JPH07258250A - Ester derivative - Google Patents

Abstract

PURPOSE:To obtain a novel derivative which has muscarine M3 receptor affinity and the receptor-antagonistic action, thus is useful as a prophylactic or therapeutic agent for dysfunction in digestive, respiratory and urinary organs and rhinitis. CONSTITUTION:This derivative is expressed by formula I {Y is a single bond or methylene; P is 1, 2; q is 0, 1; p+q is 1, 2; ring A is formula II, formula III [Z is N-R<1> (R<1> is H, a lower alkyl); m, n are 1-4 where m+n is 3-5; r, s, t are 0-3 where r+s+t is 2, 3]} or its salt, for example, 3-quinacridyl 1- phenylindoline-2-carboxylate hydrochloride. The exemplified compound is prepared by, for example, adding sodium hydroxide to a suspended mixture of methyl indoline-2-carboxylate and 3-quinaclidinol in toluene under the Ar flow atmosphere and heating the mixture under reflux for 2 hours, as the methanol formed by the reaction is removed.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ester derivative having a muscarinic receptor antagonistic action or a salt thereof.

[0002]

2. Description of the Related Art Conventionally, studies on muscarinic receptors have been conducted, and compounds having muscarinic receptor antagonistic activity have been found to have bronchodilation, gastrointestinal motility inhibition, acid secretion inhibition, dry mouth, mydriasis, bladder contraction inhibition, and sweat reduction And tachycardia are known to occur. It is known that this muscarinic receptor has at least three subtypes.
The M ₁ receptor is mainly in the brain, the M ₂ receptor is in the heart, and M
_{The 3} receptor is present in smooth muscle and glandular tissue.

There are many compounds having muscarinic receptor antagonism, but since they antagonize the M ₁ , M ₂ and M ₃ receptors in a non-selective manner, they are aimed at the treatment of specific diseases. Was not easy. In recent years, studies on subtypes of muscarinic receptors have progressed, and compounds that selectively antagonize M ₁ , M ₂ , and M ₃ receptors have been investigated (GB-
2249093, JP-A-1-131145 and JP-A-3-133980).

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a compound having a chemical structure different from that of a conventional compound, having excellent muscarinic M ₃ receptor affinity and having a muscarinic M ₃ receptor antagonistic action. To do.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on the above-mentioned compound having a muscarinic M ₃ receptor antagonistic effect, and as a result, have created a new ester derivative and completed the present invention. That is, the compound of the present invention is an ester derivative represented by the following general formula (I) or a salt thereof.

[0006]

[Chemical 3]

(However, the symbols in the formulas have the following meanings.
Y: a single bond or a methylene group, p: 1 to 2, q: 0 to 1, (where p + q is 1 to 2) A ring is any of the following general formula (IIa), (IIb) or (IIc). Indicated by.

[0008]

[Chemical 4]

[0009] Z: N-R ¹ or ^{N + (R 1a) R 2} · Q - group represented by, Z ': a nitrogen atom or N ⁺ -R ^1a · Q ^- groups represented by, Q ^-: Anion , M: an integer of 1 to 4, n: an integer of 1 to 4, (provided that m + n is an integer of 3 to 5), l: an integer of 1 to 3, (provided that m + 1 is 3 to 5)
Is an integer. ) R, s, t: integer from 0 to 3, r + s
+ T: 2 or 3, R ¹ : a hydrogen atom, a lower alkyl group, or a group represented by the formula —B—R ³ , R ^1a : a lower alkyl group, or a group represented by the formula —B—R ³ , R ² : lower alkyl group, B: single bond, lower alkylene group, lower alkenylene group, or lower alkynylene group, R ³ : 1 hetero atom
Or two of them may be condensed with the benzene ring, and
A heterocyclic group which may be substituted with 1 or 2 substituents, or an optionally substituted phenyl group, indenyl group or naphthalenyl group. ) P + q is 1 to 2
Means that the nitrogen-containing ring condensed with the benzene ring is a 5-membered ring or a 6-membered ring. Also,
p is 1 to 2, q is 0 to 1, and p + q
Is 1 to 2 means that in the first case where p is 1 and q is 0, in the second case where p is 2 and q is 0, and p is 1 That is, there is a third case where q is 1. The first case means an indoline ester derivative (IIIa).

[0010]

[Chemical 5]

The second case is 1, 2, 3,
4-Tetrahydro-quinoline ester derivative (III
means b).

[0012]

[Chemical 6]

Further, the third case is 1, 2, 3,
4-Tetrahydro-isoquinoline ester derivative (II
Ic) is meant.

[0014]

[Chemical 7]

Of these three compounds, indoline ester derivative (IIIa) and 1,2,3,4-tetrahydro-quinoline ester derivative (IIIb) are preferable,
Further, the indoline ester derivative (IIIa) is more preferable.

The ring A is saturated and contains a nitrogen atom in the ring skeleton, as shown in the general formula (IIa), (IIb) or (IIc). In addition, the compound represented by the general formula (IIa) or (II
The ring A of b) is a 5- to 7-membered ring because m + n or m + 1 is an integer of 3 to 5.

Further, Z is N-R ¹ or N ⁺ (R ^1a ) R ² ·.
Q ^- In The group represented by the general formula (IIa) or (II
The ring A represented by c) is a ring that is a tertiary amine or a quaternary ammonium salt. Similarly,
Z ′ is a nitrogen atom or a group represented by N ⁺ —R ^1a · Q ⁻ ,
It means that the ring A represented by the general formula (IIb) is a ring that is a tertiary amine or a ring that is a quaternary ammonium salt.

When ring A is represented by the general formula (IIa), compound (IVa) in which Z is N--R ^{1
When, N + (R 1a) R} 2 · Q - compound represented by (IVb)
And are illustrated. Examples of the ring A represented by the general formula (IIa) include a 5- to 7-membered ring, and specific examples thereof include a pyrrolidinyl group, a piperidinyl group and a perhydroazepinyl group.

[0019]

[Chemical 8]

When the ring A is represented by the general formula (IIb) or (IIc), there is crosslinking. General formula (II
In b), one nitrogen atom and one carbon atom form a bridgehead, but in the general formula (IIc), two carbon atoms form a bridgehead. Ring A has the general formula (IIb) or (I
When represented by Ic), the carbon atom bonded to the oxygen atom of the ester group may be any carbon atom on the ring, that is, may be a quaternary carbon atom serving as a bridgehead, or may be represented by the general formula (IIb). Alternatively, in (IIc), the carbon atom described as CH ₂ may be a methine carbon due to the bond.

Compound (Va) in which Z'is a nitrogen atom in the case where ring A is represented by the general formula (IIb)
And a compound (Vb) represented by N ⁺ —R ^1a · Q ⁻ . Examples of the ring A represented by the general formula (IIb) include 5- to 7-membered rings, specifically, a quinuclidinyl group,
Examples thereof include a 1-azabicyclo [2.2.1] heptyl group and a 1-azabicyclo [3.2.1] octyl group.

[0022]

[Chemical 9]

Further, in the case where the ring A is represented by the general formula (IIc), the compound (V in which Z is NR ¹
and ^{a), N + (R 1a} ) R 2 · Q - compound represented by (V
b) and are illustrated.

[0024]

[Chemical 10]

Regarding the A ring represented by the general formula (IIc), the case where the sum of r, s and t is 3 is exemplified in the following chemical formula 11. When 1 was 1, the left column was used, when 1 was 2, the central column was used, and when 1 was 3, the right column was used. Similarly, the case where the sum of r, s, and t is 2 is similarly illustrated in Chemical formula 12. As the ring A, the ring exemplified in Chemical formula 12 is preferable.

[0026]

[Chemical 11]

[0027]

[Chemical 12]

Further, in the compound (I) of the present invention, the condensed ring of the benzene ring and the nitrogen-containing 5- or 6-membered ring seems to affect the M ₃ affinity. When this is the case, that is, as long as ring A contains nitrogen in the ring skeleton, the ring skeleton is saturated, and is preferably a 5- to 7-membered ring, ring A is not particularly limited.

As the anion of the quaternary ammonium salt,
Ion of a halogen atom, triflate, tosylate, mesylate and the like, and particularly, an ion of a halogen atom,
That is, halide ions are preferred, but not limited to these. For example, chloride ion, bromide ion, iodide ion, triiodide ion, nitrate ion,
Sulfate ion, phosphate ion, inorganic anions such as carbonate ions, formate (HCOO ^-), acetate (CH ₃ C
Further examples include carboxylates such as OO ⁻ ), propionate, oxalate and malonate, and anions of amino acids such as glutamic acid. With halide ions,
Bromide or iodide ions are preferred. The anion can be appropriately converted into a preferable anion by an ordinary ion exchange reaction.

In the present specification, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. As the lower alkyl group, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group,
tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,
1-ethyl-1-methylpropyl group, 1-ethyl-2-
A methylpropyl group etc. are mentioned. Of these groups,
An alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group is preferable, a methyl group and an ethyl group are more preferable, and a methyl group is still more preferable.

In the present invention, R ¹ or R ^1a is of the formula --B--R ³
It may be a group represented by. “Lower alkylene group” which can be B has 1 to 6 carbon atoms.
Examples of the alkylene group, specifically, methylene group, ethylene group, methylmethylene group, trimethylene group,
Dimethylmethylene group, tetramethylene group, methyltrimethylene group, ethylethylene group, dimethylethylene group, ethylmethylmethylene group, pentamethylene group, methyltetramethylene group, dimethyltrimethylene group, trimethylethylene group, diethylmethylene group, hexamethylene group Group, methylpentamethylene group, dimethyltetramethylene group and the like. Among these groups, an alkylene group having 1 to 3 carbon atoms such as methylene group, ethylene group, methylmethylene group, trimethylene group and dimethylmethylene group is preferable,
A methylene group and an ethylene group are more preferable, and a methylene group is further preferable.

The "lower alkenylene group" is a linear or branched alkenylene group having 2 to 6 carbon atoms, a vinylene group (-CH = CH-) Specifically, propenylene (-CH ₂ CH = CH-), butenylene group, methylpropenylene group, methylpropenylene group, dimethylvinylene group, pentenylene group, methylbutenylene group, dimethylpropenylene group, ethylpropenylene group, hexenylene group, dimethylbutenylene group, methylpentenylene group Groups and the like. Among these groups, alkenylene groups having 2 to 3 carbon atoms such as vinylene group and propenylene group are preferable.

The "lower alkynylene group" is a linear or branched alkynylene group having 2 to 6 carbon atoms, specifically, ethynylene group (-CC-), propynylene group (-
CH ₂ CC-), butynylene group, methylpropynylene group, pentynylene group, methylbutynylene group, hexynylene group and the like. Among these groups, alkynylene groups having 2 to 3 carbon atoms such as ethynylene group (—CC—) and propynylene group are preferable.

R ³ is a heterocyclic group containing 1 to 2 heteroatoms, a phenyl group, an indenyl group or a naphthalenyl group. The heterocyclic group may be condensed with a benzene ring. The phenyl group, indenyl group, or naphthalenyl group is not particularly limited in the number of substituents,
It is preferably 3 or less. However, when the substituent is a halogen atom, there is no limitation on the substituent.

The "heterocyclic group containing 1 to 2 heteroatoms" means an unsaturated or saturated monocyclic or condensed heterocyclic group. Preferred is a monocyclic or bicyclic unsaturated heterocyclic group. Specifically, furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, indolyl group, indazolyl group, indolizinyl group, quinolyl group,
Quinazolinyl group, quinolidinyl group, quinoxalinyl group,
Cinnolinyl group, benzimidazolyl group, benzofuranyl group, naphthyridinyl group, 1,2-benzisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolo [4,5-b] pyridyl group, isothiazolo [5,4- b] Pyridyl group, benzothienyl group and the like.

Further, these heterocyclic groups, phenyl groups,
The indenyl group and the naphthalenyl group may be substituted with a substituent. Specifically, a halogen atom, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, a trihalogenomethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group. A lower alkyl sulfonyl group, a sulfinyl group, a lower alkyl sulfinyl group, a sulfonamide group, a lower alkyl sulfonamide group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, an amino group, a mono- or di-lower alkylamino group, Examples thereof include a lower alkylamido group, a methylenedioxy group, an ethylenedioxy group, a phenyl group and the like. The lower alkyl group may be substituted with a hydroxyl group, an amino group, a mono- or di-lower alkylamino group. The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, but may be a combination of any of these atoms. When the substituent is a halogen atom, the number of substituents is not particularly limited.

Examples of the "trihalogenomethyl group" include trifluoromethyl group, trichloromethyl group, tribromomethyl group, triiodomethyl group, dichlorobromomethyl group and the like.

The "lower alkoxy group" is a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, te.
rt-butoxy group, pentyloxy (amyloxy)
Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group,
1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group and the like can be mentioned.

The "lower alkoxycarbonyl group" is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
ec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1,2- Examples thereof include a dimethylpropoxycarbonyl group, a 1-ethylpropoxycarbonyl group and a hexyloxycarbonyl group.

The "lower acyl group" is a formyl group,
Examples thereof include an acetyl group, a propionyl group, a butyryl group, a valeryl group and a pivaloyl group. The "lower alkylthio group" means a group in which a hydrogen atom in a mercapto group is substituted with the above lower alkyl group, and includes a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a pentylthio group, a hexylthio group and the like. Is mentioned. Examples of the "lower alkylsulfonyl group" include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group and the like.

The "lower alkylsulfinyl group" is methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group,
Examples thereof include a butylsulfinyl group, a pentylsulfinyl group and a hexylsulfinyl group. Examples of the "lower alkyl sulfonamide group" include a methyl sulfonamide group, an ethyl sulfonamide group, a propyl sulfonamide group, an isopropyl sulfonamide group, a butyl sulfonamide group, a pentyl sulfonamide group, a hexyl sulfonamide group and the like.

The "mono- or di-lower alkylcarbamoyl group" means a carbamoyl group in which 1 to 2 hydrogen atoms in the carbamoyl group are substituted with the above lower alkyl group, such as a methylcarbamoyl group, an ethylcarbamoyl group, Examples thereof include a propylcarbamoyl group and a dimethylcarbamoyl group. The “mono- or di-lower alkylamino group” means an amino group in which 1 to 2 hydrogen atoms in the amino group are substituted with the above lower alkyl group,
Methylamino group, ethylamino group, propylamino group,
Examples thereof include a dimethylamino group, a diethylamino group and a dipropylamino group. The “lower alkylamide group” means an amide group in which 1 to 2 hydrogen atoms in the amide group are substituted with the above lower alkyl group, and examples thereof include a methylamide group, an ethylamide group, a propylamide group and the like.

Since the compound (I) of the present invention has an asymmetric carbon atom, optical isomers based on it exist. The present invention includes separated or mixed forms of these isomers. Some of the compound (I) of the present invention can form a salt with an acid. Such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,
Succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,
Examples thereof include acid addition salts with organic acids such as citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. Furthermore, the compound (I) of the present invention is isolated as a hydrate, a solvate such as ethanol, or a crystalline polymorphic substance.

(Production Method) The compound (I) of the present invention can be produced by applying various production methods. The typical manufacturing method will be described below. First manufacturing method

[0045]

[Chemical 13]

(In the formula, R ⁴ represents a hydrogen atom, a lower alkyl group, or A ring, and R ⁵ represents a hydrogen atom or Y—C ₆ H
Means _five . This production method is a production for obtaining an indolinyl compound represented by the general formula (VIIb) by reducing an indolyl compound represented by the general formula (VIIa). In this reaction, the indolyl compound (VIIa) is hydrogenated in the presence of a catalyst, or reduced in an alcohol such as methanol or ethanol in the presence of a metal such as magnesium or tin.

As a catalyst for the hydrogenation reaction, palladium,
Using platinum, Raney nickel, or the like, it is carried out in a solvent such as alcohol such as methanol or ethanol, water, acetic acid, or the like under a hydrogen atmosphere at room temperature or under heating and under normal pressure or under pressure. In order to accelerate the hydrogenation reaction, it may be preferable to add an acid such as hydrochloric acid or a base such as sodium hydroxide or potassium hydroxide.

Second manufacturing method

[0049]

[Chemical 14]

(In the formula, Q ¹ means a leaving group and R ⁴ has the above-mentioned meaning.) As the leaving group for Q ¹ , for example, the above Q is preferable.

In the present production method, the N-benzylation reaction is carried out (first step) and then a reduction reaction is carried out (second step) to obtain the compound of the present invention. In the first step, the general formula (VI
II) quinoline compound (or general formula (IX)
And an benzyl compound (X) in an amount corresponding to the reaction are reacted in an inert solvent at room temperature or under heating with stirring.

Examples of the inert solvent include dimethylformamide (DMF), dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF),
Examples thereof include dioxane, dimethoxymethane, diethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide and the like, and mixed solvents thereof.
The reduction reaction in the second step is performed in the same manner as the reduction reaction in the first production method.

Third method

[0054]

[Chemical 15]

(In the formula, Q ² represents a leaving group which is advantageous in this reaction, and R ⁴ , R ⁵ , p and q have the above-mentioned meanings.) This reaction is a transesterification reaction. The reaction is carried out by stirring the compound represented by the general formula (XI) and the reaction corresponding amount of the hydroxy compound represented by the general formula (XII) in an inert solvent at room temperature or under heating.

Examples of the leaving group Q ² include a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group and the like. As the inert solvent, those mentioned above can be used. In order to accelerate this reaction, it is preferable to add a base (eg, sodium, sodium hydride, sodium methoxide, sodium ethoxide, etc.) and the like.

Fourth manufacturing method

[0058]

[Chemical 16]

(In the formula, R ⁴ , R ⁵ , p and q have the above-mentioned meanings.) This reaction is an amidation reaction, and is carried out with the carboxylic acid represented by the general formula (XIII) or its reactive derivative. General formula (X
It is carried out by stirring the hydroxy compound represented by II) in an inert solvent under cooling or under heating.

The compound is used in the form of a free carboxylic acid, and is also used in the reaction as a reactive derivative of the carboxylic acid. As the reactive derivative of carboxylic acid, active ester (for example, benzotriazole ester), mixed acid anhydride, acid halide, active amide, acid anhydride, acid azide and the like are used. When the compound is used in a free carboxylic acid state, it is preferable to use a condensing agent such as N, N-dicyclohexylcarbodiimide or N, N-diethylcarbodiimide.

Depending on the kind of the reactive derivative of the carboxylic acid used, the reaction may be carried out in the presence of a base.
It may be preferable for the reaction to proceed smoothly. Such bases include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, dimethylaniline,
Organic bases such as pyridine are mentioned.

Fifth manufacturing method

[0063]

[Chemical 17]

(In the formula, ring A'means Z in the ring A is NH, and Q ³ represents a leaving group advantageous in the present production method.
R ^1a , p and q have the meanings given above. ) Q ³ means a halogen atom, a methanesulfonyloxy group, a toluenesulfonyl group or the like.

In this production method, a compound (Ia) which is a tertiary amine is obtained by subjecting a compound (Ia) in which the amine of the ring A is secondary in the compound of the present invention to an N-alkylation reaction or an N-aralkylation reaction. (Ic) is obtained. Process A is a conventional N-alkylation reaction. Compound (Ia) and an alkylating agent (XIV) in an amount corresponding to the reaction thereof in alcohol or the inert solvent under cooling to heating (or under reflux).
It is carried out with stirring.

The method B is a dehydration condensation reaction. Compound (Ia), an amount of aldehyde (XV) corresponding to the reaction thereof, and a reducing agent (for example, sodium borohydride, sodium cyanoborohydride, triethylamine, etc.) in alcohol or the inert solvent under cooling or heating ( Or under reflux) with stirring. In the production method B, the compound (I
The reaction may be carried out by subjecting a) to a reaction-corresponding amount of compound (XV) in the presence of a catalyst (for example, palladium carbon, platinum oxide, etc.) under normal pressure to elevated pressure.

Sixth manufacturing method

[0068]

[Chemical 18]

(In the formula, A ′ ring, p and q have the above-mentioned meanings.) In this production method, the compound (Ia) in which the amine of the A ring in the compound of the present invention is secondary is subjected to N-phenylation reaction. Then, a compound (Id) which is a phenyl-substituted tertiary amine is obtained. This reaction is carried out by stirring compound (Ia) and triarylbismustine (XVI) in an amount corresponding to the reaction in an inert solvent such as dichloromethane in the presence of an organic metal such as copper acetate with stirring while cooling or heating. Be seen.

Seventh production method

[0071]

[Chemical 19]

(In the formula, p, q, R ^1a , R ² and Q ³ have the above-mentioned meanings.) In this production method, the amine of ring A in the compound of the present invention is or a secondary or tertiary amine. The quaternary ammonium compound (If) is obtained by subjecting the compound (Ie) to an N-alkylation reaction. Here, the compound (Ie) means a compound represented by the general formula (IV
a), (Va) and (VIa) are referred to as compounds, and the compound (If) means the compounds represented by the general formulas (IVb) and (Vb).
And (VIb).

In this reaction, compound (Ie) and the corresponding amount of alkylating agent (XVII) are reacted in an inert solvent such as dimethylformamide, chloroform, benzene, 2-butanone, acetone or tetrahydrofuran under ice cooling or under ice cooling. It is carried out by stirring at room temperature or under heating. As the alkylating agent, a lower alkyl halide,
Lower alkyl triflate, lower alkyl tosylate, lower alkyl mesylate and the like can be mentioned.

(Other Production Method) In the compound of the present invention, the compound in which R ^{1 of the} A ring is a hydrogen atom is produced from the compound of the present invention in which R ¹ is a group represented by the formula —B—R ³ . In one production method, the compound of the present invention in which R ¹ is a group represented by the formula —B—R ³ and its reaction-corresponding amount of chloroformic acid ester (for example,
(Chloroformic acid 1-chloroethyl ester etc.) is stirred in an inert solvent at room temperature or under heating, and then a solvolysis reaction is carried out by a conventional method. In other manufacturing methods, R
It is produced by subjecting the compound of the present invention in which ¹ is a group represented by the formula —B—R ³ to hydrogenation reaction in the presence of a catalyst (for example, palladium carbon, palladium, platinum oxide or palladium hydroxide).

The compound of the present invention in which R ³ is an aminophenyl group is produced from the compound of the present invention in which R ³ is a nitrophenyl group. In one production method, the compound of the present invention in which R ³ is a nitrophenyl group is subjected to a hydrogenation reaction in the presence of a catalyst (for example, Raney nickel, palladium carbon, palladium, platinum oxide or palladium hydroxide) at room temperature to under heating. Can be obtained. In another production method, the compound of the present invention in which R ³ is a nitrophenyl group is added in the presence of an amount of a metal corresponding to the reaction, such as iron powder, tin or zinc, in an inert solvent, under ice-cooling to room temperature, depending on the case. It is obtained by carrying out a reduction reaction at a temperature. A compound in which R ⁵ is a phenyl group or a benzyl group in the compound of the present invention is produced by treating a compound in which R ⁵ is a hydrogen atom in the same manner as in the fifth or sixth production method.

The compound of the present invention thus produced may be left free or subjected to a salt-forming treatment by a conventional method,
It is isolated and purified as its salt. Isolation / purification is carried out by applying usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographies.

[0077]

The present invention compounds according to the present invention has a muscarinic M ₃ receptor affinity, various diseases M ₃ receptor is involved as M ₃ receptor resistance agents, especially gastrointestinal, respiratory and function of urinary Disorders (eg irritable bowel syndrome, spastic colitis, diverticulitis,
It is useful as a preventive or therapeutic drug for chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, urinary incontinence, pollakiuria, etc.

In particular, the compound of the present invention has high selectivity for M ₃ receptors existing in smooth muscle, glandular tissue and the like as compared to M ₂ receptors existing in heart and the like, and has less side effects on heart and the like. _It is highly useful as a _3- receptor antagonist, especially as a prophylactic or therapeutic drug for irritable bowel syndrome, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, urinary incontinence, pollakiuria and the like.

The usefulness of the affinity and antagonism of the compound of the present invention for the muscarinic M ₃ receptor was shown by the following muscarinic receptor affinity test and antagonism test.

Muscarinic Receptor Affinity Test a. Preparation of membrane preparation The cerebral cortex, heart, and submandibular gland of Wistar male rat (Japan SLC) weighing about 200 to 350 g were removed, and 5 times volume of 100 mM sodium chloride, 10 mM
20 mM HEPES buffer containing magnesium chloride (pH 7.5, hereinafter abbreviated as HEPES buffer) was added and homogenized in ice cooling. After filtering this with gauze, ultracentrifugation is performed at 50,000 × g at 4 ° C. for 10 minutes, the precipitate is suspended in HEPES buffer, and ultracentrifugation is performed again at 50,000 × g at 4 ° C. for 10 minutes. went. This precipitate was suspended in HEPES buffer and -8
Stored at 0 ° C. After that, it was melted at the time of use and tested.

B. Muscarinic M ₁ Receptor Binding Assay Method by Doods et al. (J. Pharmacol. Exp. Ther., 242 , 257,
1987.) was improved. Cerebral cortex membrane preparation, [ ³ H]
-Pirenzepine and the test compound were incubated in 0.5 ml of HEPES buffer at 25 ° C for 45 minutes, and then 5 ml of HEPES buffer was added to the glass filter (Whatman GF /
B) with suction filtration and 3 with 5 ml HEPES buffer
The filter was washed once. The radioactivity of [ ³ H] -Pirenzepine adsorbed on the filter was measured by a liquid scintillation counter. Non-receptor specific binding was determined by adding 1 μM atropine. The affinity of the compound of the present invention for the muscarinic M ₁ receptor was determined by Cheng and Prusoff (Biochem. Pharmacol., 22 ,
3099, 1973), the labeled ligand [ ³ H]-
The dissociation constant (Ki) was calculated from the concentration (IC ₅₀ ) of the test compound that inhibits the binding of pirenzepine by ₅₀ %.

C. Muscarinic M ₂ receptor binding test Heart membrane preparation as membrane preparation, [ ³ H] as labeled ligand
-Quinuclidinyl benzilate
ilate) was used, and the same method as in the muscarinic M ₁ receptor binding test described in b) above was performed. d. Muscarinic M ₃ receptor binding test Submandibular gland preparation as membrane preparation, [ ³ H] -N-methylscopolamine (N-methylscopolami) as labeled ligand
Ne) was used, and the same method as in the muscarinic M ₁ receptor binding test described in b) above was performed.

Muscarinic receptor antagonist test a. Muscarinic M ₂ Receptor Antagonistic Test After extracting the atrium from a male Hartley guinea pig, the right atrium was suspended in the Magnus tube and the heart rate was recorded under spontaneous contraction. After equilibration for about 1 hour in each sample, determine the concentration effect curve was administered bethanechol cumulatively in Magnus tubes, 50% bradycardia working concentration of bethanechol from each concentration response curve (EC ₅₀
Value) was calculated. After determining the EC ₅₀ value in the absence of the compound (control EC ₅₀ value), various concentrations of the compound were added to the Magnus tube, and the EC ₅₀ value in the presence of the compound was similarly determined. EC ₅₀ value and control EC in the presence of each compound
The rightward shift width (dose-ratio) of the concentration action curve was calculated from the ₅₀ values, which was developed on a Schild plot to determine the pA ₂ value.

B. Muscarinic M ₃ receptor antagonist test ・ Guinea pig ileum Hartley male guinea pigs are killed by exsanguination and the abdominal cavity is opened to remove the small intestine. At that time, discard about 10 cm of the terminal ileum. The intestine is left for about 90 minutes in a beaker containing Tyrode solution aerated with 95% O ₂ /5% CO ₂ while exchanging the Tyrode solution several times on the way. After that, place the intestine in a glass petri dish containing Tyrode's solution and put it in the 3-4
Cut into cm pieces. Pieces are preferentially cut from the distal end of the ileum to remove residual mesenteric tissue. The tissue was suspended in a 10 ml Magnus bath containing Tyrode's solution (37 ° C.) aerated with 95% O ₂ /5% CO ₂ , and 1.
A tension of 0 g was applied. When stable, 5 × 10 ^-7
Adjust the condition by adding M and acetylcholine to the tank. When the peak is reached, wash with Tyrode's solution immediately to remove the drug. This is repeated 4 to 5 times to stabilize the peak of contraction.

Thereafter, as a control, acetylcholine was cumulatively added to each concentration step (10 ^-9 to 10).
^-4 M) to shrink the tissue. Then, the tissue is promptly washed with Tyrode's solution for about 4 times, and after stabilizing, the compound is administered, and 10 minutes later, acetylcholine is administered as in the previous case. pA ₂ was determined by Schild plot.

Excised Guinea Pig Trachea Male Hartley guinea pigs are sacrificed by exsanguination and the trachea between the cartilage of the pharyngeal cartilage and the tracheal bifurcation is removed to remove excess fat and cut into spirals. Furthermore, the spiral was divided into two equal parts, and a spiral sample for a control group and a drug administration group was prepared for each trachea. This sample is 95% O ₂ /5%
It was suspended in a Magnus tank containing 10 ml of 37 ° C. Tyrode's solution aerated with CO ₂ and a tension of 1.0 g was applied. Thirty
The Tyrode solution in the Magnus tank is replaced every minute (about 2 hours), and then left for about 90 minutes. When the tension becomes stable, the solvent is administered to the control group and the compound is administered to the drug group, and 30 minutes later, carbachol (10 ⁻⁹ to 10 ⁻⁴ M) is cumulatively added. pA ₂ was determined by Schild Plot.

A preparation containing one or more kinds of the compound of the present invention or a salt thereof as an active ingredient is prepared by using carriers, excipients and other additives usually used for preparation. The carrier or excipient for the formulation may be either solid or liquid, for example, lactose, magnesium stearate,
Starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones can be mentioned.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid preparation, or parenteral administration such as injection such as intravenous injection and intramuscular injection, suppository and transdermal administration. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex and the like.

[0089]

EXAMPLES The compounds of the present invention and the method for producing the same have been described above. The following examples will further explain the details.

(Reference Example 1)

[0091]

[Chemical 20]

0.19 g of magnesium was added to 25 ml of a methanol solution of 1.06 g of ethyl 1-phenylindole-2-carboxylate under an argon stream under ice cooling, and the mixture was stirred overnight at 5 to 10 ° C. The reaction solution is cooled with ice, 3
The mixture was poured into 12 ml of normal hydrochloric acid, adjusted to pH 9 with aqueous ammonia, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue,
The organic layer obtained was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 40: 1 → 20: 1) to obtain 0.55 g of methyl 1-phenylindoline-2-carboxylate as a yellow oil.

Mass spectrum (m / z): 253 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 3.20 (1H, dd, J = 5.9, 14.4H)
z), 3.60 (1H, dd, J = 10.2, 14.4)
Hz), 3.71 (3H, s), 4.80 (1H, d
d, J = 5.9, 10.2 Hz), 6.7-7.5 (9
H, m).

In the same manner as in Reference Example 1, the following compound of Reference Example 2 was obtained.

(Reference Example 2)

[0096]

[Chemical 21]

Methyl 1-benzylindoline-2-carboxylate Raw material compound: Methyl 1-benzylindole-2-carboxylate Mass spec (m / z): 267 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , inside TMS) (Standard): δ: 3.18 (1H, dd, J = 7.9, 15.9H)
z), 3.37 (1H, dd, J = 10.0, 15.9).
Hz), 3.66 (3H, s), 4.25 (1H, d
d, J = 7.9, 10.0 Hz), 4.31 (1H,
d, J = 15.3 Hz), 4.50 (1H, d, J = 1
5.3 Hz), 6.44 (1H, d, J = 7.9H
z), 6.67 (1H, dd, J = 7.3, 7.9H)
z), 7.0-7.05 (2H, m), 7.2-7.4.
(5H, m).

(Reference Example 3)

[0099]

[Chemical formula 22]

Methyl 1,2,3,4-tetrahydro-
To a solution of 2.0 g of quinoline-2-carboxylate in dichloroethane, 5.53 g of triphenylbismucin and 0.95 g of cupric acetate were added, and the mixture was heated under reflux for 2 hours, and then 0.95 g of cupric acetate was added. The mixture was stirred at 80 ° C for 5 days. After cooling the reaction solution to room temperature, the insoluble matter was filtered off,
The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 10 /
Purified in 1), methyl 1,2,3,4-tetrahydro-1-phenylquinoline-2-carboxylate 0.2
3 g was obtained as a brown oil.

Mass spectrum (FAB, m / z): 267 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 2.2-2.4 (2H, m), 2.8 -2.9 (2
H, m), 3.65 (3H, s), 4.48 (1H,
t, J = 4.4 Hz), 6.5-6.7 (2H, m),
6.8-7.4 (10H, m) Table 1 shows the structural formulas of the compounds obtained in Examples 1 to 3.

[0102]

[Table 1]

Example 1 To 0.5 ml of methyl 1-phenylindoline-2-carboxylate and 0.36 g of 3-quinuclidinol in 20 ml of a toluene suspension was added 0.02 g of sodium hydride under an argon stream to produce a product. The mixture was heated under reflux for 2 hours while removing methanol. The reaction solution was cooled to room temperature, saturated saline was added, and the mixture was stirred for 5 minutes. After separating the organic layer, it was dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue is ethanol 10
Dissolve in ml, 4N hydrogen chloride-dioxane solution 1 ml
Was added and the solvent was evaporated under reduced pressure. The obtained residue was solidified with ethanol-ether and then recrystallized from ethanol-ether to give 3-quinuclidinyl 1
-0.16 g of phenylindoline-2-carboxylate hydrochloride was obtained.

Melting point 201-203 ° C. (dec.) E
tOH-Et ₂ O Elemental analysis _{(C 22 H 25 N 2 O} 2 Cl · 0.2H as _{2 O) C (%) H} (%) N (%) Cl (%) Theoretical values 68.01 6.59 7.21 9.13 Found 67.94 6.41 7.19 9.46 In the same manner as in Example 1, the following compound of Example 2 was obtained.

Example 2 3-Quinuclidinyl 1-benzylindoline-2-carboxylate fumarate Raw material compound: Methyl 1-benzylindoline-2-carboxylate Melting point 141-143 ° C EtOH Elemental analysis value (C ₂₇ H ₃₀ N ₂ O ₆ · 0.25H ₂ O) (Example 3) Ethyl 1-phenylindoline-2-carboxylate and methyl 1-phenylindoline-
To a solution of 16.1 g of 2-carboxylate (5: 3 mixture) in 200 ml of toluene, 124 g of 1-benzyl-4-piperidinol and 0.246 g of sodium hydride.
Was added and stirred at 140 ° C. for 24 hours while removing methanol produced. The reaction solution was cooled to room temperature, 300 ml of saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). 1-benzyl-
30.7 g of 4-piperidyl 1-phenylindoline-2-carboxylate was obtained as a yellow oil. 2.0 g of this was dissolved in 20 ml of dichloroethane, 1.6 ml of 1-chloroethyl chloroformate was added dropwise at room temperature, the mixture was heated under reflux for 3 hours, and then the reaction liquid was concentrated under reduced pressure. The residue was dissolved in 20 ml of methanol, heated under reflux overnight, and the solvent was evaporated under reduced pressure to give 4-piperidyl.
1-Phenylindoline-2-carboxylate.hydrochloride was obtained as a crude product. This was recrystallized from acetonitrile-ethanol to give 4-piperidyl 1-phenylindoline-2-carboxylate hydrochloride.
50 g was obtained as colorless crystals.

Melting point 193-195 ° C. CH ₃ CN Elemental analysis value (as C ₂₀ H ₂₃ N ₂ O ₂ Cl.0.2H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 66.27 6.51 7.73 9.78 Experimental value 66.51 6.45 7.78 10.10 Structural formulas of the compounds obtained in Examples 4 to 16 are shown in Tables 2 and 3.

[0107]

[Table 2]

[0108]

[Table 3]

(Example 4) 4-piperidyl 1-phenylindoline-2-carboxylate / hydrochloride 0.50
0.1 g of 3-thiophenecarbaldecht in a suspension of 10 g of dichloroethane in an argon stream at room temperature.
1, and sodium triacetoxyborohydride 0.8
8 g was added and stirred for 16 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel chromatography (chloroform / methanol =
97/3) to give 1- (3-thenyl)
0.55 g of -4-piperidyl 1-phenylindoline-2-carboxylate was obtained as a yellow oil. 1-
(3-Tenyl) -4-piperidyl 1-phenylindoline-2-carboxylate 0.55 g in ethanol 1
It is dissolved in 0 ml and a solution of 4N hydrogen chloride in ethyl acetate is added.
50 ml was added, the solvent was distilled off under reduced pressure, and the colorless solid obtained was recrystallized from acetonitrile to give 1- (3
0.32 g of -thenyl) -4-piperidyl 1-phenylindoline-2-carboxylate.hydrochloride was obtained as colorless crystals.

Melting point 204-207 ° C. CH ₃ CN Elemental analysis value (C ₂₅ H ₂₇ N ₂ O ₂ SCl) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 65.99 5.98 6.16 7.05 7.79 Experimental value 65.92 5.91 6.16 7.23 7.93 In the same manner as in Example 4, the following compounds of Examples 5 to 12 were obtained.

(Example 5) 1-furfuryl-4-piperidyl 1-phenylindoline-2-carboxylate oxalate salt raw material compound: 2-furaldehyde melting point 207-208 ° C CH ₃ OH elemental analysis value (C ₂₇ H ₂₈ N ₂ O ₇ ) (Example 6) 1- (2-pyridylmethyl) -4-piperidyl 1-phenylindoline-2-carboxylate dihydrochloride Raw material compound: 2-pyridinecarbaldehyde Melting point 116-118 ° C CH ₃ CN-i-Pr ₂ O elemental analysis value (as C ₂₆ H ₂₉ N ₃ O ₂ Cl · H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 61.91 6.19 8.33 14.06 Experimental value 62.23 5.92 8.36 13.98 ( example 7) 1-benzyl-4-piperidyl 1-phenyl-indoline-2-carboxylate hydrochloride starting compound: benzaldehyde mp 190-192 ° C. CH ₃ CN elemental analysis _{(C 27 H 29 N 2 O} 2 Cl · 0 .25 H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 71.51 6.56 6.18 7.82 Experimental value 71.81 6.51 6.25 7.82 (Example 8) 1- (3-nitrobenzyl) -4- Piperizi 1-phenyl-indoline-2-carboxylate hydrochloride starting compounds: 3-nitrobenzaldehyde mp _{177-183 ℃ CH 3 CN-i-} Pr 2 O Elemental analysis _{(C 27 H 28 N 3 O} 4 Cl · 0.25H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 65.06 5.76 8.43 7.11 Experimental value 65.23 5.70 8.37 7.25 (Example 9) 1- (4-nitrobenzyl) -4-piperidyl 1 - phenyl indoline-2-carboxylate starting compound: (as _{C 27 H 27 N 3 O 4} ) 4- nitrobenzaldehyde mp _{127-130 ℃ CH 3 OH-CH 3} CN elemental analysis (Example 10) 1- (3-hydroxybenzyl) -4-
Piperidyl 1-phenylindoline-2-carboxylate / hydrochloride Salt compound: 3-hydroxybenzaldehyde Melting point 204-209 ° C. (decomposition) EtOH-Et ₂ O Elemental analysis value (C ₂₇ H ₂₉ N ₂ O ₃ Cl.0.15H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 69.34 6.31 5.99 7.58 Experimental value 69.17 6.25 5.99 7.88 (Example 11) 1- (4-methylbenzyl) -4-piperidyl 1 - phenyl indoline-2-carboxylate hydrochloride starting compounds: 4-methyl-benzaldehyde mp 184-186 ℃ EtOH-Et ₂ O elemental analysis (as _{C 28 H 31 N 2 O 2} Cl) C (%) H (% ) N (%) Cl (%) Theoretical value 72.63 6.75 6.05 7.66 Experimental value 72.52 6.82 6.06 7.67 (Example 12) 1- (3-chlorobenzyl) -4-piperidyl 1-phenyl Indoline-2-carboxylate oxalate starting compounds: 3-chloro-benzaldehyde mp _{114-118 ℃ CH 3 CN-i-} Pr 2 O Elemental analysis _{(C 29 H 29 N 2 O} 6 Cl · 0.25H 2 O As) C (%) H (%) N (%) Cl (%) Theoretical value 64.32 5.49 5.17 6.55 Experimental value 64.21 5.45 5.09 6.89 (Example 13) 4-piperidyl 1-phenylindoline-2-carboxylate hydrochloride 0.50g, 0.38g of potassium carbonate 3 in 15ml of acetonitrile suspension
-Methylbenzyl bromide (0.24 g) was added dropwise, and the mixture was stirred at room temperature for 20 hours. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 50/1) to give 0.54 g of 1- (3-methylbenzyl) -4-piperidyl 1-phenylindoline-2-carboxylate as a pale product. Obtained as a yellow oil. This was dissolved in 20 ml of ethanol, 0.4 ml of 4N hydrogen chloride-dioxane solution was added, the solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethanol-ether to give 1- (3-
Methylbenzyl) -4-piperidyl 1-phenylindoline-2-carboxylate.hydrochloride 0.41 g was obtained as colorless crystals.

Melting point 194-196 ° C. EtOH-Et ₂ O Elemental analysis value (as C ₂₈ H ₃₁ N ₂ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 72.63 6.75 6.05 7.66 Experimental value 72.38 6.82 6.00 7.70 (Example 14) 4-piperidyl 1-phenylindoline-2-carboxylate / hydrochloride 0.50 g and potassium carbonate 0.38 g dimethylformamide suspension 15
0.57 g of 5-chloromethyl-N-tritylbenzimidazole was added to ml, and the mixture was stirred at 80 ° C. for 4 hours,
Water was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 50/1) to give 1- (N-
0.90 g of trityl-5-benzimidazolylmethyl) -4-piperidyl 1-phenylindoline-2-carboxylate was obtained as a colorless foam. Dissolve this in 30 ml of acetone, add 6 ml of 1N hydrochloric acid, and add 6 ml at room temperature.
After stirring for an hour, the mixture was concentrated under reduced pressure. Saturated aqueous sodium carbonate solution was added to the residue to make it alkaline, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform / methanol =
10/1) to give 1- (1H-benzimidazol-5-ylmethyl) -4-piperidyl 1
-Phenylindoline-2-carboxylate 0.49
g was obtained as a colorless foam. 10 ml of this
Was dissolved in water, 0.9 ml of a 4N hydrochloric acid-dioxane solution was added, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol-ether and then recrystallized from ethanol to give 1- (1H-benzimidazol-5-ylmethyl) -4-piperidyl 1-phenylindoline-2-.
0.20 g of carboxylate dihydrochloride was obtained as colorless crystals.

Melting point 168-170 ° C. EtOH Elemental analysis value (as C ₂₇ H ₃₀ N ₄ O ₂ Cl ₂ .H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 61.02 6.07 10.54 13.34 Experimental value 61.27 5.83 10.23 12.97 (Example 15) 1- (3-nitrobenzyl) -4-piperidyl 1-phenylindoline-2-carboxylate 0.63 g was dissolved in 30 ml of methanol, and in a hydrogen atmosphere in the presence of Raney nickel, Catalytic reduction was performed. After the Raney nickel was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform /
By refining with methanol = 97/3), 1-
0.13 g of (3-aminobenzyl) -4-piperidyl 1-phenylindoline-2-carboxylate was obtained as a pale yellow oil.

0.13 g of 1- (3-aminobenzyl) -4-piperidyl 1-phenylindoline-2-carboxylate was dissolved in 10 ml of methanol, and 0.3 ml of a 4N hydrogen chloride solution in ethyl acetate was added. The light yellow solid obtained by distilling off the solvent under reduced pressure was recrystallized from acetonitrile-ethanol to give 1- (3-aminobenzyl) -4-piperidyl 1-phenylindoline-
0.10 g of 2-carboxylate dihydrochloride was obtained as pale yellow crystals.

Melting point 167-173 ° C. CH ₃ CN—EtOH Elemental analysis value (as C ₂₇ H ₃₁ N ₃ O ₂ Cl ₂ .0.5H ₂ O) C (%) H (%) N (%) Cl (% Theoretical value 63.65 6.33 8.25 13.92 Experimental value 63.48 6.12 8.28 14.25 In the same manner as in Example 15, the following compound of Example 16 was obtained.

(Example 16) 1- (4-aminobenzyl) -4-piperidyl 1-phenylindoline-2-
Carboxylate 2 oxalate starting compound: 1- (4-nitrobenzyl) -4-piperidyl, 1-phenyl-indoline-2-carboxylate mp 108-112 ° C. CH ₃ CN Elemental analysis (C ₃₁ H ₃₃ N ₃ O ₁₀・ 0.25H ₂ O) (Example 17)

[0117]

[Chemical formula 23]

Methyl 1,2,3,4-tetrahydro-
1-phenylquinoline-2-carboxylate 0.23
g, 3-quinuclidinol 0.16 g in toluene solution 1
Sodium hydride (10 mg) was added to 0 ml under an argon stream, and the mixture was refluxed for 6 hours while removing generated ethanol. After cooling the reaction solution to room temperature, saturated brine was added,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 → 10/1) to give 3-quinuclidinyl 1,2,3,4-tetrahydro-1-phenylquinoline-2-carboxylate. 27 g was obtained. Fumaric acid (79 mg) was added to this methanol solution, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol-acetonitrile and recrystallized from ethanol-ether to give 3-quinuclidinyl 1,2,3,4-
Tetrahydro-1-phenylquinoline-2-carboxylate fumarate was obtained as light gray crystals.

Melting point 160-162 ° C. EtOH-Et ₂ O Elemental analysis value (as C ₂₇ H ₃₀ N ₂ O ₆ .H ₂ O) (Example 18)

[0120]

[Chemical formula 24]

3-quinuclidinyl 1-phenylindoline-2-carboxylate 0.10 ml of methyl iodide was added to a solution of 0.80 g of 2-butanone in 10 ml, and the mixture was stirred overnight at room temperature. 5 ml of diethyl ether in the reaction mixture
Was added to the precipitate, and the precipitate was collected by filtration and washed with diethyl ether to give 0.68 g of 1-methyl-3-[[(1-phenyl-2-indolinyl) carbonyl] oxy] quinuclinium iodide as a yellowish brown amorphous substance. Got as.

Mass spectrum (FABMS (Pos.),
m / z) 363 (M ⁺ ) Infrared absorption spectrum max (KBr) cm ^-1 : 1746, 15
04, 1184, 748 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.52-2.00 (4H, m), 2.12, 2.
21 (1H, s × 2), 2.94, 2.95 (3H, s
X2), 3.07-3.20 (1H, m), 3.20-
3.52 (5H, m), 3.54-3.67 (1H,
m), 3.83 (1H, t, J = 11Hz), 5.00
-5.15 (2H, m), 6.72-6.80 (1H,
m), 6.98-7.42 (8H, m) In Examples 1-1 to 1-57 below, compounds obtained by those skilled in the art by reactions similar to or similar to the above Examples To illustrate. For example, Examples 1-47 and 1-
48 is produced in the same reaction as in Example 17. Also,
Examples 1-51, 1-52, and Examples 1-56 are prepared in an alkylation reaction similar or similar to Example 18.

[0123]

[Table 4]

[0124]

[Table 5]

[0125]

[Table 6]

[0126]

[Table 7]

[0127]

[Table 8]

[0128]

[Table 9]

[0129]

[Table 10]

[0130]

[Table 11]

[0131]

[Table 12]

[0132]

[Table 13]

[0133]

[Table 14]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/55 ACV C07D 401/14 209 403/12 207 209 405/14 209 453/02 471/08 487/08 7019-4C (72) Inventor Ken Ikeda 1-2-25 Tsukushino, Abiko-shi, Chiba Corp. Tengoyama 106 (72) Inventor Hachishu Isomura 3-4-8 Yakushidai, Moriya-cho, Kitasoma-gun, Ibaraki

Claims (1)

[Claims] 1. An ester derivative represented by the following general formula (I) or a salt thereof. [Chemical 1] (However, the symbols in the formulas have the following meanings: Y: a single bond or a methylene group, p: 1 to 2, q: 0 to 1, (however,
p + q is 1 to 2) A ring has the following general formula (IIa),
Shown as either (IIb) or (IIc). [Chemical 2] Z: a group represented by N—R ¹ or N ⁺ (R ^1a ) R ² · Q ⁻ ,
Z ′: a nitrogen atom or a group represented by N ⁺ —R ^1a · Q ⁻ ,
Q ⁻ : anion, m: an integer of 1 to 4, n: an integer of 1 to 4 (provided that m + n is an integer of 3 to 5) 1:
An integer of 1 to 3 (however, m + 1 is an integer of 3 to 5) r, s, t: an integer of 0 to 3, r + s + t: 2 or 3, R ¹ : a hydrogen atom, a lower alkyl group, or Formula-B
A group represented by —R ³ , R ^1a : a lower alkyl group, or a group represented by the formula —B—R ³ , R ² : a lower alkyl group, B: a single bond, a lower alkylene group, a lower alkenylene group, or a lower group Alkynylene group, R ³ : a heterocyclic group containing 1 to 2 heteroatoms, which may be condensed with a benzene ring, and which may be substituted with 1 to 2 substituents, or is substituted. Optionally a phenyl group, an indenyl group, or a naphthalenyl group. )