JP2002193880A - Bicyclooctane derivative - Google Patents

Abstract

(57) Abstract: A bicyclooctane derivative represented by the general formula (I) or a non-toxic salt thereof (the symbols in the formula are as described in the specification). Embedded image [Effect] Since the compound represented by the general formula (I) has PDE4 inhibitory activity, inflammatory diseases, diabetic diseases, allergic diseases, autoimmune diseases, osteoporosis, obesity,
It is useful for the prevention and / or treatment of antidepressant, Parkinson's disease, ischemia-reperfusion injury, leukemia and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a bicyclooctane derivative. More specifically, the present invention relates to (1) a compound represented by the general formula (I):

Embedded image (Wherein all symbols have the same meaning as described below), or a nontoxic salt thereof, (2) a method for producing them, and (3) a drug containing them as an active ingredient. About.

[0002]

BACKGROUND OF THE INVENTION Cyclic adenosine-3 ', 5'-, an intracellular signal messenger (second messenger)
Monophosphate (c-AMP) and cyclic guanosine-
3 ′, 5′-Monophosphate (c-GMP) is decomposed into inactive 5′-AMP and 5′-GMP by a group of hydrolases called phosphodiesterase (PDE).

[0003] The PDE isozymes that inactivate them do not exist uniformly in the living body, but show differences in cell distribution, tissue distribution, and the like, and exist in the living body with localization peculiar to organs. To date, the existence of 11 families of PDE1 to PDE11 has been confirmed (Curren
t opinion in Cell Biology., 12 , 174-179 (2000)).

[0004] Among these PDEs, PDE4 is derived from airway smooth muscle, epithelial cells, inflammatory cells (macrophages, neutrophils,
It is present in various cells including eosinophils) and T-lymphocytes, and regulates intracellular c-AMP levels of these cells to control cell functions. Meanwhile, PD
E5 is present in platelets, myocardium, vascular smooth muscle, and the like, regulates intracellular c-GMP levels, and is involved in controlling the circulatory system.

[0005] Therefore, PDE4 inhibitors suppress intracellular c-AMP by inhibiting the degradation of c-AMP by PDE4.
-It is known that it has a bronchodilator action, an anti-inflammatory action, a mediator release inhibitory action, an immunosuppressive action, etc., because it causes accumulation of AMP.

[0006] Therefore, a drug that specifically inhibits PDE4 does not show the effect of PDE5 on the circulatory system, and various diseases such as inflammatory diseases (asthma, obstructive pulmonary disease, sepsis, nephritis, hepatitis, etc.). , Diabetic diseases, allergic diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, etc.),
Osteoporosis, obesity, antidepressant, Parkinson's disease, ischemia-reperfusion injury, leukemia (Exp. Opin. Invest. Drugs.,
8 , 1301-1325 (1999)) and the like.

[0007]

BACKGROUND ART As PDE4 inhibitors, for example, WO93 / 1
No. 9749, the general formula (A)

Embedded image(Where R^1AIs-(CR^4AR^5A)_rAR^6AAnd r
A represents 1 to 6; ^4AAnd R^5AAre independent
Represents a hydrogen atom or a C1-2 alkyl group;^6A
Represents a hydrogen atom, a C3-6 cycloalkyl group or the like;
^AIs Y^AR^2AAnd Y^ARepresents O or the like;^2AHame
X represents chill, ethyl, etc.^2ARepresents O, etc., and X^3AIs
X represents a hydrogen atom, etc.^4AIs

Embedded image R ^3A represents a hydrogen atom, CN, etc., X ^5A represents a hydrogen atom, etc., sA represents 0-4, and Z ^A represents C
(O) OR ^14A , C (Y ′ ^A ) NR ^10A R ^14A, etc.
R ^10A represents a hydrogen atom, OR ^{8A and the} like, R ^8A represents a hydrogen atom and the like, and R ^14A represents a hydrogen atom and the like. ) Or a pharmaceutically acceptable salt thereof has PDE4 inhibitory activity (necessary portions of the group were extracted).

[0008]

OBJECTS OF THE INVENTION The present inventors have conducted intensive studies to find a compound having PDE4 inhibitory activity. As a result, they have found that the bicyclooctane derivative represented by the general formula (I) achieves the object, and completed.

[0009]

DISCLOSURE OF THE INVENTION The present invention relates to (1) a compound represented by the general formula (I):

Embedded image (Wherein R ¹ is 1) hydroxyl group, 2) C1-8 alkoxy group, 3) —NR ⁵ OR ⁶ group, 4) —NR ⁷ R ⁸ group, 5) —NR ⁹ NR ¹⁰ R ¹¹ group, 6) —NR ¹² SO ₂ R ¹³ group, or 7) —NR ¹⁴ NR ¹⁵ SO ₂ R ¹⁶ group, wherein R ⁵ and R
⁶ each independently represent a hydrogen atom or a C1-8 alkyl group,, R ⁷ and R ⁸ each independently represent a hydrogen atom, C1-8 alkyl group, or a heterocyclic -1,, R ^9, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or a C1~8 alkyl group,, R ¹² represents a hydrogen atom or a C1~8 alkyl group,, R ¹³ is C1
8 alkyl group, a carbocyclic -1 or heterocyclic -2,, R ¹⁴ and R ¹⁵ are each independently a hydrogen atom,
Or a C1-8 alkyl group; R ¹⁶ represents a C1-8 alkyl group or carbocycle-2;

R ² represents 1) a hydrogen atom or 2) a cyano group, and R ³ and R ⁴ each independently represent: 1) a C1-8 alkyl group, 2) a C3-7 cycloalkyl group, 3) carbon Ring-3, 4) heterocycle-4, 5) C1-8 alkyl group substituted with 1 to 3 halogen atoms, 6) hydroxyl group, C1-8 alkyl group, or C1-8 alkylthio group substituted A C1-8 alkyl group, 7) a C1-8 alkyl group substituted with a C3-7 cycloalkyl group, 8) a C1-8 alkyl group substituted with a carbocycle-4, or 9) a heterocycle-4 substituted Represents a C1-8 alkyl group,

Embedded image Represents 1) a single bond or 2) a double bond,

Carbocycle-1, carbocycle-2, carbocycle-3 and carbocycle-4 are each independently a monocyclic, bicyclic or tricyclic carbocyclic aryl which may be partially saturated. Represent,
Heterocycle-1, heterocycle-2, heterocycle-3 and heterocycle-4 are each independently a monocyclic ring containing from 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, A bicyclic or tricyclic heterocyclic aryl, which may be wholly or partially saturated, and represents carbocycle-1, carbocycle-2, carbocycle-3, carbocycle-4, heterocycle-1, heterocycle -2, heterocycle-3 and heterocycle-4 may be substituted by 1 to 3 C1-8 alkyl groups, C1-8 alkoxy groups, or halogen atoms. ) Or a non-toxic salt thereof,

The present invention relates to (2) a method for producing them, and (3) a drug containing them as an active ingredient.

In the general formula (I), the C1-8 alkyl group means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof. In the general formula (I), the C1-8 alkoxy group is a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.

In the present invention, the halogen atom is chlorine,
It means bromine, fluorine and iodine atoms. General formula (I)
In the formula, the C1-8 alkylthio group means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio and isomers thereof. In the general formula (I), the C3-7 cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group.

In the general formula (I), carbocycle-1, carbocycle-
The monocyclic, bicyclic or tricyclic, partially saturated carbocyclic aryl represented by 2, carbocycle-3 and carbocycle-4 is, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, Examples include cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, indene, naphthalene, indane, tetrahydronaphthalene, fluorene, anthracene, 9,10-dihydroanthracene, and acenaphthene.

In formula (I), 1-4 selected from nitrogen, oxygen and sulfur represented by heterocycle-1, heterocycle-2, heterocycle-3 and heterocycle-4
Monocyclic, bicyclic or tricyclic, all or partially saturated heterocyclic aryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur
Monocyclic, bicyclic or tricyclic heterocyclic aryl containing two heteroatoms, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran , Oxepin, thiophene,
Thiain (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine,
Oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine,
Indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,
Indazole, quinoline, isoquinoline, phthalazine,
Naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzoxepin, benzoxazepine,
Benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, acridine,
Examples include dibenzofuran, dibenzothiophene, and phenothiazine rings.

In formula (I), 1 to 4 selected from nitrogen, oxygen and sulfur represented by heterocycle-1, heterocycle-2, heterocycle-3 and heterocycle-4
Monocyclic, bicyclic or tricyclic, all or partially saturated heterocyclic aryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur
Monocyclic, bicyclic or tricyclic, fully or partially saturated heterocyclic aryl containing, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetrazoline , Tetrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodi Azepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydro Orchids, dihydrothiophene, tetrahydrothiophene, dihydro-thia-in (dihydro thiopyran), tetrahydropyran-thia-in (tetrahydrothiopyran), dihydrooxazole, tetrahydro-oxazole (oxazolidine), dihydroisoxazole,
Tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrothiadiazole, tetrahydrothiadiazole ( Thiadiazolidine), tetrahydrooxadiazine, tetrahydrothiadiazine, tetrahydrooxazepine, tetrahydrooxadiazepine,
Perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydro Isobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline , Perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine Dihydro naphthyridine, tetrahydronaphthyridine, perhydro naphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, par tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, par hydroxy mysterious phosphorus, dihydro cinnolines,
Tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydro Acridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolan, dioxane, dithiolane, dithiane, benzodioxalane, benzodioxane, benzodithiolane, benzodithiane ring And the like.

In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Further, isomers (E, Z, cis, trans) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , An optically active substance having optical activity (D, L, d, l-form), polar forms (high-polarity forms, low-polarity forms) by chromatographic separation, equilibrium compounds, mixtures of any ratio thereof, and racemic mixtures All are included in the present invention.

In the present invention, unless otherwise specified,
Symbol as obvious to the person skilled in the art

Embedded image Indicates that it is connected to the other side of the paper (ie, α-configuration),

Embedded image Indicates that it is connected to the near side of the paper (that is, β-configuration),

Embedded image Represents α-, β- or a mixture thereof.

The compound represented by the formula (I) can be converted into a non-toxic salt by a known method. In the present specification, the non-toxic salt includes an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amine salt, an acid addition salt and the like.

The salt is preferably a non-toxic, water-soluble salt. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine and the like.

The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoate Organic acid salts such as acid, citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.

The compound of the present invention and a salt thereof can be converted into a solvate. Preferably, the solvate is non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water, alcoholic solvents (eg, ethanol, etc.).

In the general formula (I), R ¹ is preferably
A hydroxyl group or a —NR ⁵ OR ⁶ group, particularly preferably
It is a hydroxyl group or a -NHOH group. In the general formula (I), R
Preferred as ² is a hydrogen atom or a cyano group,
Particularly preferred is a cyano group.

In the general formula (I), R ³ is preferably
It is a C1-8 alkyl group, a C3-7 cycloalkyl group or a carbocycle-3, and particularly preferably a methyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or an indane group. In the general formula (I), R ⁴ is preferably a C1-8 alkyl group, a C1-8 alkyl group substituted with 1 to 3 halogen atoms, and particularly preferably
A methyl group and a difluoromethyl group.

In the general formula (I),

Embedded image Is preferably a single bond or a double bond, and particularly preferably a single bond.

Among the compounds represented by the general formula (I), preferred compounds are those represented by the general formula (IA)

Embedded image (Wherein all symbols have the same meanings as described above),

General formula (IB)

Embedded image (Wherein all symbols have the same meanings as described above),

General formula (IC)

Embedded image (Wherein all symbols have the same meanings as described above),

Formula (ID)

Embedded image (Wherein all symbols have the same meanings as described above),

Formula (IE)

Embedded image (Wherein all symbols have the same meanings as described above),

Formula (IF)

Embedded image (Wherein all symbols have the same meanings as described above),

Formula (IG)

Embedded image (Wherein all symbols have the same meanings as described above), or

Formula (IH)

Embedded image (Wherein all symbols have the same meanings as described above).

Specific compounds of the present invention are shown in Table 1
And the non-toxic salts, acid addition salts and solvates thereof. In the following tables, Me represents a methyl group, Et represents an ethyl group, i-Pr represents an isopropyl group, and the other symbols have the same meanings as described above.

[0036]

[Table 1]

[0037]

[Table 2]

[0038]

[Table 3]

[0039]

[Table 4]

[0040]

[Table 5]

[0041]

[Table 6]

[0042]

[Table 7]

[0043]

[Table 8]

[0044]

[Production Method of the Compound of the Present Invention] The compound of the present invention represented by the general formula (I) can be produced by the following methods or the methods described in Examples. [1] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a double bond, R ² represents a hydrogen atom, and R ¹ represents C
Compounds representing 1 to 8 alkoxy groups, that is, the general formula (IA)

Embedded image (Wherein R ^1-1 represents a C1-8 alkoxy group, and other symbols have the same meanings as described above). The compound represented by the formula (1) can be produced by the following method.

The compound represented by the general formula (IA) is represented by the general formula (II)

Embedded image (Wherein all symbols have the same meanings as described above), and a compound represented by the general formula (III):

Embedded image (Wherein, R ¹⁷ represents a C 1-8 alkyl group).

The reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) is known, and examples thereof include organic solvents (acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ether, dioxane, etc.) Medium, carbon monoxide gas, metal reagents (palladium acetate, nickel chloride, palladium chloride, tetrakis (triphenylphosphine) palladium, etc.) and bases (triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, N-methylmorpholine, etc.) ) In the presence, if necessary, triphenylphosphine is added and the reaction is carried out at 0 to 100 ° C.

[2] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a double bond, R ² represents a hydrogen atom and R ¹ represents a hydroxyl group, that is, a compound represented by the general formula (IB)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following methods a) to b).

A) The compound represented by the general formula (IB) can be produced by subjecting the compound represented by the general formula (IA) to a hydrolysis reaction under alkaline conditions. Hydrolysis under alkaline conditions is known,
For example, in a water-miscible solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.) or a mixed solvent thereof, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal Hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate,
Cesium carbonate) or an aqueous solution thereof or a mixture thereof at -10 to 90 ° C.

B) The compound represented by the general formula (IB) is (Wherein all symbols have the same meanings as described above). The compound can be produced by subjecting the compound to a hydrolysis reaction under alkaline conditions.

The hydrolysis reaction under alkaline conditions is known and includes, for example, an organic solvent (such as ethylene glycol).
Medium, alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate) , Cesium carbonate, etc.), an aqueous solution thereof, or a mixture thereof at 100 ° C. or higher.

[3] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a single bond, R ² represents a hydrogen atom, and R ¹ represents a hydroxyl group or a C1-8 alkoxy group, that is, a compound represented by the general formula (IC)

Embedded image (In the formula, R ^1-2 represents a hydroxyl group or a C1-8 alkoxy group, and other symbols have the same meanings as described above.) The compound represented by the following formula can be produced.

The compound represented by the general formula (IC) can be produced by subjecting the compound represented by the general formula (IA) or the compound represented by the general formula (IB) to a hydrogenolysis reaction.

The hydrogenolysis reaction is known and includes, for example, solvents (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), ketones Catalyst (palladium-carbon, palladium black, etc.) in a system (acetone, methyl ethyl ketone, etc.), a nitrile system (acetonitrile, etc.), an amide system (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof. Palladium hydroxide, platinum oxide, Raney nickel, etc.) under a hydrogen atmosphere under normal pressure or pressure or in the presence of ammonium formate,
It is performed at a temperature of 0 ° C.

[4] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a double bond, R ² represents a cyano group, and R ¹ represents C
Compounds representing 1 to 8 alkoxy groups, that is, general formula (ID)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following method.

The compound represented by the general formula (ID) has the general formula (V)

Embedded image (Wherein all symbols have the same meanings as described above), and a compound represented by the general formula (III):

Embedded image (Wherein, R ¹⁷ has the same meaning as described above).

The reaction between the compound represented by the general formula (V) and the compound represented by the general formula (III) is known, and examples thereof include organic solvents (acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ether, dioxane, etc.). Medium, carbon monoxide gas, metal reagents (palladium acetate, nickel chloride, palladium chloride, tetrakis (triphenylphosphine) palladium, etc.) and bases (triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, N-methylmorpholine, etc.) ) In the presence, if necessary, triphenylphosphine is added and the reaction is carried out at 0 to 100 ° C.

[5] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a double bond, R ² represents a cyano group and R ¹ represents a hydroxyl group, that is, a compound represented by the general formula (IE)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following method.

The compound represented by the general formula (IE) can be produced by subjecting the compound represented by the general formula (ID) to a hydrolysis reaction under alkaline conditions. The hydrolysis reaction under alkaline conditions is known. For example, in a water-miscible solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.) or a mixed solvent thereof, an alkali metal hydroxide (sodium hydroxide,
Potassium hydroxide, lithium hydroxide, etc.), hydroxides of alkaline earth metals (barium hydroxide, calcium hydroxide, etc.)
Alternatively, the reaction is performed at −10 to 90 ° C. using a carbonate (sodium carbonate, potassium carbonate, cesium carbonate, or the like), an aqueous solution thereof, or a mixture thereof.

[6] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a single bond, R ² represents a cyano group, R ¹ represents C
Compounds representing 1 to 8 alkoxy groups, that is, general formula (IF)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following method.

The compound represented by the general formula (IF) can be produced by subjecting the compound represented by the general formula (ID) to a hydrogenolysis reaction. Hydrogenolysis reactions are known and include, for example, solvents (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), ketones (acetone, etc.). , Methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water,
Ethyl acetate, acetic acid or a mixed solvent of two or more thereof)
Medium, in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate at a temperature of 0 to 200 ° C.

[7] Among the compounds of the present invention represented by the general formula (I),

Embedded image Represents a single bond, R ² represents a cyano group and R ¹ represents a hydroxyl group, that is, a compound represented by the general formula (IG)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following methods a) to b).

A) The compound represented by the general formula (IG) can be produced by subjecting the compound represented by the general formula (IF) to a hydrolysis reaction under alkaline conditions. Hydrolysis under alkaline conditions is known,
For example, in a water-miscible solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.) or a mixed solvent thereof, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal Hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate,
Cesium carbonate) or an aqueous solution thereof or a mixture thereof at -10 to 90 ° C.

B) The compound represented by the general formula (IG) is represented by the general formula (VI)

Embedded image (Wherein all symbols have the same meanings as described above). The compound can be produced by subjecting the compound to a hydrolysis reaction.

The above hydrolysis reaction is known, for example,
In an organic solvent (acetonitrile, dimethylformamide, dimethylsulfoxide, etc.) or a mixed solvent with water in the presence of aqueous hydrogen peroxide and an acid (trifluoroacetic acid, aqueous hydrochloric acid, methanesulfonic acid) at 20 to 100 ° C.
Then, the reaction is carried out by reacting a base (sodium hydroxide, potassium hydroxide, lithium hydroxide or the like) or an aqueous solution thereof at 20 to 100 ° C.

[8] Among the compounds of the present invention represented by the general formula (I), compounds wherein R ¹ represents a C1-8 alkoxy group, that is, a compound represented by the general formula (IH)

Embedded image (Wherein all symbols have the same meanings as described above) can also be produced by the following methods a) to b). a) The compound represented by the general formula (IH) is a compound represented by the general formula (VII)

Embedded image (Wherein all symbols have the same meanings as described above), and a compound represented by the general formula (VIII):

Embedded image (Wherein R ¹⁸ represents a halogen atom or a leaving group (tosyloxy group, mesyloxy group, etc.) and R ³ has the same meaning as described above) by subjecting the compound to an etherification reaction. Can be.

The above etherification reaction is known. For example, hydroxides of alkali metals (sodium hydroxide, hydroxide) in an inert organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) are used. Potassium, lithium hydroxide, etc.), alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof. The reaction is carried out at で 100 ° C.

B) The compound represented by the general formula (IH) is the same as the compound represented by the general formula (VII)

Embedded image (Wherein, R ³ has the same meaning as described above). The compound can be produced by subjecting the compound to an etherification reaction.

The above etherification reaction is known. For example, an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-) is dissolved in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.). (Azodicarbonyl) dipiperidine, 1,1′-azobis (N, N-
Dimethylformamide) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) in the presence of a corresponding alcohol compound at 0 to 60 ° C.

[9] Among the compounds of the present invention represented by the general formula (I), R ¹ is —NR ⁵ OR ⁶ group, —NR ⁷ R ⁸ group, —N
A compound representing an R ⁹ NR ¹⁰ R ¹¹ group and a —NR ¹² SO ₂ R ¹³ group, that is, a compound represented by the general formula (IJ)

Embedded image (Wherein, R ^1-3 is -NR ⁵ OR ⁶ group, -NR ⁷ R ⁸ group, -N
R ⁹ NR ¹⁰ R ¹¹ or —NR ¹² SO ₂ R ¹³
Other symbols have the same meaning as described above. The compound represented by the formula (1) can be produced by the following method.

The compound represented by the general formula (IJ) is represented by the general formula (X)

Embedded image (Wherein all symbols have the same meanings as described above) and a compound represented by the general formula (XI)

Embedded image (Wherein all symbols have the same meanings as described above), a compound represented by the general formula (XII)

Embedded image (Wherein all symbols have the same meanings as described above), a compound represented by the general formula (XIII)

Embedded image (Wherein all symbols have the same meanings as described above), or a compound represented by the general formula (XIV):

Embedded image (Wherein all symbols have the same meanings as described above), and can be produced by subjecting the compound to an amidation reaction.

Amidation reactions are known and include, for example,
(1) a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent.

These methods will be described in detail. (1) The method using an acid halide is, for example, a method in which a carboxylic acid is converted to an acid halide in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran or the like) or without a solvent. With an oxidizing agent (oxalyl chloride, thionyl chloride, etc.) at −20 ° C. to reflux temperature, and reacting the resulting acid halide with an amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.). In active organic solvents (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)
The reaction is carried out at 0 to 40 ° C. Also,
Alkaline aqueous solution (aqueous sodium bicarbonate or sodium hydroxide solution) in organic solvent (dioxane, tetrahydrofuran, etc.)
By reacting with an acid halide at a temperature of 0 to 40 ° C.

(2) A method using a mixed acid anhydride is, for example, a method in which a carboxylic acid is dissolved in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran or the like) or without a solvent, using a tertiary amine (pyridine, triethylamine, dimethylaniline, In the presence of dimethylaminopyridine), an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) and 0 to 4
The reaction is carried out at 0 ° C, and the resulting mixed acid anhydride is reacted with an amine at 0 to 40 ° C in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.).

(3) In the method using a condensing agent, for example, a carboxylic acid and an amine are reacted with a tertiary amine (pyridine, pyridine, pyridine, In the presence or absence of triethylamine, dimethylaniline, dimethylaminopyridine and the like, a condensing agent (1,3-dicyclohexylcarbodiimide (DC
C), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, etc.) -With or without hydroxybenztriazole (HOBt);
The reaction is carried out at 40 ° C.

Each of the reactions (1), (2) and (3) is desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

Further, among the compounds represented by the general formula (IJ), the compound wherein R ^1-3 represents an NHOH group, that is, the compound represented by the general formula (IJ-1)

Embedded image (Wherein all symbols have the same meanings as described above) are represented by the general formula (XV)

Embedded image (Wherein R ¹⁹ represents a protecting group for hydroxamic acid, and the other symbols have the same meanings as described above).

The protecting groups for hydrokimic acid include t-butyl, -C (CH ₃ ) ₂ -OCH ₃ , benzyl, t-butyldimethylsilyl and tetrahydropyran-1-
Examples thereof include an yl group and the like, and other groups are not particularly limited as long as they can be easily and selectively eliminated. For example,
TW Greene et al., Protective Groups in Organic Synth
esis, John Wiley & Sons, Inc., New York, 1991.

The deprotection reaction of the protecting group of hydroxamic acid is carried out by
Well-known, for example, (1) deprotection under alkaline conditions, (2) deprotection under acidic conditions, (3) deprotection by hydrogenolysis, (4) deprotection of silyl group And the like.

These methods will be specifically described. (1) The deprotection reaction under alkaline conditions is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, dimethylformamide, etc.) in the presence of an alkali metal hydroxide (hydroxide). Sodium, potassium hydroxide, lithium hydroxide, etc., hydroxides of alkaline earth metals (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.), organic amines (triethylamine, diisopropyl) The reaction is carried out at a temperature of 0 to 40 ° C. using ethylamine, piperazine or the like) or a quaternary ammonium salt (tetrabutylammonium fluoride or the like), an aqueous solution thereof or a mixture thereof.

(2) The deprotection reaction under acid conditions is carried out, for example, by using an organic solvent (methylene chloride, chloroform, dioxane,
0-100 ° C. in an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) in ethyl acetate, anisole, etc. At a temperature of

(3) The deprotection reaction by hydrogenolysis includes, for example, a solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, toluene, etc.) , Ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate,
Acetic acid or a mixed solvent of two or more thereof, in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate , 0
It is performed at a temperature of 200 ° C.

(4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0 to 40 ° C.

As can be easily understood by those skilled in the art, the desired compound of the present invention can be easily produced by properly using these deprotection reactions.

[10] Among the compounds of the present invention represented by the general formula (I), compounds wherein R ¹ represents a —NR ¹⁴ NR ¹⁵ SO ₂ R ¹⁶ group, ie, a compound of the general formula (IK)

Embedded image (Wherein all symbols have the same meanings as described above) can be produced by the following method.

The compound represented by the general formula (IK) has the general formula (XVI)

Embedded image (Wherein all symbols have the same meanings as described above), and a compound represented by the general formula (XVII)

Embedded image (Wherein, R ²⁰ represents a halogen atom, and other symbols have the same meanings as described above). The compound can be produced by subjecting the compound to a sulfonamidation reaction.

The above sulfonamidation reaction is known,
For example, in an inert organic solvent (chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, in the presence of a tertiary amine (isopropylidylethylamine, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.).
The reaction is carried out at で 40 ° C.

Formulas (II), (III), (IV),
(V), (VI), (VIII), (IX), (XI), (XI
The compounds represented by I), (XIII), (XIV), (XV) and (XVII) are known per se or can be easily produced by known methods.

For example, general formulas (II), (IV), (V),
The compounds represented by (VI) and (XV) can be produced by a method represented by the following reaction scheme.

In Reaction Schemes 1-3, p-TsOH is p-
Represents tosylic acid, n-BuLi represents normal butyl lithium, MsCl represents mesyl chloride, and Et ₃ N
Represents triethylamine, and [Ir (COD) py
(Pcy ₃ )] PF ₆ is (1,5-cyclooctadiene)
Pyridine (tricyclohexylphosphine) iridium

Represents hexafluorophosphate;
PAP stands for tetrapropylammonium perthenate, NMO stands for N-methylmorpholine-N-oxide, LiHMDS stands for lithium hexamethyldisilazane, Tf ₂ NPh stands for N-phenyltrifluoromethanesulfonimide, and TMSCN stands for N-phenyltrifluoromethanesulfonimide. Represents trimethylsilyl cyanide, NaHMDS represents sodium bis (trimethylsilyl) amide, and Tf
Represents a trifluoromethylsulfonyl group, and the other symbols have the same meanings as described above.

[0091]

Embedded image

[0092]

Embedded image

[0093]

Embedded image

In the reaction schemes 1 to 3, the compounds represented by the general formulas (XVIII), (XX), (XXVIII), (XXXII) and (XXXVIII) used as starting materials are known or known methods. Can be manufactured more easily.

In each reaction in the present specification, the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography,
Alternatively, it can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.

[0096]

[Pharmacological effect] The compound of the present invention represented by the general formula (I)
Having the DE4 inhibitory activity was proved by the following experiment.

In vitro enzyme assay [Experimental method] U937 cells (derived from human monocytes) were cultured in a PRMI1640 medium containing 10% fetal bovine serum.
U937 cells were collected and 20 mM Tris-HCl (Tris
-HCl) [pH 8.0, PMSF (1 mM), leupetin (1 μg / ml), pepstatin A
(Pepstatin A) (1 μg / ml)]. After centrifugation (15,000 rpm for 10 minutes), the supernatant was collected and filtered with a 0.45 μm filter. The sample was loaded on a MonoQ (Pharmacia company, strong anion exchange column) column and eluted with a concentration gradient of 0 to 0.8 M of NaCl. Fractions in which PDE activity was lost with 10 μM rolipram (rolipram: PDE4 selective inhibitor) were collected and used as an enzyme solution for measuring PDE4 inhibitory activity.

The measurement of the enzyme activity was carried out by the following method.
80 μl of the diluted enzyme solution (phosphate buffer (pH 7.4) containing 0.1 mg / kg bovine serum albumin), 10 μl of the compound solution of the present invention (10% DMSO) and 10 μl of ³ H
-CAMP (20,000 cpm, 10 μM) [MgSO
₄ (100 mM) and bovine serum albumin (1 mg /
ml) of imidazole buffer (100 mM, p
H7.5) was mixed and incubated for 30 minutes at room temperature. The reaction was stopped by microwave treatment for 2.5 minutes. After centrifugation (2,000 rpm for 1 minute), 10 μl of snake venom (snake
venom) (1 mg / ml, Sigma, product number V70)
00) was added and incubated at room temperature for 30 minutes. Apply 50 μl of the supernatant to an alumina column (100 μl),
Elution was performed with 0 μl of 0.005N hydrochloric acid, and the radioactivity of the eluate was measured.

The PDE4 inhibitory activity of the compound of the present invention was calculated by the following equation.

[Number 1] PDE4 activity inhibition rate (%) = (1 - the compound of the present invention the presence of radioactivity / the compound of the present invention the absence of radioactivity) × 100 IC ₅₀ values are present compound to inhibit PDE4 activity by 50% The concentration was calculated for each compound.

Table 9 shows the experimental results.

[Table 9]

[0101]

[Toxicity] The toxicity of the compound of the present invention represented by the formula (I) is very low, and it is considered that the compound is sufficiently safe for use as a medicament.

[0102]

[Application to Pharmaceuticals] The compound of the present invention has PDE4 inhibitory activity and can be used for inflammatory diseases (asthma, obstructive pulmonary disease, sepsis, nephritis, hepatitis, etc.), diabetic diseases, allergic diseases (allergic rhinitis, Allergic conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, etc.),
It is considered useful for prevention and / or treatment of osteoporosis, obesity, antidepressant, Parkinson's disease, ischemia-reperfusion injury, leukemia and the like.

In order to use the compound represented by the general formula (I), a non-toxic salt thereof or a hydrate thereof for use in the present invention for the above purpose, it is usually necessary to use systemically or topically, orally or parenterally. It is administered in the form.

The dose is determined based on the age, body weight, symptoms, therapeutic effect,
Depending on the administration method, treatment time, etc., it is usually 1 mg to 1000 mg per adult per dose.
Administered orally once to several times a day, or parenterally (preferably intravenously) once to several times a day in a range of 1 mg to 100 mg per adult per person; Alternatively, it is continuously administered intravenously for 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range.

When administering the compound represented by the general formula (I), solid compositions, liquid compositions and other compositions for oral administration and injections, external preparations and suppositories for parenteral administration are administered. Used as an agent and the like.

Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose,
It is mixed with hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and magnesium aluminate metasilicate. The composition is prepared according to a standard method.
Additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid. It may be contained. Tablets or pills as needed
It may be coated with a film of a gastric or enteric substance such as gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. This composition contains, in addition to the inert diluent, buffers such as sodium bisulfite, which provide isotonicity with stabilizers, e.g., isotonic agents such as sodium chloride, sodium citrate, or citric acid. You may. Methods for producing sprays are described, for example, in U.S. Pat.
It is described in detail in No. 95,355.

Injections for parenteral administration according to the present invention include sterile aqueous and / or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). In addition, sterile aqueous and non-aqueous solutions, suspensions, and emulsions may be mixed and used. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product.

Other compositions for parenteral administration include external solutions, ointments, salves, suppositories and suppositories for rectal administration, which contain one or more active substances and are formulated in a conventional manner. Pessaries for vaginal administration are included.

[0111]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Point of separation by chromatography,
The solvent in parentheses shown in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. N
The solvent in parentheses shown at the MR indicates the solvent used for the measurement.

Reference Example 1 cis-5,5-dimethyl-3'-oxospiro [1,3
-Dioxane-2,7'-bicyclo [3.3.0] octane]

Embedded image Dissolve cis-bicyclo [3.3.0] octane-3,7-dione (4.50 g) in benzene (40 mL) and add 2,2
-Dimethylpropane-1,3-diol (3.39 g)
And p-tosylic acid monohydrate (31 mg)
The mixture was stirred at 50 ° C. for 1 hour and heated under reflux for 7 hours. The reaction mixture was allowed to cool to room temperature, poured into a cold aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (4.20 g) having the following physical data.

TLC: Rf 0.56 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 3.48 (s, 2H), 3.44 (s, 2H), 2.82
(m, 2H), 2.55-2.40 (m, 2H), 2.35-2.23 (m, 2H), 2.
23-2.10 (m, 2H), 1.87-1.77 (m, 2H), 0.96 (s, 6H).

Reference Example 2 (1'S ^* , 3'S ^* , 5'R ^* )-5,5-dimethyl-
3'-hydroxy-3 '-(3-cyclopentyloxy-4-methoxyphenyl) spiro [1,3-dioxane-2,7'-bicyclo [3.3.0] octane]

Embedded image

3-Cyclopentyloxy-4-methoxyphenyl bromide (5.66 g) was dissolved in tetrahydrofuran (80 mL), cooled to -78 ° C, and a 1.5 M hexane solution of n-butyllithium (14.54 mL) was added.
Stirred at 78 ° C. for 30 minutes. Anhydrous cerium chloride (5.48 g) was added to the reaction mixture, and the mixture was stirred at -78 ° C for 30 minutes. The compound prepared in Reference Example 1 (3.12
g) in tetrahydrofuran (60 mL) was slowly added dropwise, and the mixture was stirred at -78 ° C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and insolubles were filtered through celite. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (3.48 g) having the following physical data.

TLC: Rf 0.39 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.05 (d, J = 2,2 Hz, 1H), 6.96
(dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1
H), 4.79 (m, 1H), 3.83 (s, 3H), 3.51 (s, 2H), 3.49
(s, 2H), 2.68 (m, 2H), 2.34 (d, J = 8.4 Hz, 2H),
2.27 (d, J = 7.8 Hz, 2H), 2.09-1.52 (m, 13H), 0.97
(s, 6H).

Reference Example 3 (1'S, 5'R) -5,5-dimethyl-3 '-(3-
Cyclopentyloxy-4-methoxyphenyl) spiro [1,3-dioxane-2,7′-bicyclo [3.3.
0] octa-2'-ene] and (1'R, 5'S)-
Mixture of 5,5-dimethyl-3 '-(3-cyclopentyloxy-4-methoxyphenyl) spiro [1,3-dioxane-2,7'-bicyclo [3.3.0] octa-2'-ene]

Embedded image

The compound (2.24 g) produced in Reference Example 2 was dissolved in methylene chloride (30 mL), and triethylamine (1.80 mL) and mesyl chloride (0.50 m
L) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (1.99 g) having the following physical data.

TLC: Rf 0.49 (hexane: ethyl acetate =
5: 1); NMR (CD ₃ OD): δ 6.99 (d, J = 2.1 Hz, 1H), 6.93
(dd, J = 8.4, 2.1 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1
H), 5.93 (m, 1H), 4.83-4.75 (m, 1H), 3.84 (s, 3H),
3.53 (s, 2H), 3.45 (s, 2H), 3.33 (m, 1H), 2.97-2.8
0 (m, 2H), 2.51-2.37 (m, 3H), 1.98-1.54 (m, 10H),
0.97 (s, 6H).

Reference Example 4 (1'S ^* , 3'S ^* , 5'R ^* )-5,5-dimethyl-
3 '-(3-cyclopentyloxy-4-methoxyphenyl) spiro [1,3-dioxane-2,7'-bicyclo [3.3.0] octane]

[Of 60]

The compound (0.68 g) produced in Reference Example 3 was replaced with argon gas, and 10% palladium carbon (0.068 g) was added.
g, 10% w / w), 1,4-dioxane (16 mL) was added, the atmosphere was replaced with hydrogen gas, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to give the title compound (0.69 g) having the following physical data.

TLC: Rf 0.65 (hexane: ethyl acetate =
5: 1); NMR (CDCl ₃ ): δ 6.82-8.72 (m, 3H), 4.76 (m, 1H),
3.81 (s, 3H), 3.51 (s, 4H), 2.93 (m, 1H), 2.68-2.
48 (m, 2H), 2.31-2.14 (m, 4H), 2.00-1.73 (m, 8H),
1.66-1.39 (m, 2H), 0.98 (s, 6H).

Reference Example 5 (1S ^* , 5R ^* , 7S ^* )-3-oxo-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] octane

Embedded image

The compound (2.49 g) produced in Reference Example 4 was dissolved in acetone (60 mL), p-tosylic acid monohydrate (0.12 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (1.85 g) having the following physical data.

TLC: Rf 0.48 (hexane: ethyl acetate =
3: 1); NMR (CDCl ₃ ): δ 6.82-6.72 (m, 3H), 4.76 (m, 1H),
3.82 (s, 3H), 3.10 (m, 1H), 2.91-2.76 (m, 2H), 2.
63-2.52 (m, 2H), 2.49-2.38 (m, 2H), 2.19-2.11 (m,
2H), 1.95-1.76 (m, 6H), 1.68-1.53 (m, 2H), 1.44
(m, 2H).

Reference Example 6 (1R, 5R, 7R) -3-cyano-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene and (1S, 5S,
A mixture of 7S) -3-cyano-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene

Embedded image

The compound (1.41 g) produced in Reference Example 5 and zinc iodide (1.41 g) were dissolved in methylene chloride (60 mL), and trimethylsilyl cyanide (0.12 g) was added.
Stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure.
The obtained residue (2.00 g) was used for the next reaction. Residue (2.
00g) was dissolved in pyridine (20 mL), phosphorus oxychloride (1.03 mL) was added, and the mixture was stirred at 120 ° C for 1 hour.
After the reaction mixture was cooled to room temperature, it was poured into cold water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1.31 g) having the following physical data.

TLC: Rf 0.62 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.81-6.77 (m, 1H), 6.75-6.70 (m,
2H), 6.59 (m, 1H), 4.77 (m, 1H), 3.82 (s, 3H), 3.
39 (m, 1H), 2.99-2.77 (m, 3H), 2.48-2.24 (m, 3H),
1.96-1.76 (m, 6H), 1.68-1.54 (m, 2H), 1.43-1.31
(m, 2H).

Example 1 (1R, 5R, 7R) -7- (3-Cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid and (1S, 5
S, 7S) -7- (3-Cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-
Mixture of en-3-ylcarboxylic acids

Embedded image

The compound prepared in Reference Example 6 (0.94 g) was dissolved in ethylene glycol (6.5 mL), and a 40% aqueous potassium hydroxide solution (5.4 mL) was added, followed by stirring at 200 ° C. for 4 hours. The reaction mixture was back-extracted with ether. The aqueous layer was made acidic with 2N hydrochloric acid (40 mL) and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the compound of the present invention (0.63 g) having the following physical data.

TLC: Rf 0.46 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.86 (m, 1H), 6.82-6.70 (m, 3H),
4.77 (m, 1H), 3.81 (s, 3H), 3.48-3.30 (m, 1H), 3.
02-2.72 (m, 3H), 2.53-2.23 (m, 3H), 1.98-1.70 (m,
7H), 1.70-1.50 (m, 2H), 1.45-1.27 (m, 2H).

Reference Example 7 (1R, 5R, 7R) -N- (1-methyl-1-methoxyethoxy) -7- (3-cyclopentyloxy-4-
Methoxyphenyl) bicyclo [3.3.0] octa-2
-En-3-ylcarboxamide and (1S, 5S,
7S) -N- (1-methyl-1-methoxyethoxy)-
Mixture of 7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

The compound (0.39 g) prepared in Example 1 was dissolved in dimethylformamide (11 mL), and (1-methoxy-1-methylethyl) oxyamine (0.18 g), triethylamine (0.24 mL), 1-hydroxybenzoate were dissolved. Triazole (HOBt; 0.23 g) and 1-ethyl-3
-(3-dimethylaminopropyl) -carbodiimide.
Hydrochloride (EDC.HCl; 0.33 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After ether was added to the extract, the mixture was washed successively with a 1N aqueous solution of sodium hydroxide, water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.50 g) having the following physical data. Was. The obtained residue was used for the next reaction as it was.

TLC: Rf 0.65 (hexane: ethyl acetate =
1: 4); NMR (CDCl ₃ ): δ 8.02 & 7.81 (s, 1H), 6.81-6.71
(m, 3H), 6.53 (m, 1H), 4.77 (m, 1H), 3.61 (s, 3H),
3.37 (s, 3H), 3.34 (m, 1H), 2.98-2.75 (m, 3H), 2.4
5-2.23 (m, 3H), 1.96-1.76 (m, 6H), 1.47 (s, 6H),
1.48-1.34 (m, 4H).

Example 2 (1R, 5R, 7R) -N-hydroxy-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7S) -N-hydroxy-7
Mixture of-(3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

The compound (0.50 g) produced in Reference Example 7 was dissolved in methanol (11 mL), and 2N hydrochloric acid (57 μL) was added.
Was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give the compound of the present invention (0.36 g) having the following physical data.

TLC: Rf 0.45 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.53 (br, 1H), 8.76 (br, 1H),
6.84-6.67 (m, 3H), 6.33 (m, 1H), 4.74 (m, 1H), 3.
68 (s, 3H), 3.34-3.15 (m, 1H), 2.96-2.55 (m, 3H),
2.40-2.11 (m, 3H), 1.90-1.50 (m, 8H), 1.32-1.12
(m, 2H).

Example 3 (1S ^* , 3R ^* , 5R ^* , 7S ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.
3.0] Octane-3-ylcarboxylic acid

Embedded image The same operation as in Reference Example 4 was performed using the compound prepared in Example 1 instead of the compound prepared in Reference Example 3, to obtain the compound of the present invention having the following physical data.

TLC: Rf 0.78 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.81-6.73 (m, 3H), 4.81-4.74 (m,
1H), 3.82 (s, 3H), 3.08 (m, 1H), 2.92 (m, 1H), 2.
66-2.55 (m, 2H), 2.30-2.19 (m, 4H), 1.97-1.78 (m,
6H), 1.78-1.37 (m, 7H).

Example 4 (1S ^* , 3R ^* , 5R ^* , 7S ^* )-N-hydroxy-7
-(3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] octan-3-ylcarboxamide

Embedded image By using the compound produced in Example 3 in place of the compound produced in Example 1, the same operation as in Reference Example 7 → Example 2 was carried out to obtain the compound of the present invention having the following physical properties.

TLC: Rf 0.48 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.35 (s, 1H), 8.64 (br, 1H),
6.82 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1
H), 6.72 (dd, J = 8.4, 1.8 Hz, 1H), 4.76 (m, 1H),
3.68 (s, 3H), 3.02 (m, 1H), 2.60-2.40 (m, 3H), 2.1
7-2.07 (m, 2H), 1.98-1.76 (m, 4H), 1.76-1.61 (m, 4
H), 1.61-1.44 (m, 4H) 1.40-1.28 (m, 2H).

Reference Example 8 (1S, 5R) -7-oxo-3- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.
0] Oct-2-ene and (1R, 5S) -7-oxo-3- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene

Embedded image By subjecting the compound produced in Reference Example 3 to the same operation as in Reference Example 5 in place of the compound produced in Reference Example 4, the title compound having the following physical data was obtained.

TLC: Rf 0.48 (hexane: ethyl acetate =
3: 1); NMR (CDCl ₃ ): δ 6.99 (d, J = 2.1 Hz, 1H), 6.93
(dd, J = 8.4, 2.1 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1
H), 5.89 (m, 1H), 4.86-4.76 (m, 1H), 3.85 (s, 3H),
3.60 (m, 1H), 3.16-3.01 (m, 2H), 2.63-2.47 (m, 3
H), 2.33 (m, 1H), 2.14-2.04 (m, 1H), 1.97-1.81 (m,
6H), 1.68-1.52 (m, 2H).

Reference Example 9 (1S, 5R, 7S) -7-Hydroxy-3- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene and 1R, 5S, 7
R) -7-Hydroxy-3- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene mixture

Embedded image

The compound (3.24 g) produced in Reference Example 8 was treated with methanol (275 mL) and tetrahydrofuran (2
75 mL), sodium borohydride (18.7 mL) was slowly added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Acetone and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.51 g) having the following physical data. The obtained residue was used for the next reaction as it was.

TLC: Rf 0.67 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 7.00 (d, J = 2.0 Hz, 1H), 6.94
(dd, J = 8.4, 2.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1
H), 6.02 (m, 1H), 4.79 (m, 1H), 4.23 (m, 1H), 3.84
(s, 3H), 3.40-3.30 (m, 2H), 3.04 (m, 1H), 2.85 (m
1H), 2.63 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 2.0
0-1.76 (m, 6H), 1.69-1.53 (m, 4H).

Reference Example 10 (1S ^* , 3R ^* , 5R ^* , 7R ^* ) 3-hydroxy-7-
(3-cyclopentyloxy-4-methoxyphenyl)
Bicyclo [3.3.0] octane

Embedded image

The compound (39 mg) produced in Reference Example 9 was dissolved in methylene chloride (690 mL), and after purging with argon gas, (1,5-cyclooctadiene) pyridine (tricyclohexylphosphine) iridium hexafluorophosphate ([Ir (COD) py (Pcy ₃ )]
PF ₆ ; 15.8 mg), and the mixture was replaced with hydrogen and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (27.6 mg) having the following physical data.

TLC: Rf 0.64 (hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 6.84-6.75 (m, 3H), 4.78 (m, 1H),
3.95 (m, 1H), 3.76 (s, 3H), 3.15 (m, 1H), 2.58-2.
45 (m, 2H), 2.21-2.11 (m, 2H), 1.88-1.56 (m, 13H),
1.27-1.16 (m, 2H).

Reference Example 11 (1S ^* , 5R ^* , 7R ^* )-3-oxo-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] octane

Embedded image

The compound prepared in Reference Example 10 (1.3 g) was dissolved in methylene chloride (20 mL), and N-methylmorpholine-N-oxide (0.72 g) and dried molecular sieve 4A (appropriate amount) were added. Stirred at room temperature for 10 minutes. Tetrapropylammonium parthenate (TPAP; 1.3 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was eluted with methylene chloride in a short column. The eluate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1.18 g) having the following physical data.

TLC: Rf 0.57 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.82-6.73 (m, 3H), 4.77 (m, 1H),
3.82 (s, 3H), 3.18 (m, 1H), 3.03-2.92 (m, 2H), 2.
65-2.54 (m, 2H), 2.16-2.08 (m, 2H), 2.06-1.76 (m,
10H), 1.67-1.55 (m, 2H).

Reference Example 12 (1R, 5R, 7S) -3-Cyano-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene and (1S, 5S,
A mixture of 7R) -3-cyano-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene

Embedded image The same operation as in Reference Example 6 was performed using the compound prepared in Reference Example 11 instead of the compound prepared in Reference Example 5, to obtain the title compound having the following physical data.

TLC: Rf 0.53 (hexane: ethyl acetate =
3: 1); NMR (CDCl ₃ ): δ 6.83-6.71 (m, 3H), 6.50-6.46 (m,
1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.56-3.46 (m, 1
H), 3.08-2.85 (m, 3H), 2.46-2.34 (m, 1H), 1.99-1.7
4 (m, 10H), 1.65-1.52 (m, 2H).

Example 5 (1R, 5R, 7S) -7- (3-Cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid and (1S, 5
(S, 7R) -7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-
Mixture of en-3-ylcarboxylic acids

Embedded image By using the compound prepared in Reference Example 12 in place of the compound prepared in Reference Example 6, and subjecting it to the same operation as in Example 1, a compound of the present invention having the following physical data was obtained.

TLC: Rf 0.56 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.82-6.71 (m, 4H), 4.76 (m, 1H),
3.82 (s, 3H), 3.52 (m, 1H), 3.10-2.89 (m, 3H), 2.
39 (m, 1H), 2.00-1.74 (m, 10H), 1.68-1.53 (m, 3
H).

Example 6 (1S ^* , 3S ^* , 5R ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.
3.0] Octane-3-ylcarboxylic acid

Embedded image The compound of Example 5 was used in place of the compound of Reference Example 3 and subjected to the same operation as in Reference Example 4 to obtain the compound of the present invention having the following physical data.

TLC: Rf 0.59 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.82-6.74 (m, 3H), 4.80-4.73 (m,
1H), 3.82 (s, 3H), 3.10 (m, 1H), 2.73-2.57 (m, 3
H), 2.34-2.24 (m, 2H), 1.96-1.78 (m, 8H), 1.75-1.4
5 (m, 7H).

Examples 7 to 7 (1) Reference examples 7 → Example 2 using the compounds prepared in Examples 5 and 6 in place of the compounds prepared in Example 1.
By subjecting the same operation to as described above, the following compound of the present invention was obtained.

Example 7 (1R, 5R, 7S) -N-hydroxy-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7R) -N-hydroxy-7
Mixture of-(3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

[Of 75]

TLC: Rf 0.64 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.52 (br, 1H), 8.79 (br, 1H),
6.81 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 1.7 Hz, 1
H), 6.71 (dd, J = 8.3, 1.7 Hz, 1H), 6.19 (m, 1H),
4.76 (m, 1H), 3.68 (s, 3H), 3.40-3.26 (m, 1H), 2.9
6-2.70 (m, 3H), 2.24 (m, 1H), 1.88-1.61 (m, 10H),
1.61-1.48 (m, 2H).

Example 7 (1) (1S ^* , 3S ^* , 5R ^* , 7R ^* )-N-hydroxy-7
-(3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] octan-3-ylcarboxamide

Embedded image

TLC: Rf 0.49 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 10.36 (s, 1H), 8.67 (s, 1H), 6.8
4-6.80 (m, 2H), 6.74 (dd, J = 8.4, 1.8 Hz, 1H), 4.
77 (m, 1H), 3.68 (s, 3H), 3.01 (m, 1H), 2.60-2.40
(m, 1H), 2.29-2.16 (m, 2H), 2.00-1.89 (m, 2H), 1.8
9-1.77 (m, 2H), 1.77-1.50 (m, 10H), 1.44-1.31 (m,
2H).

Reference Example 13 cis-4,5-bis (hydroxymethyl) cyclohex-1-ene

Embedded image

Lithium aluminum hydride (37.4 g) was suspended in tetrahydrofuran (1 L) and (3a
(R, 7aS) -4,7,3a, 7a-Tetrahydroisobenzofuran-1,3-dione (60.0 g) was slowly added, and the mixture was stirred at 0 ° C. for 2.5 hours. After methanol was added to the reaction mixture, a saturated aqueous solution of sodium sulfate was added. The solid was filtered through Celite, and the filtrate was diluted with saturated saline and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated, and the title compound (55.4
g) was obtained.

TLC: Rf 0.36 (ethyl acetate); NMR (CDCl ₃ ): δ 5.62 (br.t, 2H), 3.74 (dd, J = 1)
0.8, 6.6 Hz, 2H), 3.61 (dd, J = 10.8, 3.0 Hz, 2H),
2.40-2.00 (m, 8H).

Reference Example 14 cis-4,5-bis (mesyloxymethyl) cyclohex-1-ene

Embedded image

In an argon atmosphere, the compound prepared in Reference Example 13 (8.98 g) and triethylamine (26.4 mL)
Was dissolved in methylene chloride (100 mL), and mesyl chloride (14.7 mL) was slowly added at -78 ° C.
Stirred at C for 1 hour. The reaction mixture was diluted with a saturated saline solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (18.9 g) having the following physical data.

TLC: Rf 0.18 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 5.67 (t, J = 1.5 Hz, 2H), 4.29
(dd, J = 10.2, 7.2 Hz, 2H), 4.17 (dd, J = 10.2, 7.2
Hz, 2H), 3.04 (s, 6H), 2.50-2.35 (m, 2H), 2.35-2.
15 (m, 2H), 2.10-1.90 (m, 2H).

Reference Example 15 cis-4,5-bis (bromomethyl) cyclohexa-1
−En

Embedded image

Under an argon atmosphere, the compound prepared in Reference Example 14 (18.9 g) and lithium bromide (16.5 g) were dissolved in dimethylformamide (150 mL), and the solution was dissolved at 100 ° C.
Stirred for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with water and ether. The reaction mixture was filtered through celite, and the filtrate was extracted with ether. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (6.09 g) having the following physical data.

TLC: Rf 0.76 (hexane: ethyl acetate =
8: 1); NMR (CDCl ₃ ): δ 5.63 (t, J = 1.2 Hz, 2H), 3.41
(dd, J = 10.2, 5.4 Hz, 2H), 3.32 (dd, J = 10.2, 8.4
Hz, 2H), 2.45-2.30 (m, 2H), 2.35-2.20 (m, 2H), 2.
15-2.00 (m, 2H).

Reference Example 16 (1R ^* , 6S ^* , 8R ^* )-8-cyano-8- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [4.3.0] non-3-ene and (1R ^{* *} , 6S ^* ,
Mixture of 8S ^* )-8-cyano-8- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [4.3.0] non-3-ene

Embedded image

Dissolve 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanenitrile (1.25 g) in tetrahydrofuran (20 mL), cool to -78 ° C,
1.0 M sodium bis (trimethylsilyl) amide (N
aHMDS; 12.0 mL in tetrahydrofuran) was slowly added dropwise, followed by stirring at -78 ° C for 20 minutes. To this solution, a solution of the compound (799 mg) prepared in Reference Example 15 in tetrahydrofuran (10 mL) was slowly added dropwise at -78 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated saline and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (725 mg) having the following physical data.

TLC: Rf 0.64 (hexane: ethyl acetate =
4: 1); NMR (CDCl ₃ ): δ 7.00-6.90 (m, 2H), 6.85-6.80 (m,
1H), 5.83 (m, 2H X 1/3), 5.75 (m, 2H X 2/3), 4.81
(m, 1H), 3.84 (s, 3H X 2/3), 3.84 (s, 3H X1 / 3),
2.70-2.50 (m, 2H X 1/3), 2.50-2.20 (m, 6H + 2H X 2
/ 3), 2.20-2.00 (m, 2H), 2.00-1.70 (m, 6H), 1.70-1.
50 (m, 2H).

Reference Example 17 (1S ^* , 2R ^* , 4S ^* )-1,2-bis (formylmethyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanocyclopentane and (1S ^*
* , 2R ^* , 4R ^* )-1,2-bis (formylmethyl)
Mixture of -4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanocyclopentane

Embedded image

The compound (2.78 g) produced in Reference Example 16 was dissolved in methylene chloride (50 mL), and ozone was blown at -78 ° C for 1 hour. Triphenylphosphine (3.24 g) was added to the reaction mixture at -78 ° C, and the mixture was stirred for 30 minutes.
The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound having the following physical data.

TLC: Rf 0.50 (hexane: ethyl acetate =
1: 2).

Reference Example 18 (1S ^* , 2R ^* , 4S ^* )-1,2-bis (carboxymethyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanocyclopentane and (1
Mixture of S ^* , 2R ^* , 4R ^* )-1,2-bis (carboxymethyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanocyclopentane

Embedded image

The compound prepared in Reference Example 17 was treated with t-butanol (50 mL) and 2-methyl-2-butene (5.24 m
L) and water (10 mL) and sodium chlorite (2.98 g) and sodium dihydrogen phosphate (2.
36 g) and stirred for 3 hours. The reaction mixture is added
An aqueous solution of N sodium hydroxide (8.25 mL) was added, and the mixture was diluted with methylene chloride and extracted with water. The extract was washed with 2N hydrochloric acid (3.
20 mL) and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.25 g) having the following physical data.

TLC: Rf 0.39 (ethyl acetate).

Reference Example 19 (1S ^* , 2R ^* , 4S ^* )-1,2-bis (methoxycarbonylmethyl) -4- (3-cyclopentyloxy-
4-methoxyphenyl) -4-cyanocyclopentane and (1S ^* , 2R ^* , 4R ^* )-1,2-bis (methoxycarbonylmethyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -4- Mixture of cyanocyclopentane

Embedded image

The compound (3.31 g) produced in Reference Example 18 was dissolved in ether (60 mL), and a 1.0 M solution of diazomethane in ether (36 mL) was slowly added at 0 ° C.
Stirred at C for 1 hour. After adding acetic acid to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (2.66 g) having the following physical data.

TLC: Rf 0.35 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.00-6.90 (m, 2H), 6.85-6.80 (m,
1H), 4.81 (m, 1H), 3.84 (s, 3H), 3.70 (s, 6H X 2 /
3), 3.70 (s, 6H X 1/3), 3.10-2.90 (m, 2H X 1/3),
2.90-2.60 (m, 2H X 2/3), 2.70-2.20 (m, 8H), 2.00-
1.75 (m, 6H), 1.80-1.50 (m, 2H).

Reference Example 20 (1S ^* , 5R ^* , 7S ^* )-3-oxo-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane (Compound A) ) And (1S ^* , 5R ^* , 7R ^* )-3-oxo-7- (3-
Cyclopentyloxy-4-methoxyphenyl) -7-
Cyanobicyclo [3.3.0] octane (Compound B)

Embedded image

In an argon gas atmosphere, the compound (2.66 g) produced in Reference Example 19 was treated with 1,2-dimethoxyethane (5
0 mL) and 60% sodium hydride (1.49 g)
Was added at room temperature, and the mixture was heated under reflux for 1.5 hours. After cooling the reaction mixture to room temperature, 2N hydrochloric acid (18.6 mL) was added to neutralize it,
After dilution with water, the mixture was extracted with ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residue (2.96g)
With dimethyl sulfoxide (50 mL) and water (5.0 m
L), and sodium chloride (3.0 g) was added.
Stirred at 5 ° C. for 1 hour. After cooling the reaction mixture to room temperature,
Dilute with water and mix solvent (hexane: ethyl acetate = 2:
Extracted in 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give compound A (1.00 g) and compound B (469 mg).
I got

Compound A TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.84 (d, J =
9.0 Hz, 1H), 4.79 (m, 1H), 3.85 (s, 3H), 3.30-3.15
(m, 2H), 2.85 (dd, J = 13.2, 7.5 Hz, 2H), 2.68 (d
d, J = 19.5, 9.9 Hz, 2H), 2.17 (dd, J = 19.5, 3.9
Hz, 2H), 2.00-1.80 (m, 8H), 1.70-1.55 (m, 2H). Compound B TLC: Rf 0.29 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 6.95 (d, J = 2.1 Hz, 1H), 6.92
(dd, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.
81 (m, 1H), 3.85 (s, 3H), 3.00-2.85 (m, 2H), 2.75
2.55 (m, 4H), 2.40-2.20 (m, 4H), 2.00-1.75 (m, 6
H), 1.75-1.55 (m, 2H).

Reference Example 21 (1S ^* , 5R ^* , 7S ^* )-3- (1,3-dithiane-
2-ylidene) -7- (3-cyclopentyloxy-4
-Methoxyphenyl) -7-cyanobicyclo [3.3.
0] octane

Embedded image Under an argon gas atmosphere, 2-trimethylsilyl-1,3
Dithiane (2.21 g) in tetrahydrofuran (10 m
L), a hexane solution of n-butyllithium (1.53 M; 7.52 mL) was added dropwise at 0 ° C., and the mixture was stirred for 10 minutes.
After cooling the reaction mixture to −78 ° C., a solution of compound A (1.30 g) produced in Reference Example 20 in tetrahydrofuran (5 mL) was slowly added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was diluted with saturated saline and extracted with ethyl acetate.
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 6:
1) to give the title compound (633) having the following physical data.
mg).

TLC: Rf 0.54 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.95-6.85 (m, 2H), 6.82 (d, J =
8.0 Hz, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.00-2.85
(m, 2H), 2.90-2.75 (m, 2H), 2.80-2.40 (m, 6H), 2.4
0-2.00 (m, 4H), 2.00-1.70 (m, 8H), 1.80-1.50 (m, 2
H).

Example 8 (1R ^* , 3R ^* , 5S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxy Mixture of acid and (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid

Embedded image Acetonitrile (8 mL), water (2 mL) and trifluoroacetic acid (0.38 mL) were added to the compound (548 mg) produced in Reference Example 21, and the mixture was stirred at 30 ° C., and 30% aqueous hydrogen peroxide (1.97 mL) was added. Stirred at 80 ° C. for 30 minutes. After cooling the reaction mixture to 40 ° C., a 2N aqueous sodium hydroxide solution (18.6 mL) was added dropwise, and the mixture was stirred at 40 ° C. for 20 minutes. After cooling the reaction mixture to room temperature, 2N hydrochloric acid (16 m
L) and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 20: 1) to give the compound of the present invention (419 mg) having the following physical data.

TLC: Rf 0.52 (chloroform: methanol = 10: 1).

Example 9 (1R ^* , 3R ^* , 5S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxy acid·
Methyl ester (compound A) and (1R ^* , 3S ^* , 5
S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-
Methoxyphenyl) -7-cyanobicyclo [3.3.
0] Octane-3-ylcarboxylic acid methyl ester (Compound B)

Embedded image The compound (419 mg) prepared in Example 8 was dissolved in ether (5 mL) and tetrahydrofuran (2 mL), and a 1.0 M diazomethane ether solution (2 m) was added at 0 ° C.
L) was added slowly and stirred at 0 ° C. for 15 minutes. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
6: 1 → 4: 1) to give Compound A (80.4 mg) and Compound B (108 mg).

Compound A TLC: Rf 0.65 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 6.92 (d, J = 1.8 Hz, 1H), 6.90
(dd, J = 7.5, 1.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1
H), 4.79 (m, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 2.79
(m, 1H), 2.80-2.55 (m, 4H), 2.05-1.80 (m, 12H), 1.
70-1.55 (m, 2H). Compound B TLC: Rf 0.57 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 6.93 (d, J = 1.8 Hz, 1H), 6.91
(dd, J = 8.4, 1.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1
H), 4.79 (m, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.80
(m, 1H), 2.80-2.55 (m, 2H), 2.60-2.40 (m, 2H), 2.3
5-2.20 (m, 4H), 2.00-1.75 (m, 8H), 1.70-1.50 (m, 2
H).

Example 10 (1R ^* , 3R ^* , 5S ^* , 7S ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxy acid·
Methyl ester (compound A) and (1R ^* , 3S ^* , 5
S ^* , 7S ^* )-7- (3-cyclopentyloxy-4-
Methoxyphenyl) -7-cyanobicyclo [3.3.
0] Octane-3-ylcarboxylic acid methyl ester (Compound B)

Embedded image By using the compound B prepared in Reference Example 20 in place of the compound A prepared in Reference Example 20, the same operation as in Reference Example 21 → Example 8 → Example 9 was carried out to obtain the present invention having the following physical property values. The compound was obtained.

Compound A TLC: Rf 0.61 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 7.00-6.90 (m, 2H), 6.84 (d, J =
9.0 Hz, 1H), 4.81 (m, 1H), 3.84 (s, 3H), 3.68 (s, 3
H), 3.05-2.90 (m, 3H), 2.70-2.55 (m, 2H), 2.30-2.1
5 (m, 2H), 2.05-1.60 (m, 12H). Compound B TLC: Rf 0.58 (hexane: ethyl acetate = 2: 1); NMR (CDCl ₃ ): δ 6.95-6.85 (m, 2H), 6.83 (d, J =
8.4 Hz, 1H), 4.79 (m, 1H), 3.84 (s, 3H), 3.69 (s, 3
H), 3.15-3.00 (m, 2H), 2.81 (m, 1H), 2.70-2.60 (m,
2H), 2.05-1.75 (m, 12H), 1.70-1.55 (m, 2H).

Example 11 (1R ^* , 3R ^* , 5S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxy acid

Embedded image

Compound A prepared in Example 9 (72.9 mg)
Methanol (1 mL), tetrahydrofuran (0.5 m
L) and a 1N aqueous solution of potassium hydroxide (0.48 mL) were added, and the mixture was stirred at room temperature for 4 hours. Dilute the reaction mixture with water,
Washed with ethyl acetate. The aqueous layer was neutralized with 2N hydrochloric acid (0.5 mL) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was pulverized and filtered with a mixed solvent (ether: hexane = 1: 9) to give the compound of the present invention (63.5 mg) having the following physical data.

TLC: Rf 0.39 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.95-6.85 (m, 2H), 6.82 (d, J =
8.1 Hz, 1H), 4.79 (m, 1H), 3.84 (s, 3H), 3.03 (m, 1
H), 2.80-2.65 (m, 2H), 2.70-2.55 (m, 2H), 2.10-1.9
0 (m, 4H), 1.95-1.80 (m, 9H), 1.70-1.55 (m, 2H).

Examples 11 (1) to 11 (3) Instead of the compound A prepared in Example 9, the compound B prepared in Example 9 and the compounds A and B prepared in Example 10
By applying the same operation as in Example 11 using
The compound of the present invention having the following physical properties was obtained.

Example 11 (1) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid

Embedded image

TLC: Rf 0.39 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.95-6.85 (m, 2H), 6.82 (d, J =
7.8 Hz, 1H), 4.79 (m, 1H), 3.84 (s, 3H), 2.84 (m, 1
H), 2.90-2.60 (m, 2H), 2.55-2.40 (m, 2H), 2.40-2.2
0 (m, 4H), 2.10-1.75 (m, 9H), 1.80-1.55 (m, 2H).

Example 11 (2) (1R ^* , 3R ^* , 5S ^* , 7S ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid

Embedded image

TLC: Rf 0.56 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 7.00-6.90 (m, 2H), 6.83 (d, J =
9.0 Hz, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.10-2.95
(m, 3H), 2.70-2.60 (m, 2H), 2.40-2.20 (m, 2H), 2.0
0-1.60 (m, 10H), 1.70-1.55 (m, 3H).

Example 11 (3) (1R ^* , 3S ^* , 5S ^* , 7S ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid

Embedded image

TLC: Rf 0.56 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.93 (d, J = 2.1 Hz, 1H), 6.91
(dd, J = 8.1, 2.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H
H), 4.80 (m, 1H), 3.84 (s, 3H), 3.20-3.00 (m, 2H),
2.85 (m, 1H), 2.75-2.60 (m, 2H), 2.05-1.75 (m, 12
H), 1.70-1.55 (m, 3H).

Example 12 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-3
-Ilcarboxamide

Embedded image Example 11 (1) instead of the compound prepared in Example 1
Using the compound prepared in the above, the same operation as in Reference Example 7 → Example 2 was performed to obtain the compound of the present invention having the following physical data.

TLC: Rf 0.50 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 9.40-8.50 (br, 2H), 6.95-6.85
(m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 4.79 (m, 1H),
3.84 (s, 3H), 2.80-2.50 (m, 3H), 2.50-2.10 (m, 6H),
2.05-1.70 (m, 8H), 1.70-1.50 (m, 2H).

Reference Example 22 (1R, 5R, 7R) -3-trifluoromethylsulfonyloxy-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0]
Oct-2-ene and (1S, 5S, 7S) -3-trifluoromethylsulfonyloxy-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octa-2 Mixtures of ene

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The compound A prepared in Reference Example 20 (587m
g) was dissolved in tetrahydrofuran (10 mL), and -7 was added.
At 8 ° C., lithium hexamethyldisilazane (LiHMD)
A solution of S) in tetrahydrofuran (1.0 M; 1.73 mL) was added dropwise, and after stirring for 10 minutes, N-phenyltrifluoromethanesulfonimide (Tf ₂ NPh; 618 mg) was added, followed by stirring at 0 ° C. for 20 minutes. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give the title compound (1.54 g) having the following physical data.

TLC: Rf 0.68 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.00-6.75 (m, 3H), 5.67 (m, 1
H), 4.79 (m, 1H), 3.84 (s, 3H), 3.50-3.30 (m, 2H),
3.00-2.80 (m, 2H), 2.70-2.40 (m, 2H), 2.40-2.20
(m, 2H), 2.00-1.70 (m, 6H), 1.70-1.50 (m, 2H).

Example 13 (1R, 5R, 7R) -7- (3-Cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid Methyl ester and (1S, 5S, 7S) -7-
(3-cyclopentyloxy-4-methoxyphenyl)
Mixture of -7-cyanobicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid methyl ester

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The compound (1.54 g) produced in Reference Example 22 was treated with dimethylformamide (4 mL) and methanol (2.
20mL) and triphenylphosphine (27.3m
g), palladium acetate (11.7 mg) and triethylamine (0.48 mL) were added, and the mixture was added at room temperature in the presence of carbon monoxide.
Stirred for 0 hours. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3:
The compound of the present invention (62) having the following physical properties was purified by 1).
1 mg).

TLC: Rf 0.50 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.95-6.85 (m, 2H), 6.83 (d, J =
8.4 Hz, 1H), 6.68 (m, 1H), 4.79 (m, 1H), 3.84 (s, 3
H), 3.76 (s, 3H), 3.51 (m, 1H), 3.00-2.80 (m, 2H),
2.65-2.45 (m, 3H), 2.40-2.10 (m, 2H), 2.00-1.75
(m, 6H), 1.70-1.50 (m, 2H).

Example 14 (1R, 5R, 7R) -7- (3-benzyloxy-4
-Methoxyphenyl) -7-cyanobicyclo [3.3.
0] oct-2-en-3-ylcarboxylic acid methyl ester and (1S, 5S, 7S) -7- (3-benzyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octa Mixture of -2-en-3-ylcarboxylic acid / methyl ester

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Instead of 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanenitrile, 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanenitrile
Reference Example 16 → Reference Example 17 → Reference Example 18 → Reference Example 19 → Reference Example 20 → Reference Example 22 → Using Benzyloxy-4-methoxyphenyl) ethanenitrile, the same operation as in Example 13 was carried out. The compound of the present invention having the following physical properties was obtained.

TLC: Rf 0.46 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.47-7.26 (m, 5H), 6.96 (dd, J =
8.4, 2.2 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.87
(d, J = 8.4 Hz, 1H), 6.64 (m, 1H), 5.18 (s, 2H), 3.
89 (s, 3H), 3.75 (s, 3H), 3.44-3.25 (m, 1H), 2.90-
2.35 (m, 5H), 2.27-2.09 (m, 2H).

Examples 15 to 15 (1) The same procedures as in Example 11 were carried out, except that the compounds prepared in Examples 13 and 14 were used instead of the compound A prepared in Example 9. The following compounds of the present invention were obtained.

Example 15 (1R, 5R, 7R) -7- (3-Cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid and Mixture of (1S, 5S, 7S) -7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-en-3-ylcarboxylic acid

Embedded image

TLC: Rf 0.47 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 10.00-9.00 (br, 1H), 6.95-6.85
(m, 2H), 6.90-6.80 (m, 2H), 4.80 (m, 1H), 3.84 (s,
3H), 3.55 (m, 1H), 3.00-2.80 (m, 2H), 2.70-2.50
(m, 3H), 2.33 (dd, J = 13.5, 5.7 Hz, 1H), 2.22 (d
d, J = 12.9, 7.2 Hz, 1H), 2.05-1.70 (m, 6H), 1.70-
1.55 (m, 2H).

Example 15 (1) (1R, 5R, 7R) -7- (3-benzyloxy-4
-Methoxyphenyl) -7-cyanobicyclo [3.3.
0] oct-2-en-3-ylcarboxylic acid and (1
S, 5S, 7S) -7- (3-Benzyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0]
Mixture of oct-2-en-3-ylcarboxylic acids

Embedded image

TLC: Rf 0.33 (chloroform: methanol = 20: 1); NMR (CDCl ₃ ): δ 7.46-7.30 (m, 5H), 6.96 (dd, J =
8.4, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.87
(d, J = 2.4 Hz, 1H), 6.77 (m, 1H), 5.18 (s, 2H), 3.
89 (s, 3H), 3.43-3.30 (m, 1H), 3.00-2.00 (br, 1H),
2.88-2.66 (m, 2H), 2.57-2.39 (m, 3H), 2.29-2.21
(m, 1H), 2.17-2.09 (m, 1H).

Examples 16 to 16 (1) Using the compounds prepared in Examples 15 to 15 (1) in place of the compounds prepared in Example 1, the same procedures as in Reference Example 7 → Example 2 were carried out. By performing the above operation, the following compound of the present invention was obtained.

Example 16 (1R, 5R, 7R) -N-hydroxy-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-ene-3 -Ylcarboxamide and (1S, 5S, 7S) -N-hydroxy-7- (3-cyclopentyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-en-3-yl Mixture of carboxamides

Embedded image

TLC: Rf 0.44 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 8.80-8.20 (br, 1H), 6.95-6.85
(m, 2H), 6.83 (d, J = 9.3 Hz, 1H), 6.42 (m, 1H),
4.79 (m, 1H), 3.84 (s, 3H), 3.59 (m, 1H), 3.10-2.9
0 (m, 2H), 2.65-2.20 (m, 5H), 2.00-1.80 (m, 6H),
1.70-1.55 (m, 3H).

Example 16 (1) (1R, 5R, 7R) -N-hydroxy-7- (3-benzyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2- En-3-ylcarboxamide and (1S, 5S, 7S) -N-hydroxy-7- (3-benzyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] oct-2-
Mixture of en-3-ylcarboxamides

Embedded image

TLC: Rf 0.53 (chloroform: methanol = 9: 1); NMR (Pyridine-d ₅ + CDCl ₃ ) 7.56-7.53 (m, 2H), 7.37-
7.22 (m, 3H), 7.19 (d, J = 2.1 Hz, 1H), 7.04 (dd, J
= 8.4, 2.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.6
0 (m, 1H), 5.79 (br, 2H), 5.17 (s, 2H), 3.77 (s, 3
H), 3.36-3.22 (m, 1H), 3.07-2.94 (m, 1H), 2.72-2.
59 (m, 2H), 2.52-2.37 (m, 2H), 2.17-2.05 (m, 2H).

Reference Example 23 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-hydroxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid・ Methyl ester

Embedded image The same operation as in Reference Example 4 was performed using the compound prepared in Example 14 instead of the compound prepared in Reference Example 3, to obtain the title compound having the following physical data.

TLC: Rf 0.48 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 6.98-6.80 (m, 3H), 5.63 (s, 1H),
3.90 (s, 3H), 3.69 (s, 3H), 2.89-2.58 (m, 3H), 2.
52-2.40 (m, 2H), 2.32-2.17 (m, 4H), 1.97-1.79 (m,
2H).

Example 17 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3,4-dimethoxyphenyl) -7-cyanobicyclo [3.3.0]
Octan-3-ylcarboxylic acid methyl ester

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The compound (0.1 g) produced in Reference Example 23 was dissolved in dimethylformamide (4 mL), and potassium carbonate (0.13 g) and methyl iodide (0.06 mL) were added.
Stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound of the present invention (0.11 g) having the following physical data. The obtained residue was used for the next reaction as it was.

TLC: Rf 0.29 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.85-6.81 (m,
1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.70 (s, 3H), 2.
87-2.74 (m, 1H), 2.74-2.62 (m, 2H), 2.52-2.44 (m,
2H), 2.34-2.20 (m, 4H), 1.96-1.84 (m, 2H).

Examples 17 (1) and 17 (2) The same operation as in Example 17 was carried out using the corresponding halogen derivative in place of methyl iodide to obtain the following compounds of the present invention. Was.

Example 17 (1) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-ethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.
3.0] Octane-3-ylcarboxylic acid methyl ester

Embedded image

TLC: Rf 0.40 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.94-6.89 (m, 2H), 6.85-6.81 (m,
1H), 4.12 (q, J = 7.0Hz, 2H), 3.87 (s, 3H), 3.70
(s, 3H), 2.86-2.74 (m, 1H), 2.74-2.61 (m, 2H), 2.5
1-2.43 (m, 2H), 2.32-2.20 (m, 4H), 1.95-1.83 (m, 2
H), 1.47 (t, J = 7.0 Hz, 3H).

Example 17 (2) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclopropylmethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane -3-ylcarboxylic acid methyl ester

Embedded image

TLC: Rf 0.70 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 6.94-6.90 (m, 2H), 6.85-6.80
(m, 1H), 3.88-3.84 (m, 5H), 3.70 (s, 3H), 2.85-
2.74 (m, 1H), 2.74-2.60 (m, 2H), 2.55 -2.45 (m,
2H), 2.36-2.19 (m, 4H), 1.96-1.82 (m, 2H), 1.
40-1.22 (m, 1H), 0.70-0.60 (m, 2H), 0.41-0.35
(m, 2H).

Example 18 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (indan-2-yloxy) -4-methoxyphenyl) -7-
Cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid methyl ester

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The compound prepared in Reference Example 23 (0.1 g) was dissolved in tetrahydrofuran (3 mL), and
-Ol (63.8 mg), triphenylphosphine (124.
8 mg) and diisopropyl azodicarboxylate (DIPAD; 0.1 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the compound of the present invention (191.7m) having the following physical data.
g) was obtained.

TLC: Rf 0.65 (hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 7.28-7.16 (m, 4H), 6.99-6.95 (m,
2H), 6.87-6.83 (m, 1H), 5.25-5.17 (m, 1H), 3.81
(s, 3H), 3.70 (s, 3H), 3.38 (dd, J = 16.7, 6.6 Hz,
2H), 3.23 (dd, J = 16.7, 3.9 Hz, 2H), 2.87-2.61
(m, 3H), 2.51-2.43 (m, 2H), 2.34-2.21 (m, 4H), 1.96
-1.84 (m, 2H).

Examples 18 to 18 (11) Compounds of the present invention shown below were obtained by subjecting them to the same procedures as in Example 18 using the corresponding alcohol derivatives instead of indan-2-ol. .

Example 18 (1) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-isopropyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid methyl ester

Embedded image

TLC: Rf 0.38 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.96-6.92 (m, 2H), 6.85-6.82 (m,
1H), 4.54 (septet, J = 6.0 Hz, 1H), 3.85 (s, 3H),
3.70 (s, 3H), 2.87-2.74 (m, 1H), 2.74-2.60 (m, 2H),
2.51-2.42 (m, 2H), 2.32-2.20 (m, 4H), 1.95-1.83
(m, 2H), 1.37 (d, J = 6.0 Hz, 6H).

Example 18 (2) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (1-ethylpropoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] Octane-3-ylcarboxylic acid methyl ester

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TLC: Rf 0.49 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.83 (d, J =
8.1 Hz, 1H), 4.11 (m, 1H), 3.84 (s, 3H), 3.70 (s, 3
H), 2.86-2.73 (m, 1H), 2.74-2.61 (m, 2H), 2.50-2.4
1 (m, 2H), 2.32-2.20 (m, 4H), 1.95-1.83 (m, 2H),
1.78-1.63 (m, 4H), 0.98 (t, J = 7.4 Hz, 6H).

Example 18 (3) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclohexyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid
Methyl ester

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TLC: Rf 0.54 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.97-6.91 (m, 2H), 6.86-6.81 (m,
1H), 4.26-4.10 (m, 1H), 3.84 (s, 3H), 3.70 (s, 3
H), 2.90-2.56 (m, 3H), 2.53-2.40 (m, 2H), 2.33-2.1
8 (m, 4H), 2.08-1.68 (m, 6H), 1.68-1.42 (m, 2H),
1.42-1.22 (m, 4H).

Example 18 (4) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclobutyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane -3-ylcarboxylic acid methyl ester

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TLC: Rf 0.40 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 6.91 (dd, J = 8.4, 2.2 Hz, 1H),
6.82 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1
H), 4.68 (quintet, J = 7.0 Hz, 1H), 3.86 (s, 3H),
3.70 (s, 3H), 2.90-2.60 (m, 3H), 2.56-2.36 (m, 4
H), 2.36-2.18 (m, 6H), 1.98-1.66 (m, 4H).

Example 18 (5) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (tetrahydropyran-4-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3. 3.0] Octane-3
-Ylcarboxylic acid methyl ester

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TLC: Rf 0.39 (hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 7.03-6.96 (m, 2H), 6.89-6.83 (m,
1H), 4.50-4.34 (m, 1H), 4.08-3.95 (m, 2H), 3.85
(s, 3H), 3.70 (s, 3H), 3.60-3.48 (m, 2H), 2.89-2.5
8 (m, 3H), 2.51-2.39 (m, 2H), 2.33-2.18 (m, 4H),
2.08-1.76 (m, 6H).

Example 18 (6) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (tetrahydrofuran-2-ylmethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3 .0] octane-
3-ylcarboxylic acid methyl ester

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TLC: Rf 0.40 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 7.00-6.92 (m, 2H), 6.82 (d, J =
8.4 Hz, 1H), 4.02-4.24 (m, 1H), 4.08-3.98 (m, 2H),
3.98-3.77 (m, 2H), 3.85 (s, 3H), 3.70 (s, 3H), 2.8
9-2.55 (m, 3H), 2.55-2.41 (m, 2H), 2.32-2.20 (m, 4
H), 2.20-1.74 (m, 6H).

Example 18 (7) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (4-methylthiobutoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] Octane-3-ylcarboxylic acid methyl ester

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TLC: Rf 0.61 (hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 6.94-6.90 (m, 2H), 6.85-6.81 (m,
1H), 4.05 (t, J = 6.3Hz, 2H), 3.85 (s, 3H), 3.70
(s, 3H), 2.86-2.74 (m, 1H), 2.74-2.62 (m, 2H), 2.5
9 (t, J = 7.2 Hz, 2H), 2.51-2.43 (m, 2H), 2.32-2.2
0 (m, 4H), 2.11 (s, 3H), 2.01-1.75 (m, 4H), 1.73-1.
66 (m, 2H).

Example 18 (8) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (2-methoxyethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] Octane-3-ylcarboxylic acid methyl ester

Embedded image

TLC: Rf 0.33 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 7.00 (d, J = 2.4 Hz, 1H), 6.96
(dd, J = 8.4, 2.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1
H), 4.19 (m, 2H), 3.85 (s, 3H), 3.78 (m, 2H), 3.70
(s, 3H), 3.45 (s, 3H), 2.80 (m, 1H), 2.72-2.60 (m,
2H), 2.51-2.42 (m, 2H), 2.31-2.19 (m, 4H), 1.94-
1.83 (m, 2H).

Example 18 (9) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (2-
(Morpholin-4-yl) ethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid methyl ester

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TLC: Rf 0.47 (ethyl acetate: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.98-6.93 (m, 2H), 6.85-6.81 (m,
1H), 4.17 (t, J = 6.1Hz, 2H), 3.85 (s, 3H), 3.74
(t, J = 4.6 Hz, 2H), 3.70 (s, 3H), 2.84 (t, J = 6.1
Hz, 2H), 2.67-2.74 (m, 1H), 2.74-2.64 (m, 2H), 2.
60 (t, J = 4.6Hz, 2H), 2.50-2.42 (m, 2H), 2.32-2.2
0 (m, 4H), 1.95-1.83 (m, 2H).

Example 18 (10) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (3,
3,3-trifluoropropoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-
3-ylcarboxylic acid methyl ester

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TLC: Rf 0.46 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.01 (dd, J = 8.4, 2.4 Hz, 1H),
6.95 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1
H), 4.25 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.70
(s, 3H), 2.87-2.60 (m, 5H), 2.50-2.42 (m, 2H), 2.3
3-2.20 (m, 4H), 1.96-1.84 (m, 2H).

Example 18 (11) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-((3
S) -1-Methoxycarbonylpyrrolidin-3-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid methyl ester

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TLC: Rf 0.69 (ethyl acetate); NMR (CDCl ₃ ): δ 7.02 (d, J = 8.4, 2.4 Hz, 1H),
6.92 (d J = 2.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H),
4.99-4.88 (m, 1H), 3.83 (s, 3H), 3.72 & 3.71 (s, 3
H), 3.69 (s, 3H), 3.70-3.45 (m, 4H), 2.87-2.74 (m,
1H), 2.74-2.62 (m, 2H), 2.48-2.40 (m, 2H), 2.35-2.
14 (m, 4H), 1.95-1.82 (m, 4H).

Example 19 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3,4-dimethoxyphenyl) -7-cyanobicyclo [3.3.0]
Octan-3-ylcarboxylic acid

Embedded image The compound prepared in Example 17 (0.11 g) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and a 1N aqueous sodium hydroxide solution (1.6 mL) was added.
Stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate,
The compound of the present invention (0.1 g) having the following physical data was obtained.

TLC: Rf 0.53 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.96-6.91 (m, 2H), 6.85-6.81 (m,
1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.91-2.78 (m, 1
H), 2.78-2.65 (m, 2H), 2.52-2.44 (m, 2H), 2.36-2.2
5 (m, 4H), 2.02-1.90 (m, 2H), 1.60 (br, 1H).

Examples 19 (1) to 19 (14) Instead of the compound prepared in Example 17, Example 17 was used.
(1) to Example 17 (2) and Examples 18 to 1
Using the compound prepared in 8 (11), the following compound of the present invention was obtained.

Example 19 (1) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-ethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.
3.0] Octane-3-ylcarboxylic acid

Embedded image

TLC: Rf 0.53 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.94-6.90 (m, 2H), 6.85-6.81 (m,
1H), 4.12 (q, J = 7.1Hz, 2H), 3.87 (s, 3H), 2.90-
2.78 (m, 1H), 2.78-2.64 (m, 2H), 2.51-2.43 (m, 2H),
2.35-2.25 (m, 4H), 2.00-1.89 (m, 2H), 1.55 (br, 1
H), 1.48 (t, J = 7.1 Hz, 3H).

Example 19 (2) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclopropylmethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane -3-ylcarboxylic acid

Embedded image

TLC: Rf 0.40 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.83 (d, J =
9.0 Hz, 1H), 3.87 (s, 3H), 3.87 (d, J = 6.9 Hz, 2
H), 2.90-2.76 (m, 1H), 2.76-2.64 (m, 2H), 2.52-2.4
0 (m, 2H), 2.36- 2.24 (m, 4H), 2.00-1.85 (m, 2H),
1.62 (brs, 1H), 1.42-1.22 (m, 1H), 0.70-0.62 (m, 2
H), 0.42-0.34 (m, 2H).

Example 19 (3) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (indan-2-yloxy) -4-methoxyphenyl) -7-
Cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid

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TLC: Rf 0.52 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 7.27-7.16 (m, 4H), 6.99-6.95 (m,
2H), 6.87-6.83 (m, 1H), 5.25-5.17 (m, 1H), 3.81
(s, 3H), 3.38 (dd, J = 16.5, 6.5 Hz, 2H), 3.21 (d
d, J = 16.5, 3.9 Hz, 2H), 2.91-2.78 (m, 1H), 2.78-
2.65 (m, 2H), 2.51-2.43 (m, 2H), 2.36-2.25 (m, 4
H), 2.01-1.89 (m, 2H), 1.80-1.30 (br, 1H).

Example 19 (4) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-isopropyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid

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TLC: Rf 0.53 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.96-6.92 (m, 2H), 6.86-6.82 (m,
1H), 4.54 (septet, J = 6.0 Hz, 1H), 3.85 (s, 3H),
2.90-2.78 (m, 1H), 2.77-2.64 (m, 2H), 2.50-2.42
(m, 2H), 2.34-2.24 (m, 4H), 2.00-1.88 (m, 2H), 1.6
0 (br, 1H), 1.37 (d, J = 6.0 Hz, 6H).

Example 19 (5) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (1-ethylpropoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] octan-3-ylcarboxylic acid

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TLC: Rf 0.45 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.86-6.82 (m,
1H), 4.16-4.06 (m, 1H), 3.84 (s, 3H), 2.90-2.78
(m, 1H), 2.78-2.65 (m, 2H), 2.49-2.41 (m, 2H), 2.3
4-2.25 (m, 4H), 2.00-1.89 (m, 2H), 1.78-1.63 (m, 4
H), 1.65 (br, 1 H), 0.98 (t, J = 7.4 Hz, 6H).

Example 19 (6) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclohexyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane- 3-ylcarboxylic acid

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TLC: Rf 0.68 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.97-6.92 (m, 2H), 6.86-6.82 (m,
1H), 4.24-4.14 (m, 1H), 3.84 (s, 3H), 2.90-2.78
(m, 1H), 2.76-2.64 (m, 2H), 2.50-2.42 (m, 2H), 2.3
4-2.24 (m, 4H), 2.05-1.88 (m, 4H), 1.88-1.78 (m, 2
H), 1.63-1.49 (m, 3H), 1.42-1.25 (m, 4H).

Example 19 (7) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-cyclobutyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane -3-ylcarboxylic acid

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TLC: Rf 0.57 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.90 (dd, J = 8.3, 2.2 Hz, 1H),
6.82 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1
H), 4.68 (quintet, J = 7.5 Hz, 1H), 3.86 (s, 3H),
2.91-2.78 (m, 1H), 2.78-2.64 (m, 2H), 2.54-2.41
(m, 4H), 2.36-2.19 (m, 6H), 2.00-1.81 (m, 3H), 1.7
8-1.62 (m, 2H).

Example 19 (8) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (tetrahydropyran-4-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3. 3.0] Octane-3
-Ylcarboxylic acid

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TLC: Rf 0.49 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 7.02-6.97 (m, 2H), 6.88-6.84 (m,
1H), 4.47-4.38 (m, 1H), 4.06-3.98 (m, 2H), 3.85
(s, 3H), 3.59-3.50 (m, 2H), 2.90-2.78 (m, 1H), 2.7
8-2.64 (m, 2H), 2.49-2.40 (m, 2H), 2.34-2.25 (m, 4
H), 2.05-1.91 (m, 4H), 1.91-1.77 (m, 2H), 1.56 (b
r, 1H).

Example 19 (9) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (tetrahydrofuran-2-ylmethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3 .0] octane-
3-ylcarboxylic acid

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TLC: Rf 0.49 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.99 (d, J = 2.3 Hz, 1H), 6.95
(dd, J = 8.4, 2.3 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1
H), 4.37-4.28 (m, 1H), 4.08-3.97 (m, 2H), 3.98-3.8
9 (m, 1H), 3.87-3.79 (m, 1H), 3.85 (s, 3H), 2.90-
2.78 (m, 1H), 2.7 8-2.63 (m, 2H), 2.51-2.43 (m, 2
H), 2.34-2.24 (m, 4H), 2.15-2.02 (m, 1H), 2.02-1.87
(m, 4H), 1.87-1.74 (m, 1H), 1.58 (br, 1H).

Example 19 (10) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (4-methylthiobutoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] octan-3-ylcarboxylic acid

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TLC: Rf 0.48 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.95-6.91 (m, 2H), 6.85-6.81 (m,
1H), 4.06 (t, J = 6.3Hz, 2H), 3.86 (s, 3H), 2.91-
2.78 (m, 1H), 2.78-2.65 (m, 2H), 2.59 (t, J = 7.2 H
z, 2H), 2.51-2.43 (m, 2H), 2.35-2.25 (m, 4H), 2.12
(s, 3H), 2.01-1.88 (m, 4H), 1.88-1.75 (m, 2H),
1.61 (br, 1H).

Example 19 (11) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (2-methoxyethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3. 0] octan-3-ylcarboxylic acid

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TLC: Rf 0.54 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 7.00 (d, J = 2.2 Hz, 1H), 6.97
(dd, J = 8.3, 2.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1
H), 4.22-4.07 (m, 2H), 3.86 (s, 3H), 3.80-3.76 (m,
2H), 3.45 (s, 3H), 2.90-2.77 (m, 1H), 2.77-2.63
(m, 2H), 2.50-2.4 2 (m, 2H), 2.34-2.24 (m, 4H), 2.0
0-1.88 (m, 2H), 1.60 (br, 1H).

Example 19 (12) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (2-
(Morpholin-4-yl) ethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid

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TLC: Rf 0.43 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.99 (d, J = 2.2 Hz, 1H), 6.96
(dd, J = 8.5, 2.2 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1
H), 4.31-4.25 (m, 2H), 3.84 (s, 3H), 3.85-3.80 (m,
4H), 3.60-2.80 (br, 1H), 3.07-2.99 (m, 2H), 2.88-
2.74 (m, 5H), 2.74-2.60 (m, 2H), 2.55-2.47 (m, 2
H), 2.34-2.17 (m, 4H), 2.00-1.88 (m, 2H).

Example 19 (13) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (3,
3,3-trifluoropropoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-
3-ylcarboxylic acid

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TLC: Rf 0.68 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 7.01 (dd, J = 8.4, 2.1 Hz, 1H),
6.95 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1
H), 4.26 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 2.91-
2.78 (m, 1H), 2.78-2.60 (m, 4H), 2.50-2.41 (m, 2
H), 2.36-2.25 (m, 4H), 2.01-1.90 (m, 2H), 1.90-1.
40 (br, 1H).

Example 19 (14) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3-((3
S) -1-Methoxycarbonylpyrrolidin-3-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic acid

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TLC: Rf 0.56 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 7.02 (dd, J = 8.4, 2.4 Hz, 1H),
6.92 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1
H), 4.99-4.90 (m, 1H), 3.84 (s, 3H), 3.72 & 3.71
(s, 3H), 3.76-3.51 (m, 4H), 2.91-2.78 (m, 1H), 2.7
8-2.64 (m, 2H), 2.51-2.38 (m, 2H), 3.36-2.16 (m,
5H), 2.16-2.01 (m, 1H), 2.01-1.89 (m, 2H), 1.64 (b
r, 1H).

Examples 20 to 20 (14) Reference examples 7 → using the compounds prepared in Examples 19 to 19 (14) in place of the compounds prepared in Example 1 →
The same operation as in Example 2 was carried out to obtain the following compound of the present invention.

Example 20 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3,4-dimethoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxamide

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TLC: Rf 0.50 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.93 (br, 1H), 9.00 &
8.68 (br, 1H), 7.00-6.91 (m, 3H), 3.77 (s, 3H), 3.
74 (s, 3H), 2.64-2.37 (m, 5H), 2.28-2.18 (m, 2H),
2.02-1.92 (m, 2H), 1.77-1.66 (m, 2H).

Example 20 (1) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-Ethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxamide

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TLC: Rf 0.43 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.35 & 9.98 (br, 1H), 10.17 &
9.75 (br, 1H), 7.00-6.91 (m, 3H), 4.03 (q, J = 6.
9 Hz, 2H), 3.74 (s, 3H), 2.68-2.36 (m, 5H), 2.26-2.
17 (m, 2H), 2.02-1.92 (m, 2H), 1.77-1.65 (m, 2H),
1.31 (t, J = 6.9 Hz, 3H).

Example 20 (2) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-cyclopropylmethoxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-3
-Ilcarboxamide

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TLC: Rf 0.40 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.34 (s, 1H), 8.68 (s, 1H),
7.02-6.94 (m, 3H), 3.81 (d, J = 6.9 Hz, 2H), 3.75
(s, 3H), 2.62-2.38 (m, 5H), 2.28-2.14 (m, 2H), 2.0
2-1.90 (m, 2H), 1.78-1.62 (m, 2H), 1.28-1.12 (m, 1
H), 0.60-0.52 (m, 2H), 0.36-0.26 (m, 2H).

Example 20 (3) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (Indan-2-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxamide

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TLC: Rf 0.31 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 (s, 1H), 8.67 (s, 1H),
7.28-7.24 (m, 2H), 7.19-7.14 (m, 2H), 7.04-6.98
(m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 5.30-5.22 (m, 1
H), 3.69 (s, 3H), 3.38-3.30 (m, 2H), 3.01 (dd, J =
17.1, 2.1 Hz, 2H), 2.65-2.36 (m, 5H), 2.28-2.21
(m, 2H), 2.04-1.94 (m, 2H), 1.79-1.67 (m, 2H).

Example 20 (4) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-isopropyloxy-4-methoxyphenyl)
-7-Cyanobicyclo [3.3.0] octan-3-ylcarboxamide

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TLC: Rf 0.45 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.75 (br, 1H), 8.99 &
8.68 (br, 1H), 7.00-6.92 (m, 3H), 4.57 (septet, J
= 6.0 Hz, 1H), 3.73 (s, 3H), 2.64-2.37 (m, 5H), 2.
24-2.17 (m, 2H), 2.02-1.92 (m, 2H), 1.77-1.65 (m,
2H), 1.23 (d, J = 6.0 Hz, 6H).

Example 20 (5) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (1-ethylpropoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-
3-ylcarboxamide

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TLC: Rf 0.50 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.75 (br, 1H), 8.99 &
8.68 (br, 1H), 6.98-6.92 (m, 3H), 4.23 (quintet, J
= 5.6 Hz, 1H), 3.74 (s, 3H), 2.62-2.36 (m, 5H), 2.
25-2.18 (m, 2H), 2.02-1.92 (m, 2H), 1.77-1.66 (m,
2H), 1.63-4.53 (m, 4H), 0.88 (t, J = 7.5 Hz, 6H).

Example 20 (6) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-cyclohexyloxy-4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-3
-Ilcarboxamide

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TLC: Rf 0.38 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.75 (s, 1H), 8.99 &
8.68 (s, 1H), 7.00-6.92 (m, 3H), 4.35-4.24 (m, 1H),
3.74 (s, 3H), 2.64-2.36 (m, 5H), 2.25-2.16 (m, 2
H), 2.03-1.92 (m, 2H), 1.90-1.83 (m, 2H), 1.77-1.6
4 (m, 4H), 1.55-1.22 (m, 6H).

Example 20 (7) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-cyclobutyloxy-4-methoxyphenyl)
-7-Cyanobicyclo [3.3.0] octan-3-ylcarboxamide

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TLC: Rf 0.27 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 (d, J = 1.5 Hz, 1H), 8.6
8 (d, J = 1.5 Hz, 1H), 6.98-6.91 (m, 2H), 6.83-6.79
(m, 1H), 4.70 (quintet, J = 7.7 Hz, 1H), 3.74 (s,
3H), 2.62-2.33 (m, 7H), 2.24-2.18 (m, 2H), 2.10-
1.92 (m, 4H), 1.82-1.54 (m, 4H).

Example 20 (8) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (tetrahydropyran-4-yloxy) -4
-Methoxyphenyl) -7-cyanobicyclo [3.3.
0] Octane-3-ylcarboxamide

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TLC: Rf 0.30 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.75 (s, 1H), 8.99 &
8.67 (s, 1H), 7.06-6.95 (m, 3H), 4.57-4.46 (m, 1H),
3.88-3.80 (m, 2H), 3.75 (s, 3H), 3.49-3.40 (m, 2
H), 2.57-2.37 (m, 5H), 2.30-2.18 (m, 2H), 2.02-1.8
5 (m, 4H), 1.77-1.66 (m, 2H), 1.64-1.50 (m, 2H).

Example 20 (9) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (tetrahydrofuran-2-ylmethoxy)-
4-methoxyphenyl) -7-cyanobicyclo [3.
3.0] Octane-3-ylcarboxamide

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TLC: Rf 0.31 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 & 9.75 (s, 1H), 8.99 &
8.67 (s, 1H), 7.02-9.62 (m, 3H), 4.19-4.10 (m, 1H),
3.99-3.88 (m, 2H), 3.82-3.72 (m, 1H), 3.75 (s, 3
H), 3.70-3.62 (m, 1H), 2.57-2.34 (m, 5H), 2.24-2.1
7 (m, 2H), 2.04-1.90 (m, 2H), 1.90-1.77 (m, 4H),
1.77-1.62 (m, 2H).

Example 20 (10) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (4-methylthiobutoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxamide

Embedded image

TLC: Rf 0.38 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 (s, 1H), 8.68 (s, 1H),
6.99-6.91 (m, 3H), 3.99 (t, J = 6.2 Hz, 2H), 3.74
(s, 3H), 2.60-2.38 (m, 7H), 2.24-2.18 (m, 2H), 2.0
3 (s, 3H), 2.05-1.92 (m, 2H), 1.83-1.63 (m, 6H).

Example 20 (11) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (2-methoxyethoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane-
3-ylcarboxamide

Embedded image

TLC: Rf 0.37 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.34 (s, 1H), 8.67 (s, 1H),
7.01-6.92 (m, 3H), 4.12-4.08 (m, 2H), 3.75 (s, 3
H), 3.66-3.62 (m, 2H), 3.30 (s, 3H), 2.64-2.37 (m,
5H), 2.24-2.17 (m, 2H), 2.02-1.92 (m, 2H), 1.77-1.
65 (m, 2H).

Example 20 (12) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (2- (morpholin-4-yl) ethoxy)-
4-methoxyphenyl) -7-cyanobicyclo [3.
3.0] Octane-3-ylcarboxamide

Embedded image

TLC: Rf 0.51 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.75 (br, 1H), 10.37 (s, 1H),
10.19 (s, 1H), 7.15-7.06 (m, 2H), 7.01 (d, J = 8.
7 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.03-3.93 (m,
2H), 3.82-3.73 (m, 2H), 3.77 (s, 3H), 3.60-3.15
(m, 2H), 2.65-2.35 (m, 7H), 2.26-2.20 (m, 4H), 2.0
3-1.93 (m, 2H), 1.78-1.65 (m, 2H).

Example 20 (13) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (3,3,3-trifluoropropoxy) -4
-Methoxyphenyl) -7-cyanobicyclo [3.3.
0] Octane-3-ylcarboxamide

Embedded image

TLC: Rf 0.35 (chloroform: methanol = 10: 1); NMR (DMSO-d ₆ ): δ 10.33 (s, 1H), 8.66 (s, 1H),
7.05-7.01 (m, 2H), 6.99-6.95 (m, 1H), 4.21 (t, J =
6.2 Hz, 2H), 3.75 (s, 3H), 2.85-2.69 (m, 2H), 2.6
4-2.38 (m, 5H), 2.28-2.18 (m, 2H), 2.02-1.93 (m, 2
H), 1.78-1.66 (m, 2H).

Example 20 (14) (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3-((3S) -1-methoxycarbonylpyrrolidin-3-yloxy) -4-methoxyphenyl) -7-
Cyanobicyclo [3.3.0] octan-3-ylcarboxamide

Embedded image

TLC: Rf 0.48 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.34 (s, 1H), 8.67 (s, 1H),
7.07-6.96 (m, 3H), 5.02 (m, 1H), 3.74 (s, 3H), 3.59
& 3.58 (s, 3H), 3.55-3.25 (m, 4H), 2.62-2.40 (m,
5H), 2.25-2.19 (m, 2H), 2.14-1.92 (m, 4H), 1.77-1.
65 (m, 2H).

Example 21 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (4-hydroxybutoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octane -3-ylcarboxylic acid

Embedded image Example 1 using 4- (tetrahydropyran-2-yloxy) butanol instead of indan-2-ol
8 → Example 19 → By performing the same operation as in Example 2, a compound of the present invention having the following physical data was obtained.

TLC: Rf 0.59 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.95-6.90 (m, 2H), 6.85-6.81 (m,
1H), 4.08 (t, J = 6.0Hz, 2H), 3.86 (s, 3H), 3.74
(t, J = 6.0 Hz, 2H), 2.90-2.78 (m, 1H), 2.78-2.64
(m, 2H), 2.51-2.43 (m, 2H), 2.35-2.24 (m, 4H), 2.0
2-1.89 (m, 4H), 1.83-1.76 (m, 2H), 2.00-1.50 (br,
1H).

Example 22 (1R ^* , 3S ^* , 5S ^* , 7R ^* )-N-hydroxy-7
-(3- (4-hydroxybutoxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxamide

Embedded image The compound of Example 21 was used instead of the compound of Example 1, and the same operation as in Reference Example 7 → Example 2 was performed to obtain a compound of the present invention having the following physical data.

TLC: Rf 0.50 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 10.33 (s, 1H), 8.66 (s, 1H),
6.99-6.91 (m, 3H), 4.41 (t, J = 5.3 Hz, 1H), 3.98
(t, J = 6.5 Hz, 2H), 3.74 (s, 3H), 3.48-3.41 (m, 2
H), 2.64-2.38 (m, 5H), 2.24-2.18 (m, 2H), 2.02-1.9
3 (m, 2H), 1.78-1.66 (m, 4H), 1.60-1.50 (m, 2H).

Examples 23 to 23 (4) The compound prepared in Example 5 instead of the compound prepared in Example 1, and (1-methoxy-1-methylethyl)
The same operation as in Reference Example 7 was carried out using the corresponding amine derivative instead of oxyamine to obtain the present compound shown below.

Example 23 (1R, 5R, 7S) -N-phenylsulfonyl-7-
(3-cyclopentyloxy-4-methoxyphenyl)
Bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7R) -N-phenylsulfonyl-7- (3-cyclopentyloxy-4-
Methoxyphenyl) bicyclo [3.3.0] octa-2
Mixture of -en-3-ylcarboxamides

Embedded image

TLC: Rf 0.57 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 8.19 (br.s, 1H), 8.20-8.10 (m, 2
H), 7.66 (m, 1H), 7.60-7.50 (m, 2H), 6.78 (d, J =
8.7 Hz, 1H), 6.75-6.65 (m, 2H), 6.47 (m, 1H), 4.75
(m, 1H), 3.81 (s, 3H), 3.48 (m, 1H), 3.05-2.08
(m, 3H), 2.33 (m, 1H), 2.00-1.70 (m, 10H), 1.70-1.5
0 (m, 2H).

Example 23 (1) (1R, 5R, 7S) -N-methoxy-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3- Ilcarboxamide and (1S, 5S, 7R) -N-methoxy-7-
(3-cyclopentyloxy-4-methoxyphenyl)
Mixture of bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

TLC: Rf 0.27 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 8.22 (s, 1H), 6.79 (d, J = 8.7 H)
z, 1H), 6.75-6.70 (m, 2H), 6.43 (m, 1H), 4.76 (m, 1
H), 3.83 (s, 3H), 3.82 (s, 3H), 3.47 (m, 1H), 3.10
-2.85 (m, 3H), 2.34 (m, 1H), 2.00-1.80 (m, 10H),
1.75-1.55 (m, 2H).

Example 23 (2) (1R, 5R, 7S) -N-mesyl-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3- Ilcarboxamide and (1S, 5S, 7R) -N-mesyl-7-
(3-cyclopentyloxy-4-methoxyphenyl)
Mixture of bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

TLC: Rf 0.46 (hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 7.94 (br.s, 1H), 6.80 (d, J = 8).
7 Hz, 1H), 6.75-6.70 (m, 2H), 6.55 (m, 1H), 4.77
(m, 1H), 3.82 (s, 3H), 3.55 (m, 1H), 3.37 (s, 3H),
3.20-2.80 (m, 3H), 2.41 (m, 1H), 2.00-1.75 (m, 10
H), 1.75-1.55 (m, 2H).

Example 23 (3) (1R, 5R, 7S) -N-methyl-N-methoxy-7
-(3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7R) -N-methyl-N-methoxy-7- ( Mixture of 3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

TLC: Rf 0.61 (hexane: ethyl acetate =
1: 1); NMR (CDCl ₃ ): δ 6.79 (d, J = 8.4 Hz, 1H), 6.75-
6.70 (m, 2H), 6.31 (m, 1H), 4.76 (m, 1H), 3.81 (s,
3H), 3.68 (s, 3H), 3.50 (m, 1H), 3.26 (s, 3H), 3.2
0-2.90 (m, 3H), 2.51 (m, 1H), 2.00-1.75 (m, 10H),
1.70-1.55 (m, 2H).

Example 23 (4) (1R, 5R, 7S) -N- (3,5-dimethylisoxazol-4-ylsulfonyl) -7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3 .3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7R) -N- (3,5-dimethylisoxazol-4-ylsulfonyl) -7-
(3-cyclopentyloxy-4-methoxyphenyl)
Mixture of bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

TLC: Rf 0.66 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 8.20 (s, 1H), 6.79 (d, J = 9.0 H)
z, 1H), 6.75-6.70 (m, 2H), 6.50 (m, 1H), 4.76 (m, 1
H), 3.82 (s, 3H), 3.53 (m, 1H), 3.10-2.80 (m, 3H),
2.78 (s, 3H), 2.46 (s, 3H), 2.36 (m, 1H), 2.00-1.
75 (m, 10H), 1.80-1.55 (m, 2H).

Example 24 (1R, 5R, 7S) -7- (3-Cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1R, 5R, 7S) -7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide
(S, 5S, 7R) -7- (3-cyclopentyloxy-
Mixture of 4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamides

Embedded image

The compound prepared in Example 5 (200 mg)
Was dissolved in methylene chloride (1 mL), oxalyl chloride (57.3 μL) and dimethylformamide (1 drop) were added at 0 ° C., and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. The residue was treated with tetrahydrofuran (0.5 m
L). In another container, a 28% aqueous ammonia solution (1 mL) and tetrahydrofuran (0.5 mL) were stirred at 0 ° C., the solution prepared above was added dropwise, and the mixture was stirred for 20 minutes. The reaction mixture was diluted with 2N hydrochloric acid and extracted with methylene chloride. The extract was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
Ether was added to the residue, and the mixture was pulverized and filtered to obtain the compound of the present invention (154 mg) having the following physical data.

TLC: Rf 0.56 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 6.80 (d, J = 9.0 Hz, 1H), 6.80-
6.70 (m, 2H), 6.40 (m, 1H), 5.44 (br, 2H), 4.76 (m,
1H), 3.82 (s, 3H), 3.49 (m, 1H), 3.15-2.90 (m, 3
H), 2.38 (m, 1H), 2.00-1.70 (m, 10H), 1.70-1.55
(m, 2H).

Examples 24 to 24 (3) The same operation as in Example 24 was carried out using the compound prepared in Example 5 or the compound prepared in Example 3, and an aqueous ammonia solution or a corresponding amine derivative. As a result, the following compound of the present invention was obtained. Example 24
In (2), the reaction was carried out by further adding sodium hydride.

Example 24 (1) (1R, 5R, 7S) -N-amino-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3- Ilcarboxamide and (1S, 5S, 7R) -N-amino-7-
(3-cyclopentyloxy-4-methoxyphenyl)
Mixture of bicyclo [3.3.0] oct-2-en-3-ylcarboxamide

Embedded image

TLC: Rf 0.44 (chloroform: methanol = 10: 1); NMR (CDCl ₃ ): δ 10.32 (br, 1H), 6.75-6.60 (m, 4
H), 4.71 (m, 1H), 3.76 (s, 3H), 3.38 (m, 1H), 3.05-
2.80 (m, 3H), 3.00-2.00 (br, 2H), 2.39 (m, 1H), 2.
00-1.60 (m, 10H), 1.65-1.40 (m, 2H).

Example 24 (2) (1R, 5R, 7S) -N- (3,5-dichloropyridin-4-yl) -7- (3-cyclopentyloxy-4
-Methoxyphenyl) bicyclo [3.3.0] octa-
2-en-3-ylcarboxamide and (1S, 5
(S, 7R) -N- (3,5-dichloropyridin-4-yl) -7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-ene-
Mixture of 3-ylcarboxamides

Embedded image

TLC: Rf 0.34 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 8.55 (s, 2H), 7.29 (br, 1H), 6.8
5-6.70 (m, 3H), 6.62 (m, 1H), 4.78 (m, 1H), 3.83
(s, 3H), 3.58 (m, 1H), 3.20-3.00 (m, 3H), 2.53 (m,
1H), 2.05-1.80 (m, 10H), 1.80-1.55 (m, 2H).

Example 24 (3) (1S ^* , 3R ^* , 5R ^* , 7S ^* )-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.
3.0] Octane-3-ylcarboxamide

Embedded image

TLC: Rf 0.74 (chloroform: methanol = 9: 1); NMR (CDCl ₃ ): δ 6.81-6.73 (m, 3H), 5.39 (br, 1)
H), 5.27 (br, 1H), 4.86-4.74 (m, 1H), 3.82 (s, 3
H), 3.08 (m, 1H), 2.76 (m, 1H), 2.66-2.51 (m, 2H),
2.29-2.15 (m, 4H), 1.98-1.78 (m, 6H), 1.71-1.39
(m, 6H).

Example 25 (1R, 5R, 7S) -N-phenylsulfonylamino-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-
Ilcarboxamide and (1S, 5S, 7R) -N-
Phenylsulfonylamino-7- (3-cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.
0] Mixture of oct-2-en-3-ylcarboxamides

Embedded image The compound (50.3 mg) produced in Example 24 (1) was dissolved in pyridine (2 mL), phenylsulfonyl chloride (18.0 μL) was added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) and pulverized and filtered with isopropyl ether to obtain the compound of the present invention (54.9 mg) having the following physical data.

TLC: Rf 0.26 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 8.00-7.90 (m, 2H), 7.70-7.55 (m,
2H), 7.55-7.45 (m, 2H), 7.35 (d, J = 6.0 Hz, 1H),
6.79 (d, J = 9.0 Hz, 1H), 6.80-6.65 (m, 2H), 6.35
(m, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.44 (m, 1
H), 3.00 (m, 1H), 2.90-2.75 (m, 2H), 2.22 (m, 1H),
2.00-1.70 (m, 10H), 1.70-1.50 (m, 2H).

Example 25 (1) (1R, 5R, 7S) -N-mesylamino-7- (3-
Cyclopentyloxy-4-methoxyphenyl) bicyclo [3.3.0] oct-2-en-3-ylcarboxamide and (1S, 5S, 7R) -N-mesylamino-7- (3-cyclopentyloxy-4-methoxy Phenyl) bicyclo [3.3.0] oct-2-en-3-
Mixture of ilcarboxamide

Embedded image The same operation as in Example 25 was performed using mesyl chloride instead of phenylsulfonyl chloride to obtain the compound of the present invention having the following physical data.

TLC: Rf 0.26 (hexane: ethyl acetate =
2: 1); NMR (CDCl ₃ ): δ 7.74 (d, J = 5.0 Hz, 1H), 6.99
(d, J = 5.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.8
0-6.70 (m, 2H), 6.59 (m, 1H), 4.77 (m, 1H), 3.82
(s, 3H), 3.53 (m, 1H), 3.20-2.80 (m, 3H), 3.03 (m,
3H), 2.39 (m, 1H), 2.00-1.80 (m, 10H), 1.70-1.55
(m, 2H).

[0354]

Formulation Example 1 Formulation Example 1 The following components are mixed by a conventional method and then tableted to give a tablet 100 containing 50 mg of the active ingredient in one tablet.
I got a tablet. -(1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (indan-2-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic Acids 5.0 g Carboxymethylcellulose calcium (disintegrant) 0.2 g Magnesium stearate (lubricant) 0.1 g Microcrystalline cellulose 4.7 g

Formulation Example 2 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 5 ml portions, freeze-dried by a conventional method, and contains 20 mg of the active ingredient in one ampule. 100 ampoules were obtained. -(1R ^* , 3S ^* , 5S ^* , 7R ^* )-7- (3- (indan-2-yloxy) -4-methoxyphenyl) -7-cyanobicyclo [3.3.0] octan-3-ylcarboxylic Acid 2.0 g Mannitol 20 g Distilled water 1000 ml

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/351 A61K 31/351 4C086 31/40 31/40 4C206 31/41 31/41 4H006 31/44 31 / 44 31/5375 31/5375 A61P 3/04 A61P 3/04 9/00 9/00 19/10 19/10 25/16 25/16 25/24 25/24 29/00 29/00 35/02 35 / 02 37/02 37/02 37/08 37/08 43/00 111 43/00 111 C07C 235/40 C07C 235/40 243/36 243/36 255/47 255/47 259/08 259/08 311 / 49 311/49 311/51 311/51 323/12 323/12 C07D 207/16 C07D 207/16 213/76 213/76 261/10 261/10 295/08 295/08 Z 307/12 307/12 309 / 10 309/10 F term (reference) 4C037 CA08 4C055 AA01 BA01 CA03 CA39 DA53 DB03 DB08 4C056 AA01 AB01 AC01 AD01 AE03 FA12 4C062 AA22 4C069 AA12 BB49 BC05 4C086 AA03 BA03 BA07 BC07 BC17 BC67 ZC73 NA14 ZA ZA97 ZB02 ZB11 ZB13 ZB27 ZC02 ZC35 4C206 AA03 DA13 DA21 GA28 HA13 NA14 ZA02 ZA12 ZA36 ZA70 ZA97 ZB02 ZB11 ZB13 ZB27 ZC02 ZC35 4H006 AA01 AB20 AB21 AB22 AB26 AB27 AB28 BJ04 BP30 BP30 TA30

Claims (1)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ is 1) hydroxyl group, 2) C1-8 alkoxy group, 3) —NR ⁵ OR ⁶ group, 4) —NR ⁷ R ⁸ group, 5) —NR ⁹ NR ¹⁰ R ¹¹ group, 6) —NR ¹² SO ₂ R ¹³ group, or 7) —NR ¹⁴ NR ¹⁵ SO ₂ R ¹⁶ group, wherein R ⁵ and R
⁶ each independently represent a hydrogen atom or a C1-8 alkyl group,, R ⁷ and R ⁸ each independently represent a hydrogen atom, C1-8 alkyl group, or a heterocyclic -1,, R ^9, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom or a C1~8 alkyl group,, R ¹² represents a hydrogen atom or a C1~8 alkyl group,, R ¹³ is C1
8 alkyl group, a carbocyclic -1 or heterocyclic -2,, R ¹⁴ and R ¹⁵ are each independently a hydrogen atom,
Or it represents a C1~8 alkyl group, R ¹⁶ represents a C1~8 alkyl group or a carbocyclic -2,, R ² is 1) hydrogen or 2) a cyano group,, R ³ and R ⁴ are each independently 1) C1-8 alkyl group, 2) C3-7 cycloalkyl group, 3) carbocycle-3, 4) heterocycle-4, 5) C1-8 substituted by 1 to 3 halogen atoms. An alkyl group, 6) a C1-8 alkyl group substituted with a hydroxyl group, a C1-8 alkyl group, or a C1-8 alkylthio group, 7) a C1-8 alkyl group substituted with a C3-7 cycloalkyl group, 8) carbon A C1-8 alkyl group substituted with ring-4, or 9) a C1-8 alkyl group substituted with heterocycle-4, Represents 1) a single bond or 2) a double bond, wherein carbocycle-1, carbocycle-2, carbocycle-3 and carbocycle-4 are each independently a monocyclic, bicyclic or tricyclic Represents a carbocyclic aryl which may be partially saturated, and heterocycle-1, heterocycle-2, heterocycle-3 and heterocycle-4 are each independently selected from a nitrogen atom, an oxygen atom and a sulfur atom A monocyclic, bicyclic or tricyclic, all or partially saturated heterocyclic aryl containing from 1 to 4 heteroatoms, wherein carbocycle-1, carbocycle-2, carbocycle- 3, carbocycle-4, heterocycle-1, heterocycle-2, heterocycle-3
And heterocycle-4 may be substituted with 1-3 C1-8 alkyl groups, C1-8 alkoxy groups, or halogen atoms. A) a bicyclooctane derivative,
Or their non-toxic salts.