium bromide [magnesium (30.1 g), n-dodecyl bromide (239 g) was used instead of lithium. Prepared in tetrahydrofuran (400 mL)] in a similar manner to that described in Reference Example 21 to give 4-methoxy-4-n-octyl-1,2-dihydronaphthalene (94.7 g). was gotten. The thus obtained naphthalene (94.Og) was used to give 6-methoxy-11-n-octyl-3,4-dihydronaphthalene-12-carbaldehyde (68.2 g) according to the method described in Reference Example 22. ) was gotten. Using the aldehyde (68. Og) thus obtained, 6-methoxy-111-n-year-old tylnaphthalene-12-carbaldehyde (42.3 g) was obtained by the method described in Reference Example 23. . Using the aldehyde (42. Og) obtained in this way, the method described in Reference Example 16 was used to prepare 1- (6-methoxy-11-n-octylnaphthalene-12-yl) propane-1-1 (43.3 g) was obtained. Using the alcohol (43-Og) obtained in this way, the method described in Reference Example 11 was used to prepare 11- (6-methoxy-11-n-octylnaphthalene-12-yl) propane-11-one. (38.7g) Power << obtained. Lithium iodide (51.5 g) was added to a collidine (1 O OmL) solution of the ketone (35. Og) thus obtained, and the mixture was heated under reflux for 6 hours. After allowing to cool, 2N hydrochloric acid (1.0 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was collected and dried over magnesium sulfate to remove the solvent. The residue was purified by silica gel column chromatography (ethyl hexanoacetate 5: 1), and purified by elution with 1- (6-hydroxy-1-n-dodecylnaphthalene-1-yl) propane-1. (22. Og) was obtained. The desired product (23.5 g) was obtained by the method described in Reference Example 39 using the naphthol (22.Og) thus obtained.

¹ HNR (CDC I 3) δ ppm

 0.88 (3 H, d, J = 6.6 Hz), 1.23 (3 H, t, J = 7.2 Hz), 1.23-1.40 (8 H, m), 1.41-1.53 (2H, m), 1.61-1.74 (2H, m), 2.93 (2H, q, J = 7.2Hz), 3.08-3 . 14 (2 H, m), 3.52 (3 H, s), 5.31 (2 H, s), 7.28 (1 H, dd, J = 2.6 and 9.2 Hz ), 7.38 (1 H, d, J = 2.6 Hz), 7.49 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d, J = 8 6 Hz), 8.08 (1H, d, J = 9.2Hz).

Reference Example 43

 1- [1-(2-p-bromophenylethyl) -1-6-methoxy-2-methoxyphthalene-1-yl] propane-1-one

 A toluene (27 OmL) solution of the ketone (44.4 g), p-bromostyrene (33.3 g) and carbonyldihydridotristriphenylphosphine benzene (II) (9.9 g) obtained in Reference Example 3 Was refluxed for 4 hours. After allowing to cool, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / dichloromethane 9: 1) to obtain the desired product (10.39 g).

 1 H-NMR (CDC I 3) δ: ppm

1.19 (3 H, t, J = 7.3 Hz), 2.84 (2 H, q, J = 7. 3 H z), 2.92—3.0 1 (2 H, m), 3.38-3.47 (2 H, m), 3.54 (3 H, s), 5.29 (2 H , s), 7.15-7.22 (2 H, m), 7.33 (1 H, dd, J = 2.6 and 9.2 Hz), 7.38-7.45 (3 H, m), 7.57 (1 H, d, J = 8.7 Hz), 7.67 (1 H, d, J = 8.7 Hz), 8.13 (1 H, d , J = 9.2 Hz).

Reference example 44

 1- [1- (2-p-Hydroxyphenylethyl) -1-6-methoxime cinaphthalene-1-yl] propane-11-one

 At 70 ° C, add 1.69N n-butyllithium hexane solution (1 .26N) to a solution of diisopropylamine (4.25mL) in tetrahydrofuran (186mL).

7.9 mL) and stirred for 15 minutes to produce lithium diisopropylamide. A solution of the ketone (10.8 g) obtained in Reference Example 43 in tetrahydrofuran (90 mL) was added, and the mixture was stirred for 20 minutes. Further, a 1.69N n-butyl lithium hexane solution (37.4 mL) was added, and the mixture was stirred for 10 minutes. Trimethyl borate (60 mL) was added, and the mixture was stirred at room temperature for 40 minutes. Hydrochloric acid (1.5 mL) was added, and a 30% aqueous hydrogen peroxide solution was further added, followed by stirring for 1 hour. Saturated saline (600 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The obtained reaction mixture was purified by silica gel column chromatography (hexane Z: ethyl ethyl ester 9: 1) to obtain the desired product (4.27 g).

 1 H-N R (CDC I 3) <5: ppm

1.19 (3 H, t, J = 7.3 Hz), 2.84 (2 H, q, J = 7. 3 H z), 2.90-2.97 (2 H, m), 3.39—3.45 (2 H, m), 3.54 (3 H, s), 5.33 (2 H, m) s), 6.75—6.82 (2H, m), 7.10-7.18 (2H, m), 7.32 (1H, dd, J = 2.6 and 9 · 2 Hz), 7.41 (1 H, d, J = 2.6 Hz), 7.54 (1 H, d, J = 8.6 Hz), 7.66 (1 H, d, J = 8.6 Hz), 8.17 (1 H, d, J = 9.2 Hz).

Reference example 45

 1-[1-(2-p-benzyloxyphenylethyl) 1-6-methoxymethoxynaphthalene-1-2-yl] propane-1 -one

 Sodium hydride (0.35 g) in dimethylformamide at 0 ° C

(23 mL) was added with the phenol (4.17 g) obtained in Reference Example 44, and the mixture was stirred for 3 hours. To this was added benzyl bromide (2. OmL) and the mixture was stirred for 2 hours. Saturated saline (2 OmL) was added, and the mixture was extracted with ethyl acetate (20 mL × 4). The organic layer was collected, dried over magnesium sulfate, and the solvent was removed. The resulting reaction mixture was purified by silica gel column chromatography (hexane Z ethyl acid 10: 1) to obtain the desired product (4.11 g).

'' HNR (CDC I ₃ ) <5: ppm

1.18 (3 H, t, J = 7.3 Hz), 2.81 (2 H, q, J = 7.3 Hz), 2.90-2.99 (2 H, m) , 3.37-3.46 (2H, m), 3.53 (3H, s), 5.06 (2H, s), 5.32 (2H, s), 6.88-6 97 (2 H, m), f. 17—7.24 (2 H, m), 7.28-7.48 (7 H, m), 7.53 (1 H, d, J = 8 .6 Hz), 7.65 (1 H, d, J = 8.6 Hz), 8.16 (1 H, d , J = 9.2 Hz).

Reference Example 46

 1- (6-Methoxy methoxy 1- (2-phenylethyl) naphthalene

2-yl) 1 propane

 The target product was obtained by the method described in Reference Example 43 using styrene in place of ρ-promostyrene.

¹ H-NMR (CD CI 3) δ ppm

 1.18 (3H, t, J = 7.3Hz), 2.80 (2H, q, J = 7.4Hz), 2.97-3.06 (2H, m), 3 41 -3.50 (2 H, m), 3.53 (3 H, s), 5.32 (2 H, s), 718-7.3.35 (6 H, m), 7.41 (1H, d, J = 2.6Hz) 7.53 (1H, d, J = 8.6Hz), 7.65 (1H, d, J = 86H H), 8 . 1 8 (1 H, d, J = 9.6 H z).

Reference Example 47

_p

Dissolve sodium hydroxide (22 g) in water (100 mL), add paraacetoxystyrene (38 mL), and stir. Benzyl bromide (35 mL) was added thereto, and the mixture was stirred at 60 ° C for 1 hour. After cooling, the mixture was extracted with dichloromethane (1 OOmL X 3) and dried over anhydrous sodium sulfate. After concentration, the residue was extracted with hexane (1 OOmL × 3), concentrated, and then purified by silica gel column chromatography (hexane) to obtain the desired product (10.2 g). H-NMR (CDC I a) δ: ppm

5.05 (2 H, s), 5.12 (1 H, dd, J = 1.0 and 10.9 Hz), 5.60 (1 H, dd, J = 1.0 and 1 7.5 Hz), 6.65 (1 H, dd, J = 10.9 and 17.8 Hz), 6.88-6.95 (2 H, m), 7.27-7 . 44 (7 H, m).

Reference Example 48 (Refer to Reference Example 45)

 1- [1-(2-p-benzyloxyphenylethyl) -1-6-methoxy-methoxy-naphthalene-2-yl] propane-1-one

 Using the ketone (10. Og) obtained in Reference Example 3 and the styrene obtained in Reference Example 47 in place of p-bromostyrene, the target compound (16. 44g).

Reference 49

 6-benzyloxy 1-phenylnaphthalene 1- 2-carbaldehyde

6-Benzyloxy-1-peralone (447.1 g) was obtained by using the petrolone (324 _g ) obtained in Reference Example 12 by the method described in Reference Example 45. Using the thus obtained ethanol (33.8 g), phenyllithium was used in place of butyllithium, and 7-benzyloxy41-vinyl was obtained in the same manner as described in Reference Example 21. The phenyl-1,2-dihydronaphthalene (20.4 g) was obtained. The naphthalene obtained in this way ( Using 20.4 g), 6-benzyloxy-11-phenyl-2,4-dihydronaphthalene-12-carbaldehyde (17.4 g) was obtained by the method described in Reference Example 22. The desired product (42.3 g) was obtained by the method described in Reference Example 23 using the aldehyde (1 F. Og) thus obtained.

 1 H-N R (CD C I 3) δ: ppm

 5.22 (2 H, s), 7.17 (1 H, dd, J = 2.5 and 9.4 Hz), 7.30 (1 H, d, J = 2.6 Hz) , 7.33-7.54 (10H, m), 7.56 (1H, d, J = 9.2Hz), 7.79 (1H, d, J = 8.7H z), 8.03 (1 H, d, J = 8.6 H z), 9.82

(1 H, s).

Reference example 50

1-bromo-14-methoxy methoxybenzene

 Using p-bromophenol (31.2 g), the crude product obtained by the method described in Reference Example 39 was distilled to obtain the desired product (36.43 g, boiling point: 170 ° CZ17 mmHg).

 'H-NMR (CD C I 3) 6: ppm

 3.45 (3 H, s), 5.12 (2 H, s,), 6.88-6.95 (2 H, m), 7.33-7.40 (2 H, m) .

Reference example 5 1

6-Methoxy 11-p-Methoxy methoxyl 1-2 L-naphthalene 1-2-carbaldehyde

 6-Methoxy-1-tetralone (25. Og) was used, and instead of butyllithium, P-methoxymethoxylithium lithium [bromide (38.3 g) obtained in Reference Example 50 and 1.63N) were used. Prepared from n-butyllithium hexane solution (109 mL) in ether (17 OmL) at 178 ° C] using the same method as described in Reference Example 21. There was obtained 1,4-dimethoxy-1,4-dihydronaphthalene (25.38 g). Using the naphthalene (10. Og) obtained in this way, the method described in Reference Example 22 was used to prepare 11-p-hydroxyphenyl; enyl-16-methoxy-3,4-dihydronaphthalene-12-carbaldehyde. (17.4 g) was obtained. Using the aldehyde (8.44 g) thus obtained, 6-methoxy-1—p-methoxymethoxy 3,4—dihydrophenylnaphthalene-1-2-carbaldehyde (6 .71 g) was obtained. The desired product (2.78 g) was obtained by the method described in Reference Example 23 using the aldehyde (3. Og) thus obtained.

'H—NMR (CDC I ₃ ) <5: ppm

 3.56 (3 H, s), 3.95 (3 H, s), 5.28 (2 H, s), 7.09 (1 H, dd, J = 2.6 and 9.2 H z), 7.16-7.23 (3 H, m), 7.28-h. 34 (2 H, m), h. 6 1 (1 H, d, J = 9.2 Hz) , 7.79 (1H, d, J = 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 9.86 (1H, s).

Reference example 5 2

1-hydroxy-6-methoxynaphthalene-1 2-carbaldehyde

 Sodium methoxide (11.6 g) was suspended in a toluene (25 OmL) solution of 6-methoxy-11-tetralone (34.8 g). Under ice cooling, a solution of ethyl formate (36.5 g) in toluene (25 OmL) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The mixture was extracted with water (100 mL x 2) and 1 N sodium hydroxide solution (1 OO mL x 2), the aqueous layer was adjusted to pH 3 to 4 with concentrated hydrochloric acid (about 25 mL), and the precipitated solid was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was removed under reduced pressure to give 2-hydroxymethylene-16-methoxy-3,4-dihydro-12H-naphthalen-11-one (32.89 g). The desired product (22.67 g) was obtained by the method described in Reference Example 23 using the ketone (32.89 g) thus obtained.

 1 H-NMR (CDC I 3) δ: ppm

 3.94 (3 H, s), 7.06 (1 H, d, J = 2.3 Hz), 7.16 (1 H, dd, J = 2.5 and 9.1 Hz) , 7.24 (1H, d, J = 8.6Hz), f. 43 (1H, d, J = 8.6Hz), 8.33 (1H, d, J = 9. 2 Hz), 9.88 (1 H, s), 12.68 (1 H, s).

Reference Example 53

 1-one (6-Methoxy 1-Methoxy-Toxinaphthalene 2-Pel)

The aldehyde obtained in Reference Example 52 (9.92 g) was used and the method described in Reference Example 39 was used to give 6-methoxy-1-methoxymethoxynaphthalene 1-2-cal. Valdehyde (12.18 g) was obtained. Using the aldehyde (12.13 g) obtained in this way, the method described in Reference Example 16 was used to prepare 11- (6-methoxy-11-methoxyethoxynaphthalene-1-yl) propane. One-one (1.94 g) was obtained. The desired product (11.18 g) was obtained by the method described in Reference Example 11 using the alcohol (12.94 g) thus obtained.

 '' H-NMR (CD C I 3) δ ppm

 1.22 (3H, t, J = 7.3Hz), 3.09 (2H, q, J = 7.4Hz), 3.55 (3H, s), 3.94 (3 H, s), 5.15 (2 H, s), 7.12 (1 H, d, J = 2.6 Hz), 7.2 1 (1 H, dd, J = 2 6 and 9.2 Hz), 7.52 (1 H, d, J = 8.6 Hz), 7.6 1 (1 H, d, J = 8.6 Hz), 8.1 7 (1H, d, J = 9.2Hz).

Reference example 54

Trifluoromethanesulfonic acid 2-dimethoxymethyl-6-methoxynaphthalene-1-yl

At 0 ° C, trifluoromethanesulfonic anhydride (8.8 mL) was added to a solution of the aldehyde (10.1 g) obtained in Reference Example 52 and dimethylaminopyridine (20.2 g) in dichloromethane (50 OmL) at 0 ° C. 3. Stirred for 5 hours. The organic layer was washed with 1N hydrochloric acid (200 mL × 2) and saturated saline (20 OmL) and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain 2-formyl-16-methoxynaphthalene-11-yl 2-fluoromethanesulfonate (15.1 g). The sulfonic acid ester (10.0 _g ) thus obtained was Pyridinium p-toluenesulfonate (0.23 g) was added to a methanol (60 mL) solution, and the mixture was stirred under reflux with heating for 6 hours. After cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain the desired product (10.93 g).

1 H-NMR (CDC I ₃ ) 5: ppm

 3.42 (6 H, s), 3.93 (3 H, s), 5.74 (1 H, s), 7.16 (1 H, d, J = 2.3 Hz), 7 28 (1 H, dd, J = 2.5 and 9.4 Hz), 7.71 (1 H, d, J = 8.6 Hz), 7.78 (1 H, d, J = 8.6 Hz), 8.02 (1 H, d, J = 9.2 Hz) Reference Example 55

2-dimethoxymethyl-6-methoxynaphthalene 1-methyl percarboxylate

 The sulfonate obtained in Reference Example 54 (1.14 g), palladium acetate (0.04 g), diphenylphosphinopropane (0.74 g), triethylamine (0.83 mL), methanol (3. OmL) in dimethylformamide (6 mL) was stirred at 60 ° C for 4.5 hours in a carbon monoxide atmosphere. Saturated saline (1 O OmL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with 1N hydrochloric acid (30 mL × 2) and saturated saline (30 mL × 2), and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate 4: 1) to obtain the desired product (0.61 g).

 1 H-NMR (CD C I 3) δ ppm

3.33 (6 H, s), 3.84 (3 H, s), 3.99 (3 H, s), 5.70 (1H, s), 7.09 (1H, d, J = 2.6Hz), 7.18 (1H, dd, J = 2.6 and 9.2Hz) , 7.66 (1H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz).

Reference Example 56

 (2-Dimethoxymethyl-6-methoxynaphthalene-111) 1-p-Methoxymethoxyphenylmethanone

 At -78 ° C, 1.63N n-butyllithium hexane solution (1.23 mL) was added to a solution of the bromide (0.43 g) obtained in Reference Example 50 in petrohydrofuran (2. OmL). Stirred for 60 minutes. To this was added a solution of the ester (0.58 g) obtained in Reference Example 55 in tetrahydrofuran (2. OmL), and the mixture was stirred for 1 hour. Saturated saline (1 OmL) was added, extracted with ethyl acetate (10 mL × 3), and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl hexanoacetate 20: 1-4: 1) to obtain the desired product (0.34 g).

 1 H-NMR (CDC I a) <5: ppm

 3.16 (3H, br.), 3.26 (3H, br.), 3.46 (3H, s), 3.90 (3H, s), 5.20 (2H, br.) s), 5.38 (1H, s), 6.98-7.07 (3H, m), 7.17 (1H, d, J = 2.6Hz), 7.47 ( 1 H, d, J = 8.9 Hz), 7.71 (1 H, d, J = 8.5 Hz), 7.75 (2 H, br .d, J = 8.1 Hz) , 7.84 (1H, d, J = 8.5H2).

Reference Example 57

6-Methoxy 1 1-p-N-methoxy methoxybenzoyl naphthalene 2- Rubaldehyde

 To a solution of the acetal (0.83 g) obtained in Reference Example 56 in methanol-methylene chloride (6: 1, 7 mL) was added water (0.5 mL), and the mixture was stirred for 1 hour and then at 60 ° C for 1 hour. The mixture was allowed to cool and then strained to obtain the desired product (0.71 g).

 '' H-NR (CDC I 3) δ: ppm

 3.44 (3 H, s), 3.92 (3 H, s), 5.19 (2 H, s), 6.89-7.08 (2 H, m), 7.11 ( 1 H, d, J = 2.6 and 9.2 Hz), 7.20 (1 H, d, J = 2.6 Hz), 7.61 (1 H, d, J = 9.2 Hz), 7.71 -7. 81 (2 H, m) 7.88 (1 H, d, J = 8.6 Hz), 7.97 (1 H, d, J = 86 H ζ ), 10.00 (1 H, s).

Reference Example 58

 1-(6-Methoxy 3- 3-Methoxy methoxymethyl naphthalene 2-yl) Propane

Using 3-hydroxy-7-methoxy-2-naphthoic acid (21.8 g), the crude product obtained by the method described in Reference Example 39 was subjected to silica gel column chromatography (hexane ethyl acetate 50: 1-10). : 1) to give 3-hydroxy-7-methoxy-2-methoxymethyl naphthoate (6.92 g). Using the thus obtained ester (5.24 g) for reference According to the method described in Example 54, 7-methoxy-13-trifluoromethanesulfonyloxynaphthalene-12-methylcarboxylate (8.0 Og) was obtained. The ester (8.0 Og) thus obtained was reduced with diisobutylaluminum hydride to give 3-hydroxymethyl sulfonic acid 3-hydroxymethyl 16-methoxynaphthalene-12-yl (4.90 g). Subsequently, according to the method described in Reference Example 39, trifluoromethanesulfonic acid 6-methoxy-13-methoxymethoxymethylnaphthalene-12-yl (5.27 g) was obtained. Using the sulfonic acid ester (3.80 g) thus obtained, the method described in Reference Example 55 was used to prepare 6-methoxy-3-methoxyethoxymethylnaphthalene-12-methyl carboxylate (2.7 8g) and 2.63 g of this was reduced with diisobutylaluminum hydride to give 6-methoxy-13-methoxymethoxymethylnaphthalene-12-ylmethanol (2.47 g). The alcohol (2.46 g) thus obtained was oxidized with pyridinium chromate to give 6-methoxy-3-methoxyethoxymethylnaphthalene-12-carbaldehyde (2.23 g), of which 2.1. 11- (6-Methoxy-13-methoxymethoxymethylnaphthalene-12-yl) propan-1-ol (2.49 g) was obtained in the same manner as in Reference Example 16 using 7 g. The desired product (2.42 g) was obtained by the method described in Reference Example 11 using this alcohol (2.56 g).

1 H-NMR (CDCI ₃ ) <5: ppm

1.24 (3 H, t, J = 7.3 Hz), 3.07 (2 H, q, J = 7.3 Hz), 3.44 (3 H, s), 3.93 ( 3H, s), 4.79 (2H, s), 5.05 (2H, d, J = 1.0Hz), 7.12-7.21 (2H, m) , 78 (1H, d, J = 8.6Hz), 7.95 (1H, s), 8.20 (1H, s) Activity of compounds of the invention on hormone receptors

The method was based on the method of J. Borgna (丄 -L. Borgna). In a test tube cooled with ice, add 20 L of 17-estradiol (manufactured by Sigma) or an appropriate concentration of each test compound as a standard dissolved in ethanol for hormone determination (manufactured by Nacalai Tesque). Followed by dissolving the hormones quantitative ethanol to each tube ^{[2, 4, 6,7 - 3} H] - estradiol (Amersham Corp.) 20 / iL placed (about 10000dpm), was prepared from more © uterus estrogen Receptor (protein concentration 5. Omg / ml P50 buffer: 50 mM sodium phosphate, pH 7.0, 10% glycerol, 0.012 M monothioglycerol), add 200 μl, and stir, then 4 hours at 4 ° C Incubated with C. Then, add 250 µΐ of DCC solution (1% Norit A, 0.1% dextran (Dextran) T70, P50 buffer pH 7.0), which was stirred to homogenize 4 ° (overnight). After incubating for 4 minutes at 4 ° C, add 500 μΐ of P50 buffer at 4 ° C, centrifuge at 1900xg for 20 minutes at 4 ° C, take 500 μΐ of the supernatant, and remove 5 ml of ACS-II (Amersham). And the radioactivity was measured with a liquid scintillation counter to determine the binding ability of the test compound to the estrogen receptor.

Calculated with ₅₀ values. Table 1 shows the results.

 [Table 1] Estrogen receptor binding ability

Test compound IC _5. (nM)

17 / 3—Estradiol 1.1

 Example 3 1 500

 Example 31 1.2

 Example 45 85

 Example 52 5.9

 Example 56 2.5

Example 59 3.5 Example 6 6 0.6

 Example 9 2 2 3

 Example 9 777.1 The compound of the present invention was found to have remarkably strong estrogen receptor binding ability and an affinity comparable to Ίβ-estradiol.

Test example 2

Activity of compounds of the present invention on uterine weight recovery in ovariectomized rats

 Six-week-old female Wistar rats were preliminarily reared for one week and then used for experiments. Animals were housed in plastic cages in a breeding room at room temperature of 23.0 ± 2 ° C and humidity of 55 ± 10%, and were fed with normal feed (CE-2, CLEA Japan) and tap water freely.

 Under ether anesthesia, both ovaries including the oviduct were removed from the back, and one week later, the animals were divided into groups of 5 animals per body weight, and administration of the drug was started. The 17-day radiogram was administered subcutaneously at 0.05 mg / Kg as a sustained-release pellet. Each test compound was dissolved in a small amount of ethanol, then diluted in ethanol Z medium-chain triglyceride (5/95, V / V), and orally administered at a dose of 1.0 mg / Kg.

 One day after the final administration, the animals were necropsied and the wet weight of the excised uteri was measured. The bone mineral density of the removed proximal tibia was measured by dual energy X-ray absorption method (Dual Energy X-ray Absorptometry, DSC-600, Aroca). At the same time, the untreated group (control group) from which the ovaries were removed and the untreated non-treated group (sham operation group) were also necropsied, and the wet weight of the uterus and bone mineral density in the proximal tibia were measured.

 The average of the measured values of rats from each group was determined, and the uterine weight recovery rate and bone mineral density recovery rate were calculated by the following equations.

Recovery rate (%) = (mean value of drug group-mean value of control group) (mean value of sham operation group-mean value of control group) x 100 Table 2 shows the results.

 [Table 2] Ovariectomized rat recovery rate

 Test group Uterine weight recovery rate (%) Bone mineral density recovery rate (%) Sham operation group 1 0 0 1 0 0 Control 0 0

 17 / S-Estradiol 1 2 6 1 3 8

 Example 3 8 9 6 2

 Example 3 1 9 4 1 7 5

 Example 4 5 1 0 4 1 5 4

 Example 9 2 1 0 4 2 0 5

, 7 / 3—estradiol showed nearly equal recovery on uterine weight and bone mineral density, whereas compounds of the present invention were 1.5- to 2-fold more selective on bone mineral density. However, it was found that the recovery rate was higher.

Test example 3

Activity of compounds of the invention on uterine weight in mice

Three-week-old BALB / G female mice were preliminarily reared for one week and used for experiments. The animals were housed in plastic cages in a breeding room at room temperature of 23.0 ± 2 ° C and humidity of 55 ± 10%, and were fed with normal feed (CE-2, manufactured by CLEA Japan) and tap water freely. . Each test compound and 178-estradiol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved in a small amount of ethanol, and then triglycerides (5/95, V / V) and subcutaneously administered once a day for 3 days. The control group received only the vehicle. One day after the last administration, the animals were necropsied, the uterus was removed, and the wet weight was measured. Uterine weight was corrected for body weight, determined as a value per 10 g of body weight, and the inhibition rate of the test compound against estradiol was determined by the following formula. Inhibition rate = 100-(uterine weight of group administered with estradiol and test compound j uterine weight of one vehicle group) / (uterine weight of estradiol administered group-uterus weight of vehicle group) X 100

 Table 3 shows the results.

 [Table 3] Effect on mouse uterus weight

 Test group Dose inhibition rate

 (/ g / animal) (%)

17 / 8—Estradiol 0.1 0.00

17 One esterdiol + Example 59 0.1 + 100 29.24

 0.1 + 1000 40.10

17 / 3—Estradiol 0.5 0.00

17 / 5—Estradiol + Example 9 0.5 + 15 26.35

0.5 + 150 82.89 The compounds of Examples 59 and 97 of the present invention strongly inhibited estradiol-induced increase in uterine weight and were found to have antiestrogenic activity.

1. General formula (I)

 [In the formula, R ° represents a water atom and sua blue represents a hydroxyl-protecting group.

 R 'represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a protected hydroxyl group.

R ² is a hydrogen atom or a formula (CH ₂ ) _k— X—R ³ (where k is 0 or an integer of “! To 10; X is a single bond, one O—, one S—, One SO—, -S

 Enclosure

0 ₂ one, single CO- or formula one CON R ⁴ - (wherein, R ⁴ represents a hydrogen atom or an alkyl group having a carbon number of 1-6) represents, R ³ may have a substituent An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or an aryl group which may have a substituent Represents).

The solid line with the broken line represents a single bond or a double bond, when between R ² and R ¹ ° of the bonded carbon one-carbon is a double bond R ¹ ° is absent.

 A and E are

(1) A- when between E is a single bond, A is a methylene group, an oxygen atom or a single bond, E is wherein one GR ⁷ - (In the formula, G represents a methine group or a nitrogen atom, R ⁷ Represents the same meaning as R ² described above), a formula of CR ⁸ R ⁹ — (wherein R ⁸ and R ⁹ represent an alkyl group having 1 to 6 carbon atoms which may be the same or different) or Where A is a single bond and R ² is not a hydrogen atom, E may represent an oxygen atom or a sulfur atom,

(2) A- when between E is a double bond, A represents a methine group, E is the formula = CR ⁷ - (wherein, R ⁷ has the same meaning represents the above) represents a or a nitrogen atom. R ′ °, R ¹ ′ and R ′ ² each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms, provided that R ″ and R ¹² are simultaneously It does not become a hydrogen atom.

 Z represents a carboxyl group, a carbamoyl group, a hydroxyaminocarbonyl group, a hydroxymethyl group or a protected functional group thereof. However,

(E) -3- (6-Methoxynaphthalene-1-yl) -1-methyl-2-hexenoic acid and its carboxyl-protected derivatives are excluded. Or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R ² and R ⁷ are not simultaneously a hydrogen atom, or a geometric isomer with respect to a double bond, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein A-E is a single bond and A is a methylene group or an oxygen atom, or A-E is a double bond and A is a methine group and R ° is a hydrogen atom. The compound or its geometric isomer with respect to the double bond, or a pharmaceutically acceptable salt thereof.

4. General formula (la

 1 0 „1 1 — 1 2

Wherein R ′, R ² , R ′, R 1, R 2, R and Z have the same meanings as in claim 1), or a geometric isomer thereof relating to a double bond, Or their pharmaceutically acceptable salts. 5. The compound according to any one of claims 2 to 4, or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof, wherein Z is a carboxyl group or an alkoxycarbonyl group having 2 to 7 carbon atoms.

6-General formula (l

Wherein R ² , R ⁷ , R ′ ¹ and R ′ ² have the same meaning as in claim ^1, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Item 6. The compound according to any one of Items 2 to 5, or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof. F. X is a single bond, one O— or one CO—, and R ³ is an alkyl group having 1! To 10 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, and a cycloalkyl group having 3 to 7 carbon atoms. Or expression

 (Where m is 0 or 1, n is an integer of 1 to 10, Y is a carboxyl group

, An alkoxycarbonyl group having 2 to 7 carbon atoms or formula NR ⁵ R ° (wherein,

R ⁵ and R ° represent an alkyl group having 1 to 6 carbon atoms which may be the same or different, but R ⁵ and R ⁶ together with the nitrogen atom to which they are attached have a 5- to 6-membered The compound according to any one of claims 2 to 6, or a isomer thereof with respect to a double bond, or a pharmaceutically acceptable salt thereof. 8. Y is a group represented by the formula: NR ^5a R ^6a (wherein, R ^5a and R ^6a represent an alkyl group having 1 to 6 carbon atoms which may be the same or different), a pyrrolidino group, a piberidino group or a morpholino group A compound according to claim 7, or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof.

9. General formula (Ic)

[Where R ', 3. The compound according to claim 2, represented by the formula: or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, wherein E is a group represented by the formula: NR ⁷ — (wherein, R ⁷ has the same meaning as in claim 1), or its isomer with respect to a double bond, Or their pharmaceutically acceptable salts.

1 1. E is —O— or 1 S—, and R ² is a group represented by the formula (CH ₂ ) _k -X-R ³ (where k, X, and R ³ have the same meanings as in claim 1) 10. The compound according to claim 9, which is a group represented by the formula: or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof.

12. A medicament comprising the compound according to claim 1 or a geometric isomer thereof relating to a double bond, or a pharmaceutically acceptable salt thereof.

13. The medicament according to claim 12, which is a therapeutic agent for a disease caused by estrogen deficiency. 14. The medicament c according to claim 12, which is a therapeutic agent for estrogen-dependent diseases.

5. The medicament _{c according to} claim 12, which is a therapeutic agent for postmenopausal osteoporosis.