JPS5869881A - Novel compound - 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 novel benzamides, pharmaceutical compositions containing them, processes for their preparation and intermediates and their use in the treatment of psychosis.

South African Patent No. 54610/80 specifically describes the formula () in which Ra is a lower alkyl, trifluoromethyl or cyano group or a chlorine, bromine or fluorine atom.
and their pharmaceutically suitable salts are disclosed. Such compounds are described as having miraculous relaxing properties.

European Patent Publication No. 1313B and US Patent No. 4°273
．． No. 778 has the formula (B) [wherein, RbtiCt-s is an alkoxy group].

Rc and Rd are the same and 9 are different, and hydrogen,
Halogen, CF, CI-Cylamino, or It
or two C1-6 alkyl groups.

CI-m is alkylsulfone or amino, aminocarbonyl or aminosulfone optionally substituted with nitro; Re is hydrogen or Cl-11 alkyl;

RfFiCx-y alkyl group -(CHs)sRl
(wherein %S is 0-2 and is a RgFiCB-s cycloalkyl group), t or the group -(CHz)tuh
(where tijlfi or 2 and Rh is C1
9 for 1-1 alkenyl is Cl-41 alkyl.

1't selected from C1-a alkoxy, trifluoromethyl and halogen is a phenyl group optionally substituted with two substituents.

and s '', p and q are each independently from 0 to 2], and pharmaceutically suitable salts, N-oxides and hydrates thereof.

Benzamides of formula (B) are described as dopamine antagonists and are useful in the treatment of emesis. They are also responsible for disorders related to impaired gastrointestinal motility, such as delayed gastric nitridation, dyspepsia, bloating, esophageal reflux and indigestion, due to their balance between the peripheral and central effects of the nervous system. It has also been described as useful in the treatment of ulcers and in the treatment of central nervous system disorders such as psychosis.

In the present invention, within the scope of the above-mentioned European patent publications and US patents, and on the bridgehead nitrogen atom, % p-methyl-, p
A number of new benzamides with norgranatyl chains containing -chloro- or p-fluoro-benzyl substituents have been discovered.

Such benzamides have particularly advantageous antipsychotic activity. They also have a sustained action with fewer side effects such as extrapyramidal effects.

They are therefore particularly useful in the treatment of psychosis.

Therefore, the present invention provides the formula (1) (wherein, X is methoxy, Y is amino, 9 is C1-6 alkanoylamino, 2 is hydrogen, chloro is bromo, and tgt is methyl, chloro or fluoro) provides pharmaceutically suitable salts and solvates thereof.

Preferably X is methoxy.

When Y is Q-6 alkanoylamino.

This is preferably acetylamino. However, Y is preferably amino.

Preferably 2 is bromo or especially chloro.

The following compounds are included in formula (1).

4-amino-5-chloro-2-methoxy-N-(3'β
-(9'-(4-methylbenzyl)-9'-adabicyclo-(3,3,1)-nonyl])benzamide; 4-
Amino-5-chloro-2-methoxy-N-(3-β-(
"9'-(4-chlorobenzyl)-9'-azabicyclo-(3,3,1)-nonyl])benzamide;4-amino-5-chloro-2-methoxy-N-(3'β-(9 −
(4-fluorobenzyl)-91-azabicyclo-(a
, a, xl-nonyl]) be/zurdendo;
-Bromo-2-methoxy-N-(3'β-("9'-(
4-fluorobenzyl)-9'-azabicyclo-(3,
3,1)-nonyl])benzamide; 4-acetylamino-5-chloro-6-medoxy N-(3'β-(9'
-(4-fluorobenzyl)-9I-azabicyclo-(
3,3,1)-nonyl])penzuad; 4-acetylamino5-chloro-2-methoxy-N-(3'β'-
(9'-(4-10 Rubenzyl)-9'-Azabisiku-(3,3,1)nonyl)) Benzamide; 4-acetyl-5-chloro-2-methoxy-N-(3'
β-(9'-(4-methylbenzyl)-91-azabicyclo-(3,3,1)-nonyl])benzamide; 4-
Acetylamino-2-methoxy-N-(3'β-(9'
-(4-fluorobenzyl)-9'-azabicyclo-(
3,a,1)-nonyl])benzamide.

4-amino-2-methoxy-N-(3'β-[9'-(
4-fluorobenzyl)-9'-azabicyclo-(3,
3,1)-nonyl])benzamide; and pharmaceutically suitable salts and solvates thereof.

The most preferred compounds of formula <I) are those in which Rt is fluoro, and their pharmaceutically suitable salts and solvates.

Pharmaceutically suitable salts of the compound represented by formula (1) include conventional pharmaceutically suitable acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid, lactic acid and vinegar*. Includes acid addition salts of

Solvates of the compound represented by formula (1) include hydrates.

The present invention also provides a method for producing a compound represented by formula (I), or a pharmaceutically suitable salt or solvate thereof, which method comprises formula (1) (wherein X and 2 are as defined above). has the same meaning, R2#
iy or a protected 9-amino group, Ql is a leaving group) is a compound of the formula (III) (wherein R3 is a protective group or p-methylbenzyl, p-p
o-lupenzyl or p-fluorobenzyl), and when Rg is a protected amino group, the pupil-holding group is removed.

When R3 is a pupil-retaining group, the sieve-retaining group is removed and the oniamine is converted into a compound of formula (IV) where Ql is a leaving group and MtiCO or CHI
and R1 has the same meaning as above), then when M is CO, the resulting 9N-benzoyl compound is reduced to give
- a benzyl compound; when R1 is Y, the amino group or the C1-6 alkanoyl aino group is converted into another one; and, if desired, a pharmaceutically suitable salt or solvate thereof; Involves forming things.

The leaving group Ql is a group in which the amide bond can be easily replaced by a neonuclear oamine such as can be formed between compounds of formula (1) and (2).

It can be substituted in anionic form or in the form of a condensed by-product.

Examples of leaving groups 910 include hydroxy, halogen, acyloxy, and activated hydrocarbyloxy.

When the leaving group is hydroxy, the reaction is preferably carried out in an inert, non-hydroxyl solvent such as benzene, toluene, dichloromethane, dimethylformamide or diethyl ether with a dehydration catalyst such as dicyclohexyl carbodiimide such as carbodiimide. carried out in the presence of The reaction is carried out at any non-extreme temperature, e.g. -10
~100r.

For example, it can be carried out at θ~80C.

When the leaving group is a halogen, such as chloro or bromine, the reaction is preferably carried out at non-extreme temperatures in an inert, non-hydroxyl solvent such as benzene, toluene,
The reaction is carried out in dichloromethane/l ethyl ether. This is also carried out in the presence of an acid acceptor 1, such as an organic base 1, especially an oniamine, such as triethylamine, trimethylamine, pyridine or picoline, many of which also act as a solvent. or,
The acid acceptor may be inorganic such as calcium carbonate and the sodium carbonate t+ may be potassium carbonate.

When the leaving group is acyloxy, eg, Cl-4 alkanoyloxy, one reaction is preferably carried out in substantially the same manner as when the leaving group is hydroxy.

When the leaving group is acyloxy, e.g. Cl-4 alkoxycarbonyloxy, the reaction is preferably carried out in an inert solvent, e.g. methylene chloride, at sub-extreme temperatures.
It is carried out in the presence of an acid acceptor, for example triethylamine.

When the leaving group is activated hydrocarbyloxy, one reaction is carried out in an inert polar solvent, such as dimethylformamide. It is preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature. ' Preferably, Ql is and droxy, chlor or.

Particularly Cl-4 alkoxycarbonyloxy, such as ethoxycarbonyloxy.

The protected nine-amino group as R2 is an amino group substituted with a protecting group. Such protecting groups include the Cl-6 alkanoyl group 1, for example acetyl.

Probionyl, n- and isobutyryl and 2,2-dimethylprobanoyl or C1-4 alkyl.

selected from C1-4 alkoxy, trifluoromethyl and nido4; 91tIe is a benzoyl optionally substituted on the phenyl ring with two substituents;
-4 alkoxycarbonyl, such as tert-butoxycarbonyl.

Examples of protecting groups when defined as R3 include those for sRx when it is protected and is a nonamino group. Furthermore, %R3 may also be a benzyl group optionally substituted as defined above for a benzoyl-protecting group.

Removal of protecting group R3 and /1 or protected nine amino group R
Removal of the protecting group from 1 is accomplished according to known techniques. For example, removal of the C1-6 alkanoyl or optionally substituted benzoyl protecting group is accomplished by acid or base hydrolysis, preferably at heating temperatures. be done. Furthermore, C
Removal of the l-4 flukoxycarbonyl protecting group is accomplished using trifluoroacetic acid. The optionally substituted benzyl protecting group is then removed by hydrolysis using a transition metal catalyst such as platinum or palladium on charcoal at ambient temperature in a solvent such as ethanol at atmospheric pressure or under pressure. This can be achieved by what you do.

Whenever R2 is a protected amino group and R3 is a protecting group, it is preferred that the protecting groups are independently removable, e.g. one of the protecting groups can be removed by acid or base hydrolysis. (and the other may be a benzyl group which can be removed by catalytic hydrogenolysis; conveniently, Rs is benzyl and R1 is C1-4 alkanoylamino, for example acetylamino.

Also, whenever R1 is a protected amino group and R3 is a protecting group, the protecting group R3 is removed, the resulting oniamine is reacted with a compound of formula (IV), and then the protected It is preferable to remove the protective group for the amino group R2.

The leaving group Q 2 Fis of formula (IV) is a urogroup that is easily substituted by a nucleophilic oniamine so that an amine or amide is formed. Examples of such leaving groups include chloro, bromo, iodo, mesyloxy and hytosyloxy when 1M is CH2;
When is CO, the groups listed above for leaving group Q1 are included. Particularly preferred examples of C2 include chloro, bromo and iodo.

oniamin and represented by the formula (IT), where M is CHI
The reaction of the compound represented by is carried out under usual alkylation conditions, for example, using an inert solvent 1 such as dimethylformamide,
It can be carried out in the presence of an acid acceptor such as potassium carbonate. in general.

The reaction is carried out at sub-extreme temperatures, for example at ambient temperature or at slightly elevated temperatures.

The reaction of oniamine with a compound of formula (IV) in which %M is CO is carried out under usual aroylation conditions, for example as described above for the reaction between compounds of formula (1) and (1). The resulting nine N-benzoyl compounds can be reduced according to known reduction techniques, e.g. by reduction with lithium aluminum hydride or diborane, to give the corresponding N-benzoyl compounds. In this regard, the reaction with the benzoyl conductor of formula 1 (mV) and subsequent reduction is conveniently carried out in a single operation using sodium cyanoborohydride under acidic conditions.

However, R2 is an amino group, 19 is a protected amino group, and R3 is p-methylben-zyl.

More preferably p-chlorobenzyl or especially p-fluorobenzyl is thus preferred.

The protecting group R3 is removed, and the resulting nineioniamine is expressed by the formula ([V)
Avoid the additional step of reacting with the compound represented by

Of the compound represented by formula (1), in which Rx is anno, the corresponding compound represented by formula (1), in which Hz is Cl
Conversion to compounds which are -6 alkanoylaminos can be carried out according to known techniques, for example by reaction with suitable acylating derivatives of Cl-6 alkanoic acids, such as their anhydrides or acid halides.

From the above, compounds of the formula (1) in which R1 is amino or Cl-6 alkanoyl adeno can function as antipsychotic agents and as useful intermediates.

Are the compounds represented by formulas (I) and (If) known or can be produced in the same manner as in the production of known compounds?

The compounds represented by the formula (set) can be produced by reduction of the compound represented by the formula (v) (wherein Hm has the same meaning as above).

In order to preferentially obtain the β isomer of formula (1), the reduction is carried out with an alkali metal, for example sodium, and C
This is carried out using a 1-6 alkanol, for example an azal alcohol. Reducing agents that give mixtures of α and β isomers can also be used, since the desired β-isomer can be separated from the mixture by conventional techniques. However, any such separation is preferably carried out later in the synthesis when the isomers are more tractable. It is particularly preferred to carry out reactions between compounds which are C1-6 alkanoylamino such as amino and compounds represented by the formula (set).

The compound represented by the formula (V) is a compound represented by the formula (Vl) (wherein R1
It can be produced by reacting a compound represented by (has the same meaning as above) with sidroxyluane.

It is represented by the formula (W), in which Bs is p-methylbenzyl, p-chlorobenzyl is p-fluoro (in the formula, Rs
It can be produced by reacting a compound represented by Fi (having the same meaning as above) with glutardialdehyde and 1,3-acetonedicarboxylic acid. The other 1 set (Vl
), in which s R is adjacent to the nitrogen atom and causes a carbonyl function 1 For example, Cl-6 alkanoyl, benzoyl optionally substituted as defined above, or 7taC1-4 Compounds which are alkoxycarbonyl are represented by formula 1 (Vl), in which %R8 has the same meaning as above, by removing the optionally substituted benzyl protecting group as defined above.

Next, this onia f is expressed by the formula (Vl), where:

Produced by conversion to a compound where R3 is a carbonyl-containing protecting group as defined.

The compound represented by formula (■) is known or can be produced in the same manner as known compounds.

1 During reduction of the compound of formula (v) when R3 is p-10 lupendyl 9 Fip-fluorobenzyl,
Some unwanted hydrogenolysis of carbon-chlor or carbon-fluor appears to occur. When R1 is p-chlorobenzyl, this appears to occur to a higher extent than when R3 is 1)-fluorobenzyl. However, carbon-chlorine 19 uses conditions more favorable for the reduction of oxime double bonds and less favorable for the hydrogenolysis of carbon-fluoro bonds, such as shorter time and lower temperature, resulting in lower yields. However, it is still possible to obtain the desired product.

The above-mentioned side reactions occur for the ninth time.The present invention provides another method for producing the compound represented by the formula (■), and this method is based on the formula (■).
%1) (wherein R1 has the same meaning as above, and one of R4 and R8 is a monovalent carrier 1ifI and the other is hydrogen, or R4 and R11 together are 2 This method involves removing a valency-protecting group from a compound represented by the formula (which is a value-protecting group).

Protecting groups can be removed under conditions such that their removal does not significantly affect the remainder of the compound.

In particular, there must be no significant removal of the p-substituted pendyl moiety. A particularly preferred example of a monovalent retention II group is C1-8 alkanoyl, such as acetyl, which can be removed by the desired method of mt or base hydrolysis. An example of a divalent protecting group is phthaloyl, which can be removed in a desirable manner by basic hydrolysis.

This other manufacturing method is represented by formula (1).

It is advantageous to prepare these compounds in which R1 is chloro or fluoro. The method of -10,000 is expressed by formula (1),
It is advantageous to produce these compounds in which srs is other than p-chlorobenzyl or p-fluorobenzyl, and in particular 83 is p-methylbenzyl.

The compound represented by formula (■) is represented by formula (II) (wherein R4
and RIs have the same meanings as above) and a compound represented by formula (IV) having the same meanings as above.

The reaction is carried out under conventional alkylation conditions, for example in an inert solvent 1, such as dimethylformamide, in the presence of an acid acceptor, such as potassium carbonate.

The compound represented by the formula (E[) is the compound represented by the formula (X) (wherein R4
and Hs have the same meanings as above).

Hydrogenolysis is conveniently carried out at room temperature and atmospheric pressure using 10% palladium on charcoal.

The compound represented by the formula (X) is a compound represented by the formula
It can be produced and cured by reacting with a reagent that preserves it.

Compounds represented by the formula (set) are known.

The present invention provides another method for preparing a compound represented by formula (1) in which %2 is chlor or bromine, or a pharmaceutically suitable salt or solvate thereof, which method comprises the formula (
II) 2 (wherein, X and R2 have the same meanings as above.

and R3' is hydrogen or R3 as defined above; or bromination; when R2 is a protected amino group, removing the protecting group;
' is R31 and is a time-keeping group, by removing the protecting group, it is represented by the formula (Xl), and in the formula 1, fl
A compound is obtained in which s I is hydrogen; when fl s I is hydrogen, this oniamine is reacted with a compound represented by formula (mV) having the same meaning as above; and when M is CO, By reducing the obtained nine N-benzoyl compounds, the corresponding N-benzyl compounds can be obtained; R2
is Y, if desired, an amino group or C1-6
This includes converting the alkanoylamino group into other forms; and, if desired, forming pharmaceutically suitable salts or solvates thereof.

Chlorination or prophylaxis is preferably carried out under acidic conditions using, for example, acetic acid.

For example, R2 in formula (■) is a protected amino group 1.

CI-II alkanoylamino is highly preferred. The reason is that otherwise dichlorination or dibromination could occur.

The present invention further provides another method for preparing a compound of formula (I), or a pharmaceutically suitable salt or solvate thereof, which method comprises the following methods: O2 (SX and 2 and RS / has the same meaning as above); When R3' is R3 and is a protecting group, the protecting group is removed to form the formula (to)
Obtain a compound represented by formula 1, in which 83' is hydrogen; 8
When 3' is hydrogen, this oniamine is reacted with a compound of formula (IV) as defined above; and when M is CO, the resulting 7tN-benzoyl compound is reacted by reducing Obtain the N-benzyl compound; if desired.

Converting the ohamino group to a Cl-6 flukanoylamino group; and, if desired, forming a pharmaceutically suitable salt thereof includes forming a solvate.

Reduction can be carried out using hydrogen chloride and concentrated hydrochloric acid, or hydrogen and Raney nickel.

The present invention further provides another method for producing a pharmaceutically suitable salt or solvate of the compound represented by formula (1), which method comprises formula (9) (wherein X and 2 and R3 / has the same meaning as above).
an) perform the decomposition; R3' is R3;

and is a protecting group, removing the protecting group yields a compound represented by formula (9) in which Rs' is hydrogen; when R3' is hydrogen, this oniamine is defined as and when M is CO, the resulting 9N-benzoyl compound is reduced to give the corresponding N-benzyl compound; if desired, -5? -Converting the amino group to a C1-11 alkanoylamino group.

and, if desired, forming pharmaceutically suitable salts or solvates thereof.

Hoffman decomposition preferably involves metal hypohalites.

For example, primary sodium hypochlorite is used.

The present invention further provides a method for producing a compound represented by formula (1) or a pharmaceutically suitable salt or solvate thereof, which method comprises formula (5) (wherein 2, R2 and Rs / are the above-mentioned ) is methylated or ethylated; when R2 is protected and is a 9-amino group, the protecting group is removed; when R1' is R3 and is a protecting group, the protected Removal of the group gives a compound of formula (5) in which Rs I is hydrogen; when R3' is hydrogen, this oniamine is of formula (If) as defined above. When M is CO, the resulting 9N-penzoyl compound is reduced to give an N-benzyl group; when R8 is Y, if desired, an amino group or C1- 6 Alkanoylamino groups may be converted into other forms; and, if desired, their pharmaceutically suitable salts may be converted to form solvates.

The alkylation reaction is carried out using methyl iodide or ethyl iodide in the presence of potassium carbonate in acetone or dimethyl sulfate in the presence of sodium hydroxide.
It is preferred that R2 therein is a protected amino group. It is also highly preferred that Rs' is R3 and is a C1-alkanoyl or benzoyl protecting group.

Formulas (Xll), (XI[), (X[V) and (
The compound represented by 5) can be produced in the same manner as the compound represented by formula (I). However, the formula (
In the preparation of the precursor of the compound of formula 5), the hydroxy functionality is protected during the coupling reaction between compounds similar to the compound of formula 5 and (III), and If a good compound similar to a compound represented by the formula where Ql is other than hydroxy is prepared from a similar compound where Ql is hydroxy, it is better to preserve it.

Examples of zero-tethered groups include, when it is a bound amino group,
Protective groups for Rz include those mentioned above.

There are a number of intermediates that are new and form part of this invention for use in the methods described above. A group of intermediates has the formula (9) where R7 is methoxy or ethoxy.

R8 is nitro, nine is aminocarbonyl, and R8 is
9 is hydrogen, chloro or bromine, R) is hydroxy, Rs is amino or C1-6
alkanoyl ξ, R9 is hydrogen, chloro or bromine, and M is CHI or CO).

Others are of the formula (■ (where X is amino or C1-8 alkanoylamino and Y is hydrogen, or X and Y, together with the longitudinal atom to which they are attached, are an oximino group. and R1 has the same meaning as above).

Other useful intermediates are of formula (VI), where R1
The compound is 1df9-fluorobenzyl.

The compounds of the invention are β-isomers, i.e. where the amino bond is attached to the bicyclic ring system, the configuration is as follows: where X%Y, Z and R1 have the same meaning as above. expressed.

Therefore, intermediate compounds which can also exist in two isomeric forms are preferably used as the β isomer.

However, the intermediate compound can also be used as a mixture of α and β isomers, and the undesired α isomer can be separated in a conventional manner at some stage, preferably at the stage mentioned above.

Pharmaceutically suitable salts of the compounds of the invention are prepared by simply reacting the basic compounds of the invention as pharmaceuticals with a suitable organic or inorganic acid.

Pharmaceutically suitable solvates of the compounds of the invention are prepared during the preparation of the compounds, during their work-up and during their recrystallization.

The present invention also provides a pharmaceutical composition comprising a compound represented by formula (Xia) or a pharmaceutically suitable salt or solvate thereof and a pharmaceutically suitable carrier.

Such compositions can be prepared by mixing and are preferably made suitable for oral or parenteral administration, including tablets, capsules, oral liquid formulations, powders, a-granules,
Lozenges, powders for the preparation of solutions, solutions or suspensions for injection and infusion can take the form of suppositories. Compositions for oral administration are preferred.

Tablets or capsules for oral administration are usually presented in unit dosage form and include 1 customary excipients, such as binders, fillers,
Compression tablets containing lubricants, disintegrants and wetting agents can be coated by nine methods well known in the art. Oral liquid preparations usually take the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs;
Alternatively, it may be provided as a dry powder that can be reconstituted with water or other suitable vehicle to form a liquid formulation before use. Liquid preparations like this □ are anti-settling agents and emulsifiers.

The non-aqueous medium (which may contain edible oil), preservatives and flavor 1+ may contain conventional additives such as colorants.

For parenteral administration, a compound of the invention and a sterile vehicle are combined in an i&
A liquid unit dosage form is prepared having the following properties:

The compound, depending on the vehicle and concentration, can be either suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle, filter sterilizing, filling into a suitable vial or ampoule, and sealing. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers are also dissolved in the vehicle.

Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, sterilized by exposure to ethylene oxide, and filled into sterile containers. Advantageously, a surfactant or wetting agent is included in the pellets to promote uniform distribution of the composition of the invention.

The invention further comprises administering to a mammal an antipsychotically effective amount of a compound of the invention, or a pharmaceutically suitable salt or solvate thereof, or a pharmaceutical composition, as defined above. Provided are methods for treating mental illness in mammals, including.

The amount effective to treat the above-mentioned nine disorders will depend on the relative potency of the compounds of the invention, the nature and virulence of the disorder being treated, and the nature of the mammal. Depends on weight. However, a unit dose - usually 0.1 to 20 Da, e.g.

Contains 0.5-101% F of the compound of the invention. The unit dose is usually 18 and the total dose is usually 0. The dose is administered once every 18 days, and three times between 2 and 9 days, so that the dose is 01-10 da/immediately.

The present invention also provides a compound of formula (1), as defined above, and a pharmaceutically suitable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of disorders of the central nervous system. do.

Hereinafter, the production of the compound will be shown using actual examples, and the production of the intermediate will be shown using Production Example 19.

Production Example 1 3β-acetylamino-9-benzyl-9-azabicyclo(3,3,1) nonane (Dl) 3β-amino-9-benzyl-9-azabicyclo(3,3,1) nonane (7,
2#) and excess acetic anhydride in ethanol (10011
7) The middle solution was stirred at room temperature for 48 hours. Evaporate the solvent and dissolve the residue in water and dichloromethane. This was made basic with potassium carbonate, extracted with dichloromethane, and separated.

Drying and evaporation gave 3β-acetylamino-9-benzyl-9-azabicyclo(3,3°1]nonane (6,5,9,73%).

Production Example 2 3β-acetylamino-9-azabicyclo (3,3゜1
) nonane (D2) 3β-acetylamino-9-benzyl-9-azabicyclo(3,3,1) nonane (6II) in ethanol (30
The solution was hydrogenated at room temperature under atmospheric pressure over 10% palladium on charcoal. Strain the solution.

By evaporating the solvent, the title compound 1<4-1l4-
100%).

Production example 3 3β-acetylamino-9-(4-fluorobenzyl)
-9-azabicyclo-(3,3,1)nonane (D3) 3β-acetylamino-9-azabicyclo-(3,3,
1) Nonane (3F), 4-fluorobenzyl chloride (
2,4N) and potassium carbonate (4g) in DMF (10
The solution in 0m) was stirred at room temperature for 48 hours. The solution was evaporated and the residue was dissolved in water.

3β-acetylamino-9-(4-fluorobenzyl)-9-azabicyclo-(3,3°1)nonane (4
, 2 g, 90%) was obtained.

Production Example 4 3β-amino-9-(4-fluorobenzyl)-9-azabicyclo-(3,3,1)nonane (D4) 3β-acetylamino-9-(4-fluorobenzyl)-9-azabicyclo - A solution of (3,3,1)nonane (4,2 g) in ethanol (60 volumes) and concentrated hydrochloric acid (1[11]) was heated under reflux for 24 hours. Evaporate the solution, dissolve the residue in water,
It was made basic with potassium carbonate and extracted with dichloromethane. 3β-Amino-9-(4-fluorobenzyl)-9-azabicyclo-(3,3,1)nonane (2,6p, 72%) was obtained from the solvent 11MK, and this was carried out in the next step without purification. It was used in

Production Example 5 9-(4-fluorobenzyl)-9-azabicyclo-(
3,3,1) Nonan-3-one (D5) A solution of 4-fluorobenzylamine (2511) in dilute hydrochloric acid (5N, 4ON) was dissolved in glutardialdehyde (50%, 4811j).
was added to a water (800117) solution with stirring. 1
．． A solution of 3-a7tone dicarboxylic acid (29.2 g) and sodium acetate (16.4 g) in water (20011 J) was then added and the mixture was stirred at room temperature for 24 hours. Then, an additional 1! of dilute salt was added. (10111) was added and the mixture was stirred for a further 48 hours.

This was made acidic and the acidic solution was washed with ether. The acidic solution was then made basic and extracted with ether. Wash the ether extract with water and dry.

Crude ketone by evaporation (32,5L65N)
I got it. This was purified by treating a solution in ethyl acetate with alcohol.

Production Example 6 9-(4-fluorobenzyl)-9-azabicyclo-(
3,3,1) Nonan-3-one oxime (D6) N-(
4-fluorobenzyl)-9-azabicyclo-[3,3
゜l] Nonan-3-one (32,5Ii), hydroxylamine hydrochloride (9,5,9) and pyridine (511J
) in ethanol (5QQd) was refluxed for 1 hour.

The solution was evaporated and the residue was dissolved in ethyl acetate and water.

This was basified with potassium carbonate and the ethyl acetate extract was separated and dried.

The crude oxime was obtained by evaporation. The oxime (26,79
, 78%).

Production example 7 3β-amino-9-(4-fluorobenzyl)-9-7
Zabicyclo(3,3,1)nonane(DI)H 9-(4-fluorobenzyl)-9-azabicyclo-(
3,3,1) Dissolve nonan-3-one oxime (10 g) in amyl alcohol (1501j).

Heat to reflux. Sodium (IOII) was added in portions while the solution was stirred. After all the sodium had dissolved, the solution was cooled, diluted with ether, acidified with dilute hydrochloric acid, and the acid extract was washed with ether.
Make basic with excess potassium carbonate.

Crude 3β-amino-9-(4-fluorobenzyl) was obtained by extraction with ethyl acetate and then evaporation of the solvent.
-9-Azabicyclo(3,3,1)-nonane(6,51
7o%) was obtained and used in the next step without purification.

The amine represented by formula (DI) is mainly one type of isomer and has a 3β configuration.

Preparation Example 8 3β-amino-9-(4-chlorobenzyl)-9-azabicyclo-(3,3,1)-nonane (D8) The title compound was prepared in a similar manner to the preparation of the compound in Preparation Example 4.

Production Example 9 9-(4-methylbenzyl)-9-azabicyclo-(3
,3,1)-nonan-3-one (D9) A solution of 4-methylbenzylamine (12 g) in dilute hydrochloric acid (sN, 20 aJ) was mixed with glutardialdehyde (50%, 24 mg) in water (
100 IIJ) was added to the solution with stirring. 1.3-
A solution of a7tone dicarboxylic acid (14,6Ii) and sodium acetate (s, zg) in water (100M) was then added and the mixture was stirred at room temperature for 24 hours. Further 1 portion of dilute hydrochloric acid (5M) was added and the mixture was stirred for a further 4 hours.

This was made acidic and the acid solution was washed with ether.

The solution was then basified and extracted with ether.

The crude ketone was obtained by washing the ether extract with water, drying and evaporating. This thing.

The yield was 13.5.9 (56%) by purifying the solution in ethyl acetate with alumina.

Production Example 10 9'-(4-methylbenzyl)-9-7zabisic rho(3,3,1)-nonan-3-one oxime (DIO)
N-(4-methylbenzyl)-9-azabicyclo-(3
,3,1)-nonan-3-one (5g), hydroxylamine hydrochloride (1,s9) and pyridine (0,75
A solution of 11J) in ethanol (10ON) was heated to reflux for 1 hour. The solution was evaporated and the residue was dissolved in ethyl acetate and water. The crude oxime was obtained by basification with potassium carbonate, separation of the ethyl acetate extract, drying and evaporation, and the oxime (4,9,77%) was obtained by recrystallization from ethyl acetate/gas oil. Obtained.

Production Example 11 3β-amino-9-(4-methylbenzyl)-9-azabicyclo(3,3,1,)-nonane (DI 1 ) 1 9-(4-methylbenzyl)-9-azabicyclo-(3
,3,1)-nonan-3-one oxime (4II) was dissolved in amyl alcohol (10011j).

Heat to reflux. Add sodium (2g) little by little,
The solution was stirred during that time. After all the sodium has dissolved,
Cool the solution and dilute with ether.

Acidified with dilute hydrochloric acid. The acid extract was washed with ether and then basified with excess potassium carbonate.

Crude 3-amino-9-(4-methylbenzyl)-9 was obtained by extraction with ethyl acetate and then evaporation of the solvent.
-Azabicyclo(3,3,1)-nonane(3,6J,9
5%) was obtained and used in the next step without purification.

This amine consists primarily of one isomer and has a 3β configuration.

Practical example 1 (A) 4-acetamino-5-chloro-2-methoxy-
N-(3'β-(9'-(4-yluobenzyl)-9
1-Azabicyclo(3,3,1)-nonyl)benzamide (EIA) NHCOCH3 4-acetylamino-5-chloro-2-methoxybenzyl chloride (2,78 g) in dichloromethane (50 ml
1) and 3β in a mixture in triethylamine (311j)
A mixture of -amino-9-(4-fluorobenzyl)-9-azabicyclo-(3,3,1)-nonane (2,98 g) in dichloromethane (50+j) was added. The reaction mixture was stirred at room temperature for 30 minutes. This was then diluted with water, made basic with potassium carbonate, and then extracted with dichloromethane. The crude product was obtained by evaporating the dichloromethane extract, which was converted into alumina (neutral, secondary)
4-acetylamino-5-chloro-2-methoxy-N-(3'β-(9
'-(4-fluorobenzyl)-91-azabicyclo(3,3,1)nonyl])benzamide (3,4160
%) obtained 9.

(B) 4-Amino-5-chloro-2-methoxy-N-(
3'β-(9'-(4-fluorobenzyl)-9'-azabicyclo(3,3,1)nonyl])benzamide (E
IB) H2 The product (3,4,F) of the above reaction was converted into potassium hydroxide (1
, 3 g) along with ethanol (200117) and water (1
The mixture was heated to reflux for 2 hours in 0d) and then cooled and evaporated under reduced pressure. The residue was dissolved in dichloromethane and water. Drying and evaporation of the dichloromethane extract gave the crude product t-, which was recrystallized from ethyl acetate/gas oil to give the title compound (2.2 g, 71%).
I got it. Melting point 221-222C.

Actual example 2 (A) 4-acetylamino-5-chloro-2-methoxy-N-(3'β-(9'-(4-chlorobenzyl)
-9'-Azabicyclo[3,3,11-nonyl])benzamide (E2A) The title compound was prepared analogously to the preparation of the compound in Actual Example IA.

(B) 4-Amino-5-chloro-2-methoxy-N-(
31β-(9'-(4-chlorobenzyl-9'-azabicyclo(3,3,1)-nonyl))benzamide (E
2B) NH2 The title compound was prepared analogously to the preparation of the compound of Example IH (mp 208-210r).

Actual example 3 (A) 4-acetylamino-5-chloro-2-methoxy-N-(3'β-(s'-(4-methylbenzyl)-9
'-Azabicyclo(3,3,1) nonylbenzamide (E3A) 4-acetylamino5-chloro-2-methoxybenzoyl chloride (3,86,9) dichloromethane (10
0aj) and triethylamine (3M) in a medium temperature mixture of 3β
-Amino-9-(4-methylbenzyl)-9-azabicyclo-(3,3,1)nonane (3,6,!i') in dichloromethane (100w) was added at medium temperature. The reaction mixture was stirred at room temperature for 30 minutes. This was then diluted with water, basified with potassium carbonate, and extracted with dichloromethane. The crude product was obtained by evaporation of the dichloromethane extract.

This was chromatographed on alumina (neutral, secondary) using an ether/ethyl acetate mixture as eluent and 4-acetylamino-5-chloro-2-methoxy-
N-(3'β-(9'-(4-methylbenzyl)-91
-azabicyclol''3.3.11-nonyl])benzamide (4,5,lir, 65%).

(B) 4-Amino-5-chloro-2-methoxy-N-(
,3'β(9'-(4-methylbenzyl)-9'-azabicicF C3,3,1)-nonyl])benzamide (
E3B) HI The product (4,511) of the above reaction was converted into potassium hydroxide (1
, 5, 9) together with ethanol (10011J) and water (
The mixture was heated to reflux in a 1011 J) for 2 hours, then cooled and evaporated under reduced pressure. The residue was dissolved in dichloromethane and water. Dry the dichloromethane extract,
Evaporation gave the crude product, which was recrystallized from ethyl acetate/gas oil to give the title compound (3
, 07, 9, 75%) obtained. Melting point 215-216C.

Practical example 4 4-amino-5-bromo-2-methoxy-N-(3'β
-(9'-(4-fluorobenzyl)-9'-azabicyclo(3,3,1)-nonyl])benzamide (E4) H2 4-amino-5-bromo-2-methoxybenzoic acid 11(1
Ethyl chloroformate (0,5114) was added to a warm mixture of dichloromethane (som) and triethylamine (0,71117) and the reaction mixture was stirred at room temperature for 15 minutes. 3β-amino-9-(4'-fluorobenzyl)-9-azabicyclo(3,3,l]nonane(1,
A warm mixture of 24g of dichloromethane (tow) was added dropwise over 15 minutes and the reaction mixture was stirred at room temperature for 1 hour.
Then 10% sodium hydroxide solution was added and dichloromethane was separated.

Dry. The crude product was obtained by evaporating the dichloromethane extract, which was recrystallized from ethyl acetate to give 4-amino-5-prom-2-methoxy-N
-(3'β-(9'-(4-fluorobenzyl)-91
-Azabicyclo(3,3,1)-nonyl])benzamide (1,49,59%) was obtained. Melting point 221-213C
.

Practical example 5 (A) 4-7ceteramino-2-methoxy-N-(3'
β-(9'-(4-fluorobenzyl)-9'-azabicyclo(3,3,1)-nonyl])benzamide (E5
A) % 4-acetylamino-2-methoxybenzoic acid (x, oag) t4-acetylamino-2-methoxy-N-(3'β-[9'-(“4
-fluorobenzyl) -9'-azabicyclo(3,3
,1)-nonyl])benzand (1,21155%)
It was converted to Melting point 187-189C.

Purification was accomplished by chromatography on alumina (basic, secondary), eluting with an increasing gradient of dichloromethane and ethyl acetate.

(B) 4-amino-2-methoxy-N-(3'β-(9
'-(4-fluorobenzyl)-9'-7zabicyclo(
3,3,1]-nonyl])benzamide (E5B) NHs (EdaB) However, according to the procedure described for the preparation of the compound represented by 2EIB in Actual Example 1.

A compound of Formula 1 EA5 (70011 g) was converted to the title compound (500 af!) using a reflux time of 18 g#.

79%) K conversion. Melting point 192-193C.

Example 6 4-acetylamino-5-ria-2-methoxy-N-
(3'β-[9'-(4-fluorobenzyl)-9'-
Azabicyclo(3,3,1)-nonyl])benzamide (EIA) 4-acetylamino-2-methoxy-N-(3'β-(
9'-(4-fluorobenzyl)-91-azabicyclo(3,3,1)-nonyl])benzamide (E5A) (
40011) in acetic acid (5v) at a moderate temperature K.

A solution of chlorine (70iv) in acetic acid (1,5IEj) was added dropwise with stirring. After 30 minutes, the solution was poured onto ice, basified with potassium carbonate, and extracted with ethyl acetate.

The crude product was obtained by drying (KICOm)@evaporation of the ethyl acetate extract, which was recrystallized from ethyl acetate/@oil to give the title compound (270 da%63%). Melting point 168-169c.

Actual example 7 4-amino-5-chloro-2-methoxy-N-(3'β
-(9'-(4-fluorobenzyl)-9'-azabicyclo(3,3,1)-nonyl])benzamide (EIB
) 4-Amino-5-chloro-2-methoxy-N-(3'β
-(9'-(4-fluorobenzyl)-9'-azabicyclo(3,3,1)-nonyl])benzamide was added to ethanol, and Raney nickel was added dropwise. Hydrogenation was continued until theoretical hydrogen uptake had taken place. The catalyst was removed by filtration and the P solution was evaporated. The title compound was obtained by recrystallizing the residue from ethyl acetate/light oil.

Pharmacological data The results of the table below are standard tests. Figure 3 is illustrative of the antipsychotic activity of nine compounds of the present invention as demonstrated by inhibition of apomorphine-induced climbing in mice.

Suppression of Apomorphine-Induced Climbing in Mice
tin, J, and Schwartz J, C, (1
976L Psychopharmacology.

50.1-6.

Mice were given a dose of 1 da/immediately apoL rufuin;
For example, when placed in an inverted wire cage, they have been observed climbing around the walls. This behavioral phenomenon is caused by the nucleus accumbens.
This is thought to be the result of stimulation of post-synaraptic dopamine (D, A,) receptors in ). Apomorphine-induced inhibition of climbing is therefore postsynalapsial in the constellation A.
This is indicative of receptor blockade.

Each group of 10 male CDI mice weighing 25-30p was treated with different doses of the test compound or vehicle at an appropriate time before subcutaneous administration of a submaximal dose of apomorphine (1 da/hr). Pretreated by oral administration at i intervals.

Immediately after the apomorphine injection, mice were placed in all-mesh climbing cages J, and their climbing behavior 10 and 20 minutes after apomorphine administration was scored as shown below.

4 cocage on the floor =:=0 Forepaws on the cage wall; 1 4 cocage on the wall = 2 The previous score was calculated for each mouse group and expressed as climbing inhibition rate.

EDIIO and confidence limits are Lltchfield and
d Calculated according to Wilcoxon's method. Here, ED50 is the dose that produced a 50% inhibition rate of apomorphine-induced climbing.

The table below shows the dose for 50% inhibition when administered orally 4 hours after administration of the drug.

No toxic effects were observed in the studies reported above.

Patent attorney Masamitsu Akizawa and one other personContinued from page 1 Priority claim @ July 7, 1982 ■ United Kingdom (6B
)■19721 (h 1111
Showa, October 7 #s Patent Office Officials 1, Indication of the case, Request for the display of the case, Showa Tafu No. 17λIfg B, No. 3, Relationship with the person making the amendment.

Claims (1)

Claims: (13 Formula (1) where X is methoxy or ethoxy, Y is amino or tfct-8 alkanoylamino, 2 is hydrogen, chloro or bromo, and R1 is methyl ,
A compound represented by chlorot7'tFifluor) or a pharmaceutically suitable salt or solvent thereof. (2) The compound according to claim (1), wherein X is methoxy. (3) The compound according to claim E (1) or (2), characterized in that Y is amino. (4) 1 that z is Kroll! /# The compound according to any one of claims E(1) to (3), which is defined as a mold. (5) 4-amino-5-chloro-2-methoxy-N-3
'β-[9'-(4-methylbenzyl)-9'-azabicyclo-(3,3,1)-nonyl])benzami
Do 0 4-amino-5-chloro-2-methoxy-N-(3'β
-[9'-(4-chlorobenzyl)-91-azabicyclo-[3,3,1]-nonyl])penzaide;4-azuno5-chloro-2-methoxy-N-(3'β
-[9'-(4-fluorobenzyl)29'-azabicyclo-[3,3,1]-nonyl])benzado:4-amino-5-bromo-2-methoxy-N-(3'β
−[”9′ −(4-fluorobenzyl), −9′=−
Azabicyclo-(3,3,1)-nonyl])penzuabad; 4-acetylamino-5-chloro-2-methoxy-N-
(3'β-(9'-(4-fluorobenzyl)-9'
-azabicyclo[3,3,1]nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-
(3'β-("9'-(4-chlorobenzyl)-9
'-Azabicyclor3.3.1)nonyl])benzamide; 4-acetylamino-5-chloro-2-methoxy-N-
(3'β-("9'-(4-methylbenzyl)-9
'-azabicyclo[3,3,11nonyl])benzamide;4-acetylamino-2-methoxy-N-(3'β-(
9'-(4-fluorobenzyl)-9'-azabicyclo-[3,3,11nonyl])benzamide;4-amino-2-methoxy-N-(3'β-[9'-(4-fluorobenzyl) The compound according to claim E(1), which is a pharmaceutically suitable salt or solvate of (olbenzyl) -9'-azabicyclo(3,3,1)nonyl])benzamide or Soera. (6) 4-azuno-5-chloro-2-methoxy-N-(
3'β-[9'-(4-fluorobenzyl)-9'-azabicyclo['3.3.1)-nonyl])benzamide or a pharmaceutically suitable salt or solvate thereof E (Compound according to item 51. (7) Percentage of Claims E) A pharmaceutical composition characterized by containing the compound according to any one of E (1) to (6) and a pharmaceutically suitable carrier. (8) Formula (厘) 2 (wherein, X and 2 have the same meaning as in claim O(1), and R1 is A compound represented by the formula (11) (wherein R3 is a protecting group, i9 is p-methylbenzyl, and p- chlorobenzyl or p-fluorobenzyl); when R3 is protected and is a 9() group, the protecting group is removed; when R3 is a protecting group, the protecting group is removed; Then, this oniamine is expressed by the formula (ff) (wherein Q-value is a leaving group and MFiCO19 is CHI
and R1 has the same meaning as in claim (1)), and M is CO. The corresponding N-benzyl compound is obtained by reducing the obtained 9N-benzoyl compound; if the R value is Y? !
1 If desired, the amino group may be converted into another CI-@alkanoylamino group and, if desired, form a pharmaceutically suitable salt or solvate thereof.t-Characterized by the formula ( A method for producing a pharmaceutically suitable salt or solvate of the compound represented by 1). (9) Formula (X group night (wherein, chlorinated or brominated, and R3' is hydrogen or R3 as defined in claim (8);
When R is a protected amino group, the protecting group is removed; R3' is 83; When R3' is hydrogen, the compound represented by 2) is obtained by removing the protecting group, and in formula 1, 83' is hydrogen; when R3' is hydrogen, this Onia 2, as claimed in the patent React with a compound represented by formula (■) as defined in section (8), and when M is CO,
The resulting 9N-benzoyl compound was reduced to [the corresponding N-
A benzyl compound is obtained; when R1 is Y, the amino group or the C1-6 alkanoyl atono group is converted into another, if desired, and a pharmaceutically suitable salt thereof is obtained. A method for producing a compound represented by formula (1), wherein 2 is chlorine and 9 is bromine, or a pharmaceutically suitable salt or solvate thereof, which forms a solvate. 11 Formula (X set (wherein, When R3' is 83 and is a protecting group, the protecting group is removed to reduce the compound represented by the formula (■), in which R3' is obtain a compound that is hydrogen; R3'
is hydrogen, this oniamine is reacted with a compound represented by the formula (ff) as defined in claim (8), and when M is CO, the obtained The corresponding N-benzyl compound is obtained by reducing the N-benzoyl compound; if desired, converting the oa-amino group to a C1-6 alkanoyl group; and
A process for producing a compound of formula (T) or a pharmaceutically suitable salt or solvate thereof, which comprises forming a pharmaceutically suitable salt or solvate thereof, if desired. Formula 09 (Xff) (wherein, Hofmann decomposition is performed on the compound represented by ); Rsl is 8
3 and is a protecting group, it is represented by formula (XIV) by removing the protecting group and in formula 1. A compound in which flml is hydrogen is obtained: when 83' is hydrogen, the oniamine is reacted with a compound of formula (mV) as may be defined in claim O(8): and M is CO, the resulting 9N-benzoyl compound is reduced to give the corresponding N-benzyl compound, converting the oa-amino group to a C1-6 alkanoyl-ζ group, if desired, and A method for producing a compound represented by formula (1) or a pharmaceutically suitable salt or solvate thereof, which comprises preparing a pharmaceutically suitable salt or solvate thereof. 03 Formula (XV) 1 (wherein 2 has the same meaning as in claim E(1), [1 has the same meaning as in Claim E(8)) , and g31 has the same meaning as in claim E(9)); When R1 is protected and is a 9-amino group, the protecting group is removed; R3 ' is R3
and when this is a protecting group, the protecting group is removed to obtain a compound represented by formula (XIV) in which R3' is hydrogen, and when Rs' is hydrogen, this oniamine is M
is CO, the resulting 7′tN-benzoyl compound is reduced to give the corresponding N-benzyl compound, and R snow becomes Y
If desired, the amino radical is characterized in that it converts the C1-6 alkanoylamino group into another and, if desired, forms a pharmaceutically suitable salt or solvate thereof. A method for producing a compound represented by formula (I) or a pharmaceutically suitable salt or solvate thereof. αS % A patent in which R3 in claim O(8) and Rs' in claims O(9) to αi are p-methylbenzyl, p-chlorobenzyl, and 9 is p-fluorobenzyl. A method according to any one of claims (8) to Q3. I Antipsychotically effective amount of Claim O(1)
A compound according to any one of items 1 to 3) or a pharmaceutically suitable salt or solvate thereof. Alternatively, the method includes administering the pharmaceutical composition according to claim (4) to a mammal suffering from mental illness. Methods for treating psychosis in mammals. -Formula <xvr> 8 (In the formula, R71j methoxy, 9 is ethoxy, and R8
is nitro or aminocarbonyl, and R9 is hydrogen, chloro or bromo. Or R7 is hydroxy, R8 is amino or Ch-s alkanoylamino, and R is hydrogen, chloro or bromo, and MFiCH! or CO, and has the same meaning as in claim E(1) of the Rstf patent. αe Formula (1) where %Xa amino or Cl-6 alkanoylamino, and Y is hydrogen, or X and Y together with the carbon atom to which they are attached are an oximiimino group, and RtFi A compound represented by the following claim (having the same meaning as in Item 11): αη A compound represented by the formula (Vl) (wherein R3 is p-fluorobenzyl and h).