JPS5967284A - Cyclic carboxylic acid piperidyl ester and amide derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to piperidyl ester derivatives of benzoic acid,
Benzoic acids (121 types, including polycarbocyclic and polycyclic carboxylic acids)

The present invention provides alkylene-bridged piperidyl esters or amides of dicarbocyclic or heterocyclic carboxylic acids, or alkylene-bridged piperidyl esters or amides of benzoic acid having substituents on the nucleus. However, a) benzoic acid esters with an alkylene bridge between two carbon atoms of the piperidine ring must have at least one substituent at the ortho or meta position of the phenyl ring, and b) hydrogen or halogen at the meta or para position. For piperidyl esters of benzoic acid with alkylene bridges between ring carbon atoms, which are unsubstituted at both ortho positions or have a halogen or alkyl group at at least one ortho position, at least 3 in the alkylene bridges. C) For benzoic acid esters having an alkylene bridge between the nitrogen atom of the piperidyl group and the ring carbon atom (I8) and one oxy substituent, the benzoic acid nucleus has an oxy substituent. d) a 6-membered monocyclic heterocyclic carboxylic acid amide or ester containing a nitrogen atom in the ring; e) In the case of a cyclic heterocyclic carboxylic acid amide containing 3 acid atoms, there is an alkylene bridge between the nitrogen atom of the piperidyl group and the ring carbon atom; f) have no alkyl or hydroxy or halogen substituents in any ortho position in the benzoic acid amide; g) chenoyl and naphthoyl-8-aza-bicyclo(3, 2,1]] Octo-3-yleste shall be excluded.

The above compounds and their salts, eg, acid addition salts and quaternary ammonium salts of the nitrogen atom of a piperidyl group. Hereinafter, all of these compounds and their salts belong to the compounds of the present invention.

The compound can be substituted at any position.

In the case of benzoic acid esters and amides, any substituents do not form a ring. of compounds] i! Y is a dicarbocyclic acid. Another group of compounds are heterocyclic acids - preferably bicyclic, and advantageously containing a heteroatom in one ring.

The alkylene bridge has at least 3 carbons, or alternatively
The bridge may be directly connected to the nitrogen atom of the piperidine ring.

The present invention also relates to the following formula (1): A -C0-R-1,) (wherein A is a group represented by the following formula 11); -X is -Cl-12-1-
NR3---0-1 or -S-; R, and 1(
2 is independently hydrogen, halogen, (C,,,) alkoxy, hydroxy, amino(C1-4) alkylaminodi(C1-4) alkylamino, mercapto, or (C1-4) alkylthio;
1 (3 represents hydrogen, (C1-4) alkyl, (C3-5) alkenyl, aryl or aralkyl group.

A also represents a group represented by the following formula (1): In the formula (2), 4 to R7 each independently represent hydrogen, (CI,')alkylamydedi(C1-4)alkylamy8 Halogen, (C1-4)
It represents an alkoxy, (C1-4) alkyl, (C1-4) alkanoylamino or pyrrolyl group. However, R4
At least one of 5 and 5 is a group other than hydrogen.

B represents -0- or -NH-.

D is a group represented by the following formula (2): (20) In the formula (2), n is 2, 3 or 4; 8 is hydrogen;
(C1-7) represents an alkyl, (C3-5'' alkenyl or aralkyl group).

Alternatively, D represents a group represented by the following formula (2).

However, in formula 1, (1) A is a group of formula ■[, B is N
When H-, D is a group of formula ■; (II) A is a group of formula II
In the group I, 4 is hydrogen, or R4 is halogen or alkyl, and 5 to 7 are halogen or hydrogen, and when B or -0-1D is a group of formula (■), n is 3. or 4; 1D When A is a group of formula TIT (7), any one of R4-R7 is an alkoxy group, and D is a group of formula (■),
In addition, one of 4 to 7 is a group other than hydrogen and alkoxy, or R4 to I (only two of 7 are an alkoxy group;
(tv) When A is a group of formula (1) and R4 is alkyl or halogen, B is 10-. ] Compounds represented by, and acid addition salts thereof and quaternary
grade ammonium salts.

As alkyl, methyl, ethyl or propyl groups are preferred. The alkoxyl group is preferably a methoxy or ethoxy group, and the aralkyl group is aryl (C1-
4) γ-alkyl group is convenient. The alkenyl group is preferably an allyl or methallyl group.

The aromatic aryl moiety can be an unsubstituted phenyl group, or a (C1-4) alkyl group, such as a methyl group, a nitrogen group, such as a fluorine, a hydroxyl group, or a (C1-4) alkoxy group, such as a methoxy group, by one or two groups. A phenyl group having a substituent is desirable. As the substituted aromatic aryl group, a monosubstituted group is preferable. Aralkyl is conveniently a benzyl group. Norogens are fluorine, chlorine, bromine or iodine.

A is conveniently a group of formula (■).

In the group of formula (■), the carbonyl side chain is 2°3.4.
It may be attached to the 5.6 or 7 ring carbon atom, with the 4 and 5 positions being preferred. The most preferred position of the carbonyl group is especially the 3-position of the ring containing X. Preferred A is an indole group.

kl is attached to the 4, 5, 6 or 7 ring carbon atom of the nucleus, preferably the 5 position -- is attached to the 2 or 3 ring carbon atom of the nucleus. For example, tautomers when I is at the 2-position and represent a hydroxy group or a mercapto group are also included in formula (2).

R3 is conveniently hydrogen or alkyl. n is 3 or 4
-3 is more desirable.

In the group of formula (1), it is preferable that 1 (is a halogen) and (C1-4) alkylamino group is (
CI-4) alkoxy; 5 is halogen or hydrogen; R6 is hydrogen, amine nitro, (C1-4) alkylamino, or di(C14') alkylamino-halogen or l-pyrrolyl; R7 is hydrogen or halogen; and R6 is conveniently other than hydrogen, halogen or pyrrolyl group. In the group of formula (1), R7 is halogen, preferably chlorine or iodine, especially chlorine.

Other examples of groups of formula (■) include 3,5-dimethoxy (23
) phenyl, 3,5-dimethylphenyl and especially 3゜5
- Dichlorophenyl group is included. Alternatively, as a group of formula (1), 3-chloro, 3-methyl or 3,4.5
-Trimethoxyphenyl group may also be used.

Different configurations exist for the group of formula (■). For example, a six-membered ring containing nitrogen and carbon to which the B moiety is bonded (hereinafter referred to as a piperidine ring) takes a chair-shaped, matrix-shaped, or intermediate-shaped configuration.

There are two different configurations in the B portion. This can be understood by drawing a plane through the carbon atoms of the piperidine ring and considering the arrangement of the group (2) with reference to this plane. The nitrogen atoms are on the top side of the plane and the alkylene bridges are on the bottom side of the plane. When part B is below the plane and on the same side as the alkylene bridge, it has an α-configuration. This arrangement is an end arrangement;
It also corresponds to the placement of tropin, etc. When part B is above the plane and on the same side as the nitrogen bridge, it has a β configuration. This is an exo configuration and also corresponds to the configuration of pseudotropin and the like. The exo/endo nomenclature will be used below. Endoisomers are preferred.

(24) R8 is alkyl, particularly preferably a methyl group.

A quinuclidinyl group is also known as a group of formula (1). 3
- or 4-quinuclidinyl groups are convenient, especially 3-quinuclidinyl groups.

One group of compounds has the formula I, a: 5Pa [wherein R4Pa is halogen, (C1-4)alkylamine or (C,-4)alkoxy group] a is hydrogen R6Pa is ami/-(C,,)alkylamino or di(C1-4)alkylamino group 7. a is 8Pa for hydrogen or fluorine, chlorine or bromine
is a hydrogen-(C0-7)alkyl or aralkyl group. ], and their acid addition salts and quaternary ammonium salts.

Another group of compounds are the impellecherin (homotropane) esters of benzoic acid - in particular those with the formula ■Pl) di5Pa (wherein R4Pa-R5Pa, di6Pa-R8Pa
is as defined above and R7Pb is hydrogen or halogen. ), and their acid addition salts and quaternary ammonium salts.

Ru3 (In the formula, the free valence is attached to any of the condensed rings, and n'
is 2 or 3, kl, R2, R3 and 8 are as defined above. ), and their acid addition salts and quaternary ammonium salts.

(27) Another group of compounds are tropine or isopellecherine (homotropane) esters of indole carboxylic acids, particularly those of the formula IQ+)'](3q+), where the free valence is attached to either of the fused rings. ,k1
□b and R,9,) are each independently hydrogen, halogen or (C1-4)alkyl-R3q b is hydrogen or (C]-4)alkyl, k8Ql) is hydrogen or (C1-4)alkyl
1-7) alkyl, n' is as defined above. ], and their acid addition salts and quaternary ammonium salts.

Yet another group of compounds are the indolecarphonic acid tropine and isotropin (homotropane) amides, in particular those of the formula ■9c: (28) 3 [wherein the free valence is attached to any of the fused rings and k2
QC is a group other than (C1-4) alkoxy and hydroxy among R2 defined above, and is a group other than n', kl, R3,
R8 is as defined above. ), and their acid addition salts and quaternary ammonium salts.

Another group of compounds are the quinuclidinyl esters of benzoic acid, in particular those of the formula 'sa' with 5Pa (-4,3, R5,a, 6.a and 7Pa).
is as defined above. ), and their acid addition salts and quaternary ammonium salts.

Yet another group of compounds are the quinuclidinyl amides of benzoic acid - in particular 5pa of the formula 'sb', where R4Pa-R5Pa-R6,a and 1(7,
l) is as defined above. ), and their acid addition salts and quaternary ammonium salts.

The invention further relates to a suitable dicarbocyclic or heterocyclic carboxylic acid or benzoic acid or a reactive acid derivative thereof, or a precursor or derivative thereof, and a suitable alkylene-bridged piperidylamine or piperiditul or a precursor thereof. or, if necessary, convert the synthesized piperidyl ester or amide, or acid addition salt or quaternary ammonium salt thereof, to the desired piperidyl ester or amide, or acid addition salt thereof, or quaternary ammonium salt thereof. Provided is a method for producing the compound of the present invention, which comprises converting the compound into a salt and recovering the obtained piperidyl ester or its acid addition salt or quaternary ammonium salt.

In particular, the present invention relates to compounds of the same type and their acid salts or quaternary ammonium salts, and provides a manufacturing method including the following means. That is, 21) The following formula ■: A-GO-01( VI (in the formula,
A is as defined above) or a highly reactive derivative thereof, or a precursor or derivative of an acid, and the following formula ■:I■B-D
VII (wherein B and D are as defined above) with a suitable compound or a precursor of that compound. or b) means for alkylating a compound of formula (1) having a secondary amine group to produce a compound of formula 1 having a quaternary amine group.

or (31) C) a means for deprotecting the protected form of the compound of formula (1) to obtain a compound of formula (2). or d) A means of halogenating a compound in which -A is a group of the formula 1 and is 2-S hydrogen in the formula 1 to produce a corresponding compound 11f in which -R2 is 710. or e) a means of alkoxylating a compound of formula (1) in which the group of formula (8) is 2+t-rogen to obtain a corresponding compound in which (2) is an alkoxyl group. The method includes means for recovering the compound of formula (1) itself, or its acid addition salt or quaternary ammonium salt.

The condensation process of the invention to obtain amides and esters is carried out by conventional methods carried out with analogous compounds.

For example, especially for the production of amides, carbonic acid groups are activated in the form of highly reactive acid derivatives.

Suitable highly reactive acid derivatives can be made by reaction with N,N'-carbonylimidazole to form the intermediate carboxylic acid imitazolide or by reaction with N-hydroxysuccinimide (32). Alternatively, acid chlorides may also be used, for example produced by reaction with oxalyl chloride.

For the production of esters, alcohols may be used, for example in the form of alkali metal salts, preferably lithium salts. Such salts can be made by conventional methods, for example, by reacting n-butyllithium with an alcohol in tetrahydrofuran. If necessary, especially for the production of amides,
Heterocyclic or tertiary amines such as pyridine or triethylamine may also be present.

A suitable reaction temperature is about -10° to about 10°C.

In the case of a compound in which B is Nl (and D is a group of the formula (2)), the reaction temperature may be increased to, for example, about 100° C., for example in boiled methanol or ethanol.

Other suitable inert organic solvents include, for example, tetrahydrofuran and dimethoxyethane.

(33) In these reactions, it is believed that the endo or exo configuration of B with substituents of the group of formula ■ remains intact. The compound of formula (II) may, if desired, be reacted as a mixture of endo and exo isomers and the pure endo or exo isomers separated, for example by chromatography or crystallization.

Invention compounds can be converted into other invention compounds, for example, by conventional methods. Certain interconversions are b), C), d) and C
) is exemplified by the process.

The alkylation reaction in step b) is carried out in a conventional manner. Any free amino group can be alkylated, especially the compounds of formula (1) with X--NH. Preferred conditions for the alkylation reaction are the reaction with an alkyl halide in the presence of sodium alcoholate. A suitable temperature is about -50 to about -30°C.

The deprotection reaction in step C) is carried out, for example, with a compound of formula (1) having a secondary amino group such as R8-H or with 6-Nl-1.
It is particularly suitable for producing a compound (34) having a primary amino group such as 2.

For example, a protected version of the compound of formula (1) may be prepared in which 8 is substituted with a secondary amine protecting group such as benzyl. The benzyl group is removed by conventional methods such as hydrogenation, and R
The corresponding compounds of formula (1) in which 8 is hydrogen can be produced.

Suitable hydrogenation reactions are carried out in the presence of palladium on activated carbon at room temperature or at slightly elevated temperatures. Suitable solvents are acetic acid, ethyl acetate or ethanol.

The primary amine group of R6 may be protected with an N-benzyloxycarbonyl group or the like. This group is eliminated by a hydrogenation reaction similar to that described above. If there is a benzyl group,
Since the N-benzyloxycarbonyl group is usually eliminated first, this group is suitable for selective elimination reactions.

The amine group may also be in the form of a nitro group. This can be selectively reduced by conventional methods such as iron and hydrochloric acid.

The halogenation reaction in step d) is carried out according to a conventional method. For example, it is chlorinated by using N-chloro-succinimide. Such reactions are carried out in suspension in chloroform.

The reaction using N-iodosuccinimide instead results in iodination.

Replacement of the reactive halogen by step e) is carried out in a conventional manner, for example by reaction with a suitable alcohol at room temperature for a minimum of 10 to 20 hours.

If desired, precursors of the starting materials may be used.

Although such a precursor can be converted into a starting material by conventional methods, the process of the present invention is instead carried out using a precursor and another starting material or materials or precursors thereof. The product material is converted to the invention material in a conventional manner, e.g., by using the same reaction conditions that converted the precursor material into the starting material. protection type of the starting material.

The invention substance can be separated and purified by conventional methods.〇(35) As far as the method for producing the starting material is concerned, well-known methods such as
Or, there is no particular description of compounds produced by methods similar to well-known compounds, methods similar to those described in Examples in this patent, or methods well known as methods for producing similar substances. do not have.

The compounds of formula (1) in which B is -N)I-1D is a group of formula IV and n is 4 are new and form part of this patent. These compounds fall within various general disclosures, although they have never been suggested individually until now.

Those compounds have, for example, interesting pharmacological properties;
For example, it is a hitherto unknown serotonin M antagonist, and is also useful as an intermediate for the production of amides with other activities as shown below.

These compounds of formula (1), like other compounds of formula (2) in which B is -NH-, can be produced, for example, by reducing the corresponding oxime. A compound of formula (1) in which B is →- can be produced by reducing the corresponding ketone in a conventional manner.

(36) All of the above reductions can include, for example, catalytic hydrogenation reactions with platinum (which are believed to produce primarily endo isomers),
For example, Bouveault-Bl with sodium/amyl alcohol or butanol.
anc ) reactions (believed to yield primarily exo isomers), or by aluminum hydride or sodium borohydride methods (often yielding endo/exo isomer mixtures).

All exo and endo isomer mixtures are separated by chromatographic methods.

The free base form of the invention compounds can be converted into the salt form.

For example, acid addition salts can be prepared by reaction with a suitable acid in a conventional manner, and vice versa. Suitable salt-forming acids include hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, malic acid, fumarelic acid, methanesulfonic acid, oxalic acid and tartaric acid. The quaternary ammonium salt of the compound of the present invention can be produced by a conventional method such as reaction with methyl iodide.

All temperatures in the following examples are expressed in degrees Celsius,
It is uncorrected. All nuclear magnetic resonance spectra values are P
Shown in pm (tetramethylsilane=Oppm).

Nomenclature endo-8-methyl-8-asa-bicyclo [3°2.1
] Oct-3-yl-tropyl or α-tropylexo-8-methyl-8-aza-bicycloC3,2゜1
[Oct-3-yl-pseudo- or β-tropylendo-9-methyl-9-aza-bicyclo[,3,3゜1]non-3-yl-isopellecherinyl or α-homotrononogynylexo-9-methyl -9-aza-bicyclo [3,3゜1
]Non-3-yl β-impelecherinil or β-
Homotropanil or pseudoperechelinyl 1-Asa-bicyclo[2,2,21octyl-quinuclidinyl Examples A-2; A-3; It was believed that the steric configuration of the starting material of formula (1) was followed.

In the table, the column entitled ``6 Configuration'' indicates the configuration of the 'B-D group as endo or exo.

The column entitled "Production" shows the number of the eight series of examples that describe the production method.

Abbreviations used: ]II-I -5-chloro-2-methoxy-4-methylaminophenyl m-II = 2-methoxy-4-dimethylaminophenyl III-m = 4-amino-5-chloro-2-methoxyphenyl M-]V-4-amino-2-methoxyphenyl II
IV = 3-iodo-2-methoxyphenyl-4-
Methylaminophenyl I[-VI-5-chloro-2-methoxy-4-dimethylaminophenyl (6sono■-■ -2-chloro-4-aminophenyl■-■ =
3-iodo-4-amino-2-methoxyphenyl JII-IX = 2-methoxy-4-methylaminophenyl III-X = 2-chloro-4-nitrophenyl ll
l-Xl-4-bromo-2-methoxyphenyl]1[-
XI -3,5-dichlorophenyl 1■-5-chloro-2-methoxy-4-(1-pyrrolyl)phenylIT-XIV=2-methoxy-4-(1-pyrrolyl)phenyl■) Acidic maleate 2 ) acidic maleate 3) decomposition 4) bis[base]fumarate 5) obtained by reduction of the corresponding 4-nitro compound 6) hydrobromide 7) via imidazolyl intermediate 8) exo form C-(40) 3H broad multiplet at about 5.15 ppm in HN, M, R,. End type is 5゜I PP
C-3H double triplet in m. Exo alcohol is silica gel-CI-I261215%C]30H15
%NlI40I-■ 9) Acidic oxalate eluted by the solvent before the endo isomer 10) Example A-1: N(endo-9-methyl-9-aza-
Bicyclo[3,3,1]non-3-yl)indole-
3-ylcarboxylic acid amide, also known as N-(3α-homotropanyl)-indol-3-ylcarboxylic acid amide (a
method) (In the compound of formula ■, A = bonded at the 3-position ■; R = to 2
2H; X=NH; TS=NH; D-]V, α configuration; n = 3; , 2M) in 150 ml of anhydrous methylene chloride. Oxalic acid chloride 26+++l (0.3M) was added to the ffi stirring mixture at 20°C.
, add in 30 minutes. Gas is generated. Mixed liquid at 20℃
Stir for 31/2 hours. Add 1.50 ml of hexane. The mixture was stirred for an additional 20 minutes, and the title compound produced was collected, washed with methylene chloride/hexane 1:1, and dried at 20° C. under reduced pressure to obtain beige crystals. Melting point 135-136° (decomposed). Do not purify the ice crystals (they will be used in the next reaction).

1)) 9-Methyl-9-aza-bicyclo(3,3,1E
Nonan-3-one oxime (also known as 3-homotropanone oxime) Grind 176 g (2,15 M) of sodium acetate and 150 g (2,1,5 M) of hydroxylamine hydrochloride in a mortar until it becomes a thin paste, and add methanol. Extract with 1 liter of water, remove the salt, and add 99.5 g of endo-9-methyl-9-aza-bicyclo[3,3,1]nonan-3-one (3-homotropane) (0.65 M ). The oxime begins to crystallize after 10 minutes. The mixture is stirred for a further 4 hours at 20°C. After the reaction is completed, the mixture is concentrated under reduced pressure and extracted with chloroform containing the remaining (43) tuburobanol.

The organic layer is separated, washed with a small amount of water, dried over sodium sulfate, and concentrated to obtain the title compound. Melting point 126-127°
(Recrystallized from toluene/hexane).

C) Endo-9-methyl-9-aza-bicyclo[3
,3,1]non-3-ylamine (also known as 3α-amino-
A solution of 50.5 ml (0.95 M) of concentrated sulfuric acid in 200 ml of anhydrous tetrahydrofuran was mixed with 73 g (1.9 M) of lithium aluminum rhamnohydride in 900 ml of anhydrous tetrahydrofuran. Add the cold solution within 2 hours at -10°C with stirring. Leave the mixture overnight. endo-9-methyl-9-azahincro[3,3,1]nonane-3-
A solution of 80 g (0.4-75 M) of onoxime in 1.4 liters of anhydrous tetrahydrofuran was added dropwise to the mixture over 30 minutes with stirring at 30°, and the mixture was further reacted at 40° C. for 3 hours. After the reaction is completed, the reaction mixture is cooled to 100 ml, and water is added to 15 ml of water.
Carefully add 150 rnl mixture of 0 mi Tetrahydro7ran. The mixture (44) was stirred at 30°C for 1 hour. The generated crystals are removed.

The ρ residue is washed with methylene chloride and ether.

The title compound (boiling point 1
．． 15-119°).

(As is well understood, reduction primarily gives the endo isomer. 8-methyl-8-aza-bicyclo[3,2,
1:]] A similar reduction reaction of octane-3-oneoxy yields the exo isomer).

rl) N-(endo-9-methyl-9-aza-bicyclo[3,3,1]non-3-yl)indol-3-ylcarboxylic acid amide endo-9-methyl-9-aza-bicyclo[3゜3.1
] A solution of 715.4 g (0.1 M) of non-3-ylamine in 50 ml of anhydrous pyridine was dissolved in 14.5 g (0.08 M) of indol-3-ylcarphonic acid (produced in step a) in anhydrous methylene. Chloride 50 - Add dropwise to the stirred suspension at 0°C to 0°C.

The resulting yellow suspension is warmed to 20'C and stirring is continued overnight. After the reaction is complete, 2N aqueous sodium carbonate solution is added. The mixed solution is extracted several times with methylene chloride, and then treated in a conventional manner. The title compound is obtained by recrystallizing three times. Melting point 24.7-24.9 (decomposed).

Example A-2: Indol-3-ylcarboxylic acid endo-8-methyl-8-aza-bicyclo[3,2゜1]oct-3-yl ester (method a) (in the compound of formula ■, A=
T [;R1=R2−=H; X=NTT bonded at the 3rd position
; n=o; D: ■, α position; n-2; R8-C
Tl3) Endo-8-methyl-8-aza-bicyclo[3°2.1
] Octan-3-ol (tropin) 6.35 g (45
20.mM) of anhydrous tetrahydrofuran. , a solution of butyllithium in 2 molar hexane from 17° to 00°
Process with. Stir the mixture for an additional 30 minutes. The lithium salt is obtained by distilling off the hexane under reduced pressure and adding the corresponding amount of tetrahydrofuran instead.

4.8 g of indol-3-ylcarboxylic acid chloride (
A 2 omz solution of 27 mM) in tetrahydrofuran is added to this mixture and the beige suspension is kept stirring at 20° C. overnight. The mixed solution is treated with methylene chloride and sodium carbonate in a conventional manner to obtain a crude product of the title compound. This is subjected to chromatography on silica gel (250 glt-) using methylene chloride containing 10% methanol and 0.5% aqueous ammonia as the eluent. Melting point 201°-2
02° (recrystallization solvent, methylene chloride/ethyl acetate). Hydrochloride salt, melting point 283°-285° (decomposed). Metheodite, melting point 285°-287° (decomposed).

instead of indol-3-ylcarboxylic acid chloride);
It is also possible to form an imidazolide by reacting with 'N,N'-carbonyldiimidazole, which can be reacted with the lithium salt of '-' in tetrahydrofuran at 10° to 15°.

No
-Methyl-9-aza-vinculo[3,3,1]non-3
-yl)indol-3-ylcarboxylic acid amide, also known as 1-methyl-N-(3α-homotropanyl)-indol-3-ylcarboxylic acid amide II; R1=R2-
H,
Dissolve 6 g (20 mM) of chloride and dropwise add 1.3 ml (22.5 mM) of absolute ethanol diluted with anhydrous ether.The resulting colorless suspension of IJ ethylate was stirred at -50° for 15 min. . N-(endo-9-methyl-9-aza-bicyclo-[3,3,1]-
Non-3-ylcarboxylic acid amide 4.46 g (15
(mM) is added to this to obtain a clear liquid. 5 parts of the mixture
Stir at 0° for 10 minutes and add 1.25 ml (2 mL) of methyl iodide.
Add a solution of 0 mM) in anhydrous ether.

The mixture was further heated at 150 degrees at 41. / Stir for 2 hours. After the reaction is complete, ammonia is removed under reduced pressure. Methylene chloride and water are added to the residue to separate the layers, and the mixture is treated in a conventional manner to obtain a colorless foam. This is chromatographed on 1.20 g J- of silica gel (47) using an eluent of methylene chloride containing 5% methanol/3% ammonia, and the title compound is eluted from the acid. Melting point 210°-212° (recrystallization solvent, ethyl acetate/methanol). Hydrochloride salt, melting point 295-297° (decomposition).

This compound is also prepared separately in a manner analogous to Example 1 starting from 1-methyl-indol-3=ylcarboxylic acid.

Illustrative Example A-4: 5-Fluoro-1-methyl-indol-3-ylcarboxylic acid endo-9-aza-bicyclo[
3,3,1]] Non-3-yl ester also known as (N-desmethyl-3α-homotropanyl)-5-fluoro-1-
Methyl-indole-3-1 carboxylic acid ester (C
method) (IT attached at the A-3 position in the compound of formula I; R
,=5-F; R2=TI;X==NCI(
3: R== -〇-; D two TV, α-configuration; n-
3;R8-I() In 200 ml of ethanol, 5-fluoro-1-methyl-indol-3-ylcarboxylic acid endo-9-benzyl-9-aza-bicyclo[3,3,1]]non-3-
4.9f of ester is hydrogenated at room temperature and normal pressure in the presence of 1.5 g of activated carbon-coated (10%) palladium catalyst and 1,000 ml. After 45 minutes, absorption of about 230 ml of hydrogen is completed and the catalyst is evaporated. The solvent is evaporated under reduced pressure to obtain a crystalline residue of the title compound. Melting point 130-131°. (Recrystallized from ethanol/a small amount of hexane) Example A-5: 2-Methoxyindolyl-3-ylcarboxylic acid (endo-8-methyl-8-aza-bicyclo[
3,2,1) Oct-3-yl ester, also known as 2-methoxy-indol-3-ylcarboxylic acid tropyl ester (methods d and e) (in compounds of formula I, 11. attached at the A-3 position: R1-11; R2 engineering 2-OCi (3;
=NI-I: B-work O; D-U IV, a position; n =
2; Rs -CH3)N-chlorosuccinimide 4
Indol-3-ylcarboxylic acid endo-8-methyl-8-aza-bicyclo[3,2,1
1 oct-3-yl ester 5.681 (20mM)
Add. The mixture was stirred for 3 hours at 20° and a yellow clear solution of 2-chloro-indol-3-ylcarboxylic acid (endo-8-methyl-8-aza-bicycloC3,2,11oct-3-yl) ester was obtained. get.

The clear yellow solution is treated with 1.0.4 ml of absolute methanol and heated overnight. Add IN aqueous sodium carbonate solution and methylene chloride to the mixed solution and separate the mixture according to a conventional method to obtain a crude product. This was chromatographed on silica gel (30 to 1 volume) and eluted with methylene chloride containing 10% methanol and 0.5% ammonia to give the title compound.

Melting point 204-206° (recrystallized from ethanol).

Example A-6: 3-iodoindole-4-ylcarboxylic acid endo-8-methyl-aza-pic/\[3,2,1':l oct-3-yl ester (formula I
In the compound, M bonded at A=4 position: R,= rl
: R2=3-1;X2N II: n=-〇-;
D = iV, α configuration: n = = 2; R8 = Cr13
) (method d) N-iodosuccinimide 2.48 g (1
Indol-4-ylcarboxylic acid endo-8-methyl-8-aza-picloC3,2,1 was suspended in 200 ml of anhydrous chloroform and stirred at 15°.
] A solution of 2.841 oct-3-yl ester is added dropwise to stale. The mixture is stirred for a further 30 minutes at 20°.

IN aqueous sodium carbonate solution and methylene chloride are added to separate the layers, and treated according to a conventional method to obtain the title compound. Melting point: 163-165° (decomposition) (recrystallized from ethanol). This compound can be prepared by the same method as shown in Example 2 from CζA 3-iodo-indol-4-ylcarboxylic acid. .

Example A-7: 5-chloro2-methoxy-4-methylaminobenzoic acid]-aza-bicyclo[2,2°2]oct-3-yl ester, also known as 5-chloro2-methoxy-4-methylamine Benzoic acid quinuclidin-3-yl ester (method a) (in the compound of formula I, A, =I[:R42〇Cl-R3; R5: ■I; 6.,:NTlCl-R
3: Bonds to R7=C at n=-0-; n=3 position■
] a) 5-chloro-4-methylamino-2-methoxybenzoic acid imidazolide 12 g of N,N'-carbonyl-diimidazole was dried with 8 g of 5-chloro-4-methylamine-2-methoxybenzoic acid!・Rahydrofuran 300 rn20 in 1m liquid
Add with stirring at ~25°. The mixture is stirred under anhydrous conditions for about 1 hour and the solvent is distilled off at 35-45°. The remaining 7 samples were dissolved in methylene chloride.

Wash the mixture 2-3 times with water and apply it on magnesium sulfate (:)
Dry, filter and condense. The title compound crystallizes from methylene chloride/hexane. Melting point 152-154°
.

b) 5-Chloro-4-methylamino-2-methoxybenzoic acid 1-aza-picro[2,2,2]]oct-3-yl ester ■-acerbicyclo[2,2,2]octan-3-ol ( Quinuclidin-3-ol) 5.569 was added to a 10 o ml solution of anhydrous tetrahydro7ran in a stream of dry nitrogen.
n-Butyllithium 27i (1,
6 mol) of hexane solution is added dropwise. The mixture is further 10
Stir at 0-5° for ~15 min, then 5-chloro-4-
A solution of methylamino-2-methoxybenzoic acid imidazolide in 100 ml of anhydrous tetrahydrofuran is added and stirred for 1 hour. Add 5 ml of a saturated aqueous solution of potassium bicarbonate and decant the solution.

Wash the residue twice with tetrahydrofuran. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated.

Treatment of the 11 product with an equivalent amount of malonic acid yields the malonate salt of the title compound. Melting point: 170-172° (recrystallized from acetone).

Example A-8: 4-amino-5-chloro-2-mer-
+ Cybenzoic acid echin-8-azabicyclo [3゜2
．． 1] Oct-3-yl ester, also known as 4-amino-5
-Chloro-2-methoxybenzoic acid 8-benzylpseudo-nor-tropyl ester (Method C) (in compounds of formula I:
A=I[r;R420CTl3;R5-1T: R6
-Nl-I2;B7-Cz;, B==O: p=■,
β-configuration; n-2; Rs-benzyl] a) 4-(N-benzyloxycarbonyl)ami/-2-methoxybenzoic acid methyl ester 4-amino-2-methoxybenzoic acid methyl ester 4219 in toluene 600 m/l The solution was refluxed with 60 ml of chloroformic acid phenyl ester.
Time υ1 is over. Cool the solution and count the precipitated title compound. Melting point 137-138°.

1)) 4-G'J-benzyloxycarbonylamino)
-5-Chloro-2-methoxybenzoic acid methyl ester 4-(N-benzyloxycarbonylamino-(55) A solution of 61.4 g of 2-methoxybenzoic acid methyl ester in 1 liter of chloroform was stirred at 20° while chlorine gas ( Pass 918 g of the dried product through sulfuric acid over a period of 20 to 25 minutes. The reaction mixture is concentrated under reduced pressure to obtain crystals of the title compound. Motoichi uses it as is in the next reaction.

c) 4-(N-benzyloxycarbonylamino)-5
200 mt of a 2N aqueous sodium hydroxide solution of -chloro-2-methoxybenzoic acid is added dropwise to a solution of 721 g of the benzoic acid methyl ester prepared by method B in 800 mt of dioxane with stirring. The mixture is stirred for 20 hours and the organic solvent is distilled off under reduced pressure. The residue (dissolved by adding water and corrected to pi-15-6 with 3N hydrochloric acid. The title compound was separated and washed with water. Melting point 182-1-83° (recombined from methanol).

d) 4-(N-benzyloxycarbonylamino]-5
-Chloro-2-methoxybenzoic acid imidazolide This compound is prepared in a manner analogous to Example A-7a (56).

e) 4-(N-hair syloxycarbonylamino)-5-chloro-2-methoxybenzoic acid exo-8-benzyl-8-aza-bicyclo[3,2,1]]oct-3-yl ester compound Produced in a similar manner to Example A-71).

"]4-Amine-5-chloro-2-methquinebenzoic acid exo-8-aza-bicyclo[3,2,1]]oct-3-yl ester-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy 54g of benzoic acid to 100g of ethanol
Hydrogenation is carried out in the presence of 07 g (10%) of palladium on activated carbon in mt under normal pressure for 50 minutes (absorbing 1 equivalent of hydrogen). The mixture is filtered through a filter aid (Hyfloth-Purcel) and Concentrate the solution. The residue is subjected to sol gel chromatography using methylene chloride containing 5-functional methanol as the eluent to obtain the title compound as a free base. Melting point 241-242° (hydrobromide is dissolved in ethanol). made from lT11r].

Example A-9: 4-amino-5-chloro-2-methoxybenzoic acid echin-8-aza-bicyclo[3°2.1]oct-3-yl ester, also known as 4-amino-5-chloro-2-methoxy Benzoic acid pseudotrutropyl ester (C method) (In the compound of formula I, A=11T; R420Cll3; R
5:H:R=N112; R7goCl;B20ar)
UTV, β-configuration; n-2: Rs = I-I) 4-(N-benzyloxycarbonylamine)-5-chloro-2-methquine exo-8-benzyl-8
-Aza-bicyclo[3,2,1]]oct-3-yl ester 8.4 was dissolved in ethyl acetate or acetic acid 250 d in the presence of 12 g of 10% palladium on activated carbon at a normal pressure of 20 to 25 g.
Hydrogenation is carried out for 2 hours at °C. The mixture is filtered, for example through Hy fl O], the P solution is evaporated to dryness and the residue is dissolved in methylene chloride.

The organic layer is washed with IN aqueous sodium hydroxide solution and then with water, dried over magnesium sulfate and concentrated. The product was chromatographed on silica gel using methylene chloride - 5% methanol and methylene chloride + 20% methanol. The title compound crystallizes as the hydrochloride salt.

Melting point 258-259° (recrystallized from ethanol) Example A-10: Indol-4-ylcarboxylic acid endo-
8-Methyl-8-aza-binculo[32,1]octo-
3-yl ester, also known as indo-△ 4-ylcarboxylic acid tropyl ester (in the compound of formula ■, A=4-position bonded to ■; □:=4
2;17; R3-NtI: n=o: D,,
, IV, α-configuration; 11-2; to 8-CI-13) Endo-8-methyl-8-aza-bicyclo[321]octan-3-ol (tropin) 7 g (50 mM) in 15 mt, m Add 20m/(40mM) of a 2M hexane solution of butyllithium to the solution.
Drop treatment at 0-15°.

The mixture is stirred at 20° for 30 minutes and then concentrated to a total volume of about 10 ml by distilling off the hexane to obtain lithium erulate. Tetrahydrofuran 10
rn! , add.

48g dry indol-4-ylcarboxylic acid (30mM
) in 15 ml of anhydrous tetrahydrofuran solution with N,N'-
Treat in portions with 5.8 Fl (36 mM) of carbonyl-diimidazole. Leave the mixture at 206 for 90 minutes,
The lithium erulate is then added dropwise. The resulting suspension was stirred at 20° C. overnight, and separated into layers by adding methylene chloride/isopronol and 1N aqueous sodium carbonate solution. The organic layer is washed, dried over sodium sulfate and evaporated to dryness to give the title compound. Melting point 220-222° (decomposed) (crystallized from ethanol) Example A-11: Indol-4-ylcarboxylic acid endo-9-aza-bicyclo[3,3,1]non-
3-yl ester, also known as 3α-homotropanylindole-4-ylcarboxylic acid ester (in the compound of formula
==II bonded at the 4-position; X=NH:R12R2=H;
Ra2N tT, B20; D-■, α configuration; n
-==3: ni8-CI■3) (method a) 3] End-
9-Methyl-9-aza-piclo[(59) 3.31]/nan-3-ol 7.65 g (53mM
) in 15 ml of anhydrous tetrahydrofuran solution with 2 molar concentration of butyllithium hexane G7 (1-20 mA (40
m M ) is added dropwise at 10-15°. The resulting mixture is stirred at 20° for 30 minutes. The hexane is then evaporated and replaced with tetrahydrofuran to form a solution of the lithium salt.

”) Dry indol-4-ylcarvone M4.ll
5.85 g of N,N'-carbonyl-diimidazole (30 mM) in 15 m/dissolution of anhydrous tetrahydrofuran overnight
36 mM) in portions at room temperature. After the gas generation is completed, the solution is allowed to stand at 20° for 90 minutes, and then the lithium salt described in “1” is added dropwise at 10 to 1!5°. After the resulting suspension was stirred at 200° C. for 15 hours, methylene chloride/a small amount of inpropatol and IN sodium carbonate aqueous solution were added for liquid separation. The organic layer is washed with water, dried over sodium sulfate, and evaporated to dryness to obtain the title compound.

mA189-1.90° (recrystallized from ethanol).

(60) Hereinafter, Part 1) is 21 Koshu, which produced the compound of formula I, which is the compound 2). . , -8. --.

Part C prisoner to ω of ω of ω of
The ω size, the scarcity la. . . . La rack. Canter.

nephew 111111111111 ba ni) co ni) ω ω ω ω ni) ω
) ω (1) State. . ,D++? -1 Miyako 8 Oke To No No To He He Nita 3 (65) E 0 0 0 0 0 0 0
0 0 0 0 00 + he box - prisoner ω size z (D t-ω
■ --- Xi 111111111111 111K to) ω to) ω to) ω ω - to) to) to) to) (66) ) to) - groan
ni) ni) In a similar manner to the method described in ``Example of the D series'', the person can formulate the following formula ■[
A B n RB Configuration Melting point Preparation method I) 1 m-f 0 2 C) I3
End 193-19ri°1)71)-211I-
If. 2.7jii exo, □2-114”2)
71)-3lll-1ff 0 2 G(
3 ends, 154-15!5”' 71)-4
lll-lff O2HI7t168-169'''
91) -51r -TV 0 2
Hz-71"184.-185" 9D
-6m-ya. 2H exo, 66-□67
"" 9D 7 11T-IV O2CH3 end 245-246°4) 7D8 11r-VT
O2CH3 end 146-14f'2) 7D-9
1L-Vll O2CH3x7 210-211”
5)7r)-10,'ltVllll 0 2
CH3x7t216°6)7r)-11m-V O
3CH3 end 164-166° 7I)-12
MF-■X 03 CH3 end 163-164
° 7D-13111-X O2CH3 End 7D -14m -XI
O2G (3 ends 91-92° 7D-151f
f-■ 03CH3 End 7 Example A BnRB Configuration Melting point
Manufacture υyo D-16@-Xm O2CH3x711.15
8-1.5<f” 7D-47ftJ-XIV 02
Q 13 A
B I) Substitution position Melting point Manufacturing method. 4)
3) E-1 indol-3-yl 0 3
219-221 7E-2m-INII 3
145-147'154-156"" 7. E-3TIT-■ 0 3
Boil in ethanol for 7 days if desired.

Typical starting material of formula ■ Carn RB Configuration B Characteristic Common name a)
2 CH3 engineering Om, p, 59-6f
) o bin c) 2 CH3 end N
T-1b, p, 82'/12mm l, 05. - Mia e) 3 CH3xnd NT (b, p,
utton'17mm (67) ")3 Cf (3 ends 0r-I amorphous 1g
) 3 Henshil End OHm, p, 69-70°+h
) 2 n-C3B-17xnd 0I-1 oil 114-Na Manufactured by reduction of ketone with BT-14 and separated from isomers.

Produced by reduction of ketone with NaBT (4).

Main product i) N-methyl-10-aza-bicyclo(4,3,
1) Thiku-8-ylamine (Example B-35) Thorium 152 was converted into 10-methoxy-10-aza-bicyclo[4
,,3,1, ]] Decane-8-one oxime acetate [melting point 253-253.5°C. 19.6 made by a method similar to that shown in Example A-1b! l and Example j below]
The mixture was reacted in a manner similar to that shown in 2.2 and treated in accordance with conventional methods to obtain a curved material having a boiling point of 1 of 10.9 mm.

1tl, N, M, R (2QQMf(z) 3.2
7-3.04 (Multiplet, 2H1r-IC-(
1) and H-Cte9; 2.59 (singlet, 3
H, H-C(II)), 2.01-1. ．． 49 (Multiplet, 131-I 6 x 2 H-C (68
) and H, -Cf8+); 1.24 (singlet, 2H; 2,1-(-N D20 variable);
13CN, M, 125.2MHz) 56.
41 (d) doublet), 42.85 (Quartet C-11), 4], 44 (doublet), 37.13
() riplets, c-7 and C-9), 32.54 (
1-replet, C-2 and C-5) and 24. ．．
88 (triplets C-3 and C-4). The configuration is believed to be exo.

j) N-methyl-10-azabicyclo[4,3,1]]
Decan-8-ol Example B-36) 8-Methyl-10-azabicyclo[4,3,'l]]
Decan-8-one 3.5 dry n-butanol 100r
Heat the nl solution and add 5 g of Natrium pieces to it.

The mixture is refluxed for 1 hour and, after cooling, acidified to μI2 with concentrated hydrochloric acid. The mixture is evaporated to dryness and the residue is treated with hydroxide. The mixture is extracted with chloroform, dried and distilled. Boiling point 90-9 de 10.025 ph.

ll-1,N,M,R,(,200MI-TZ) 4.
07-4.23 (Multiplet, 1■I-C-(8
) Half width approximately 2QI-Tz); 3.63-3.69 ()
Replet, 0.331 (, j== 7 LTz,
1 (Q-,, c-[s) one isomer is variable with D20), 2.13-1.38 (multiplet, 121
-I.

6 x CH2).

13C,N,M,iL,(25,2Ml-Iz)6
3.10 (doublet C-8), 56.80 (doublet, C-1 and C-6), 43.13 (quartet, NCH3), 36.30 (replet-c-7 and C-9), 34 = 80 (1-triplet, c-2 and C-5), 25.4.0 (triplet C-3 and C-4).

The configuration is believed to be exo.

The compounds of the invention exhibit pharmacological activity and are therefore useful, eg, as therapeutic agents.

In particular, these compounds exhibit serotonin M receptor antagonism as shown in standard tests. For example, in one test, the Littipo-Neto principle [European Journal of Pharmacology (1978) 49 351
-356) and described by Oakley and Shatter (Experimental Neuropsychology,
Under conditions in which action potentials generated in spinal nerve fibers (A fibers) such as Lahorat'J -- Manu 1978, pp. 85-96 can be distinguished from action potentials generated in small unmyelinated nerve fibers (C fibers), These compounds were observed to impair the action of serotonin, which reduces the amplitude of action potentials from isolated vagus nerves in rabbits. Serotonin itself exhibits its effect selectively on C fibers, and This action of serotonin is caused by the serotonin antagonist rrctitepine, rre-thys, which blocks serotonin D receptors but not M receptors.
ergidide, not blocked by ROL-148 (Gaddam and Piccarelli, British Journal of Pharmacology (1957), 1
2.

323-328). Therefore, serotonin appears to reduce the amplitude of action potentials carried by C fibers through effects mediated by serotonin M receptors localized in these nerve fibers.

The test is carried out by preparing the nerves and establishing a serotonin response (72) (ll) -7-(3 curve (10-5X10M).The serotonin is washed away and the activity of L and C fibers 16 After the potential and amplitude were restored to the original amplitude, the solution of the compound of the present invention prepared at a concentration of about 10 M to about 1.0 M was added to the nerve for 30 minutes.
Incubate for 0-60 minutes. Various concentrations (10-7 to
10 −4 M) of serotonin is applied.

The M receptor antagonists of the present invention either completely block the action of serotonin (noncompetitive antagonists) or cause a parallel shift of the serotonin/dose-response curve to the right (i.e., the onset of effect increases the required serotonin concentration) (
competitive antagonist).

1) The l)2 value or pAz value is calculated according to conventional methods.

Serotonin M receptor antagonism has also been shown in J.R.
Journal of Pharmacology (1,978) 4
9, pp. 109-112) using the compound of the present invention at a concentration of 10 to 10' molar, the serotonin effect on isolated rabbit hearts was also shown by the β-mark. The pD2 or pA2 value is calculated in a conventional manner (therefore).

The effect of the compound as a serotonin M receptor antagonist on analgesic therapy is approximately 01-1.0 (119/!i'
This was confirmed by the effect of subcutaneous or oral administration in a hot plate test.

8 Serotonin M receptor antagonism is also demonstrated in the cantharidin red base test at a concentration of approximately 10 M. Redness occurs when cantharidin is used on the forearm of human volunteers. Applying serotonin to the base of such redness produces a measurable pain of intensity proportional to the applied concentration of serotonin. This method is described by C. A. Kale and F. Armstrong (Substances Producing Pain & Itsch, Nidward Arnold, London, 1964.30-57).

This nociceptive effect of serotonin is not imprinted by serotonin D receptor antagonists such as lysergic acid dimethylamide and its bromine derivatives.

Instead of the maximum amplitude, it is measured by means of area-on-the-curve calculations by means of a linear integrator connected to a pain intensity testing device operated by the volunteer. An excellent dose-response curve for serotonin is obtained as the concentration of serotonin increases. When a reaction with an increase in serotonin concentration no longer occurs, the serotonin is washed away and the erythema is applied with a compound of the invention, preferably at least a -2 or A-3 compound, in a physiological buffer. The test substance is pre-incubated with the red base for 30 minutes at a concentration of approximately 10 M before applying the various concentrations of Se=80 tonin.

The pAz value is calculated by conventional methods.

The compounds of the invention are thus useful as serotonin M receptor antagonists, for example in the treatment of pain, in particular migraines, vascular and generalized headaches and trigeminal neuralgia, and also in the treatment of disorders of the cardiovascular system such as sudden death. , and possibly for use as an antipsychotic.

The indicated daily dose is usually about 0.5-500 m7
So, the compound is about 0.2 to about 25 (III?
2 to 4 times a day as a dosage form containing the compound (75
) The compounds of the present invention further exhibit antiarrhythmic activity as indicated by their serotonin M receptor antagonism and as demonstrated in a standard test. For example, the compounds inhibit norepinephrine-induced arrhythmia in anesthetized rabbits. In this study, norepinephrine infusion (3 to
10 micrograms per animal body weight) until an arrhythmia phase lasting more than 10 seconds is obtained as measured by electrocardiograph. After three consecutive injections of norepinephrine as a control;
About 10 to about 500 micrograms/9 of the compound of the present invention
Animal weight is injected following the norepinephrine injection.

Arrhythmia is reduced or eliminated depending on the dose of test compound.

As such, the compounds are indicated for use as antiarrhythmic agents. The indicated daily dose is from about 0.5 to about 500 mg, usually administered orally or by injection, in divided doses 2 to 4 times per day, or as a single dose containing about 0.2 to 250 mg.
Administered in dosage form or sustained release dosage form.

(76) Therefore, the present invention provides compounds of the invention in a pharmaceutically acceptable form, such as a free base, or in the form of a pharmaceutically acceptable acid addition salt, or in the form of a quaternary ammonium salt. Use as a serotonin M antagonist, especially for diseases where serotonin M receptor blocking action is expected to be effective, for example, as an analgesic, especially as a migraine treatment agent.
Also provided for use as an antiarrhythmic agent.

Preferred indications are analgesic indications. Preferred compounds are the title compounds of Examples A2 and A3.

The compounds of the invention may be administered in free base form or in the form of pharmaceutically acceptable salts, such as appropriate acid addition salts and quaternary ammonium salts. Such salts exhibit the same potency of activity as the free base. Therefore, the present invention is also characterized in that it includes an inventive compound, in particular a compound represented by formula (1) or an acid addition salt thereof or a quaternary ammonium salt thereof, accompanied by a pharmaceutical excipient or diluent. A pharmaceutical composition is provided. Such compositions can be formulated in conventional manner, eg as solutions or tablets.

The uninvented compound is given a clinically used drug for the considered use, e.g. 7 Toclobramide in the case of migraine (J, 1S, Hughes, Medical Journal op Aus 1- Laria, 1977, No. 5
80, published October 22, 1977) (in this case, metoclopramide 1 omy intravenous 71': injection is sufficient).

The exact value for a particular compound will vary depending on a number of factors, particularly relative activity. The compounds of Example/1-2 and A-3, which are preferred non-inventive compounds, each showed a pA2 value of 0 in the rabbit heart test, whereas the PA2 value of metoclopramide was 7.1. Met. Therefore, these compounds can be administered at lower monthly doses than the same dose size as metoclopramide.

.・ - Hoof , -゛-1 One group of compounds of the present invention is represented by A or Formula 11 in formula (■)
is a group in which R1 and 2 are independently hydrogen,
halogen, (cl-4)alkyl, or (C1-4)
Alkoxy, bonded to the 1 or 5 position of R27J, R3 or hydrogen, or (C1-4) alkyl, with a free valence of 3.
is bonded to the 4 or 5 position, or is a group of the formula (1), in which 4 is hydrogen, hydrogen, or (C1-4) alkoxy, R5 is hydrogen or halogen, R6 is amine, (CI-4) alkylamino, or di(, Cl
-4) Alkylamine, halogen, or 1-pyrrolyl, R7 is hydrogen or /S rogen, D is a group of formula (■), and in the formula, 8 is hydrogen, (C1-4) alkyl or benzyl or a group of formula (1), in which the free valence is bonded to the 3-position, and follows the provisions of formula (P) with respect to formula T.

One group of compounds is the compounds described in the examples in formula I,
For example, the compound of Example A2 or A3 is excluded.

r79) 221100 6675-4
C223100) 71
69-4C priority claim [Phase] November 30, 1982 [Phase] Switzerland (CH) @ 6950/82 [Phase] November 30, 1982 [Phase] Switzerland (CH) @
6951/82 [Phase] December 22, 1982 [Phase] Switzerland (CH)■
7494/82 ■December 1982 220 [phase] Switzerland (CH) ■74
95/82 6 March 9th, 1983 [Phase] Switzerland (CH) [Yes] 12
56/83 @ Inventor Beter Donatsch Zäher, Switzerland 4123 Allschbill Herrenbeek No. 34 0 Inventor Günther Engel De-7858 Pyle im Basengarten No. 11 @ Inventor Bruno Hjuj Zäher, Switzerland 4148 Pfüfingen Hauptstratzja 86a Ichiban@ Inventor Brian Beter Richardson Switzerland Zeher - 4312 Macden im Hoffatz Force - No. 8 Inventor Paul Statler Switzerland Zeher - 4105 Beer - Behnken-Jacobsbeke Procedural Amendment No. 7 (voluntary) 2. Name of the invention Cyclic carboxylic acid piperidyl ester and amide derivatives 3. Address of patent applicant: Basel, Switzerland (no address indicated) Name: Sand-Ackchendeselschaft 4 , Agent 541 Address 6 Kokugi Building, 2-10 Honmachi, Higashi-ku, Osaka-shi, Osaka
, Column 7 of the detailed description of the invention in the specification to be amended and pages 67 and 68 of the specification of contents of the amendment are amended as shown in the attached appendix.

(Attachment) D-series Examples In a similar manner to the method described above, the person below has the formula Ill
and D is a group of the formula TV.
yY, q3-19f1)7D-211I-□. 26
7 Jiuekitsu, 1□-n12') 71, -3□1, -
4I O2QT3 air, □54-□ze2)72) 1)-411I-ffl 0 2 H end 168-169° 9.11) 1)-5ntirv O2tl end 18
4-185 9D-6■-ya. 2 II Misaki 166-167-no.

D-7III-IV 0 2 CH3m7)'
245-246”) 7D-81l-Vl 02
clI3 x7v 146-147"' 71)-9
l1l-Vll O2CH3et 210-211
"" 7D-1On+-m O2CH3F)'
21e” 7D 11 III-V
O3Ct13 End 164-16- 7
D-12111-■ 0 :(Q(3 end 16
3-164° 7D-13TI[X O2CH
3 end ]'52-],'53' 7D-1
4■-xx O2CH3 end 9l-9r
7D 15'Wi-Xll O3C
1 (3 end 17°-1-7107 (attached sheet)--' Example A I3 n Soku Ritoshi (Blood Melting Point Manufacturing Method 1) -16lll-X1f1.0
2 CH3'end 158-15. f”
71)-17III-XTV 02 G(3xyY
159-16 (f" 7I Series Examples The following are examples A in which a person has prepared a compound of formula (1) or a group of formula (2), and D is a group of (2).
B l) Displacement position t1t Melting point Manufacturing method E
-1i, /'f-tv-3-hv 0 3
219-221”)3) 7E-2m-IN)
I 3 145-147″″154-156″
” 7be E-3m-■ 03:'159-]6
007λ Boil in ethanol if desired.

Typical starting material for formula VU car 1nR8 optical device B Characteristics Common name a)
2 CJ (3 ends Om, p, 59-6f
) Lopin C) 2 C) 13
End NHb, p, 8non'12. ,l+
) Ebinami d) 2 C (■3 Exo
” b, p, 75'A, 05 mm pseudotropinamine e) 3 CH3 end Nl (bp, 1
1 ¥'17mm (67) Procedural amendment (voluntary) 1 Indication of the case Patent Application No. 116788 of 1988 2 Name of the invention Relationship to the case Patent applicant address Basel, Switzerland (no street address indicated) Name Sand Ac Chengesellschaft 4 Agent 5 Date of amendment order: Voluntary 6 Subject of amendment: Detailed description of the invention column (68
) °7. In the contents of the sleeve 11', ``Details jjf52 +'+, in the last line of the page, insert r(C,,)alkyl, -1 in the city of r(C, -,)alkyl, 1.

that's all

Claims (1)

[Scope of Claims] (1) Compounds selected from alkylene-bridged piperidyl esters or amides of carbocyclic or heterocyclic carboxylic acids, or alkylene-bridged piperidyl esters or amides of substituted benzoates, as well as their acid addition salts and A method for producing a quaternary ammonium salt (wherein, among the above compounds, a) a benzoic acid ester having an alkylene bridge between two carbon atoms of the piperidine ring has at least one of the ortho or meta positions of the Hensen ring. 8 has been replaced
b) is unsubstituted at both ortho positions, or has a halogen or alkyl at at least one of the ortho positions, and only hydrogen or halogen at the meta or para position, and two carbon atoms of the piperidine ring; A benzoic acid ester having an alkylene bridge between atoms has at least 3 carbon atoms in the alkylene bridge; C) has an alkylene bridge between the nitrogen atom of the piperidine ring and one ring carbon atom; and benzoic acid esters having an oxy substituent (J, having at least one substituent other than an oxysubstituent on the pentene nucleus, or having only two oxy substituents; d) a heterocyclic or ring nitrogen Monocyclic heterocyclic carboxylic acid amides or esters that are 6i rings containing atoms, or cyclic heterocyclic carboxylic acid amides or esters in which the heterocycle contains two oxygen atoms, have a nitrogen atom of the piperidine ring and one ring e) the benzoic acid amide has an alkylene bridge bonded between the nitrogen atom of the piperidine ring and one ring carbon atom; f) the benzoic acid amide has an alkylene bridge bonded between the nitrogen atom of the piperidine ring and one ring carbon atom; g) thenoyl and naphthoyl-8-aza-bicycloC, also having alkyl or hydroxy or halogen substitution;
3,2,1) oct-3-yl ester shall be excluded, and the production method described in -1- may be performed using a suitable dicarbocyclic or heterocyclic carboxylic acid or benzoic acid, or a reactive derivative thereof, or the above-mentioned comprising the step of condensing an acid or a precursor of a reactive derivative with a suitable alkylene-bridged piperidylamine or piperiditul, or a precursor thereof, optionally the resulting piperidyl ester or amide or an acid addition salt thereof or a quaternary A method comprising converting an ammonium salt into a desired piperidyl ester or amide, or an acid addition salt or quaternary ammonium salt thereof, and recovering the resulting piperidyl ester or amide itself, or an acid addition salt or quaternary salt thereof. (2) Formula ■ /1-CO-B-D I [In the formula, A is the formula ■ (In the formula, the free valence is any of the condensed rings (assumed to be bonded to this), and X is -C1- to 2- 1-N1 (3-1-〇-1 or -5-1R1 and 2 are independently hydrogen,
rogene, (C1-4')alkyl, (C1-4)alkoxy, hydroxy, amine, (C1-4)alkylamino, di(C1-4)alkylamino, mercapto, or (C1-4)alkylthio, 1( 3 is hydrogen, (CI-
4) alkyl, (C3-5) alkenyl, aryl or aralkyl, or formula 5 (wherein R4 to 7 are independently hydrogen, ami8nitro, (C,4)alkylamihedi(C; , 4) Alkylamino, halogen, (C1-4) alkoxy, (C1
-4) represents alkyl, (C1-4) alkanoylamino, or pyrrolyl, and at least one of R4 and R5 is other than hydrogen), B is 10- or - NH-, or 1) has the formula I■ (where n is 2.3 or 4, R8 is hydrogen, (C1-7
) alkyl, (C3-5)alkenyl, or aralkyl) or a group represented by the formula V, (1) If A is a group of the formula ■ and B or -NH-,
D is a group of formula (1), and (11) A is a group of formula (1), where 4 is hydrogen, or where 4 is halogen or alkyl and R5 to 7 are halogen or hydrogen. selected, B is -0-, D is a group of formula (1), n is 3 or 4, (111) A is a group of formula (1), R4 to I (one of 7 is alkoxy and D
is a group of formula (1) (one of the remainder of R4 to R7 is hydrogen or alkylthio, or
to R7, only two are alkoxy, and IV)
When A is a group of formula (■) and R4 is alkyl or halogen, B is 10-], and the production of acid addition salts and quaternary ammonium salts thereof a) a suitable compound of the formula A-Go-OHVT, or a reactive derivative thereof, or a precursor of the acid or reactive derivative thereof; and a suitable compound represented by the formula ■ HB-1) (wherein B and D have the same meanings as above) or a precursor of the above compound, or 1)) a secondary amino group. Alkylating a compound of formula ■ having a tertiary amine group to obtain a compound of formula ■ having a tertiary amine group, or
or d) halogenate a compound of formula (■) in which A is a group of formula (■) and R2 is hydrogen to obtain a corresponding or e) alkoxylating a compound of the formula (2) in which A is a group of the formula (2) to obtain a compound of the corresponding alkoxy group, A process comprising recovering the compound of formula (1) as it is or as its acid addition salt or quaternary ammonium salt. (3) An ester or amide of a dicarbocyclic or heterocyclic carboxylic acid or a substituted benzoic acid according to claim 1, or an acid of a diester or amide described in any of the Examples. Method for producing addition salt or quaternary ammonium salt. (4) Esters or amides of di-carbocyclic or heterocyclic carboxylic acids or substituted benzoic acids, or acid addition salts of the above esters or amides, produced by the method according to claim 1.2 or 3. or quaternary ammonium salts. (5) In di-carbocyclic or heterocyclic carboxylic acid alkylene-bridged piperidyl esters or amides, or substituted benzoic acid alkylene-bridged piperidyl esters or amides, a) a benzoic acid having an alkylene bridge between two carbon atoms of the piperidine ring; The ester is substituted at at least one of the ortho or meta positions of the benzene ring, and b) both ortho positions are unsubstituted, or at least one of the ortho positions has a halogen or alkyl and the meta or para position is substituted. A benzoic acid ester having only hydrogen or halogen in the position and having an alkylene bridge between two carbon atoms of the piperidine ring has at least 3 carbon atoms in the alkylene bridge, and C) a nitrogen atom of the piperidine ring. A benzoic acid ester having an alkylene bridge between one ring carbon atom and one oxy substituent has at least one substituent other than the oxy substituent on the benzene nucleus, or two d) a monocyclic heterocyclic carboxylic acid amide or ester in which the heterocycle is a six-membered ring containing a ring nitrogen atom, or a cyclic heterocycle in which the heterocycle contains two oxygen atoms; Cyclic carboxylic acid amides have an alkylene bridge between the nitrogen atom of the piperidine ring and one ring carbon atom, and C) Benzoic acid amides have an alkylene bridge bonded between the nitrogen atom of the piperidine ring and one ring carbon atom. f) the benzoic acid amide has no alkyl or hydroxy or halogen substitution in any ortho position; g) thenoyl and naphthoyl-8-aza-bicycloC;
3,2,1) Compounds and acid addition salts and quaternary ammonium salts thereof, excluding oct-3-yl esters. (6) Compounds of formula (1) as described in claim 2, and acid addition salts and quaternary ammonium salts thereof. (7) Aryl is unsubstituted phenyl, or (CI-4)
Alkyl, halogen, hydroxy, mojiku (C1-4
) phenyl mono- or polysubstituted with alkoxy, aralkyl, unsubstituted phenyl, or (C1-4
) alkyl, halogen, hydroxy, or (C1-
4) The compound according to claim 6, which is (CI-4)alkyl substituted with phenyl mono- or polysubstituted with alkoxy, as well as acid addition salts thereof and
grade ammonium salt. (In the formula, k4P3 is halogen, (CI-4) alkylamino, or (CI-4) alkoxy, R5Pa is hydrogen, R6Pa is amine, (CI-4) alkylamino,
or di(C1-4)alkylamino, R7Pa is hydrogen, or fluorine, chlorine or bromine, R8, a is hydrogen, (
C1-7) meaning alkyl or aralkyl), as well as acid addition salts and quaternary ammonium salts thereof. (In the formula, R4Pa, 5Pa, 5k6Pa and R8
, a is the meaning as defined in claim 8, R7, b is hydrogen or halogen, and the compound according to claim 6, and its acid addition salts and quaternary ammonium salts. 3 (wherein, the free valence shall be bonded to any of the condensed rings, n' means 2 or 3, R1, R2, l(3,
and R8 is a compound as defined in claim 6), and the acid addition salt and quaternary ammonium salt thereof. (In the formula, the free valence is bonded to any of the fused rings, k], qb and R2q b are independently hydrogen, halogen, or (C1-4) alkyl, k3qb is hydrogen,
or (C1-4)alkyl, Rs 9t) is hydrogen, (
C1-7) alkyl or aralkyl, n' means 2 or 3), and acid addition salts and quaternary ammonium salts thereof. 3 (wherein, the carbonyl group is bonded to any of the condensed rings, and R29c is R defined in claim 2)
2, (C1,) refers to a group other than alkoxy and hydroxy; Compounds according to scope 6, as well as acid addition salts and quaternary ammonium compounds thereof. (13) Formula ■sa (In the formula, R4, a, 5.a, 6.a and R7pb
(meaning as defined in claim 9) The compound according to claim 6, as well as its acid addition salt and quaternary ammonium compound. (14) Formula ■5b l(5Pa (wherein, R4Pa ' R5Pa , R6,a and R
7pb has the meaning as defined in claim 9.) The compound according to claim 6, as well as its acid addition salt and quaternary ammonium compound. (15) A is a group of the formula ■, in which 1 and ](2 are independently hydrogen, halogen, (CI-4) alkyl,
or (C1-4)alkoxy, k2 is bonded to the 4th or 5th position, 1 (3 is hydrogen, or (CI-4)alkyl, free valence is bonded to the 3.4th or 5th position, or It is a group of formula ■, in which 4 is Norigen, or (C1
-4) Alkoxy Rs is hydrogen or halogen, λ6 is amine, nitro, (C1-4) alkylamino, or di(C1-4) alkylamino, halogen, or 1-
pyrrolyl, k7 is hydrogen or halogen, ■) is a group of formula ■, in which R8 is hydrogen, (C1-4) alkyl or benzyl, or a group of formula V, in which free The bond is bonded to the 3rd position, and the proviso provisions (1) to (iV)i regarding formula 1 described in claim 2
6. The compound according to claim 6, and its acid addition salt and quaternary ammonium salt. (16) N-(endo-9-methyl-aza-bicycloC
The compound according to claim 6, which is 3,3,1)non-3-yl)indol-3-ylcarboxylic acid amide, and its acid addition salt and quaternary ammonium salt. (17) Indol-3-ylcarboxylic acid-endo-8
-Methyl-8-aza-bicyclo(3,2,],, )]
The compound according to claim 6, which is oct-3-yl ester, and its acid addition salts and quaternary ammonium salts. (18) 1-methyl-N-(endo-9-methyl-aza-bicycloC3,3,1)non-3-yl)indol-3-ylcarboxylic acid amide according to claim 6 Compounds and acid addition salts and quaternary ammonium salts thereof. (1,9) The compound according to claim 6, which is a group of formula (1) or (1), and its acid addition salt and quaternary ammonium salt. (20) The compound according to claim 19, which is n or 3, and its acid addition salt and quaternary ammonium salt. (21) The compound according to claim 6, wherein D is a group of formula (1), and its acid addition salt and quaternary ammonium salt. (22) The compound according to claim 6, wherein A is indolyl, and its acid addition salt and quaternary ammonium compound. (23) Claim 4-2 for use as a medicine
"Compounds described in any one of Section 2 and pharmaceuticals thereof"
- Acceptable acid addition salts or quaternary ammonium salts. (24) Used as a serotonin M antagonist, analgesic, anti-migraine agent or anti-arrhythmic agent, Claim 4-2
Compounds described in any of Item 2, and pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof. (2. Compound described in any one of claims 1-p of claims P4-22, or a pharmaceutically acceptable thereof) consisting of an acid addition salt or quaternary ammonium salt, and a pharmaceutical carrier or dispensing agent. , pharmaceutical composition. (26) A compound of formula (2) according to claim 2, wherein B is NH, D is a group of formula (2), and n is 4. a-ka