JPH0556345B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to antipsychotic drugs containing carboxamides, particularly N-(piperidinyl-alkyl)-carboxamides and salts thereof.

The invention particularly relates to the following general formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar ₁ represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar ₂ represents a phenyl group or a phenyl group substituted with halogen, provided that Ar ₁
N-lower alkylamino as a substituent of -
The present invention relates to an N-(piperidinyl-alkyl)-carboxamide, or a salt thereof, and a psychotropic drug containing the same.

The phenylene radical Ar ₁ is a phenylene further mono- or polysubstituted in addition to the radical R and the CO (carbonyl) group, in particular 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.

The pyridinylene group Ar ₁ is a pyridylene further substituted in one or more positions, in particular a pyridylene whose carbamoyl group is bonded to the 3-position of the pyridylene ring and the group R is bonded to its 2-position, e.g. 2,3
-, 3,2-, 2,4-, 2,5-, 2,6-,
Represents 3,4- or 3,5-pyridylene.
In the phenylene to pyridylene groups, preferably a carbamoyl group is bonded to the C atom adjacent to the group R.

Examples of further substituents of the aforementioned phenylene or pyridylene groups include lower alkyl, lower alkoxy, cyano, carbamoyl unsubstituted or mono- or disubstituted by lower alkyl, monosubstituted by substituted alkyl. amino, sulfamoyl or sulfinyl, unsubstituted or mono- or di-substituted by lower alkyl, halo-lower alkyl, lower alkoxycarbonyl. 1 by lower alkyl
Examples of substituted or disubstituted carbamoyl or sulfamoyl include N-lower alkyl- or N,N-dilower alkylcarbamoyl, N-lower alkyl- or N,N-dilower alkylsulfamoyl.

An alkylene radical alk in which both N atoms are separated by at least 2 C atoms is an alkylene group alk in which both N atoms are separated by at least 2 C atoms, such as 2 to 7, especially 2 or 3 C atoms. It is an alkylene having a C atom.

Various terms used in this invention have the following meanings unless otherwise defined.

The expression "lower" means that the organic radical or compound in question preferably has no more than 7, especially no more than 4 carbon atoms.

Halogen means in particular halogens with atomic number up to 35, such as fluorine, chlorine or bromine or iodine.

Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy,
n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and further,
Also meant are the corresponding pentyloxy, hexyloxy and heptyloxy groups.

Lower alkyl is, for example, methyl, ethyl, n
-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also the corresponding pentyl and heptyl groups.

Halo-lower alkyl is, for example, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl.

Lower alkoxycarbonyl is, for example, methoxy-, ethoxy-, propyloxy- or pivalyloxy-carbonyl.

N-lower alkyl-carbamoyl is, for example,
N-methyl-, N-ethyl-, N-(n-propyl)- or N-isopropyl-carbamoyl; N,N-dilower alkyl-carbamoyl is, for example, N,N-dimethyl- or N,N
-Means diethyl-carbamoyl.

N-Lower alkyl-amino is, for example, N-methyl-, N-ethyl-, N-(n-propyl)- or N-isopropyl-amino.

N-Lower alkyl-sulfamoyl is, for example, N-methyl- or N-ethylsulfamoyl and N,N-di-lower alkyl-sulfamoyl is, for example, N,N-dimethyl- or N,N-diethyl- It is sulfamoyl.

Lower alkanesulfinyl or -sulfonyl is, for example, methane-, ethane-, n-propane- or isopropane-sulfinyl or -sulfonyl.

2- or 3-membered alkylene having 2 to 7, especially 2 or 3 C atoms is, for example,
Ethylene, 1,3-propylene, 1,2-propylene or 2-methyl-1,2-propylene.

Salts of compounds of formula () are especially pharmaceutically acceptable salts. A compound of formula () can, for example, form an acid addition salt due to its one or more basic groups. Acid addition salts include, for example, strong inorganic acids (e.g. mineral acids such as sulfuric acid, phosphoric acid or hydrohalic acids), strong organic acids (e.g. lower alkane carboxylic acids such as acetic acid, optionally unsaturated dicarboxylic acids, For example, oxalic acid, malonic acid,
Oxycarboxylic acids such as maleic or fumaric acid, tartaric or citric acid, aryl (aromatic) carboxylic acids such as benzoic acid). Similarly, to generate acid addition salts,
Sulfonic acids such as lower alkanesulfonic acids such as methanesulfonic acid or optionally substituted benzenesulfonic acids (eg p-toluenesulfonic acid) are also suitable. Salts which are not suitable for pharmaceutical use are also included in the invention, since they can be used, for example, in the isolation or production of the corresponding free compounds of formula () and their pharmaceutically usable salts.

The compounds according to the invention may also be in the form of structural isomers. For example, when a compound of formula () has a C atom exhibiting chirality, ie an asymmetric carbon atom, for example when X in formula () represents free hydroxymethylene, the compound according to the invention
For example, it may be in the form of a pure enantiomer or a mixture of enantiomers (e.g. a ceramicompound), or in the form of a diastereomer or a mixture of diastereomers if at least one center exhibiting chirality or asymmetric center is present. It's okay to be hot.

The compounds of formula () and their pharmaceutically usable salts can be used, for example, as medicaments such as antipsychotics, or in prophylactic or therapeutic treatments of the human and animal bodies. That is, the expression ()
The compounds possess particularly useful pharmacological properties. These exhibit particularly excellent psychosis-healing effects. As an example, a compound of formula () is B.
Brain Research 123 , 89−111 by Costall et al.
(1977), about 1
When administered intraperitoneally at doses of mg/Kg or higher, it exhibits antagonizing effects on stereotypy in rats induced by amphetamine.

PC Waldmeier, Experientia 36 , 1092-4.
(1980) using the test device of about 0.1 to about 100 mg/
Experiments in which the active substance was administered intraperitoneally to rats in a dose range of Kg showed that the compound of formula () has excellent antidopamine activity. This is confirmed by the rate of production of metabolites of the neurotransmitter dopamine (DA). That is D.A.
This is because increased conversion can be seen as an indicator of dopamine receptor blocking.

DA-receptor blocking by the compound of formula () is shown at [ ³ H] in the rat ammonium angle.
Direct confirmation is also provided by in vivo inhibition of spiperone binding. S. Bischoff et al., European J.
The radiation receptor test by Pharmacol., 68, 305-315 (1980) revealed that the
Excellent dopamine receptor inhibiting effect was confirmed by intraperitoneal administration at a dose of about 100 mg/Kg.

Correspondingly, compounds of formula () and salts thereof, for example, due to their strong antidopamine activity,
For example, it can be used as a psychotic drug, particularly due to its action on the dopamine system. It is particularly advantageous that little or no extrapyramidal side effects are observed when using compounds of formula ().

The uses of the compounds of formula () include, in addition to therapeutic and prophylactic uses, also the industrial adaptation of the active substances.

The present invention particularly applies to compounds of formula () (in formula (), R represents a lower alkoxy group or a halogen atom, and when Ar ₁ represents a phenylene group,
It is unsubstituted or mono- or polysubstituted by halo-lower alkyl, halogen, lower alkoxy, cyano, carbamoyl, N-lower alkyl-amino, sulfamoyl and/or N,N-di-lower alkyl-sulfamoyl. and when Ar ₁ represents a pyridinylene group, it is mono- or polysubstituted with lower alkoxy and/or halogen; alk represents an ethylene group or a 1,3-propylene group, and X represents a carbonyl group or represents a hydroxymethylene group,
Ar ₂ represents an unsubstituted or halogen-substituted phenyl group) and salts thereof, as well as psychotropic drugs containing the same.

The present invention particularly relates to compounds of formula () (in formula (), R represents a lower alkoxy group, and Ar ₁
is unsubstituted or halo-lower alkyl,
alk represents a phenylene group mono- or polysubstituted by halogen, lower alkoxy, cyano, carbamoyl, N-lower alkyl-amino, sulfamoyl and/or N,N-di-lower alkyl-sulfamoyl; alk is ethylene or 1,3 - represents _a propylene group; .

The present invention particularly relates to compounds of formula () (formula ()
in which R represents lower alkoxy, in particular lower alkoxy with up to 4 C atoms (e.g. methoxy) or halogen, in particular halogen with atomic number up to 35 (e.g. fluorine), and Ar ₁ is substituted. or halo-lower alkyl, especially halo-lower alkyl with an atomic number of up to 35 and a number of C atoms of up to 4 (e.g. trifluoromethyl),
Halogen, especially halogen with atomic number up to 35 (e.g. bromine), lower alkoxy, especially lower alkoxy with up to 4 C atoms (e.g. methoxy), cyano, carbamoyl, lower alkylamino, especially 4 Lower alkylamino (e.g. methylamino) having C atoms of Sulfamoyl (e.g. N,N-dimethyl-sulfamoyl)
or, on the other hand, R represents lower alkoxy, in particular lower alkoxy with up to 4 C atoms (e.g. methoxy);
Ar ₁ is unsubstituted or lower alkoxy,
In particular, it represents pyridylene substituted by lower alkoxy (e.g. methoxy) having up to 4 C atoms, in particular 3,2-pyridylene, alk represents an ethylene or 1,3-propylene radical, X
represents a carbonyl group or a hydroxymethylene group, and Ar ₂ represents a halogen, in particular phenyl substituted by a halogen having an atomic number of 35 or less (eg, fluorine)) and salts thereof.

The present invention particularly relates to compounds of formula () (formula ()
in which R is methoxy, for example 4
represents lower alkoxy having up to 4 C atoms, Ar ₁ is unsubstituted or halo-lower alkyl, e.g. halogens with an atomic number of up to 35 such as chlorine or bromine, lower alkoxy, e.g. lower alkoxy with up to 4 C atoms such as methoxy, cyano, carbamoyl, N-lower alkylamino, e.g. methylamino N-lower alkylamino, sulfamoyl and/or N with up to 4 C atoms, such as
N-di-lower alkyl-sulfamoyl, further substituted in one or more positions (-substituted or represents a phenyl group (substituted),
alk represents an ethylene or 1,3-propylene group, X represents a carbonyl group or a hydroxymethylene group, and Af ₂ represents a phenyl group substituted with a halogen, for example, a halogen having an atomic number of 35 or less such as fluorine. ) and a salt thereof.

The present invention relates to compounds of the formula () (in the formula (), the group R-Ar ₁ is of the formula: (wherein, on the one hand, Ra is lower alkoxy (e.g. methoxy) having up to 4 carbon atoms)
Rb and Re represent hydrogen; Rc represents a lower alkylamino having up to 4 carbon atoms (e.g. methylamino), and Rd represents a halogen having an atomic number of up to 35 (e.g. chlorine ), or Rc represents hydrogen or a halogen with an atomic number below 35 (e.g. chlorine) and Rd represents cyano; or on the other hand, Ra, Rd and Re
represents hydrogen, R represents a halogen having an atomic number of up to 35 (e.g. bromine), and R represents a group R, in which R represents a lower alkoxy having up to 4 carbon atoms (e.g. methoxy); and each In the case of , _alk represents an ethylene group; Provide for medicine.

The present invention particularly provides compounds of formula () in which the group R-Ar ₁ is of formula b (wherein one of Ra and Rb represents hydrogen or a halogen having an atomic number of 35 or less (for example, bromine)). , the other represents a hydrogen atom,
Rc represents a group R that is a halogen (e.g., fluorine) with an atomic number of 35 or less; Rd and Re each represent hydrogen; alk represents an ethylene group; X represents a carbonyl group; and Ar ₂ represents 4 - represents a fluorophenyl group)) and a salt thereof.

The invention particularly relates to the compounds shown in the Examples, their salts and isomers.

Compounds having the formula () and salts thereof are, for example, a) formula R-Ar ₁ -X ₁ (a) (in the above formula, X ₁ is carboxy or a (reactive) carboxy mechanically converted to be reactive) ), the formula or a salt thereof, or b) Formula as well as (In the above formula, X ₂ represents hydrogen, one of the groups X ₃ and X ₄ represents hydrogen,
The other represents a group having the formula -alk-X ₅ , where X ₅ represents a reactive esterified hydroxy group), or alk
To prepare compounds of formula () representing a 2- or 3-membered alkylene with 2 to 7 C atoms, X ₂ , X ₃ commonly represent alk', alk' being 2 to 7
represents a 2- or 3-membered alkylene having C atoms, and X ₄ represents hydrogen;
b) The compound or its salt is subjected to intermolecular condensation, or the compound of formula (in the above formula, X ₅ represents a reactive esterified hydroxy), or c) alk has 2 to 7 C atoms and both N-
To prepare compounds of formula () representing an alkylene group whose atoms are separated by two or three C atoms, the formula (wherein alk' represents an alkylene group having 2 to 7 C atoms and separating the C and N atoms by 2 or 3 C atoms) or d) with a compound having the formula or a salt thereof (in the above formula, X ₇ represents a group that can be converted into R), converting X ₇ to R and, if desired, converting the compound obtained according to the method of the present invention or another method. converting into another compound according to the invention and/or converting the salt obtained according to the process according to the invention into the free compound or another salt; and/or
By converting the compound having salt-forming ability obtained according to the method of the present invention into a salt and/or separating the isomer mixture obtained according to the method of the present invention into separate isomers, It is manufactured by a known method.

Process form a) Reactive, functionally modified carboxy X ₁
represents, for example, an esterified, in particular reactive esterified carboxy, anhydrized carboxy or amidated carboxy.

Examples of esterified carboxy include optionally substituted lower alkoxycarbonyl (e.g. ethoxycarbonyl), in particular reactive esterified carboxy such as optionally lower alkoxy, or to carbamoyl which may be substituted. Thus further activated vinyloxycarbonyl (e.g. 1-lower alkoxyvinyloxycarbonyl such as 1-ethoxyvinyloxycarbonyl or 2-(N-ethylcarbamoyl)-vinyloxycarbonyl)
-(N-lower alkyl-carbamoyl), phenoxycarbonyl or thiophenoxycarbonyl substituted if necessary, for example by nitro, halogen, lower alkanesulfonyl or phenylazo (for example 4-nitro-, 2,4 , 5-trichloro-, pentachloro-, 4-methanesulfonyl-, 4-phenylazo-phenoxycarbonyl,
thiophenoxy- or 4-nitrothiophenoxycarbonyl), as well as similarly activated, e.g. substituted by cyano, and substituted by carboxy, which may also be esterified.
Methoxycarbonyl, especially cyanomethoxycarbonyl. Reactive esterified carboxy is
1,1- or 1,3-disubstituted 2-isoureidocarbonyl, e.g. , 1,1-diethyl-, 1,1-diphenyl- or 1,1-dibenzyl-2-isoureidocarbonyl), 1,3-dicycloalkyl-for example 1,3-dicyclohexyl-2-isoureido-carbonyl, N-alkyleneaminooxycarbonyl, e.g. N-piperidinyl-
It can be oxycarbonyl as well as N-imido-oxycarbonyl, such as N-succinimido-oxy- or N-phthalimido-oxy-carbonyl.

Examples of anhydride carboxy are lower alkoxycarbonyloxycarbonyl, optionally with branching (e.g. ethoxy- or isobutyloxycarbonyl), halocarbonyl (e.g.
chlorocarbonyl), azidocarbonyl, halophosphoryloxycarbonyl (e.g. dichlorophosphoryloxycarbonyl), lower alkanoyloxycarbonyl which may be substituted by halogen or aryl (e.g. pivaloyloxy, trifluoroacetyloxy- or phenylacetoxycarbonyl) ). The dehydrated (anhydrized) carboxy may also be a symmetrically anhydrified carboxy having the formula R-Ar ₁ -CO-O-CO-.

An example of a reactive amidated carboxy is 1-imidazolyl- or 1-pyrazolylcarbonyl (eg 3,5-dimethyl-pyrazolylcarbonyl), optionally substituted, for example by lower alkyl.

The condensation (N-acylation) according to the process of the invention is carried out in a manner known per se, if necessary, in particular in the presence of a basic condensing agent. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates,
triphenyl methylide, di-lower alkylamide,
aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines,
There are basic heterocyclic compounds, ammonium hydroxide, and carbocyclic amines. Particularly preferred examples include sodium hydroxide, sodium hydride, sodium amide, potassium tertiary butyrate, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-
(aminopropyl)-amide, potassium-bis-
(trimethylsilyl)-amide, dimethylaminonaphthalene, di- or triethylamine, ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyl-trimethyl-hydroxide
Ammonium, 1,5-diazabicyclo [4.3.0]
These include nonene-5 (DBN) as well as 1,8-diaza-bicyclo[5.4.0]undecene-7 (DBU), phosphines (eg triphenylphosphine), halosilanes (eg tetrachlorosilane).
When X ₁ represents carboxy, the corresponding ammonium salt is first formed, which can be treated by heating or by using a suitable dehydrating agent, such as a carbodiimide (e.g.
N,N'-dilower alkyl-, such as N,N'-diethyl-, N,N'-diisopropyl- or N,N'-dicyclohexyl-carbodiimide);
or by treatment with N,N'-dicycloalkyl-carbodiimide, advantageously N-hydroxysuccinimide, 1-hydroxy-benzotriazole (optionally substituted with halogen, lower alkoxy or lower alkyl), N-hydroxy-
5-norbornene-2,3-dicarboxamide,
Alternatively, it can be dehydrated with addition of N,N-carbonyldiimidazole. Intermediately, for example, the corresponding 1-isoureido carbonyl compounds can also be formed with carbodiimides. In addition, as a hydrophilic condensing agent, N-ethoxycarbonyl-2-
Ethoxy-1,2-dihydroquinoline, phosphoryl cyanamide or -azide (e.g. diethylphosphoryl cyanamide or diphenylphosphoryl azide), triphenylphosphine-disulfide or 1-lower alkyl-2-halo-piperidinium-halide (e.g. , 1-methyl-2-chloro-piperidinium diodide) may also be used.

N-acylation is carried out, for example, in the absence, usually in the presence, of a suitable solvent, diluent or corresponding mixture, for example from about -20°C to about 150°C, preferably from about 0°C to about 100°C. or at room temperature, if necessary in a closed container and if necessary under pressure and/or in an inert gas atmosphere, in a manner known per se.

The starting materials used in this process variant a) may be currently known substances and may also be prepared by methods known per se.

A compound having the formula (a) in which X ₁ is
In order to prepare optionally substituted lower alkoxycarbonyl), the free acid (X ₁ represents carbonyl) or an acid anhydride (X ₁ represents e.g. halocarbonyl) is usually used as a starting material. This is then reacted, for example, with the corresponding alcohol, if necessary in reactive form, such as a lower alkyl halide. The preparation of compounds having the formula (a) (in which X ₁ represents vinyloxycarbonyl, optionally further activated) can be produced, for example, by reaction of a lower alkyl ester with vinyl acetate (activated vinyl ester process); 1, according to the free acid of the compound of formula (a) and a lower alkoxyacetylene (e.g., ethoxyacetylene method) or, for example, the Woodward method.
This can be accomplished by reaction with 2-oxazolium salts. A compound of formula (a) containing an optionally substituted phenoxy- or thiophenoxycarbonyl is prepared by reacting it with the corresponding (thio-)phenol starting from the free acid, for example by the carbodiimide method. It can be manufactured by Similarly, starting from the free acid of formula (a), this can be reacted, for example, with a haloacetonitrile (e.g. chloroacetonitrile) (cyanomethyl ester method) or with a carbodiimide or cyanamide (carbodiimide or cyanamide method). Compounds of formula (a), in which X ₁ represents activated methoxycarbonyl or 1,1- or 1,3-disubstituted 2-isoureidocarbonyl, are obtained. The N-alkyleneaminooxycarbonyl- or N-imido-oxycarbonyl compounds of formula (a) can be prepared, for example, from the corresponding N-hydroxy compound using the free acid of formula (a) by converting the activated N-hydroxy It can be carried out with carbodiimides according to the ester method. To produce a compound of formula (a) (X ₁ in the formula represents lower alkoxycarbonyloxycarbonyl, halophosphoryloxycarbonyl, or optionally substituted alkanoyloxycarbonyl, which may have a branch) , for example, a free acid of formula (a) may be used as a starting material, which free acid may be, for example,
Corresponding halides (e.g. optionally substituted lower alkyl carbonate halides) (mixed o-
(anhydrous carbonic acid method) or with a phosphoryloxyhalide (e.g. phosphoroxychloride method) or with an optionally substituted lower alkanoyl halide (mixed carboxylic acid halide method). The azide compound of formula (a) can be obtained, for example, by treating the corresponding hydrazide with nitric acid (azide method). A compound of formula (a) (wherein X is optionally substituted 1-imidazolyl-carbonyl or 1
-pyrazolyl-carbonyl), the free acid of formula (a) is reacted, for example with di-(1-imidazolyl)-carbonyl (imidazolide process) or the related hydrazide, for example with , 3-diketone (pyrazolide method).

The starting material of formula (b) (X represents a carbonyl group) can be, for example, a compound of formula _Ar2 -H(c) reacted with pyridine-4-carboxylic acid or a reactive derivative thereof in the same manner as in the Friedel-Crafts reaction. acylation in the presence of a Lewis acid. formula This obtained compound, denoted by the formula
Hal-alk-NH ₂ (e) (in the formula, Hal is halogen,
(for example, bromine) in the presence of a base to convert it into the corresponding compound of formula (b). Reducing the carbonyl group X to form a hydroxymethylene group can be achieved by formula (d) or (
Starting from the compound of b), for example with a suitable metal hydride, such as lithium aluminum hydride or sodium borohydride, and the reductive conversion of the carbonyl group via the oxymethyl group to the methylene group, For example, each can be carried out by catalytic hydrogenation in the presence of a hydrogenation catalyst.

In the compound of formula (b), the carbonyl group is
For example, by converting methylene groups by catalytic hydrogenation, the product compound with a halonitrile, such as chloroacetonitrile, is condensed in the presence of a base, such as ethyl-diisopropylamine, and then by catalytic hydrogenation, the cyano group The compound of formula (b) (in the formula, X represents a methylene group) can also be obtained by converting into an amino group.

Process form b) Reactive _esterified hydroxy , halosulfonyloxy (e.g. fluorosulfonyloxy), lower alkanesulfonyloxy optionally substituted by halogen (e.g. methane- or trifluoromethane-sulfonyloxy), cycloalkanesulfonyloxy (e.g. cyclohexane-sulfonyloxy), ), if necessary, e.g.
Benzenesulfonyloxy substituted by lower alkyl or halogen (e.g. p-brolphenyl- or p-toluenesulfonyloxy), optionally lower alkanoyloxy substituted by e.g. halogen (e.g. acetyl- or trifluoroacetyloxy) ) or optionally represents benzoyloxy substituted, for example by lower alkyl, lower alkoxy, halogen and/or nitro.

Condensation (N-alkylation) according to the method of the invention
is carried out in a manner known per se, if necessary in the presence of a base. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines. , basic heterocyclic compounds, ammonium hydroxide as well as carbocyclic amines may be used. Examples of bases include sodium hydroxide, sodium hydride, sodium amide, potassium tert-butyrate, potassium carbonate, lithium-triphenylmethylide, lithium-triphenylmethylide, lithium-diisopropylamide, potassium-3- (aminopropyl)-
Amide, potassium-bis-(trimethylsilyl)-
Amide, dimethylaminonaphthalene, diethylamine, triethylamine, ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5
-Diaza-bicyclo-[4.3.0]nonene-5
(DBN), 1,8-diaza-bicyclo[5.4.0]undecene-7 (DBU), phosphine (eg, triphenylphosphine), and halogensilane (eg, tetrachlorosilane).

The N-alkylation can be carried out, for example, in the absence of suitable solvents or diluents or corresponding mixtures, or
usually in its presence, at room temperature or under heat, for example at a temperature of about 0°C to about 200°C, preferably at a temperature of room temperature to about 150°C, if necessary in a closed container,
If necessary, it is also carried out under pressure and/or under an inert gas.

The starting materials used in this process configuration may be known or may be prepared according to methods known per se.

For example, the starting material of formula (a) (wherein _X2 represents hydrogen and _X3 represents a group -alk- _X5 ) may be a carboxylic acid of formula R- _Ar1 -COOH (d) or its reactive Starting from an acid derivative, in particular a halogenated carboxylic acid, this can be prepared with the formula X ₅ -alk-NH ₂
Obtained by treatment with amine (e). The starting material of formula (a), in which X ₂ and X ₃ together represent alk', alk' represents a 2- or 3-membered alkylene having 2 to 7 C atoms, in particular ethylene, is As an example, obtained by N.acylation of the corresponding aziridine or azetidine with a compound of formula (a) or a reactive acid derivative thereof, for example in the presence of a base (eg triethylamine). The starting material of formula (a), in which X ₂ and X ₃ represent hydrogen, is the starting material of formula (d)
is obtained by reacting the corresponding compound of or a reactive derivative thereof with ammonia.

Starting material of formula (b) or a salt thereof (wherein X ₄
represents _{a group} -alk- first introducing an -alk-OH group, for example by treatment with ethylene oxide, propylene oxide or a compound of formula _X5 -alk-OH (formula f) in the presence of a base (e.g. triethylamine);
Next, the hydroxyl group of this group is subjected to reactive esterification.

Starting materials of formula (c) may, for example, have the formulas R-Ar ₁ -CO-NH-alk-NH ₂ (g) and is obtained by reacting the compound with cleavage of an equivalent amount of H-X ₅ in the presence of the aforementioned bases customary for N-alkylation, for example pyridine. Depending on the choice of reaction conditions, e.g. condensation conditions, N-alkylation can produce equivalent amounts of another H-X ₅
can directly lead as such to the corresponding target compound of formula ().

The compound of formula (g) or a salt thereof is the compound of formula (d)
or its reactive acid derivative with the formula H ₂ N-
It can be obtained by amidation under normal conditions with an excess of the compound alk- _NH2 (h). The compound of formula (i) may, by way of example, have the formula _CH2 - _CH2
-CO-Ar ₂ (j) in which X ₆ represents, for example, alkoxy, is reacted with ethylene oxide in the presence of a base catalyst, for example sodium amide, and then the ether is reacted with It can be produced by cleavage. Ether cleavage can be carried out, for example, with a Lewis acid such as boron trifluoride or a hydrohalic acid such as hydrobromic acid or hydroiodic acid. By selecting the hydrohalic acid used in excess, compounds of formula (i) are obtained in which X is a carbonyl group and X ₅ is a halogen. If desired, the carbonyl group may be reductively converted to a hydroxymethylene or methylene group by conventional methods.

Process form c) The reaction according to this process form is carried out by methods known per se, if necessary in the presence of a base. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, (alcoholates), carbonates, triphenylmethylide,
Di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines, basic heterocyclic compounds, ammonium hydroxide or carbocyclic amines may be used. Examples of bases include sodium hydroxide,
Sodium hydride, sodium amide, potassium tert-butyrate, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium-3-(aminopropyl)-amide,
-bis-(trimethylsilyl)-amide, dimethylaminonaphthalene, diethylamine, triethylamine, ethyldiisopropylamine, N-methyl-piperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4.3.0]nonene -5 (DBN), 1,8-diaza-bicyclo[5.4.0] undecene-7 (DBU),
phosphine (e.g. triphenylphosphine),
Halogen silane (e.g. tetrachlorosilane)
There is.

In the absence or usually in the presence of suitable solvents or diluents or corresponding mixtures thereof, under cooling or heating or at room temperature, for example about -
20℃ to about 200℃, preferably room temperature to about 150℃
temperature range, in a closed container if necessary,
The reaction is carried out in a manner known per se, optionally under pressure and/or under an inert gas atmosphere.

The starting materials used in this process configuration are known or can be prepared in a manner known per se.

That is, the starting material of formula (a) may be, for example, of formula R
-Ar ₁ -COOH (d), in particular a carboxylic acid or its reactive acid derivative, starting with an acid halide, which is converted to the formula X ₅ -alk-NH ₂ (c), where X ₅ is (Represents reactive esterified hydroxy)
and then the obtained formula (In the formula, X ₂ represents hydrogen, and X ₃ is a group −alk′−
A _carboxylic acid amide represented by
Obtained by treatment with triethylamine or ethyl-diisopropylamine.

Process form d) The group X ₇ convertible into R can, by way of example, be of the formula N ₂
A (wherein A is an anion of a strong protic acid,
represents the anion of a mineral or complex metal acid, such as, for example, chloride, perchlorate, sulfate, tetrafluoroborate or hexachloroantimonate; .

The substitution of the diazonium group X ₇ by hydroxy in compounds of formula () can be carried out in an aqueous medium analogous to "phenol enrichment", but the diazonium salt of formula () can be replaced with an aliphatic alcohol, especially , a lower alkanol leads to a compound of formula () in which R represents hydroxy etherified with an aliphatic alcohol.

The substitution of X ₇ with chlorine, bromine or iodine in the compound of formula () can be carried out, by way of example, by reaction with the corresponding halide, for example an alkali metal halide. In this case, the halide corresponding to the halogen atom is the anion A
It exists as.

For this reaction, for example, Cu() ions can be used as a catalyst according to the Sandmeyer reaction, copper powder according to the Gutzterman reaction, and Cu() ions according to the Kellner-Contaldei reaction. . In order to introduce fluorine into the corresponding compound of formula (), a diazonium salt of formula () is used as a starting material according to the Seeman reaction, and this is combined with hydroborofluoric acid or its salt, in particular an alkali metal It is reacted with a salt or, according to a variant of this reaction, with the corresponding pentafluorosilicate or hexafluorophosphate. The salt having the corresponding diazonium fluorine complex produced in this case can be thermally decomposed, especially in a dry state, to form a compound of the formula (2) (wherein R represents fluorine).

Substitution of the _group
It can be carried out in the temperature range from .degree. C. to 120.degree. C., if necessary in a closed container, by methods known per se.

To prepare the starting material of formula () (in which X ₇ represents an ionic group -N ₂ A), the formulas X ₈ -Ar ₁ -X ₁ (a) and (In the above formula, X ₁ has the above meaning,
X ₈ represents an amino group, if necessary advantageously protected by a readily cleavable acyl group. condensation and recleavage of any amino protecting groups that may be dependent. The expression obtained in this way In the compound represented by , the amino group can be converted into the corresponding ionic group X ₇ by diazotization in the conventional manner in the presence of an acid, for example with nitric acid or nitrite, as known per se. can.

Diazotization of the aromatic amino compound (b) and the obtained compound having formula () is then converted into a compound of formula () by directly removing the corresponding compound of formula () without isolating it. It is desirable to do so. However, in this method form the isolation may also be carried out analogously to the Schiemann reaction.

The group X ₇ convertible into R may represent an acyloxy group derived from an organic carboxylic acid, which may be, for example, a lower alkanoyloxy or aroyloxy substituted, if necessary, by halogen or aryl, e.g. , may represent optionally substituted benzoyloxy.

Corresponding compounds of formula () are converted into compounds of formula () in which R represents hydroxy, for example by hydrolysis or esterification in the presence of an acid or a base. In that case, the hydroxy groups esterified with aliphatic alcohols are
As long as Ar ₁ and Ar ₂ are substituents, they are correspondingly hydrolyzed or esterified at the same time.

Compounds of formula () (in which R represents hydroxy etherified by an aliphatic alcohol) is obtained.
In this case it is preferably operated in the presence of a base. Hydroxy groups esterified with organic carboxylic acids as substituents of aromatic groups Ar ₁ and Ar ₂ can be simultaneously converted into hydroxy groups etherified with aliphatic alcohols during the reaction. .

The group X ₇ which can be converted into R may represent a hydroxy group protected by a hydroxy protecting group which is widely described in the literature in this technical field,
These protecting groups include, for example, 1-aryl lower alkoxycarbonyloxy (e.g. benzyloxycarbonyloxy optionally substituted in the phenyl ring, e.g. by halogen), 1-aryl lower alkoxy (e.g. for example benzyloxy substituted in the phenyl moiety by, for example, halogen or lower alkoxy) or silyloxy (for example tri-lower alkylsilyloxy optionally substituted).
There is. Examples of corresponding preferred groups include benzyl-, 2- or 4-bromobenzyloxycarbonyloxy, benzyloxy, 3-bromo-,
2,6-dichloro- or 4-methoxybenzyloxy or trimethylsilyloxy.

These groups X ₇ can be converted into hydroxy R in methods known per se, for example by hydrolysis, acidolysis or reduction.

Hydrolytic cleavage of hydroxy protecting groups may be carried out, if necessary, in the presence of bases or acids that promote hydrolysis, such as, for example, alkali metal or alkaline earth metal hydroxides or carbonates; Further, as the acid, an organic or inorganic protonic acid is suitable.

The 1-aryl lower alkoxycarbonyloxy or silyloxy group is preferably converted to a hydroxyl group by hydrolysis.

For acidolysis, strong acids such as mineral acids (e.g. hydrohalic acid), perchloric acid, if necessary,
Optionally substituted lower alkane carboxylic acids or sulfonic acids (eg, optionally substituted benzenesulfonic acid) or mixtures of these acids are typically used.

Preferred acids include, for example, hydrofluoric acid,
Hydrobromic acid/glacial acetic acid or trifluoroacetic acid.

Examples of corresponding groups convertible to hydroxy R include 1-aryl lower alkoxycarbonyloxy or 1-aryl lower alkoxy.

These groups can be subjected to hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst, e.g. 1-aryl lower alkoxycarbonyloxy, in addition to reduction with a metal system consisting of a metal component and a hydrogen donating component, such as a sodium/ammonia system. Therefore, it can also be reductively converted to hydroxy.

These reactions are carried out in a manner known per se, at low or high temperatures, in the presence of solvents or diluents, if necessary, in a temperature range of about 50°C to about 150°C, in closed containers, and if necessary. For example, it can be carried out under an inert gas atmosphere.

Starting materials of formula (), in which X ₇ represents an acyloxy group or a protected hydroxy group, can be prepared by preparing a compound having the formula X ₇ -Ar ₁ -X ₁ (d) by the method shown in process mode a). Similarly, it can be obtained by condensation with a compound having formula (a).

Compounds according to the invention obtained according to the process according to the invention or other processes can be converted into further compounds according to the invention by methods known per se.

For example, in compounds of the invention having free hydroxy groups and/or hydroxymethylene groups,
Oxymethyl groups can be esterified with organic carboxylic acids, such as lower alkane carboxylic acids. This esterification can be carried out if necessary in the presence of an acid, for example a protic acid (for example a mineral acid or a sulfonic acid) or a Lewis acid (for example the corresponding halide of an element of main group 3 or a corresponding subgroup). , by treatment with the desired carboxylic acid or reactive derivative, for example an acid anhydride or a halide, in a manner known per se.

The esterification may be carried out in the presence of bases, such as alkali metal hydroxides or carbonates, amines or cyclic organic nitrogen-containing bases, or dehydrating agents, such as customary carbodiimides. Conversely, the hydroxy group in a group having an esterified hydroxy can also be liberated, for example, by solvolysis using a base catalyst.

These reactions are carried out in the presence or absence of a solvent or diluent, with cooling or heating if necessary, e.g.
Alternatively, it can be carried out under pressure, optionally in a closed container.

Compounds according to the invention containing hydroxy are
The etherification can be carried out by methods known per se. This etherification may be carried out, for example, with alcohols (eg, optionally substituted lower alkanols) or reactive esters thereof. Reactive esters of the desired alcohols include esters of strong organic or inorganic acids, such as the corresponding halides, sulfates, lower alkanesulfonates, optionally substituted benzenesulfonates (e.g. chlorides). , bromide, iodide, methanesulfonate, benzenesulfonate or p-toluenesulfonate).
Etherification may be carried out, for example, in the presence of a base, an alkali metal hydride, hydroxide or carbonate, or a basic amine. Conversely, strong acids, such as mineral acids (hydrohalic acids such as hydrobromic acid or hydroiodic acid, preferably present in the form of halogenated pyridines) or Lewis acids, such as those of the third main group or the corresponding The corresponding ethers, for example lower alkoxy compounds, can be decomposed by means of the halides of elements of the subgroups (halides of elements of the subgroups). These reactions are carried out under inert gas and/or pressure, in the absence or presence of a solvent or diluent, with cooling or heating if necessary, e.g., at temperatures from about -20°C to about 100°C. , if necessary, can be carried out in a closed container.

In compounds according to the invention having a hydroxy lower alkyl group, the hydroxy group can be converted to a halogen, for example chlorine, by treatment with a suitable halogenating agent, for example thionyl chloride.

When the aryl groups Ar ₁ and Ar ₂ have a cyano group as a substituent, this cyano group can be removed, for example, by hydrolysis, preferably under acidic or basic conditions, for example in the presence of an alkali metal hydroxide. ,
If desired, it can also be converted to a carbamoyl group in the presence of hydrogen peroxide in a water-alcoholic solvent. These reactions are carried out in the presence or absence of a solvent or diluent, with cooling or heating if necessary, e.g., in the temperature range of about 0°C to about 150°C, sometimes even higher. This can be carried out under inert gas and/or pressure, if necessary in a closed container.

In the compounds of the present invention, when Ar ₁ or Ar ₂ contains cyano as a substituent, these compounds can be treated with an alcohol (e.g., lower alcohol) in the presence of an acid (e.g., hydrochloric acid). For example, it can be converted to alkoxycarbonyl.

In compounds of formula () in which Ar ₁ or Ar ₂ has an esterified or amidated carboxy group as a substituent, this group can be removed, for example by hydrolysis, from an inorganic base, such as an alkali metal or alkaline earth In the presence of basic reagents such as metal hydroxides (e.g. sodium hydroxide, potassium hydroxide or calcium hydroxide) and in the presence of acidic reagents such as mineral acids, free carbonyl groups can be isolated. can be converted to .

In addition, in the compound of formula () (in which Ar ₁ or Ar ₂ has a carboxy group as a substituent), a suitable esterification agent, such as an acidic reagent (such as hydrochloric acid, trifluoroacetic acid or in the presence of organic and inorganic acids such as p-toluenesulfonic acid or Lewis acids such as zinc chloride) or hydrophilic condensing agents (e.g. carbodiimides such as N,N'-dichlorohexyl-carbodiimide). For example, a carboxy group can be converted to an esterified carboxy group by treatment with an alcohol such as a lower alkanol, or alternatively by treatment with a diazo reagent (eg, a diazo lower alkane such as diazomethane).
This esterified carboxy group is present in the compound of formula () (in the formula, Ar ₁ or Ar ₂ is in the form of an ammonium salt or a metal salt (for example, an alkali metal salt such as a sodium salt or a potassium salt)). reactive esters of alcohols (such as methyl chloride, ethyl chloride, methyl bromide, ethyl bromide, methyl iodide or ethyl iodide) lower alkyl halides)
or by treatment with an organic sulfonic acid ester (for example methanesulfonic acid- or p-toluenesulfonic acid methyl or -ethyl ester).

Compounds of formula () (in the formula, Ar ₁ or
Ar ₂ has an esterified carboxy group as a substituent) is a suitable esterifying agent, such as a basic reagent (sodium acetate, sodium methylate,
An alcohol (usually corresponding to that of the carboxy group to be esterified in the starting material) in the presence of an alkali metal lower alcoholate such as sodium ethylate, sodium tert-butyrate or sodium cyanide) or in the presence of a suitable acidic reagent. If necessary, the corresponding alcohol can be separated off by distillation, for example, to obtain the formula
can be converted into another ester compound. Starting material is the corresponding so-called activated ester having the formula (in which Ar ₁ or Ar ₂ carries an activated esterified carboxy group as a substituent as described below) (see below), and this It is also possible to convert them into other esters by treating them with alcohols, for example substituted alkanols.

Compound of formula () (in the formula, Ar ₁ or Ar ₂ has an amidated carboxy group as a substituent)
are also advantageously obtained from acid or ester compounds corresponding to the formula () in which Ar ₁ or Ar ₂ optionally carries an esterified carboxy group as a substituent. For example, a compound of formula () having a free carboxy group, e.g.
formamide, reacted with urea at elevated temperatures of 0.degree.
For example, by reacting with dimethylformamide at elevated temperature or with a suitable condensing agent, e.g. a carbodiimide such as N,N'-diethyl-carbodiimide, a phosphine (e.g. with bis-2-pyridyl-disulfide), e.g. triphenyl. By reacting with an amine in the presence of a phosphine, or a silane, e.g. trichlorosilane (e.g. together with pyridine), the corresponding amide compound of formula (), where Ar ₁ or Ar ₂ is an amidated carboxy group having as a substituent) can be produced. Furthermore, the corresponding ammonium salt,
For example, by treating with a dehydrating agent such as phosphorus pentoxide,
or also by reacting the corresponding alkali metal salt, e.g. the sodium salt, with an amine, preferably in the presence of a suitable condensing agent, e.g. In the formula, Ar ₁ or Ar ₂ has a carboxy group as a substituent which is present in the salt form).

In compounds of formula () in which the carboxy group has a carboxy group as an Ar ₁ or Ar ₂ substituent, the carboxy group can be removed from the mixed anhydride (e.g. by treatment with a thionyl halide such as thionyl chloride). anhydrides, including reactive derivatives such as acid halides (e.g. chlorides), or (halogen esters such as chloroformates, e.g. lower alkyl esters) salts, e.g. ammonium salts or alkali metal salts. or alternatively (by treatment with a suitable condensing agent, e.g.
activated esters (by treatment with the corresponding hydroxy compound in the presence of N,N'-dicyclohexyl-carbodiimide), e.g. cyan methyl ester, nitrophenyl ester (e.g. 4
-nitro-phenyl ester) or polyhalogen phenyl (eg pentachlorophenyl ester), respectively. This reactive derivative is then reacted with ammonia or an amine (in derivative form if necessary) to give an amide compound of formula (), where Ar ₁ or Ar ₂ carries an amidated carboxy group as a substituent. be able to. This compound is obtained both directly and via intermediates. That is, an activated ester of a compound of formula () having a carboxy group (e.g. 4-
A 1-imidazolyl carbonyl compound obtained by first reacting a nitrophenyl ester) with a 1-unsubstituted imidazole may be reacted with ammonia or an amine. Alternatively, other unactivated esters, such as lower alkyl esters, of the compound of formula () (in which Ar ₁ or Ar ₂ has as a substituent, e.g. lower alkoxycarbonyl) can be reacted with ammonia or an amine. You may let them.

In compounds according to the invention in which the radicals Ar ₁ or Ar ₂ carry a free amino, carbamoyl or sulfamoyl group, the respective amino group can be substituted mono- or disubstituted, as described above in connection with process mode b). It can be done. Similarly, the Lutzkart-Waltzha reaction (or Eschweiler)
Clarke reaction), using formic acid as a reducing agent, convert primary or secondary carbonyl compounds into
It is also possible to reductively alkylate primary amino groups.

In the compound of the present invention in which X represents a carbonyl group, a suitable hydride (a complex hydride may also be used) produced from an element of the first and third main groups of the periodic table.
For example, a carbonyl group can be converted to an oxymethyl group X by treatment and reduction with sodium borohydride or sodium cyanoborohydride. The oxymethyl group X itself can be reduced with hydrogen, for example, using a hydrogenation catalyst to form a methylene group.

In compounds according to the invention in which X represents a carbonyl group, this group is substituted with an alcohol such as a lower alkanol in the presence of an acid such as a mineral acid (e.g. sulfuric acid or hydrochloric acid) or a sulfonic acid (e.g. p-toluenesulfonic acid). or lower alkanediols, such as ethanol or glycols, and the acetalized carbonyl group X can be hydrolysed in turn with acids of the type mentioned above.

When the aromatic ring Ar ₁ is substituted with lower alkylthio, this can be oxidized in a conventional manner to form the corresponding lower alkanesulfinyl or -sulfonyl. Examples of suitable oxidizing agents to oxidize to the sulfoxide stage include inorganic peracids,
For example, mineral peracids (e.g. periodic acid or persulfuric acid), organic peracids such as the corresponding percarboxylic or persulfonic acids (e.g. performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid or p-Toluene persulfonic acid or a mixture of hydrogen peroxide and an acid, such as a mixture of hydrogen peroxide and acetic acid.

Oxidation is often carried out in the presence of a suitable catalyst;
Examples of acids suitable as catalysts in this case include optionally substituted carboxylic acids such as acetic acid or trifluoroacetic acid or oxides of transition metals such as oxides of elements of the subgroup (e.g. vanadium, molybdenum or There are various oxides of tungsten).
Oxidation is carried out under mild conditions, for example at temperatures of about -50°C to about +100°C.

The oxidation to the sulfone stage can be carried out in the presence of oxygen at correspondingly low temperatures using dinitrogen tetroxide as a catalyst, similar to the direct oxidation of lower alkylthio to lower alkanesulfonyl. However, in this case an excess amount of oxidizing agent is usually used.

When the aromatic ring Ar ₁ or Ar ₂ has a hydrogen atom as a substituent, this hydrogen atom can be exchanged with a halogen atom using a halogenating agent in a conventional manner, such as bromine, hypobromous acid, acyl hypobromite. acids or other organic bromine compounds such as N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridine perbromide, dioxane dibromide,
1,3-dibromer-5,5-dimethylhydantoin, brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one),
or, for example, halogenated hydrocarbons (e.g.
Chlorination is carried out with elemental chlorine in chloroform) while cooling to a temperature of, for example, about -10°C to about +10°C.

Also with cyano compounds such as alkali metal cyanides (e.g. potassium cyanide) or especially copper cyanide (), preferably from about 60°C to about 250°C.
aromatic rings, for example by exchanging a halogen atom (especially iodine or bromine) with a cyano group, by reaction under heating, in the presence or absence of a solvent or diluent, and preferably in an inert gas.
A cyano group can be introduced into Ar ₁ .

When the aromatic group Ar ₁ or Ar ₂ in the compounds of the invention has an amino group, a nitrite, e.g. By treatment with sodium nitrate, the amino group can be diazotized in a conventional manner. The abovementioned diazonium groups in the salt form thus obtained can be substituted by hydroxy groups in the presence of water, e.g. by analogous methods and analogous to phenol enrichment;
Treatment with the corresponding alcohol and substitution by an alkoxy group (with supply of energy) or substitution by a fluorine atom in analogy to the Siemann reaction for thermal decomposition of the corresponding diazonium tetrafluoroborate. Halogen elements such as chlorine, bromine, etc. can be prepared by first cooling to about 5°C and then heating from about 60°C to about 150°C, similar to the Sandmeyer reaction with the corresponding copper() salt. Alternatively, it can be substituted with iodine or a cyano group.

The compounds according to the invention contain an aryl group Ar ₁ or
If Ar ₂ carries a nitro group, this group can be reduced to an amino group in a manner known per se, for example by catalytic hydrogenation.

Further, the aromatic ring Ar ₁ or Ar ₂ can be alkylated with a lower alkanol, a lower alkyl halide, or a phosphoric acid lower alkyl ester in the presence of a Lewis acid (Friedel-
Crafts-alkylation reaction). In compounds of formula () in which the aromatic ring has bromine, bromine can be exchanged with lower alkyl by reacting with bromide of lower alkyl in the presence of an alkali metal.

When the aromatic ring has a hydrogen atom as a substituent,
This atom can be exchanged for an acyl group by methods known per se. Lewis acids such as aluminum chloride, antimony chloride ()
or by reaction of reactive acyl-functional derivatives such as halides or anhydrides of organic carboxylic acids in the presence of iron chloride (2), zinc chloride (2), or boron trifluoride. Crafts-acylation reaction (GAOlah, Friedel-Crafts
and Related Reactions, vol.1, Interscience,
New York, 1963-1965).
Acyl groups can be inserted.

If the compounds of formula () contain unsaturated groups, such as lower alkenyl or lower alkadienyl groups, these groups can be converted into saturated groups, as is known per se. For example, multiple bonds can be hydrogenated by performing catalytic hydrogenation in the presence of a hydrogenation catalyst. For this purpose, noble metals or their derivatives, such as oxides, such as nickel, Raney nickel, palladium, platinum oxide, are suitable, which may, if necessary, be deposited on a support material such as carbon or calcium carbonate. Hydrogenation may particularly be carried out at a pressure of 1 to about 100 atmospheres and a temperature of about -80°C to about 200°C, especially room temperature to about 100°C. Also preferably a solvent such as water,
The reaction is suitably carried out in a lower alkanol (eg ethanol, isopropanol or n-butanol), an ether (eg dioxane) or a lower alkane carboxylic acid (eg acetic acid).

The present invention provides, among other things, the methods illustrated in each example.

If the starting material has a basic center, for example, acid addition salts can also be formed, and starting materials with acidic groups form salts with bases, by way of example.

Depending on the choice of reaction conditions, the starting materials may be used in free form or as salts, and the compounds of the invention having salt-forming properties can be obtained both in free form and in salt form.

The acid addition salts obtained can thus be converted into the free compounds in a manner known per se, for example by treatment with a base (for example an alkali metal hydroxide) and with a suitable acid or derivative thereof. Each can be converted into another salt by treatment. The free compounds obtained which are salt-forming and basic can be converted into their salts, for example by treatment with acids or corresponding anion exchangers.

Since there is a close relationship between a salt-forming compound and a free form of a salt-forming compound, in the description of this specification, the expression free compound or salt refers to the corresponding salt. or free compounds are intended to be included according to the meaning and purpose of this invention. Salts which are unsuitable for pharmaceutical use are also encompassed by the aforementioned salts, since they can be used for the isolation or purification of the free compound and its pharmaceutically usable salt according to the invention.

The compounds according to the invention, including the salts of the corresponding salt-forming compounds, can also be obtained in the form of their hydrates, the crystals of which may, for example, contain the solvent used for crystallization.

Depending on the choice of the starting materials and the mode of operation, the novel compounds according to the invention can be obtained in the form of possible isomers or as mixtures thereof, and also in pure optically isomeric forms, e.g. according to the number of asymmetric carbon atoms. They may exist as isomers, such as enantiomers, or as isomeric mixtures, such as racemates, diastereomeric mixtures or racemic mixtures.

The obtained diastereomeric and racemic mixtures can be separated into pure isomers on the basis of the physicochemical differences of their components, for example by chromatography using adsorbents exhibiting chirality and/or by fractional distillation. It can be resolved by known methods into compounds, diastereomers or racemates. The racemates obtained can be further processed according to known methods, e.g. by recrystallization from optically active solvents, with the aid of microorganisms, e.g. via clathrates, using crown ethers exhibiting chirality. resolution with an insolubilizing enzyme (in this case, the enantiomers form a complex), or an optically active acid or an optically active carboxylic acid that forms a salt with a racemic base, or a reactive derivative thereof and a basic racemic target substance. reaction and separation of the diastereomeric mixture thus produced into individual diastereomers on the basis of their solubility differences, and then action of appropriate reagents to liberate the desired enantiomer. Conversion of stereomers into salts or esters resolves them into their optical antipodes. Preferably, the active enantiomer is isolated.

The invention provides for the use as starting materials of the compounds obtained as intermediates in the appropriate process steps for carrying out the subsequent steps or also for the use of derivatives or salts and/or their racemates or enantiomers, in particular producing under reaction conditions,
Embodiments of the method of the invention are also provided.

The process of the invention particularly employs starting materials that lead to the formation of the compounds listed above as particularly useful. Also included within the scope of the invention are new starting materials specifically developed for the preparation of the compounds according to the invention, for example their use as intermediates or pharmaceutically active substances, as well as processes for their preparation, in which R, AR ₁ ,
Symbols such as alk, X and _Ar2 have preferred meanings for each preferred group of compounds of formula ().

The dosage of the active substance (administered alone or together with customary carrier substances and auxiliary substances) depends on the species to be treated, its age, individual condition and the mode of administration. The individual dose, e.g. when administered orally to a person weighing about 70 Kg, is preferably from about 0.5 to
100mg or approximately 0.7-70mg range.

The invention further provides a process for the preparation of pharmaceutical preparations containing as active substance a compound of formula () or a pharmaceutically acceptable salt of these salt-forming compounds.

The pharmaceutical preparations according to the invention are intended for enteral administration, e.g. oral or rectal administration, as well as parenteral administration to warm-blooded animals, in particular in corresponding dosage unit forms for oral administration, e.g. Dragees, tablets or capsules preferably contain from about 1 to about 100 mg of the compound of formula () or a pharmaceutically acceptable salt thereof, particularly from about 1 to about 25 mg.
mg, together with a pharmaceutically acceptable carrier material.

Preferred carrier materials are in particular fillers, such as sugars (for example lactose, sutucarose, mannite or sorbitol), cellulose preparations and/or calcium phosphates (for example calcium triphosphate or calcium hydrogen phosphate), binders,
For example, starch paste (corn starch, wheat starch,
(Using rice starch or potato starch)
Gelatin, tragacanth, methylcellulose and/or, if desired, disintegrants, such as the starches mentioned above, carboxymethyl starch, cross-linked polyvinyl-pyrrolidone, agar, alginic acid or its salts (eg sodium alginate). Auxiliaries are primarily lubricants and lubricants, such as silicic acid, talc, stearic acid or its salts (eg magnesium or calcium stearate), and/or polyethylene glycols. The core of the dragee can be provided with a suitable, if necessary, antigastric coating, which in particular contains a concentrated sugar solution (if necessary, gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide) or a lacquer solution in a suitable organic solvent or solvent mixture; or (in the case of anti-gastric coatings)
A solution of a suitable cellulose preparation (eg acetylcellulose phthalate or oxypropylmethylcellulose phthalate) is used. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or identification of the various active substance doses.

Other orally administrable pharmaceutical preparations include insert capsules made of gelatin and closed capsules made of gelatin and a softening agent, such as glycerin or sorbitol. The plug-in capsules can contain the active substances in the form of granules in a mixture consisting of a filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, if necessary, stabilizers. May be contained. In soft capsules, the active substance may be dissolved or suspended in a suitable liquid, for example fat, paraffin oil or liquid polyethylene glycol, to which stabilizers may also be added. Capsules that are not only easily chewable but also swallowable without chewing are particularly suitable.

Pharmaceutical preparations that can be used for rectal administration include suppositories, which consist of a combination of the active substance and a suppository base, which may contain, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, Polyethylene glycols or higher alkanols are suitable. Gelatin-rectal capsules containing a binder between the active substance and the base may also be used;
This base material includes, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Suitable for parenteral administration are primarily aqueous solutions of the active substances in aqueous form, for example aqueous salt forms, and also suspensions of the active substances, such as the corresponding oily injection suspensions. , in which case suitable lipophilic solvents or excipients, such as fats and oils (for example sesame oil), synthetic fatty acid esters (for example ethyl oleate) or triglycerides, and also thickeners such as sodium carboxymethylcellulose, sorbitol and/or Alternatively, aqueous injection suspensions containing dextran and, optionally, stabilizers are employed.

The pharmaceutical preparations according to the invention can be prepared in a manner known per se, for example by customary mixing, granulating,
It is produced by methods such as sugar coating, dissolution, or lipophilization. Thus, pharmaceutical preparations for oral use are prepared by combining the active substance with a solid carrier, granulating the mixture obtained if necessary, and converting the mixture or granules into tablets after adding appropriate auxiliary substances, if desired or desired. Alternatively, it is manufactured by processing the core of sugar-coated pills.

Next, the present invention will be explained using specific examples, but these examples are not intended to limit the present invention. Temperatures are given in degrees Celsius (°C).

Example 1 4-(p-fluorobenzoyl)-piperidine
Dissolve 41.4g (0.2mol) in 120ml of dioxane,
28.3 g (0.1 mol) of N-(2-bromoethyl)-5-cyano-2-methoxy-benzamide was added;
Stirred at room temperature for 60 hours. Next, potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride solution was washed neutral with water and concentrated under reduced pressure with a stream of water. 200% of the remaining pale yellow crystals
The suspension was suspended in 1 ml of ethanol and stirred for 2 hours. The solid product is then filtered and added to freezing point ethanol.
Washed with 20ml. 5-cyano-N- from the filtrate
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide was obtained as a white powder with a melting point of 167-169°C.

To convert to the hydrochloride salt, the free base was then dissolved in methylene chloride and reacted with an ethereal solution of hydrochloric acid until the Congo indicator showed acidity. Ether was then added until crystallization started. This results in 5-cyano-N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-2-methoxy-benzamide-hydrochloride (melting point 193-194°C) was obtained.

The starting material was prepared as follows.

39.1 g (0.2 mol) of crude 5-cyano-2-methoxy-benzoic acid chloride prepared according to French Patent No. 1525M/72CAM and 45 g (0.22 mol) of 2-bromoethylamine-hydrobromide are dissolved in 300 ml of methylene chloride. 64.6 g (0.5 mol) of ethyldiisopropylamine was added dropwise to this mixture with stirring at room temperature. The clear solution obtained was stirred for 2 hours at room temperature. The methylene chloride solution was then shaken twice with 2N hydrochloric acid and once with water, dried over magnesium sulfate and concentrated by evaporation. Obtained N
-(2-bromoethyl)-5-cyano-2-methoxy-benzamide was recrystallized once from methylene chloride-ether for purification. Melting point 119-120℃.

Example 2 In the same manner as in Example 1, 41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine and N-(2
-bromoethyl)-4-chloro-5-cyano-2
- From a solution obtained by dissolving 31.8 g (0.1 mol) of methoxy-benzamide in 240 ml of dioxane, the melting point
4-chloro-5-cyano-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide-methanesulfonate was obtained.

The starting material was prepared as follows.

4-chloro-2-methoxybenzoic acid 37.3g
(0.2 mol) in 500 ml of acetic acid and 500 ml of water, 10.7 ml (33.6 g; 0.21 mol) of bromine was added at room temperature with stirring. Next, stirring was continued for another hour, 500 ml of water was added, and the precipitated 5-bromo-4
-Chloro-2-methoxy-benzoic acid was filtered off, and the filtrate was washed with water.

A solution obtained by dissolving 26.5 g (0.1 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid in 150 ml of ethanol was saturated with hydrogen chloride gas and left for 15 hours. It was then evaporated under reduced pressure with a stream of water and the residue was taken up in methylene chloride and washed with sodium bicarbonate. The methylene chloride solution was dried over magnesium sulfate and then evaporated under reduced pressure with a stream of water. 5-bromo-4-chloro- as a residue
2-Methoxy-benzoic acid-ethyl ester (melting point
79°C to 81°C).

14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid ethyl ester, 5.4 g (0.06 mol) of copper cyanide, and 8 ml of dimethylformamide were stirred in a nitrogen gas atmosphere for 3 hours. Heated to 190°C. After cooling, the reaction mixture was thoroughly stirred with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portion was then removed and the layers were separated in a separatory funnel. The methylene chloride solution was washed with water until neutral and evaporated. The 4-chloro-5-cyano-2-methoxy-benzoic acid ethyl ester obtained as a residue melted at 102-103° C. after recrystallization from methylene chloride-hexane.

For saponification, 500ml methanol, 100ml water
and 4-chloro-5- dissolved in 1N caustic soda.
24 g (0.1 mol) of cyano-2-methoxy-benzoic acid-ethyl ester was stirred for 15 hours. The methanol is then removed by suction under reduced pressure with a water jet, and 4-chloro-5 is extracted from the residual liquid by adding dilute sulfuric acid.
-Cyano-2-methoxy-benzoic acid was precipitated. This material was filtered and recrystallized from dioxane. 4-chloro-5-cyano-2-methoxy-benzoic acid with a melting point of 191-192°C was obtained.

In the same manner as in Example 3, 8.5 g (0.04 mol) of 4-chloro-5-cyano-2-methoxy-benzoic acid and thionyl chloride were dissolved in 120 ml of chloroform.
4-chloro-5-cyano-2-methoxy-benzoic acid chloride was obtained from 12 ml (19 g; 0.16 ml).

In the same manner as in Example 1, 23 g (0.1
mol), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide and 27.1 g (0.21 mol) of ethyl-diisopropylamine, melting point 127-129
N-(2-bromoethyl)-4-chloro-5- at °C
Cyano-2-methoxy-benzamide was obtained.

Example 3 In the same manner as in Example 1, 43.5 g (0.21 mol) of p-fluorobenzoyl-piperidine and 37.1 g (0.1 mol) of N-(2-bromoethyl)-5-bromo-4-chloro-2-methoxy-benzamide were added. From a solution obtained by dissolving in 200 ml of dioxane, 5-bromo-
4-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]ethyl]-2-methoxy-benzamide (melting point 166-168°C) was obtained.

The starting material was prepared as follows.

10ml chloroform and 6.6ml thionyl chloride
5-bromo-4 dissolved in (10.7 g; 0.09 mol)
-Chloro-2-methoxy-benzoic acid 13.6g (0.05
mol) was heated to boiling for 2 hours. It was then evaporated in a rotary evaporator to yield 5-bromo-4-chloro-2-methoxy-benzoic acid chloride residue as a white powder.

5.7 g (0.02 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid chloride and 4.1 g (0.02 mol) of 2-bromoethylamine-hydrobromide were dissolved in 30 ml of methylene chloride in the same manner as in the example.
and ethyl-diisopropylamine 5.2 g (0.04
mol) to obtain N-(2-bromoethyl)-5-bromo-4-chloro-2-methoxy-benzamide with a melting point of 99-100°C.

Example 4 4-(p-fluorobenzoyl)-piperidine dissolved in 120 ml of dioxane as in Example 1.
41.4g (0.2mol) and N-(2-bromoethyl)
-4-fluoro-2-methoxy-benzamide
From 27.6 g (0.1 mol), N with a melting point of 211°C (decomposed)
-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide-hydrochloride was obtained.

Analogously to Example 1, 18.9 g (0.1 mol) of 4-fluoro-2-methoxy-benzoic acid chloride (prepared according to U.S. Pat. No. 3,177,252), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide.
and ethyl-diisopropylamine 27.1g (0.21
mol) to give N-(2-bromoethyl)-4-fluoro-2-methoxy-benzamide with a melting point of 92-94°C.

Example 5 4-(p-fluorobenzoyl)-piperidine dissolved in 200 ml of dioxane as in Example 1.
45.5g (0.22mol) and N-(2-bromoethyl)
-5-Bromo-4-fluoro-2-methoxy-benzamide from 35.5 g (0.1 mol), melting point 152 ~
5-Bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4- at 153°C
Fluoro-2-methoxy-benzamide was obtained.

The starting material was prepared as follows.

4-Fluoro-2-methoxy-benzoic acid dissolved in 90 ml of acetic acid and 140 ml of water as in Example 2.
3.4 g (0.02 mol) and bromine 1.07 ml (3.35 g; 0.21
mol) to 5-bromo-4- with a melting point of 176-178°C
Fluoro-2-methoxy-benzoic acid was obtained.

Analogously to Example 3, 5-bromo-4-fluoro-benzoic acid was prepared from 5.0 g (0.02 mol) of 5-bromo-4-fluoro-2-methoxy-benzoic acid, 4.3 ml (7.1 g; 0.06 mol) of thionyl chloride and 15 ml of chloroform. -2-
Methoxy-benzoic acid chloride was obtained as a white powder.

5.4 g (0.02 mol) of 5-bromo-4-fluoro-2-methoxy-benzoic acid chloride, 4.1 g (0.02 mol) of 2-bromoethylamine-hydrobromide, dissolved in 30 ml of methylene chloride, as in Example 1.
and ethyl-diisopropylamine 5.2 g (0.04
mol) to obtain N-(2-bromoethyl)-5-bromo-4-fluoro-2-methoxy-benzamide with a melting point of 91-95°C.

Example 6 41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine dissolved in 180 ml of dioxane and N
-(2-bromoethyl)-2-methoxy-5-trifluoromethyl-benzamide 32.6 g (0.1 mol)
from N-[2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-methoxy-5-trifluoromethyl-benzamide-hydrochloride was obtained.

The starting materials were as in Example 1 (French patent no.
)-2-methoxy-5 prepared according to No. 1472025
-Trifluoromethyl-benzoic acid chloride 23.9g
(0.1 mol), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide and 27.1 g (0.21 mol) of ethyl-diisopropylamine, melting point 85~
N-(2-bromoethyl)-2-methoxy- at 86℃
5-trifluoromethyl-benzamide was obtained.

Example 7 In the same manner as in Example 1, dimethylformamide 250
From 45.5 g (0.22 mol) of 4-(p-fluorobenzoyl)-piperidine and 33.7 g (0.1 mol) of N-(2-bromoethyl)-2-methoxy-5-sulfamoyl-benzamide dissolved in ml, melting point 183 ~
2-methoxy-5-sulfamoyl-N at 185°C
-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained.

The starting material was prepared analogously to Example 1 as follows.

26.5 g (0.1 mol) of 2-methoxy-5-sulfamoyl-benzoic acid chloride (prepared according to French Patent No. 1472025), 20.5 g of 2-bromoethylamine-hydrobromide and triethylamine
From 21.2 g (0.21 mol), N-(2-bromoethyl)-2-methoxy-5-sulfamoyl-benzamide having a melting point of 179 DEG C. (decomposed) was obtained.

Example 8 24.1 g (0.1
22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine and 120 ml of dioxane were boiled for 18 hours in a nitrogen atmosphere. The dark brown solution obtained was evaporated under reduced pressure with a water jet. The viscous oil obtained was dissolved in 300 ml of acetone and an ethereal solution of hydrogen chloride was added under stirring until the Congo indicator showed acidity. At this time recrystallization of the product started. The precipitated 5-chloro-N-[2-[4-(p-fluorobenzoyl)-
Piperidinyl]-ethyl]-2-methoxy-4-methylamino-benzamide-hydrochloride was filtered off. This material melted (decomposed) at 230°C.

The starting material was prepared as follows.

5-chloro- dissolved in 250 ml of methylene chloride
2-Methoxy-4-methylamino-benzoic acid 21.6
g (0.1 mol) (J.Med.Chem. 1981 , (24), 1224,
11.2 g of triethylamine (manufactured by S. Iwanami et al.) in a nitrogen atmosphere with stirring.
(0.11 mol) was added dropwise. The obtained solution was heated to −10 °C.
chloroformic acid ethyl ester 10.9g (0.1 mol)
was added. 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide for a further 30 minutes at this temperature.
and 10.1 g (0.1 mol) of triethylamine. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 4 hours. For work-up, it was reacted with 1 part of methylene chloride and 1 part of water, the aqueous phase was adjusted to pH 5 with 2N hydrochloric acid, and the layers were separated using a separatory funnel.

The aqueous phase was mixed with sodium bicarbonate and extracted with methylene chloride. After evaporating the methylene chloride, 2-(5-chloro-2-methoxy-4-methylamino-phenyl)-2-oxazoline was obtained with a melting point of 159-161°C.

Example 9 In the same manner as in Example 8, 28.4 g (0.1 mol) of 2-(5-dimethylsulfamoyl-2-methoxy-phenyl)-2-oxazoline, 20.7 g (0.1 mol) of 4-(p-fluorobenzoyl)-piperidine mol) and 140 ml of dioxane, N- with a melting point of 172°C (decomposed)
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-dimethylsulfamoyl-benzamide-hydrochloride was obtained.

The starting material was prepared analogously to Example 8 as follows.

5-dimethylsulfamoyl-2-methoxy-
Benzoic acid 24.3g (0.1mol), triethylamine
21.3 g (0.21 mol), 10.9 g (0.1 mol) of chloroformic acid-ethyl ester and 20.5 g (0.1 mol) of 2-bromoethylamine hydrobromide, melting point
2-(5-dimethylsulfamoyl-2-methoxy-phenyl)-2-oxazoline was obtained at 135-138°C.

Example 10 N-(5-cyano-2-methoxy-benzoyl)
-Aziridine 20.2g (0.1mol), 4-(p-fluorobenzoyl)-piperidine 22.8g (0.11mol)
and 250 ml of toluene were heated to 80° C. with stirring for 5 hours. 5-cyano-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide was filtered and washed with a small amount of toluene. Melting point is 167~
It was 169℃.

The starting material was prepared as follows.

100ml of 0.5N caustic soda dissolved in 30ml of toluene
ml and 2.3 g (0.53 mol) of aziridine,
A solution of 9.8 g (0.05 mol) of 5-cyano-2-methoxy-benzoyl chloride in 50 ml of methylene chloride was added dropwise with good stirring at a reaction temperature of 3 to 5°C, and the reaction mixture was then stirred for a further 1 hour. Stir at ℃. The layers were then separated using a separatory funnel and the organic phase was shaken with 50 ml of water, dried over magnesium sulfate and evaporated under reduced pressure with a stream of water. Melting point 99~
N-(5-cyano-2-methoxy-benzoyl)-aziridine at 101°C was obtained as a residue.

Example 11 25.6 g of 2-(3-bromo-4-methoxy-phenyl)-2-oxazoline was prepared in the same manner as in Example 8.
(0.1 mol) and 4-(p-fluorobenzoyl)-
From a solution of 20.7 g (0.1 mol) of piperidine in 75 ml of toluene, 3-bromo-N-[2-[4-(p-fluorobenzoyl)-
Piperidinyl]-ethyl]-4-methoxy-benzamide-methanesulfonate was obtained.

The starting material was prepared analogously to Example 8 as follows.

3-Bromo-4-methoxy-benzoic acid 15.2g
(0.1 mol), triethylamine 21.3g (0.21 mol),
Chloroformic acid-ethyl ester 10.9g (0.1mol)
and 2-bromoethylamine-hydrobromide
2-(3-bromo-4-methoxy-phenyl)-2-oxazoline having a melting point of 95 DEG C. was obtained from 20.5 g (0.1 mol).

Example 12 In the same manner as in Example 8, 17.7 g (0.1 mol) of 2-(2-methoxy-phenyl)-2-oxazoline, 4
-(p-fluorobenzoyl)-piperidine 10.7g
(0.1 mol) and 40 ml of dioxane, melting point 205℃
(Decomposition) of N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-
Benzamide-hydrochloride was obtained.

The starting material was prepared analogously to Example 8 as follows.

15.2 g (0.1 mol) of 2-methoxybenzoic acid, 21.3 g (0.21 mol) of triethylamine, 10.9 g (0.1 mol) of chloroformic acid-ethyl ester and 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide.
mol) to give 2-(2-methoxy-phenyl)-2-oxazoline with a melting point of 35-38°C.

Example 13 5-cyano-N- suspended in 50 ml of ethanol
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide
Sodium borohydride 0.38 in 4.1g (0.01mol)
g (0.01 mol) was added under stirring and stirred for 1 hour at room temperature. The clear solution obtained was mixed with 1 ml of acetone and then evaporated under reduced pressure with a water jet. The residue was taken up in methylene chloride and water, the layers were separated in a separatory funnel and the organic phase was dried over magnesium sulfate and then evaporated to dryness. 5-cyano-N-[2-[4-[(4
-fluorophenyl)-hydroxymethylene]-piperidinyl]-ethyl]-2-methoxy-benzamide was obtained.

Example 14 32.3 g (0.1 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine hydrochloride dissolved in 250 ml of methylene chloride and 3-
A mixture of 24 g of bromo-4-fluorobenzoyl was heated to -10°C to 0°C under nitrogen atmosphere with stirring.
45 g (0.35 mol) of diisopropylethylamine
was dripped. The reaction mixture was then heated to room temperature and held at this temperature for 4 hours. Then 1N caustic soda 200
ml, the layers were separated, the organic phase was washed neutral with water, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. Melting point 135℃
3-bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained as a residue.

The base was then converted to hydrochloride by dissolving it in methylene chloride and adding an ethereal solution of hydrogen chloride. The melting point of this hydrochloride is
The temperature was 189-190℃.

N-(2-aminoethyl) used as starting material
-4-(fluorobenzoyl)-piperidine-hydrochloride was produced as follows.

4-(p-fluorobenzoyl)-piperidine-hydrochloride suspended in 50 ml of methylene chloride.
24.4 g (0.1 mol) and 8.3 chloroacetonitrile
g (0.11 mol) of ethyl-diisopropylamine
29.5 g (0.23 mol) was added dropwise with stirring. The reaction mixture was stirred for 5 hours at room temperature. then ether 150
ml and shaken with 2N hydrochloric acid. The acid extract was made alkaline with 2N caustic soda and the separated base was shaken with a 3:1 mixture of ether-methylene chloride. The product obtained was washed neutral and evaporated to dryness over magnesium sulphate. N- with a melting point of 133-134℃ as a residue
(Cyano-methyl)-4-(p-fluorobenzoyl)-piperidine was obtained.

14.1 g (0.05 mol) of N-(cyanomethyl)-4-(p-fluorobenzoyl)-piperidine was dissolved in acetic acid.
1.51 and 30 ml of concentrated hydrochloric acid, and hydrogenated with 2 g of platinum oxide in a hydrogen atmosphere. After 6 hours, a theoretical amount of 2.25 hydrogen was absorbed. The catalyst was then filtered off and the liquid was concentrated under water jet vacuum to approximately 30 ml. The resulting crystal sludge was mixed with 5 ml of isopropanol and 15 ml of ether and filtered. N-(2-aminoethyl)-4-(p
-fluorobenzoyl)-piperidine-hydrochloride melted (decomposed) at 265°C after recrystallization from methanol.

The 3-bromo-4-fluoro-benzoyl chloride used as the starting material was prepared analogously to Example 3.
Bromo-4-fluorobenzoic acid 21.9g (0.1mol)
(prepared according to J. Indian Chem. Soc. 21 , 115 (1944)) and 10 ml of thionyl chloride.

Example 15 3.23 N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride dissolved in 25 ml of methylene chloride as in Example 14.
g (0.01 mol), 2-bromo-4-fluoro-benzoyl chloride 2.6 g (0.01 mol) and ethyl-diisopropylamine 4.5 g (0.035 mol), 2-bromo-4-fluoro-N having a melting point of 123-125°C. −
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained.

32.3 g (0.1 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride dissolved in 200 ml of methylene chloride, 2,
From 20 g of 6-dimethoxy-benzoyl chloride and 45 g (0.35 mol) of ethyl-diisopropylamine,
N-[2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2,6-dimethoxy-benzamide-hydrochloride was obtained.

Example 16 In the same manner as in Example 1, add 25 ml of dimethylformamide.
From 6.2 g (0.03 mol) of 4-(p-fluorobenzoyl)-piperidine and 7.4 g (0.03 mol) of N-(2-bromoethyl)-4-fluorobenzamide dissolved in N-
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide-hydrochloride was obtained.

Example 17 In the same manner as in Example 10, N dissolved in 16 ml of toluene
From 5.2 g (0.02 mol) of -(5-bromo-2-methoxybenzoyl)-aziridine and 4.4 g (0.021 mol) of 4-(p-fluorobenzoyl)-piperidine, 5-bromo-N with a melting point of 213°C (decomposed) -[2-
[4-(p-fluorobenzoyl)-piperidinyl]
-ethyl]-2-methoxy-benzamide-hydrochloride was obtained.

The starting material was prepared analogously to Example 10 as follows.

N-(5- Bromo-2-methoxy-benzoyl)-aziridine was obtained.

By a method similar to that described in Example 10, N-(3-cyano-4-methoxybenzoyl)
- From a solution obtained by dissolving 20.2 g (0.1 mol) of aziridine and 22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine in 120 ml of toluene,
3-cyano-N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-4-methoxy-benzamide-hydrochloride was obtained.

4.52 g (0.105 mol) of aziridine, 12.9 g (0.1 mol) of ethyldiisopropylamine and 19.6 g (0.1 mol) of 3-cyano-4-methoxy-benzoyl chloride.
N-(3-cyano-4-
Methoxy-benzoyl)-aziridine was obtained.

Example 18 Analogously to Example 14, N-
(2-Aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride 3.23g
(0.01 mol), 3,5-dichloro-2-methoxy-
2.54 g (0.01 mol) of 4-methyl-benzoylchloride and 4.5 g of ethyl-diisopropylamine
(0.035 mol) to 3,5-dichloro-N-[2-[4-(p-fluorobenzoyl), melting point 112-114°C
-piperidinyl]-ethyl]-2-methoxy-4-
Methyl-benzamide-methanesulfonate was obtained.

N-(2-aminoethyl) in 30 ml of methylene chloride
-4-(p-fluorobenzoyl)-piperidine-
Hydrochloride 3.23 g (0.01 mol), 2-methoxy-5-methylmercapto-benzoyl chloride 2.17
g (0.01 mol) and ethyl-diisopropylamine 4.5 g (0.035 mol), melting point 209°C (decomposition)
N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methylmercapto-benzamide-hydrochloride was obtained.

N-(2-aminoethyl) in 50 ml of methylene chloride
-4-(p-fluorobenzoyl)-piperidine-
Hydrochloride 6.5g (0.02mol), 2-methoxy-5-methanesulfonyl-benzoyl chloride 4.99g
(0.02 mol) and ethyldiisopropylamine 9
g (0.07 mol) to N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methanesulfonyl-benzamide-hydrochloride was obtained.

Example 19 Similarly to Example 14, N-
(2-Aminoethyl)-4-(p-fluorobenzoyl)-piperidine-dihydrochloride 4.6g
(0.015 mol), 5-cyano-2-methoxy-benzoyl chloride 2.93 g (0.015 mol) and ethyldiisopropylamine 6.4 g (0.05 mol), melting point
5-cyano-N-[2-[4-(p-
fluorobenzyl)-piperidinyl]-ethyl]-
2-Methoxy-benzamide-hydrochloride was obtained.

N-(2-aminoethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride used as a starting material was produced as follows.

4-(p-fluorobenzoyl)- in 120 ml of trifluoroacetic acid containing 5 g of palladium on carbon (5%) at 70 °C until the theoretical amount of hydrogen has been absorbed.
Piperidine-hydrochloride 24.4g (0.10mol)
was hydrogenated. The catalyst was then removed and the liquid was evaporated under reduced pressure with a water stream. Dissolve the residue in 150 ml of water, add 50 ml of concentrated caustic soda, and then dissolve in ether.
Extracted with 250ml. When the ether solution thus obtained was adjusted to be slightly Congo acidic with hydrogen chloride gas, 4-(p-fluorobenzoyl)-piperidine-hydrochloride having a melting point of 166-166.5°C was precipitated.

4-(p-fluorobenzyl)-piperidine-hydrochloride suspended in 75 ml of methylene chloride 23
g (0.10 mol) and chloroacetonitrile 8.3 g
(0.11 mol) was added dropwise with stirring to 28.4 g (0.22 mol) of ethyl-diisopropylamine. The reaction mixture was stirred for 15 hours at room temperature. Next, 150ml of ether
and shaken with 2N hydrochloric acid. This acid extract was adjusted to alkalinity with 2N caustic soda, and the precipitated base was shaken with methylene chloride. This material was washed with water until neutral, dried over sodium sulfate, and then concentrated by evaporation. The residue was dissolved in a small amount of isopropanol, adjusted to weak Congo acidity with an ethereal solution of hydrogen chloride, and dissolved in N with a melting point of 158-160 °C.
-(cyanomethyl)-4-(p-fluorobenzyl)
-Piperidine-hydrochloride precipitate was obtained.

N-(cyanomethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride 13.44g
(0.05 mol) was dissolved in 300 ml of acetic acid and 7 ml of concentrated hydrochloric acid, and hydrogenated with 1 g of platinum oxide in a hydrogen atmosphere. After 4 hours, a theoretical amount of 2.25 hydrogen was absorbed. The catalyst was then removed and the liquid was concentrated to about 30 ml under water jet vacuum. Add 5 ml of isopropanol and 10 ml of ether to the formed crystal mud,
passed. N-(2-aminoethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride was obtained, which melted at 171-173°C after recrystallization from ethanol-ether.

Example 20 6.69 g of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamino-hydrochloride
(0.015 mol), methanol 50 ml and toluene 50 ml
ml. Hydrogen chloride gas was introduced at 0° C. with stirring and cooling until a clear solution was obtained. Next, 100 ml of ice water was gradually poured into the mixture, and the mixture was further heated to 70°C for 1 hour. After cooling, the mixture was carefully made slightly alkaline with potassium and the mixture thus obtained was extracted with methylene chloride. The methylene chloride solution was washed neutral with water, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy- obtained as a residue
5-Methoxycarbonyl-benzamide was dissolved in methylene chloride-ether (1:1) and converted to the hydrochloride salt with an ethereal solution of hydrogen chloride. Take this and mix it with methylene chloride-acetone.
It was recrystallized twice (melting point 221°C (decomposition)).

Example 21 6.69 g of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide-hydrochloride
(0.015 mol) in 85% sulfuric acid 60 in nitrogen atmosphere
ml and left at room temperature for 7 days. This solution was added dropwise to a mixture of 200 g of ice and 130 ml of concentrated ammonia with stirring, resulting in the formation of a white precipitate.
This product was taken and recrystallized from methylene chloride-methanol. This results in a melting point of 236-238℃.
-Carbamoyl-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide- was obtained.

For conversion to the hydrochloride salt, the free base was suspended in methylene chloride and to this was added ethereal hydrogen chloride solution with stirring until the Congo indicator showed acidity, producing a clear solution. Ether was then added until crystallization started. 5-Carbamoyl-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-
Benzamide hydrochloride (melting point 240°C (decomposition)) was obtained.

Example 22 2.14 g (0.01 mol) of 2-methoxy-5-methanesulfinylbenzoic acid and 3.23 g (0.01 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-dihydrochloride. It was dissolved in 10 ml of dimethylformamide and 2.13 g (0.021 mol) of triethylamine was added. 3.26 g of triphenyl phosphite in a nitrogen atmosphere with stirring
(0.0105 mol) and the resulting reaction mixture
Heated to 85-90°C for 2.5 hours. After cooling, an ether solution of hydrogen chloride was added until the Congo indicator showed acidity, and the precipitated ether solution was decanted.
The residue was mixed with methylene chloride and potassium carbonate solution, and the methylene chloride solution was dried over potassium carbonate and concentrated. Residue N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2
-Methoxy-5-methanesulfinyl-benzamide was converted to the hydrochloride salt with ethereal hydrogen chloride solution in methylene chloride-methanol. This was precipitated by addition of ether. N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-2-methoxy-5-methanesulfinyl-benzamide hydrochloride was obtained which, after one recrystallization from methylene chloride-methanol, melted (decomposed) at 194°C.

Example 23 As in Example 10, 4.95 g (0.03 mol) of p-fluorobenzoyl-aziridine in 25 ml of toluene.
and 5.85 g of 4-(2-thenoyl)-piperidine
(0.03 mol) gave p-fluoro-N-[2-[4-(2-thenoyl)-piperidinyl]ethyl]-benzamide-hydrochloride with a melting point of 204-205°C.

From 4.04 g (0.02 mol) of N-(5-cyano-2-methoxy-benzoyl)-aziridine and 4.46 g (0.02 mol) of 4-(p-chlorobenzoyl)-piperidine in 20 ml of toluene, a solution with a melting point of 177-178°C N
-[2-[4-(p-chlorobenzoyl)-piperidinyl]-ethyl]-5-cyano-2-methoxy-benzamide-methanesulfonate was obtained.

From 3.3 g (0.02 mol) of p-fluorobenzoyl-aziridine and 4.46 g (0.02 mol) of 4-(p-chlorobenzoyl)-piperidine in 20 ml of toluene, N-[2-[4-( p-chlorobenzoyl)-piperidinyl]-ethyl]-p-
Fluoro-benzamide-methanesulfonate was obtained.

Example 24 In the same manner as in Example 10, N-(p
-fluorobenzoyl)-2,2-dimethyl-aziridine 1.93 g (0.01 mol) and 4-(p-fluorobenzoyl)-piperidine 2.07 g (0.01 mol)
p-fluoro-N-[3
-[4-(p-fluorobenzoyl)-piperidinyl]-2-methylpropyl]-benzamide-hydrochloride was obtained.

N-(p-fluorobenzoyl)-2,2-dimethylaziridine used as starting material was prepared from Example 10.
It was manufactured in the same manner as follows.

2,2-dimethyl- in 30.6 ml of 1N caustic soda
From 2.13 g (0.03 mol) of aziridine and 4.76 g (0.03 mol) of p-fluorobenzoyl chloride, a viscous oily N-(p-fluorobenzoyl)-2,2
-dimethyl-aziridine was obtained.

Example 25 4-(p-fluorobenzoyl)-piperidine-
26.8 g (0.11 mol) of hydrochloride, 34.5 g (0.25 mol) of potassium carbonate and 25.3 g (0.1 mol) of N-(3-chloropropyl)-5-cyano-2-methoxy-benzamide were mixed with 0.5 g of potassium iodide in ethanol. The mixture was heated and boiled in a 250 ml solution for 15 hours with stirring. The reaction mixture was then evaporated under reduced pressure with a stream of water and the residue was taken up in ether, a little methylene chloride and water. After separating the aqueous phase,
The base component was separated from the organic phase by shaking with 2N methanesulfonic acid. The acid extract was adjusted to pH 9 with caustic soda, and then extracted with methylene chloride. The methylene chloride solution was washed with water until neutral, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. The crude product thus obtained was subjected to flash chromatography and the desired 5-cyano-N-[3
-[4-(p-fluorobenzoyl)-piperidinyl]-propyl]-2-methoxy-benzamide was eluted.

To convert to the hydrochloride salt, the free base was dissolved in methylene chloride and to this solution an ethereal solution of hydrogen chloride was added until the Congo indicator showed acidity, then ether was added until crystallization started. . This produced 5-cyano-N-[3-[4-(p-fluorobenzoyl) with a melting point of 171°C (decomposition).
-Piperidinyl]-propyl]-2-methoxy-benzamide was obtained.

Example 26 2-(2,6-dimethoxy-pyridinyl)-2-
20.8 g (0.1 mol) of oxazoline, 22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine, 12.9 g (0.1 mol) of diisopropyl-ethylamine.
80 mol) and 120 ml of dioxane for 16 hours under stirring.
heated to ℃. Next, methylene chloride and water were added to this, and the pH was adjusted to 9 with saturated potassium carbonate solution. The layers were separated in a separatory funnel and the organic phase was evaporated under reduced pressure with a stream of water. The obtained residue is dissolved in 150 ml of methanol and mixed with water under stirring,
N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxy-nicotinamide was obtained.

In order to convert the free base to the methanesulfonate salt, it is dissolved in a small amount of methylene chloride and an ethereal solution of methanesulfonic acid is added under stirring until it shows weak Congo acidity, and as a precipitate, N-[2-[4-
(1-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-nicotinamide-methanesulfonate was obtained. The crude product was recrystallized once from isopropanol (mp 170-172°C).

The starting material was prepared as follows.

110.6g (0.8mol) of potassium carbonate, 120ml of water
and cooled to 10°C. Transfer this solution to ether
150 ml of methylene chloride, and to the reaction mixture was added 49.2 g (0.24 mol) of 2-bromoethylamine-hydrobromide and 40.3 g (0.24 mol) of 2,6-dimethoxy-nicotinyl chloride in 100 ml of methylene chloride. A solution of 0.2 mol) was quickly added dropwise at a reaction temperature of 15-20°C. The product was heated to room temperature and stirred at this temperature for an additional hour. The product was mixed with 50 ml of water and the layers were separated in a separatory funnel. The organic phase was evaporated under reduced pressure with a stream of water to give 2-(2,6-dimethoxy-pyrimidyl)-2-oxazoline as a pale yellow crystalline residue.

Example 27 Active ingredients such as 5-cyano-N-[2-[4-
Tablets containing 25 mg of (p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide were prepared as follows.

Composition (per 1000 tablets) Active ingredient 25.0g Lactose 100.7g Wheat starch 7.5g Polyethylene glycol 6000 5.0g Talc 5.0g Magnesium stearate 1.8g Deionized water Appropriate amount Manufacture All solid ingredients were passed through a sieve with a mesh size of 0.6 mm. The active ingredients, lactose, talc, magnesium stearate and half the amount of starch were then mixed. The remaining half of the starch was suspended in 40 ml of water and this suspension was added to a boiling polyethylene glycol solution in 100 ml of water. The obtained starch component was added to the main portion, and the resulting mixture was granulated, adding water as necessary. The obtained granules were dried at 35° C. overnight, passed through a sieve with a mesh size of 1.2 mm, and pressed into biconcave tablets with a mesh size of about 6 mm.

Example 28 0.02 g of methanesulfone hydrochloride of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide
Tablets containing the following were manufactured as follows.

Composition (per 10000 tablets) Active ingredients 200.00g Lactose 290.80g Barchi 274.70g stearic acid 10.00g Tarc 200.00g of stearate 2.50g Colloid -shaped 1.50g Coroid -like silicon 32.00g Ethanole appropriate amount of active ingredients
194.70 g of the mixture was moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silicon dioxide are mixed and the mixture is pressed into 0.1 g, which can be provided with part-cuts for more precise adaptation to the dosage, if necessary.
It was made into tablets of the same weight.

Example 29 Active ingredients such as 5-cyano-N-[2-[4-
Capsules containing 0.025 g of (p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide were prepared as follows.

Composition (per 1000 capsules) Active ingredient 25.00g Lactose 249.00g Gelatin 2.00g Corn starch 10.00g Talc 15.00g Water Appropriate amount Mix the active ingredient with lactose, uniformly wet the mixture with an aqueous gelatin solution, and mesh size.
It was granulated through a 1.2-1.5 mm sieve. The resulting granules were mixed with dried corn starch and talc, and 300 mg was added to hard gelatin capsules (size 1).
Filled with each.

Test example Blockade of dopamine receptor sites in vivo was performed using S.
Bischoff et al., European J. Pharmacol. 68, 305−
315 (1980), the rate of inhibition of ³ H-spiroperone binding in rat hippocampus was measured by intraperitoneal administration.

Results: Compound ED ₅₀ (mg/Kg) Intraperitoneal administration (% inhibition) 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide 0.75 ( 50) N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxynicotinamide 4.6(50) 4-chloro-5-cyano-N-[2-[4 -(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-methoxybenzamide 1.25(50) 5-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-4-methylaminobenzamide 6.2(50) 3-bromo -N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxybenzamide 30(71) 5-cyano-N-[2-[4-((p-fluorophenyl) -hydroxymethylene)-piperidinyl]-
ethyl]-2-methoxy-benzamide 30(80) 3-bromo-4-fluoro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 30 (97) 2-bromo-4-fluoro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 30 (74) 4-fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 0.16 (97) In addition, the present invention The toxicity of these compounds is low, and among the above compounds, acute toxicity tests in rats were conducted on compounds with high potential for development as antipsychotic drugs, and the following results were obtained.

5-Cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl-2-methoxybenzamide LD ₅₀ >150mg/Kg (intraperitoneal administration) 4-chloro-5-cyano-N-[ 2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-Methoxybenzamide 500mg/oral No deaths due to administration 4-Fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide LD ₅₀ = 150mg/Kg (intraperitoneal administration)

Claims (1)

[Claims] 1. General formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar ₁ represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar ₂ represents a phenyl group or a phenyl group substituted with halogen, provided that Ar ₁
N-lower alkylamino as a substituent of -
N-(piperidinyl-alkyl)-carboxamide or a salt thereof. 2 R represents a lower alkoxy group; Ar ₁ represents a phenylene group on the other hand, and this group is unsubstituted or halo-lower alkyl, halogen, lower alkoxy, cyano, carbamoyl, N-lower alkylamino, sulfamoyl, is mono- or polysubstituted by N,N-di-lower alkylsulfamoyl; or on the other hand represents a pyridylene group, which is mono- or polysubstituted by lower alkoxy and/or halogen;
Claims represented by the formula: alk represents an ethylene group or a 1,3-propylene group; X represents a carbonyl group or a hydroxymethylene group; and Ar ₂ represents a phenyl group substituted with a halogen. The compound according to item 1 or a salt thereof. 3 The group R-Ar ₁ has the formula: (wherein, on the one hand, Ra represents a group R in which Ra is lower alkoxy having up to 4 carbon atoms,
Rb and Re represent hydrogen, Rc represents a lower alkylamino having 4 or less carbon atoms, and Rd represents a halogen with an atomic number of 35 or less, or Rc represents hydrogen or a halogen with an atomic number of 35 or less. , Rd
represents cyano; or, on the other hand,
Ra, Rd and Re represent hydrogen, and Rb has atomic number 35
represents a group R representing the following halogen and Rc is lower alkoxy having up to 4 carbon atoms; and in each case alk represents an ethylene group; X represents a carbonyl group or a hydroxymethylene group; and Ar ₂ represents a 4-fluorophenyl group), or a salt thereof according to claim 1, represented by the formula: 4 The group R-Ar ₁ has the formula b (wherein one of Ra and Rb represents hydrogen or a halogen with an atomic number of 35 or less,
the other represents a hydrogen atom, Rc represents a group R that is a halogen with an atomic number of 35 or less, Rd and Re each represent a hydrogen atom; alk represents an ethylene group;
The compound according to claim 1, or a salt thereof, represented by the formula, wherein X represents a carbonyl group; and _Ar2 represents a 4-fluorophenyl group. 5 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or salt thereof; 4-chloro-5-cyano-N-[2-[4 −(p
-fluorobenzoyl)-piperidinyl]-ethyl]-2-benzamide or its salt; 5-bromo-4-chloro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide or a salt thereof; 5-bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide or a salt thereof; N-[2-[4- (p-fluorobenzoyl)-piperidinyl]-ethoxy]-2-methoxy-5-trifluoromethyl-benzamide or salt thereof; 2-methoxy-5-sulfamoyl-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or its salt; 5-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy -4-methylaminosulfamoyl-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl-ethyl]-2-methoxy-5-dimethylsulfamoyl-benzamide or a salt thereof; 3-Bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxy-benzamide or salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl] ]-ethyl]-2-methoxy-benzamide or its salt; and 5-cyano-N-[2-[4-[(4-fluorophenyl)-hydroxymethylene]-piperidinyl]
-ethyl]-2-methoxy-benzamide or a salt thereof. 6 3-Bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or a salt thereof; 2-bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxy-benzamide or a salt thereof; 4 -Fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or a salt thereof; 5-bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl] -ethyl]-2-methoxy-benzamide or a salt thereof; and 3-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxy-benzamide or a salt thereof; A compound according to claim 1. 7 3,5-dichloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-
2-methoxy-4-methyl-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methanesulfonyl-benzamide or a salt thereof; and 5 A compound according to claim 1 selected from -cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or a salt thereof. 8 General formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar ₁ represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar ₂ represents a phenyl group or a phenyl group substituted with halogen, provided that Ar ₁
N-lower alkylamino as a substituent of -
An antipsychotic drug containing N-(piperidinyl-alkyl)-carboxamide or a salt thereof as an active ingredient.