JPH07300455A - 3-phenylpyrrolidine derivative - Google Patents

Abstract

(57) [Summary] [Structure] The following general formula (I): R ¹ : C ₁ -C ₄ alkyl group R ² : tetrahydrofuranyl group, C ₁ -C ₇ alkyl group, C ₃ -C ₈ cycloalkyl group, etc. A: Etc. Y: —O—, —NH—, etc. R ³ : A 3-phenylpyrrolidine derivative represented by a heterocyclic residue which may have a substituent, its optical antipode or its salt, its N— Oxide derivatives, hydrates or solvates thereof. [Effect] The 3-phenylpyrrolidine derivative of the present invention is
It has an excellent phosphodiesterase IV inhibitory action and can be used as a therapeutic drug for asthma and the like.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 3-phenylpyrrolidine derivative, more specifically, a 3-phenylpyrrolidine derivative having a phosphodiesterase (PDE) IV inhibitory effect, its optical antipode, its salts, and their N -Oxide derivatives, their hydrates or their solvates.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION cA
MP is an important second messenger involved in the relaxation of airway smooth muscle and the regulation of inflammatory cell function, which is degraded by phosphodiesterase (PDE) to an inactive 5'-AMP. Therefore, it is considered that bronchodilation and anti-inflammatory effects can be obtained by suppressing the degradation by PDE and increasing the concentration of cAMP, and there is interest in PDE inhibitors (suppressing the degradation of cAMP) as a therapeutic agent for asthma. It is rising. In addition, in recent years, five types of PDE isozymes (PDE I, II, III, IV, V) have been isolated,
Their specific tissue distribution has become clear (Ad
v. Second Messenger Phosph
oprotein Res. , 22 , 1 (1988),
Trends Pharm. , Sci. , 11 , 150
(1990)).

Among the inhibitors for these isozymes, it has been suggested that a specific inhibitor for PDEIV may be useful in the treatment of asthma (Thorax,
46 , 512 (1991)). Examples of the compound having a specific inhibitory action on PDEIV include, for example, JP-A-50-15.
The compound (rolipram) described in 7360 is known.

[0004]

[Chemical 6]

Other than this, various compounds are known (Japanese Patent Application Laid-Open No. 4-253945, Japanese Patent Application Laid-Open No. 5-1172).
39 gazette, WO9115451 gazette, WO9207
567, EP497564, WO9219
No. 594, etc.) has not been clinically applied so far, and further useful compounds are desired to be developed.
J. Pharm. Sci. , 73 , 1585 (198
4) has the following formula

[0006]

[Chemical 7]

The compounds represented by and their dopamine activity have been described. Eur. J. Med. , 2
7 , 407 (1992) has the following formula

[0008]

[Chemical 8]

The compounds represented by and their affinity for dopamine receptors have been described. J. Or
g. Chem. , 58 , 36 (1993) has the following formula

[0010]

[Chemical 9]

Although the compound represented by the formula is described, there is no description about its physiological activity. Swiss Patent No. 5265
The following formula for No. 35

[0012]

[Chemical 10]

The compound represented by is described as a synthetic intermediate. Japanese Patent Publication No. Sho 49-16871 discloses the following formula

[0014]

[Chemical 11]

The compound represented by the formula is described as having an anti-peptic ulcer action. JP-A-50-1573
No. 60 publication has the following general formula

[0016]

[Chemical 12]

(In the above formula, R ¹ and R ² represent a C ₁ -C ₅ alkyl group, R ³ represents a hydrogen atom or a methoxy group, and R ⁴ represents a hydrogen atom, an alkyl group, an aryl group or an acyl group. And X represents an oxygen atom or a sulfur atom.)
The compound represented by is described as a therapeutic agent for neuropsychiatric disorders. Japanese Patent Publication No. 61-2660 discloses the following general formula.

[0018]

[Chemical 13]

(In the above formula, R ¹ and R ² may be the same or different and may be a C _{1 to} C ₅ alkyl group, R ⁵ may be up to C ₈ O-aralkyl group, O-aryl group, NH-aryl. Group, NH-aralkyl group, N- (alkyl) ₂ group, N
-(Aryl) ₂ groups or

[0020]

[Chemical 14]

Represents a group. ) Are described as therapeutic agents for neuropsychiatric disorders. JP-A-2-12196
No. 4 publication has the following formula

[0022]

[Chemical 15]

The compound represented by the formula is described as having calcium antagonistic activity. European Patent 3
No. 44577 has the following formula

[0024]

[Chemical 16]

The compound represented by the formula is described as a therapeutic agent for ischemic heart disease.

[0026]

The present inventors have found that PVE IV
As a result of conducting a search for the purpose of providing a novel compound having an inhibitory action, it was found that a specific 3-phenylpyrrolidine derivative has excellent physiological activity, and the present invention has been completed. That is, the gist of the present invention is the following general formula (I)

[0027]

[Chemical 17]

[In the above formula, R ¹ represents a C _{1 to} C ₄ alkyl group, R ² is a tetrahydrofuranyl group, and C _{1 to} C ₇
Alkyl group, C ₁ -C ₇ haloalkyl group, C ₂ -C
₇ alkenyl groups, bicyclo [2,2,1] hept-2
An yl group or a C ₃ -C ₈ cycloalkyl group,
A is

[0029]

[Chemical 18]

(R^Four Is C₁ ~ C_Four The alkyl group of
You ), Y is -O-, -S-, -ON-CH = CH.
-, -NR^Five -(R^Five Is a hydrogen atom, C₁ ~ C_Four The archi
Lu group, C₂~ C_FourAlkylcarbonyl group or pyridinium
Represents a methyl group. ) Or a single bond, R³ Is replaced
C which may have a group₁ ~ C₇ Or an alkyl group of
(CH₂ ) _n-B (n represents an integer of 0 to 4, B is it)
Phenyl group and naphthyl, each of which may have a substituent
Represents a group or a heterocyclic residue. However, -A-Y-R³ But

[0031]

[Chemical 19]

And R ¹ and R ² do not simultaneously represent a methyl group. ) Represents. ] Represented by 3
A phenylpyrrolidine derivative, an optical antipode thereof, a salt thereof, an N-oxide derivative thereof, a hydrate thereof, or a solvate thereof, and a pharmaceutical composition containing the same as an active ingredient. The present invention will be described in detail below. The following general formula (I)
At

[0033]

[Chemical 20]

R ¹ is a C ₁ -C ₄ linear or branched alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group). Group, etc.), preferably a methyl group or an ethyl group, and more preferably a methyl group.

R² Is a tetrahydrofuranyl group, C₁ ~ C
₇ Straight or branched chain alkyl groups (methyl, ethyl
Group, n-propyl group, isopropyl group, n-butyl group,
Isobutyl group, sec-butyl group, t-butyl group, n-
Pentyl group, 1,2-dimethylpropyl group, 1,1-di
Methylpropyl group, n-hexyl group, 1-methylpentyl
Group, 2-methylpentyl group, 3-methylpentyl group,
4-methylpentyl group, 1,1-dimethylbutyl group,
2,2-dimethylbutyl group, 3,3-dimethylbutyl
Group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl
Group, 1,2,2-trimethylpropyl group, heptyl
Group, 5-methylhexyl group, 2,2-dimethylpentyl group
Group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group
Group, 1,2-dimethylpentyl group, 1,3-dimethyl
Cylpentyl group, 1,4-dimethylpentyl group, 1,
2,3-trimethylbutyl group, 1,1,2-trimethyl
Butyl group, 1,1,3-trimethylbutyl group, etc.), C₁
~ C₇Haloalkyl groups (chloromethyl group, bromomethyl group
Group, dichloromethyl group, 1-chloroethyl group, 2-chloro group
Roloethyl group, 3-chloropropyl group, 4-chlorobutyi
Group, 5-chloropentyl group, 6-chlorohexyl group,
Difluoromethyl group, trifluoromethyl group, etc.), C ₂
~ C₇Alkenyl groups (vinyl, allyl, 2-pro
Penenyl group, isopropenyl group, 3-butenyl group, 4-pentenyl group
Intenyl group, 5-hexenyl group, etc.), bicyclo [2,2
2,1] Hept-2-yl group or C₃ ~ C₈ The cyclo
Alkyl group (cyclopropyl group, cyclobutyl group, cyclo)
Ropentyl group, cyclohexyl group, cycloheptyl group
Etc.), preferably a tetrahydrofuranyl group, C₃ 
~ C₆ Alkyl group or C_Four ~ C₆ Cycloalkyl
A group, more preferably a cyclopentyl group. A is

[0036]

[Chemical 21]

{R ⁴ is a C ₁ -C ₄ linear or branched alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t- Butyl group, etc.), and preferably

[0038]

[Chemical formula 22]

Represents Y is -O-, -S-, -ON =
CH-, -NR ⁵ {R ⁵ is a hydrogen atom, a C ₁ -C ₄ linear or branched alkyl group (methyl group, ethyl group, n-
Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, etc.) or pyridylmethyl group. } Or a single bond, preferably —O—, —S—, —NR ⁵ — (R ⁵ is as defined above) or a single bond, more preferably —O— or —NR ⁵ — (R ⁵ is As defined above).

R ³ is a substituent [halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C ₁ -C ₄
Linear or branched alkoxy group (methoxy group, isopropoxy group, butoxy group, etc.), C ₁ -C ₄ linear or branched alkylthio group (methylthio group, isopropylthio group, butylthio group, etc.), C _1- C ₄ linear or branched alkylsulfinyl group (methylsulfinyl group, isopropylsulfinyl group, butylsulfinyl group, etc.), C ₁ -C ₄ linear or branched alkylsulfonyl group (methylsulfonyl group, isopropylsulfonyl group, butyl) Sulfonyl group, etc.), cyano group, nitro group,
Amino group, hydroxy group, carboxy group, benzyloxy group, C ₁ -C ₄ acyl group (formyl group, acetyl group, propionyl group, etc.), C ₂ -C ₄ alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group) Etc.), C ₁ -C ₄ linear or branched alkylamino groups (methylamino group, isopropylamino group, butylamino group, etc.), C ₂ -C ₆ linear or branched dialkylamino groups (dimethylamino group) , Diethylamino group, etc.),

[0041]

[Chemical formula 23]

{R⁶ , R⁸ , R⁹ Each independently water
Elementary atom or C₁ ~ C_Four Straight or branched chain alkyl
Groups (methyl group, ethyl group, n-propyl group, isopropyl group
Group, n-butyl group, isobutyl group, sec-butyl
Group, t-butyl group, etc.), R ⁷ Is C₁ ~ C_Four Straight chain of
Or branched chain alkyl group (methyl group, ethyl group, n-type
Ropyl group, isopropyl group, n-butyl group, isobutyl group
Group, sec-butyl group, t-butyl group, etc.). }etc
One or more substituents selected from the group consisting of,
Halogen atom, C₁ ~ C_Four The alkoxy group of hydroxy
Base, C₁ ~ C_Four Alkylamino group and C₂ ~ C₆ of
One or more units selected from the group consisting of dialkylamino groups
C, which may have a substituent]₁ ~ C₇ Straight or minute
Branched chain alkyl group (same as above) or-(CH₂ )_n−
B {n represents an integer of 0 to 4, preferably an integer of 0 to 2
Represents a number, more preferably 1 or 2. B is each
Is a substituent [halogen atom (fluorine atom, chlorine atom, bromine
Atom, iodine atom, etc.), C₁ ~ C _Four Straight chain or branched
Chain alkyl group (methyl group, ethyl group, n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec
-Butyl group, t-butyl group, etc.), C₁ ~ C_Four Straight chain if
Or branched chain alkoxy group (methoxy group, isopropoxy group)
Group, butoxy group, etc.), C₁ ~ C_Four Straight or branched chain
Alkylthio group (methylthio group, isopropylthio group,
Butylthio group), C₁ ~ C_Four Straight or branched chain
Rukylsulfinyl group (methylsulfinyl group, isoprene
Ropilsulfinyl group, butylsulfinyl group, etc.), C
₁ ~ C_Four Linear or branched alkylsulfonyl group
(Methylsulfonyl group, isopropylsulfonyl group,
Tylsulfonyl group, etc.), cyano group, nitro group, amino
Group, hydroxy group, carboxy group, C₁ ~ C_Four The acyl
Group (formyl group, acetyl group, propionyl group, etc.), C
₂ ~ C_Four Alkoxycarbonyl group of (methoxycarbonyl
Group, ethoxycarbonyl group, etc.), C₁ ~ C_Four Straight chain
Or branched-chain alkylamino groups (methylamino group,
Propylamino group, butylamino group, etc.), C₂ ~ C₆ of
Linear or branched dialkylamino group (dimethylamido)
Group, diethylamino group, etc.),

[0043]

[Chemical formula 24]

(R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above),

[0045]

[Chemical 25]

{R^TenIs C₁ ~ C_Four Straight or branched chain
Alkyl group (methyl group, ethyl group, n-propyl group, iso
Propyl group, n-butyl group, isobutyl group, sec-butyl
A tyl group, a t-butyl group, etc.), R¹¹Is C₃~ C₈of
Cycloalkyl group (cyclopropyl group, cyclobutyl
Group, cyclopentyl group, cyclohexyl group, cyclohep
Cyl group) or C₁ ~ C_Four Straight or branched chain
Kill group (methyl group, ethyl group, n-propyl group, isop
Ropyl group, n-butyl group, isobutyl group, sec-butyl
Group, t-butyl group, etc.). } And pyridyl groups, etc.
One or more substituents selected from the group consisting of,
Halogen atom, C₁ ~ C_Four Alkyl group of C ₁ ~ C_Four of
Alkoxy, cyano, nitro, amino, hydro
Selected from the group consisting of xy, phenyl and pyridyl groups.
Optionally substituted one or more substituents], phenyl
Group, naphthyl group or heterocyclic residue (thienyl group, furyl
Group, pyrrolyl group, imidazolyl group, pyrazolyl group, tri
Azolyl group, tetrazolyl group, pyridyl group, pyrrolidini
Group, piperidyl group, piperidino group, oxazolyl group,
Isoxazolyl group, thiazolyl group, isothiazolyl
Group, morpholinylyl group, morpholino group, piperazinyl
Group, pyridazinyl group, pyrazinyl group, pyrimidinyl group,
Triazinyl group, 1,2,3,4-tetrahydroquinoli
N-2-yl group, 5,6,7,8-tetrahydro-1,
Oxygen such as 6-naphthyridin-6-yl group and indolyl group
1 hetero atom selected from atom, sulfur atom and nitrogen atom
Having 4 to 4 and having a total number of atoms constituting the ring of 5 to 10,
Preferably, it is a thienyl group, a furyl group, an imidazolyl group or a phenyl group.
Razolyl group, pyridyl group, pyrrolidinyl group, piperidyl
Group, piperidino group, oxazolyl group, isoxazolyl
Group, thiazolyl group, isothiazolyl group, pyridazinyl
Group, pyrazinyl group, pyrimidinyl group, 1,2,3,4-
Tetrahydroquinolin-2-yl group, indolyl group or
Is 5,6,7,8-tetrahydro-1,6-naphthyridyl
N-6-yl group, more preferably pyridyl group, piperidi
Group, piperidino group, piperazinyl group, pyridazinyl
Group, pyrazinyl group, pyrimidinyl group etc. as a hetero atom
Represents a 6-membered heterocyclic residue having 1 or 2 nitrogen atoms
You And B is preferably a substituent (as defined above).
Ri. ) Which may have a heterocyclic residue (as described above
Ri. ), Particularly preferably an unsubstituted heterocyclic residue
You } Is represented. However, -A-Y-R³ But

[0047]

[Chemical formula 26]

And R ¹ and R ² do not represent a methyl group at the same time. In the compound represented by the general formula (I), R ³ represents — (CH ₂ ) _n —B (n is as defined above), and B is a heterocycle having at least one nitrogen atom as a hetero atom. When it is a residue, it may be present in the form of an N-oxide derivative. In addition, as the salt of the compound represented by the above general formula (I), physiologically acceptable salts are preferable, for example, hydrochloride, hydrobromide,
Inorganic acid salts such as hydroiodide, sulfate, and phosphate, and oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methane Organic acid salts such as sulfonic acid salts and p-toluenesulfonic acid salts may be mentioned. Since the compound of the formula (I), its N-oxide derivative and its salt may exist in the form of hydrate or solvate, these hydrates and solvates are also included in the compound of the present invention. Be done. Examples of the solvent of the solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like.

The compound of the general formula (I) has an asymmetric carbon atom, and isomers exist. These isomers are also included in the present application. The compound of the present invention can be produced, for example, by the following method. Manufacturing method 1

[0050]

[Chemical 27]

(In the above formula, R ¹ , R ² , R ³ , A and Y are as defined above, and X ¹ represents a halogen atom.) The above reaction is solvent-free or acetone, ethylmethylketone, etc. Ketones; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether, tetrahydrofuran and dioxane; acetic acid esters such as ethyl acetate and isobutyl acetate; acetonitrile; N, N-dimethylformamide; dimethyl sulfoxide; N -Methylpyrrolidone; in the presence of an organic base such as triethylamine, pyridine, N, N-diethylaniline, or an inorganic base such as sodium carbonate or sodium hydride in a solvent such as an aprotic polar solvent such as 0 to 150 ° C. It is performed in the range of.
The compound of the general formula (II), which is the starting material for the reaction, is, for example, a compound represented by the following reaction formula from the compound of the following general formula (III) produced according to the method described in JP-A-50-157360. Can be manufactured according to.

[0052]

[Chemical 28]

(In the above formula, R ¹ and R ² are as defined above.) Production Method 2A

[0054]

[Chemical 29]

When Y is --O--, --S--, --ON--CH-- or --NR ^5- (R ⁵ is as defined above), the compound of the following general formula (V) is It can also be produced by the method.

[0056]

[Chemical 30]

(In the above formula, R ¹ , R ² , R ³ and Y are as defined above, and X ² represents an oxygen atom or a sulfur atom.) The above reaction is solvent-free or acetone, ethyl methyl ketone Such as ketones; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether, tetrahydrofuran, dioxane; acetic acid esters such as ethyl acetate, isobutyl acetate; acetonitrile; N, N-dimethylformamide; dimethyl sulfoxide; 0-150 in the presence of an organic base such as triethylamine, pyridine, N, N-diethylaniline or an inorganic base such as sodium carbonate or sodium hydride in a solvent such as an aprotic polar solvent such as N-methylpyrrolidone; It is performed in the range of ° C.
In addition, the compound of the general formula (IV), which is a raw material for the above reaction, can be produced from the raw material (II) of the production method 1 according to the following reaction formula.

[0058]

[Chemical 31]

(In the above formula, R ¹ , R ² and X ² are as defined above.) When the compound of the present invention is used as a therapeutic agent, it is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the solubility, chemical properties, administration route, administration schedule, etc. of the compound.

For example, it may be orally administered in the form of granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or solutions, or intravenously as an injection. Administration may be intramuscular or subcutaneous. Alternatively, it may be made into powder for injection and prepared at the time of use.
Pharmaceutical organic or inorganic solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used with the compounds of this invention. Examples of the excipient used when producing the solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin and the like. Liquid preparations for oral administration, that is, emulsions, syrups, suspensions, solutions and the like, include a commonly used inert diluent such as water or vegetable oil. In addition to an inert diluent, this formulation may contain auxiliary agents such as wetting agents, suspension auxiliary agents, sweetening agents, aromatic agents, coloring agents or preservatives. It may be made into a liquid formulation and contained in a capsule of a substance that can be disintegrated in the body such as gelatin. Formulations for parenteral administration, that is, as a solvent or suspending agent used in the production of injections and the like, for example, water,
Propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like can be mentioned. The preparation method of the preparation may be a conventional method.

When used by oral administration, the clinical dose is generally 1 for the adult compound of the present invention.
The daily dose is 0.01 to 1000 mg, preferably 0.0
It is 1 to 100 mg, but it is more preferable to increase or decrease as appropriate depending on the age, medical condition, symptoms, presence or absence of simultaneous administration, and the like. The above-mentioned daily dose of the drug (the compound of the present invention) may be administered once a day, or divided into two or three times a day at appropriate intervals, or may be administered intermittently. When used as an injection, the compound of the present invention for an adult is 1
It is preferable to administer a dose of 0.001 to 100 mg continuously or intermittently.

[0062]

EXAMPLES The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited to the following examples and test examples as long as the gist thereof is not exceeded.

Example 1 Synthesis of 3- (3-cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethylaminocarbonyl) pyrrolidine (Compound No. 22 in Table-1) 3- (aminomethyl) pyridine 216 mg and triethylamine 202 mg were dissolved in tetrahydrofuran 5 ml, and 1-chloroformyl-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine 545 was stirred under ice cooling.
What dissolved mg in tetrahydrofuran 3ml was dripped. After completion of dropping, the mixture was stirred at room temperature for 6 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (432 mg).

Example 2 3- (3-Cyclopentyloxy-4-methoxyphenyl) -1- (ethoxycarbonyl) pyrrolidine (Table-1
Compound No. Synthesis of 4) 3- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine 460 mg and triethylamine 21
4 mg was dissolved in 15 ml of dichloromethane, cooled in an ice bath, and 229 mg of ethyl chlorocarbonate was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 1 hour, poured into ice water, and extracted with dichloromethane. Wash the organic layer with water,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography,
492 mg of the title compound was obtained. Example 3 According to the methods of Examples 1 and 2, the compounds shown in Table 1 below were synthesized.

[0065]

[Table 1]

[0066]

[Table 2]

[0067]

[Table 3]

[0068]

[Table 4]

[0069]

[Table 5]

[0070]

[Table 6]

The following amorphous compound and oily compound (represented by the compound No. in Table 1 above) have the following NMR spectra. No. 1 ¹ HNMR (CDCl ₃ ) δppm: 1.48 (s, 9
H), 1.53-1.69 (m, 2H), 1.73-
2.00 (m, 7H), 2.14-2.28 (m, 1
H), 3.16-3.86 (m, 5H), 3.83.
(S, 3H), 4.70-4.81 (m, 1H), 6.
73-6.85 (m, 3H) No. 2 ¹ HNMR (CDCl ₃ ) δppm: 1.28 (s, 9
H), 1.50-1.68 (m, 2H), 1.73-
2.04 (m, 7H), 2.13-2.33 (m, 1
H), 3.16-4.10 (m, 5H), 3.83.
(S, 3H), 4.71-4.80 (m, 1H), 6.
71-6.85 (m, 3H)

No. 3 ¹ HNMR (CDCl ₃ ) δppm: 1.52-1.6
5 (m, 2H), 1.76-2.05 (m, 7H),
2.18-2.36 (m, 1H), 3.24-3.92
(M, 5H), 3.82 (s, 3H), 4.72-4.
79 (m, 1H), 5.16 (s, 2H), 6.74-
6.83 (m, 3H), 7.24-7.38 (m, 5
H) No. _{^{4 1 HNMR (CDCl 3) δppm}} : 1.24-1.3
1 (m, 3H), 1.54-1.70 (m, 2H),
1.74-2.04 (m, 7H), 2.18-2.32
(M, 1H), 3.22-3.90 (m, 5H), 3.
83 (s, 3H), 4.12-4.22 (m, 2H),
4.77 (m, 1H), 6.74-6.84 (m, 3
H)

No. 5 ¹ HNMR (CDCl ₃ ) δppm: 1.08 (br
s, 9H), 1.54-2.38 (m, 10H), 2.
21 (brs, 2H), 3.22-4.06 (m, 5
H), 3.83 (s, 3H), 4.70-4.80.
(M, 1H), 6.75-6.81 (m, 3H) No. _{^{6 1 HNMR (CDCl 3) δppm}} : 0.90-0.9
8 (m, 3H), 1.34-2.04 (m, 13H),
2.18-2.32 (m, 1H), 3.24-3.92
(M, 5H), 3.82 (s, 3H), 4.08-4.
13 (m, 2H), 4.76 (m, 1H), 6.74-
6.83 (s, 3H)

No. 7 ¹ HNMR (CDCl ₃ ) δppm: 1.56-1.7
0 (m, 2H), 1.76-2.42 (m, 8H),
3.24-3.94 (m, 5H), 3.83 (brs,
3H), 4.70-4.80 (m, 1H), 6.71-
6.82 (m, 3H), 7.38-7.43 (m, 3)
H), 7.54 to 7.56 (m, 2H) No. 8 ¹ HNMR (CDCl ₃ ) δppm: 1.48 (s, 9
H), 1.80-2.28 (m, 4H), 3.15-
4.09 (m, 9H), 3.84 (s, 3H), 4.8
9-5.00 (m, 1H), 6.73 (brs, 1
H), 6.84 (brs, 2H)

No. 9 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.4
4 (m, 10H), 3.28-4.16 (m, 5H),
3.82 and 3.84 (a pair of
3H), 4.72-4.80 (m, 1H), 6.70-
6.83 (m, 3H), 7.32-7.40 (m, 1
H), 7.86-7.92 (m, 1H), 8.64-
8.69 (m, 1H), 8.81 (m, 1H) No. 10 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.4
2 (m, 10H), 3.26-4.08 (m, 5H),
3.66 (brs. 2H), 3.83 (brs, 3)
H), 4.75 (m, 1H), 6.72-6.84.
(M, 3H), 7.24-7.30 (m, 1H), 7.
68-7.74 (m, 1H), 8.50-8.52
(M, 2H)

No. 12 ¹ HNMR (CDCl ₃ ) δppm: 1.53-1.6
8 (m, 2H), 1.75-2.00 (m, 7H),
2.15-2.28 (m, 1H), 2.85 (s, 6
H), 3.18-3.31 (m, 1H), 3.39.
(T, 1H, J = 9 Hz), 3.46-3.61 (m,
2H), 3.70 (dd, 1H, J = 7 and 9)
Hz), 3.83 (s, 3H), 4.71-4.80.
(M, 1H), 6.74-6.84 (m, 3H) No. 13 ¹ HNMR (CDCl ₃ ) δppm: 1.51-1.7
0 (m, 2H), 1.75-2.04 (m, 7H),
2.18-2.34 (m, 1H), 3.23-3.53
(M, 3H), 3.58-3.96 (m, 2H), 3.
83 (s, 3H), 4.68-4.80 (m, 1H),
5.18 (s, 2H), 6.70-6.84 (m, 3
H), 7.26-7.35 (m, 1H), 7.73
(M, 1H), 8.57 (m, 1H), 8.65 (m,
1H)

No. 17 ¹ HNMR (CDCl ₃ ) δppm: 1.51-1.7
0 (m, 2H), 1.75-2.09 (m, 7H),
2.20-2.35 (m, 1H), 3.25-3.53
(M, 3H), 3.63-3.75 (m, 1H), 3.
80-3.93 (m, 1H), 3.83 (s, 3H),
4.71-4.81 (m, 1H), 5.13 (brs,
2H), 6.70-6.86 (m, 3H), 7.27.
(M, 2H), 8.16 (m, 1H), 8.28 (m,
1H) No. 18 ¹ HNMR (CDCl ₃ ) δppm: 1.54-2.0
8 (m, 9H), 2.22-2.36 (m, 1H),
3.28-3.92 (m, 5H), 3.83 (s, 3
H), 4.76 (m, 1H), 5.12 (brs, 2)
H), 6.75-6.84 (m, 3H), 7.27-
7.32 (m, 2H), 8.17-8.21 (m, 2)
H)

No. 19 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
2 (m, 9H), 2.24-2.36 (m, 1H),
3.30-3.90 (m, 5H), 3.83 (s, 3
H), 4.77 (m, 1H), 5.19 (brs, 2
H), 6.76-6.86 (m, 3H), 7.26-
7.30 (m, 2H), 8.57-8.61 (m, 2)
H) No. 20 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
6 (m, 9H), 2.14-2.28 (m, 1H),
3.16-3.90 (m, 5H), 3.81 (s, 3)
H), 4.68-4.76 (m, 1H), 6.61-
6.78 (m, 3H), 7.48-7.56 (m, 1
H), 8.13-8.16 (m, 1H), 8.94 (b
rs, 1H), 9.10 (brs, 1H)

No. 21 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
6 (m, 9H), 2.30-2.40 (m, 1H),
3.30-3.48 (m, 1H), 3.64-4.26
(M, 4H), 3.83 (brs, 3H), 4.74-
4.80 (m, 1H), 6.77-6.83 (m, 3
H), 8.52-8.56 (m, 1H), 8.62-
8.66 (m, 1H), 9.17 (s, 1H) No. 23 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
8 (m, 9H), 2.26-2.42 (m, 1H),
3.34-4.16 (m, 5H), 3.83 (s, 3
H), 4.72-4.80 (m, 1H), 6.78-
6.88 (m, 3H), 7.32 (m, 1H), 7.5
5-7.60 (m, 1H), 8.47 (m, 2H)

No. 24 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
0 (m, 2H), 1.73-2.04 (m, 7H),
2.20-2.35 (m, 1H), 3.25-3.59
(M, 3H), 3.66-3.78 (m, 1H), 3.
83 (s, 3H), 3.86-3.96 (m, 1H),
4.70-4.79 (m, 1H), 5.28 (brs,
2H), 6.71-6.84 (m, 3H), 7.16-
7.26 (m, 1H), 7.39 (t, 1H, J = 7H
z), 7.65-7.74 (m, 1H), 8.58.
(M, 1H), 8.65 (m, 1H) No. 25 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
6 (m, 9H), 2.28-2.44 (m, 1H),
3.34-4.06 (m, 5H), 3.84 (s, 3)
H), 4.74-4.80 (m, 1H), 6.77-
6.83 (m, 3H), 7.23-7.27 (m, 2
H), 8.06-8.09 (m, 1H), 8.19.
(S, 1H)

No. 26 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
0 (m, 2H) 1.75-2.10 (m, 7H), 2.
22-2.40 (m, 1H), 3.30-3.62
(M, 3H), 3.68-3.83 (m, 1H), 3.
84 (s, 3H), 3.89-4.00 (m, 1H),
4.70-4.81 (m, 1H), 5.44 (brs,
2H), 6.74-6.86 (m, 3H), 7.20-
7.35 (m, 2H), 7.36-7.45 (m, 1
H), 8.25 (m, 1H) No. 27 (diastereomixture) ¹ HNMR (CDCl ₃ ) δppm: 1.52-2.4
0 (m, 17H), 2.27 and 2.29 (a
pair of s, 3H), 2.78-2.94.
(M, 2H), 3.24-4.08 (m, 7H), 3.
83 (s, 3H), 4.72-4.80 (m, 1H),
6.75-6.86 (m, 3H)

No. 28 ¹ HNMR (CDCl ₃ ) δppm: 1.56-1.7
2 (m, 2H), 1.76-1.94 (m, 6H),
2.04-2.16 (m, 1H), 2.33-2.42
(M, 1H), 3.34-3.93 (m, 5H), 3.
83 (s, 3H), 4.73-4.80 (m, 1H),
6.32-6.38 (m, 2H), 6.75-6.86
(M, 3H), 7.72-7.77 (m, 2H) No. 29 ¹ HNMR (CDCl ₃ ) δppm: 1.51-1.6
9 (m, 2H), 1.74-2.01 (m, 7H),
2.15-2.30 (m, 1H), 2.29 (s, 3
H), 2.31 (s, 3H), 2.60 (m, 2H),
3.22-3.50 (m, 3H), 3.57-3.72
(M, 1H), 3.75-3.91 (m, 1H), 3.
82 (s, 3H), 4.22 (t, 2H, J = 5H
z), 4.70-4.80 (m, 1H), 6.71-
6.84 (m, 3H)

No. 30 ¹ HNMR (CDCl ₃ ) δppm: 1.51-1.6
9 (m, 2H), 1.74-2.05 (m, 7H),
2.19-2.34 (m, 1H), 2.80 (brs,
1H), 3.23-3.74 (m, 7H), 3.83.
(S, 3H), 4.23-4.31 (m, 2H), 4.
70-4.81 (m, 1H), 6.72-6.85
(M, 3H) No. 31 ¹ HNMR (CDCl ₃ ) δppm: 1.30-1.3
7 (m, 6H), 1.54 to 1.68 (m, 2H),
1.78-2.04 (m, 7H), 2.20-2.32.
(M, 1H), 3.10-3.18 (m, 1H), 3.
24-3.50 (m, 3H), 3.60-3.68
(M, 1H), 3.83 (s, 3H), 4.00-4.
16 (m, 4H), 4.72-4.80 (m, 1H),
6.75-6.83 (m, 3H)

No. 32 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
6 (m, 9H), 2.18-2.30 (m, 1H),
2.72-2.96 (m, 2H), 3.24-3.92
(M, 7H), 3.83 (s, 3H), 3.85 (s,
3H), 3.86 (s, 3H), 4.40 (s, 2)
H), 4.72-4.80 (m, 1H), 6.59.
(S, 1H), 6.62 (s, 1H), 6.77-6.
86 (s, 3H) No. 33 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
6 (m, 9H), 2.16-2.32 (m, 1H),
2.81 (s, 3H), 3.22-3.36 (m, 1
H), 3.43 (t, 1H, J = 9 Hz), 3.54-
3.60 (m, 2H), 3.72-3.81 (m, 1
H), 3.83 (s, 3H), 4.43 (d, 1H, J
= 12 Hz), 4.50 (d, 1H, J = 12 Hz),
4.72-4.80 (m, 1H), 6.75-6.84
(M, 3H), 7.25-7.30 (m, 1H), 7.
68-7.71 (m, 1H), 8.52-8.56
(M, 2H)

No. 34 (diastereo mix
true) ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
8 (m, 10H), 2.18-2.36 (m, 2H),
3.20-3.94 (m, 10H), 3.83 (s, 3
H), 4.72-4.80 (m, 1H), 6.76-
6.84 (m, 3H), 7.16-7.19 (m, 2
H), 8.53-8.55 (m, 2H) No. 35 ¹ HNMR (CDCl ₃ ) δppm: 1.90-2.1
0 (m, 1H), 2.19-2.33 (m, 1H),
3.24-3.51 (m, 3H), 3.60-3.95
(M, 2H), 3.87 (s, 6H), 5.18 (br
s, 2H), 6.70-6.86 (m, 3H), 7.2
7-7.34 (m, 1H), 7.68-7.76 (m,
1H), 8.57 (m, 1H), 8.65 (m, 1H)

No. 36 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
6 (m, 9H), 2.16-2.28 (m, 1H),
3.12-3.88 (m, 7H), 3.83 (s, 3)
H), 4.48 (t, 2H, J = 7 Hz), 4.75
(M, 1H), 6.72-6.83 (m, 3H), 7.
10-7.24 (m, 2H), 7.54-7.64.
(M, 1H), 8.54 (m, 1H) No. 37 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
2 (m, 9H), 2.22-2.38 (m, 1H),
3.50-3.58 (m, 3H), 3.68-3.94
(M, 2H), 3.83 (s, 3H), 4.77 (m,
1H), 5.16 (brs, 2H), 6.76-6.8.
5 (m, 3H), 7.12-7.21 (m, 1H),
7.31-7.33 (m, 1H), 8.34-8.38
(M, 1H)

No. 38 ¹ HNMR (CDCl ₃ ) δppm: 1.51-1.6
8 (m, 2H), 1.73-2.04 (m, 7H),
2.19-2.33 (m, 1H), 3.23-3.52
(M, 3H), 3.57-3.92 (m, 2H), 3.
83 (s, 3H), 4.70-4.80 (m, 1H),
5.15 (brs, 2H), 6.70-6.84 (m,
3H), 7.29-7.36 (m, 1H), 7.67-
7.74 (m, 1H), 8.42 (m, 1H) No. 39 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
1 (m, 2H), 1.74-2.11 (m, 7H),
2.23-2.40 (m, 1H), 3.30-3.64.
(M, 3H), 3.70-3.85 (m, 1H), 3.
84 (s, 3H), 3.90-4.05 (m, 1H),
4.71-4.83 (m, 1H), 6.73-6.85
(M, 3H), 7.33 (t, 1H, J = 9Hz),
7.76 (t, 1H, J = 9Hz), 8.14 (d, 1
H, J = 9 Hz), 8.43 (d, 1H, J = 9H
z), 8.64 (brs, 1H)

No. 40 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
6 (m, 9H), 2.28-2.42 (m, 1H),
3.32-4.28 (m, 5H), 3.83 (brs,
3H), 4.72-4.78 (m, 1H), 5.56.
and 5.57 (a pair of s, 2H),
6.71-6.84 (m, 3H), 7.26-7.34
(M, 1H), 7.72-7.76 (m, 1H), 8.
54-8.62 (m, 1H), 8.65-8.69
(M, 1H) No. 41 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
8 (m, 9H), 2.32-2.42 (m, 1H),
3.32-3.46 (m, 1H), 3.54-3.66
(M, 1H), 3.72-3.90 (m, 2H), 3.
83 (s, 3H), 3.94-4.06 (m, 1H),
4.48 (brs, 1H), 4.60 (s, 2H),
4.72-4.80 (m, 1H) 6.75-6.85
(M, 3H), 7.28-7.30 (m, 1H), 8.
02 (s, 1H)

No. 42 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.0
8 (m, 9H), 2.22-2.36 (m, 1H),
3.26-3.56 (m, 3H), 3.66-3.96
(M, 2H), 3.83 (s, 3H), 4.72-4.
80 (m, 1H), 5.50 and 5.51 (a
pair of s, 2H), 6.75-6.84.
(M, 3H), 7.46-7.53 (m, 1H), 7.
58-7.66 (m, 1H), 9.14-9.16.
(M, 1H) No. 43 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
0 (m, 9H), 2.20-2.36 (m, 1H),
3.28-3.56 (m, 3H), 3.70-3.96
(M, 2H), 3.83 (s, 3H), 4.77 (m,
1H), 5.32 and 5.33 (a pair o)
fs, 2H), 6.75-6.84 (m, 3H),
8.53-8.56 (m, 2H), 8.70-8.71
(M, 1H)

No. 44 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
0 (m, 2H), 1.74-2.04 (m, 7H),
2.18-2.40 (m, 1H), 2.24 (brs,
3H), 3.22-3.92 (m, 5H), 3.82.
(Brs, 6H), 4.70-4.80 (m, 1H),
5.10 (brs, 2H), 6.08 (brs, 1
H), 6.69-6.84 (m, 3H) No. 45 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.6
9 (m, 2H), 1.75-2.03 (m, 7H),
2.18-2.30 (m, 1H), 3.23-3.93
(M, 5H), 3.82 (s, 3H), 4.70-4.
80 (m, 1H), 5.02 (brs, 2H), 6.4
6 (m, 1H), 6.70-6.84 (m, 3H),
7.39 (m, 1H), 7.48 (m, 1H)

No. 46 ¹ HNMR (CDCl ₃ ) δppm: 1.56-2.1
2 (m, 9H), 2.22-2.38 (m, 1H),
3.30-3.58 (m, 3H), 3.68-3.96
(M, 2H), 3.84 (s, 3H), 4.74-4.
80 (m, 1H), 5.27 (brs, 2H), 6.7
6-6.85 (m, 3H), 8.02 (m, 1H),
8.17-8.19 (m, 1H), 8.41-8.43
(M, 1H)

Example 4 (+)-3- (3-Cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine and (-)-3- (3-Cyclopentyloxy-4-methoxy) Preparation of phenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine (±) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine (Compound No. in Table-1 .13) 145 m
g was separated by HPLC (eluent: ethanol / hexane = 10/90) using an optical isomer separation column CHIRALPAKAS (Daicel Chemical Industries), and (+)-3- (3
-Cyclopentyloxy-4-methoxyphenyl) -1
-(3-Pyridylmethoxycarbonyl) pyrrolidine (Compound No. 47) 64 mg [α] _D ²⁵ = + 22.3 ° (c0.91, methanol), and (-)-3- (3-cyclopentyloxy-4-methoxy). Phenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine (Compound No. 48) 61m
g [α] _D ²⁵ = -23.7 ° (c1.02, methanol) was obtained.

Example 5 The compounds shown in Table 1 below were synthesized according to the methods of Examples 1 and 2.

[0094]

[Table 7]

[0095]

[Table 8]

[0096]

[Table 9]

No. 49 ¹ HNMR (CDCl ₃ ) δppm: 1.50-2.1
0 (m, 9H), 2.20-2.38 (m, 1H),
3.2-3.7 (m, 4H), 3.8 (m, 1H),
3.82 (s, 3H), 4.23-4.57 (m, 4
H), 4.60-4.83 (m, 1H), 6.63-
6.93 (m, 3H), 7.20-7.40 (m, 2)
H), 7.57-7.76 (m, 2H), 8.40-
8.68 (m, 4H) No. 50 ¹ HNMR (CDCl ₃ ) δppm: 1.49-2.1
0 (m, 9H), 2.20-2.36 (m, 1H),
2.9-3.8 (m, 9H), 3.83 (s, 3H),
4.73 (s, 2H), 4.70-4.80 (m, 1
H), 6.70-6.85 (m, 3H), 6.80 (d
d, 1H), 7.41 (d, 1H), 8.43 (d, 1)
H)

No. 51 ¹ HNMR (CDCl ₃ ) δppm: 1.49-1.7
1 (m, 2H), 1.74-2.09 (m, 7H),
2.20-2.36 (m, 1H), 3.2-4.1
(M, 5H), 3.82 (s, 3H), 4.20 (s,
2H), 4.69-4.79 (m, 1H), 6.69-
6.84 (m, 3H), 7.19-7.41 (m, 5
H) No. 52 ¹ HNMR (CDCl ₃ ) δppm: 1.53-1.7
0 (m, 2H), 1.75-2.08 (m, 7H),
2.20-2.38 (m, 1H), 3.2-4.1
(M, 5H), 3.82 (s, 3H), 4.13 (m,
2H), 4.65 (m, 2H), 4.70-4.80.
(M, 1H), 6.70-6.85 (m, 3H), 7.
25-7.43 (m, 5H)

No. 53 ¹ HNMR (CDCl ₃ ) δppm: 0.94 (t, 3
H), 1.39 (m, 2H), 1.51-2.09
(M, 11H), 2.23-2.35 (m, 1H),
2.77 (t, 2H), 3.25-3.48 (m, 3
H), 3.55-3.66 (m, 1H), 3.8 (m,
1H), 3.83 (s, 3H), 4.44 (d, 2)
H), 4.53 (t, 1H), 4.69-4.79.
(M, 1H), 6.73-6.85 (m, 3H), 7.
11 (d, 1H), 7.60 (dd, 1H), 8.44
(D, 1H) No. 54 ¹ HNMR (CDCl ₃ ) δppm: 1.53-1.7
0 (m, 2H), 1.75-2.08 (m, 7H),
2.19-2.35 (m, 1H), 3.00 (m, 3)
H), 3.20-3.51 (m, 5H), 3.55-
3.90 (m, 2H), 3.83 (s, 3H), 4.5
7 (m, 2H), 4.70-4.81 (m, 1H),
6.70-6.85 (m, 3H)

No. 55 ¹ HNMR (CDCl ₃ ) δppm: 1.52-1.7
4 (m, 2H), 1.75-2.07 (m, 7H),
2.17 (s, 3H), 2.20-2.38 (m, 1
H), 3.1-3.9 (m, 5H), 3.83 (s, 3)
H), 4.63-4.93 (m, 3H), 6.54-
6.84 (m, 3H), 7.27 (m, 1H), 7.7
5 (m, 1H), 8.47-8.63 (m, 2H) No. 56 ¹ HNMR (CDCl ₃ ) δppm: 1.47-1.7
4 (m, 2H), 1.74-2.10 (m, 7H),
2.18-2.37 (m, 1H), 3.18-3.53
(M, 3H), 3.58-3.94 (m, 2H), 3.
80 (s, 3H), 4.54 (d, 2H), 4.70-
4.80 (m, 1H), 5.84 (t, 1H), 6.7
3-6.83 (m, 3H), 7.15 (m, 1H),
7.30 (m, 1H), 7.62 (m, 1H), 8.4
9 (m, 1H)

No. 57 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
0 (m, 2H), 1.72-2.04 (m, 7H),
2.18-2.34 (m, 1H), 3.01 (t, 2)
H), 3.22-3.85 (m, 7H), 3.83.
(S, 3H), 4.68-4.79 (m, 1H), 5.
34 (t, 1H), 6.73-6.83 (m, 3H),
7.08-7.20 (m, 2H), 7.57-7.64.
(M, 1H), 8.50 (m, 1H) No. 59 ¹ HNMR (CDCl ₃ ) δppm: 1.47-2.1
5 (m, 9H), 2.22-2.42 (m, 1H),
3.28-4.03 (m, 5H), 3.83 (s, 3
H), 4.70-4.80 (m, 1H), 6.61 (b)
s, 1H), 6.75-6.85 (m, 3H), 7.2
2 (m, 1H), 8.09 (m, 1H), 8.24
(M, 1H), 8.48 (m, 1H)

No. 60 ¹ HNMR (CDCl ₃ ) δppm: 1.48-1.7
0 (m, 2H), 1.70-2.05 (m, 7H),
2.16-2.33 (m, 1H), 2.98 (t, 2)
H), 3.16-3.33 (m, 3H), 3.45-
3.75 (m, 4H), 3.81 (s, 3H), 4.3
7 (t, 1H), 4.70-4.80 (m, 1H),
6.65-6.95 (m, 3H), 7.00 (m, 1
H), 7.06-7.23 (m, 2H), 7.35.
(M, 1H), 7.62 (m, 1H), 8.67 (b
s, 1H) No. 62 ¹ HNMR (CDCl ₃ ) δppm: 1.50-1.7
0 (m, 2H), 1.75-2.05 (m, 7H),
2.18-2.35 (m, 1H), 2.81 (t, 2
H), 3.23-3.55 (m, 6H), 3.59.
(S, 3H), 3.70-3.87 (m, 1H), 3.
83 (s, 3H), 4.45 (t, 1H), 4.70-
4.80 (m, 1H), 5.92 (m, 1H), 6.0
5 (m, 1H), 6.57 (m, 1H), 6.73-
6.83 (m, 3H)

No. 63 ¹ HNMR (CDCl ₃ ) δppm: 1.52-1.7
0 (m, 2H), 1.74-2.07 (m, 7H),
2.18-2.39 (m, 1H), 3.3-3.8
(M, 5H), 3.83 (s, 3H), 4.56 (m,
1H), 4.63 (d, 2H), 4.70-4.80.
(M, 1H), 6.73-6.83 (m, 3H), 6.
92-7.00 (m, 2H), 7.22 (m, 1H) No. 64 ¹ HNMR (CDCl ₃ ) δppm: 1.53-1.7
2 (m, 2H), 1.75-2.23 (m, 7H),
2.30-2.47 (m, 1H), 3.47-3.66
(M, 3H), 3.79 (m, 1H), 3.84 (s,
3H), 3.98 (m, 1H), 4.73-4.83.
(M, 1H), 6.27 (bs, 1H), 6.78-
6.86 (m, 3H), 8.48 (s, 2H) Specific examples of compounds that can be synthesized according to the methods of Examples 1 and 2 are shown in Table 2 below.

[0104]

[Table 10]

[0105]

[Table 11]

[0106]

[Table 12]

[0107]

[Table 13]

[0108]

[Table 14]

[0109]

[Table 15]

[0110]

[Table 16]

[0111]

[Table 17]

Example 6 Preparation of tablets Well-ground 3- (3-cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine hydrochloride (Compound No. 15 in Table-1)
1000 g, lactose 5900 g, crystalline cellulose 2000
g, low-substituted hydroxypropyl cellulose 1000
g, and 100 g of magnesium stearate are mixed well,
A plain tablet containing 10 mg of the above-mentioned compound in 100 mg of one tablet was produced by the direct compression method. The uncoated tablets were sugar-coated or film-coated to produce sugar-coated tablets and film-coated tablets.

Example 7 Preparation of Capsules Well-ground 3- (3-cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethoxycarbonyl) pyrrolidine p-toluenesulfonate (Table 1
Compound No. 14) 1000 g, corn starch 3000 g, lactose 6900 g, crystalline cellulose 100
1g by mixing 0g and 100g magnesium stearate
A capsule was prepared containing 10 mg of the compound in 120 mg of capsule.

Example 8 Preparation of Inhalant Well-ground 3- (3-cyclopentyloxy-4-methoxyphenyl) -1- (3-pyridylmethylaminocarbonyl) pyrrolidine (Compound No. 22 in Table-1) 5
g, 10 g of medium-chain saturated fatty acid triglyceride, and 0.2 g of sorbitan monooleate were well mixed to give a mixture of 15.2 each.
mg was weighed in a 5 ml aluminum container for aerosol, and Freon 12/114 (1: 1 mixture) 8 per container
After cold-filling with 4.8 mg, a fixed-quantity inhaler containing 5 mg of the compound in 1 container of 5 ml was prepared by attaching a fixed-volume injection adapter of 10.0 μl.

The results of the pharmacological tests of these compounds are shown below in order to show the usefulness of the compounds of the present invention. Rolipram in Table 2 is represented by the above-mentioned structure, and has a PVEIV-specific inhibitory action in Adv. Second Messe
nger Phosphoprotein Res. ，
22 , 1 (1988) and the like, JP-A-50.
It is a compound described in 157360.

Test Example 1 Action on Type IV Phosphodiesterase (PDEIV) Enzyme Activity The enzyme was Nic from the human monocyte-like cell line U937 cytoplasmic fraction.
holson et al. [Br. J. Pharmacol. , 9
7 , 889 (1989)], followed by crude purification with a Q-sepharose column, and Hidaka et al. [Biochem.
Med. , 10 , 301 (1974)] using 0.4 μM ³ H-cAMP as a substrate in an amount of 0.1 mg / m 2.
l BSA, 1 mM EDTA, 5 mM MgCl ₂
1 at 30 ° C in 50 mM Tris buffer (pH 8.0)
The reaction was carried out for 5 minutes, the produced ³ H-5'-AMP was separated by a cation exchange column, and the radioactivity was measured to measure the enzyme activity. After the test compound was added and incubated at 30 ° C. for 15 minutes, the substrate was added, and the inhibition rate at each concentration was calculated by setting the reaction when the test compound was not added as 100%, and the concentration showing the 50% inhibition rate was determined using probit analysis (IC ₅₀ ) was calculated.

[0117]

[Table 18]

[0118]

INDUSTRIAL APPLICABILITY The compound of the present invention has an excellent PDEIV inhibitory action and is effective in treating asthma and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/14 207 403/06 207 403/12 207 405/12 207 C07F 9/572 Z 9155-4H

Claims (8)

[Claims] 1. The following general formula (I):[In the above formula, R¹ Is C₁ ~ C_Four Represents an alkyl group of R² Is a tetrahydrofuranyl group, C₁ ~ C₇ The alkyl
Base, C₁~ C₇Haloalkyl group, C₂~ C₇Arche
Nyl group, bicyclo [2,2,1] hept-2-yl group
Or C₃ ~ C₈ Represents a cycloalkyl group of and A is(R^Four Is C₁ ~ C_Four Represents an alkyl group. ), Y
Is -O-, -S-, -ON-CH =, -NR^Five -(R
^Five Is a hydrogen atom, C₁ ~ C_Four Alkyl group of C₂~ C_Fourof
Represents an alkylcarbonyl group or a pyridylmethyl group
You ) Or a single bond, R³ Is C which may have a substituent₁ ~ C₇ The alkyl
Group or-(CH₂ ) _n-B (n represents an integer of 0 to 4)
And B is phenyl which may have a substituent.
Represents a group, a naphthyl group or a heterocyclic residue. However, -A
-Y-R³ IsWhen representing¹ And R² Do not represent a methyl group at the same time
To be ) Represents. ] 3-phenylpy represented by
Rolidine derivative, its optical antipode, its salt, its N-O
Xide derivatives, hydrates or solvates thereof. 2. The compound according to claim 1, wherein R ¹ is a methyl group and R ² is a cyclopentyl group. 3. R ³ is — (CH ₂ ) _n —B (n is 0 to ₂ )
And represents a heterocyclic residue which may have a substituent. ) Is a compound according to claim 1 or 2. 4. R ³ is — (CH ₂ ) _n —B (n represents 1 or 2 and B represents a 6-membered heterocyclic residue having 1 or 2 nitrogen atoms as hetero atoms.) The compound according to claim 1 or 2, which is 5. A is And Y is —O—, —S—, —NR ⁵ — (R ⁵ represents a hydrogen atom, a C _{1 to} C ₄ alkyl group, a C _{2 to} C ₄ alkylcarbonyl group or a pyridylmethyl group.) Alternatively, the compound according to claim 1, 2, 3 or 4 which is a single bond. 6. A is And Y is —O— or —NR ⁵ — (R ⁵ represents a hydrogen atom, a C _{1 to} C ₄ alkyl group, a C _{2 to} C ₄ alkylcarbonyl group or a pyridylmethyl group). The compound of 1, 2, 3 or 4. 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmacologically acceptable carrier. 8. An anti-asthma drug comprising the compound according to any one of claims 1 to 6.