KR800000079B1 - Method for preparing N-[(1-piperidinyl) alkyl] carboxamide derivative - Google Patents

Abstract

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Description

Method for preparing N-[(1-piperidinyl) alkyl] carboxamide derivative

The present invention relates to N-[(1-piperidinyl) alkyl / arylcarboxamide derivatives.

Any N-[(2-pyridinyl) methyl] benzamide having pharmaceutical properties with any N-[(dialkylamino) alkyl] benzamide, including N-[(1-piperidinyl) alkyl] benzamide In the literature. Examples of known compounds of this class are, for example, 4-amino-5-chloro-N- [2-diethylamino) ethyl] -2-methoxybenzamide, commonly referred to as metoclopramide and useful as antiemetic agents. 5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl) methyl] -2-methoxybenzamide is useful as an antiemetic and neurological agent called sulfide.

The compounds of the present invention differ from conventional compounds by the nature of the substituted piperidine nucleus attached to the alkyl-side chain. Various conventional compounds can be found in the literature.

C.A., 59,11358 C;

U.S. Patent 3,342,826

C.A., 71, P811 413C.

The novel N-[(1-piperidinyl) alkyl] arylcarboxamide derivatives of the present invention can be represented by the following structural formula.

In the above formula

Ar is an aryl group selected from phenyl, substituted phenyl, 2-thienyl, 2-furanyl, pyridinyl and 1-methyl-2-pyrrolyl, wherein the substituted phenyl is halo, lower alkyl, lower alkyloxy, trifluoro Phenyl having 1-3 substituents independently selected from rommethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino and when one or more of these substituents is hydroxy, amino , Lower alkylcarbonyloxy and lower alkylcarbonylamino.

R is selected from channel and lower alkyl

n is an integer from 2-3

라디칼은 하기 라디칼중에서 선택한 것임.

The radical is selected from the following radicals.

a) a radical having the general formula

In the formula

R ¹ and R ² are independently selected from channel, halo, lower alkyl and trifluoromethyl.

b) radicals having the general formula

In the food

R ³ and R ⁴ are each selected from hydrogen, halo, lower alkyl and trifluoromethyl; M is selected from hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanoethyl; Y is selected from O, S and lower alkylcarbonylimano, and the dashed line indicates that the double bond between the 3- and 4-carbon atoms of the piperidine nucleus is optional and if the double bond between the 3- and 4-carbon atoms When present, Y is 0 and M is hydrogen.

c) radicals having the general formula

In the food

R ³ and R ⁴ are each independently selected from hydrogen, halo, lower alkyl, and trifluomethyl

d) radicals having the general formula

In the food

R ⁵ is selected from hydrogen and methyl;

R ⁶ is selected from hydrogen and halo

R ⁷ is hydrogen, halo, lower alkyl and trifluomethyl.

As used herein, "lower alkyl" is straight or branched and has 1-5 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl. The term "halo" refers to halogens having an atomic weight of 127 or less, such as pulluro, chromo, bromo and iodo.

가 상술한 의미를 갖고, R는 수소이며 n는 2인 일반식(1)의 화합물(1-a)은 일반적으로 Ar가 상술한 의미를 갖는 일반식(Ⅱ)의 적당히 치환된 1-아로일아지리딘을

군이 상술한 의미를 갖는 일반식(Ⅲ)의 적당한 피페리딘 유도체와 반응시킴에 의하여 제조한다.Ar and

Is a compound of formula (1) wherein R is hydrogen and n is 2, in general, the appropriately substituted 1-aroyl of formula (II) Aziridine

The group is prepared by reacting with a suitable piperidine derivative of formula (III) having the above meanings.

The reaction may be carried out with a suitable reaction-inert organic solvent such as methanol, ethanol, propanol, butanol and the like; Aromatic hydrocarbons such as methylbenzene, dimethylbenzene and the like; Ketones such as 4-methyl-2-pentanone, ethers such as 1,4-dioxane, 1,1'-oxybisethane; N, N-dimethylformamide; It is carried out in a mixture of nitrobenzene and these solvents. In order to increase the reaction rate, an elevated temperature is suitable, particularly at the reflux temperature of the reaction mixture. In the next process the reaction product is separated from the medium and further purified by application of methods known in the art as required.

The compounds of formula (1) wherein R is lower alkyl and n is 3 are also the corresponding alcohols, wherein Ar, R and n are as described above and X is for example halo, methanesulfonyl, 4-methylbenzenesulfonyl and the like. It is prepared by reacting a suitable reactive ester of formula (IV) which is a suitable reactive ester group derived from and a suitable piperidine derivative of formula (III).

The reaction is carried out in a suitable organic solvent such as, for example, N, N-dimethylformamide, N, N-dimethylacetamide, 4-methyl-2-pentanone, 2-propanol, methanol, ethanol, 2-propanol and the like. . The addition of suitable bases such as alkali or earth metal carbonates or bicarbonates is used to remove the free acid during the reaction. A slightly elevated temperature is suitable to increase the reaction rate, in particular the reaction is carried out at reflux temperature.

Another method for preparing a compound of formula (I) is to form an appropriately substituted aroyl halide of formula (V) according to the known method for preparing amides starting from aryl halides and amines. To react with a suitable amine.

The reaction may be carried out with a suitable reaction-inert organic solvent such as lower alkanols such as methanol, ethanol, propanol, butanol and the like; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Ketones such as 4-methyl-2-pentanone; Ethers such as 1,4-dioxane, 1,1'-oxybisethane and the like; N, N-dimethylformamide; By reacting the reactants together in nitrobenzene or mixtures thereof. In order to increase the reaction rate, an elevated temperature is suitable, especially at the reflux temperature of the reaction mixture.

The compounds of formula (I) wherein Ar is a group of phenyls having amino groups alone or with other substituents within 2, can be used to prepare the corresponding nitro-substituted analogues according to known processes, for example, palladium on ranei-nickel glide Or nitro is reduced to amine by treating catalytic hydrogenation or nitro compounds with a platinum dioxide catalyst or iron-ammonium chloride or zinc-vinegar acid.

Wherein compounds of formula (1), wherein Ar is a group of phenyls having lower alkylcarbonylamino or lower alkylcarbonyloxy in 2, are used for the halides derived from the appropriate lower alkyl carboxylic acids, for example with the corresponding amino or hydroxy substituted derivatives. Or by acylation with a suitable acylating agent such as anhydride. The acylation reaction is carried out using a suitable lower alkylcarboxylic acid in water.

Compounds of the general formula (1) represented by the following general formula (1-b) may be prepared by appropriate acylating agents derived from suitable lower alkyl carboxylic acids, such as acyl, with the corresponding unsubstituted compounds of the general formula (1-c) It can be prepared by acylating with a halide or anhydride.

The acylation reaction is carried out using a suitable anhydride in a suitable organic solvent such as benzene, methylbenzene, dimethylbenzene and the like.

The compounds of the general formula (1) represented by the following general formula (1-d) include suitable polyamines of the following general formula (i), for example, emulsified carbons, thiourea, carbonothiodichromide, ammonium thiocyanate, and the like. Prepared by ring closure as the same sulfur-containing cyclic burner.

Compounds of the general formula (1) represented by the following general formula (1-e) are exemplified by S-alkylation of the corresponding compound of the general formula (1-d) according to a standard S-alkylation process. d) is prepared by reacting with a suitable halo lower alkane or a suitable di (lower alkyl) sulfate.

Starting materials used in the preparation are obtained according to the following process described below.

Aroyl aziridine intermediates of the general formula (II), which are known compounds, are formulated in the presence of a suitable formula (V) in the presence of a suitable base, for example by neutralizing the acid liberated during the reaction by applying known processes described in the literature. Aroyl halides of) are readily prepared by reacting with aziridine. The reaction is carried out in a suitable solvent system such as, for example, a mixture of water and tricrotomethane, which reaction is illustrated by the following scheme.

Some intermediates of general formula (IV) described in the literature can be prepared by, for example, the appropriate aminoalkanols of general formula (A) with the appropriate alloyl halide (V) or with the appropriate lower alkyl of general formula (III) N-alloylated with arylcarboxylate, followed by conversion of the hydroxyl groups on the alkyl side chains obtained (XI) to reactive esters according to known processes. In the preparation of halides, conventional halogenating agents are used, for example carbonic dichloride, sulfinyl chromide, sulphryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride. It is prepared from the corresponding chromide or iodide by replacing halogen with iodine when the reactive ester is iodide. Other reactive esters such as methanesulfonate and 4-methylbenzenesulfonate are obtained by reacting alcohols with, for example, methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride. The reactions can be described by the following schemes.

Compound (IV-a) of Formula (IV), wherein the valent is halo, is, for example, N, N-dimethylformamide (DMF) and N, N-dimethylacetamide angles in N, N-diethylethanamine in a suitable solvent. A suitable aroyl halide (V) is obtained in one step by reaction with a suitable halo-alkanamine (XII) in the presence of the same suitable base.

The reaction is carried out in an alkali medium and the corresponding marziridine of formula (II) is obtained by using an intermediate of formula (XII) wherein R is hydrogen and n is 2.

Intermediates of formula (VI) are prepared as follows.

By reacting a suitable lower alkyl N- (haloalkyl) carbamate of the general formula (XIII) with a suitable piperidine derivative of the general formula (III) according to a conventional N-alkylation process, for example, the reactants may be reacted together appropriately. Reaction by heating in an organic solvent, i.e., lower alkanol such as methanol or ethanol, to give a carbamate of the general formula (XIV), and then hydrolyzing the acid or alkali to decarboxylation, resulting in the desired intermediate of the general formula (VI). To obtain.

In carrying out alkali hydrolysis, metal bases such as sodium hydroxide and potassium are used. Acids that can be used for acid hydrolysis include strong inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like.

가 하기 일반식을 갖일 때 (XⅢ) 대신에 해당하는 페닐메틸카르바메이트를 사용하는 것이 적당하고 이러한 경우 다음의 탈카르복실화는 활탄상의 팔라듐 같은 적당한 촉매를 사용하여 촉매적 수소화에 의하여 실시한다.In intermediate (VI)

It is suitable to use phenylmethylcarbamate instead of (XIII) when the following general formula has the following formula, in which case the following decarboxylation is carried out by catalytic hydrogenation using a suitable catalyst, such as palladium on charcoal. do.

Intermediates of formula (VI) are additional forms of the invention as novel and useful intermediates for preparing compounds of formula (1).

The intermediate of formula (VII) reacts N- (2-nitrophenyl) -4-piperidineamine of formula (XV) with aziridine of formula (II) or a reactive ester of formula (IV) Aroyl alkyl is introduced into the general formula (XV) N- (2-nitrophenyl) -4-piperidineamine, and then the nitro bacteria of (XVI) obtained are reduced according to the standard procedure of reducing the above-mentioned nitro to amine. Faint by catalytic hydrogenation using a suitable catalyst such as palladium.

Intermediates of formula (VI) are additional forms of the invention as novel and useful intermediates for preparing compounds of formula (1).

The intermediate of formula (VII) reacts N- (2-nitrophenyl) -4-piperidineamine of formula (XV) with aziridine of formula (II) or a reactive ester of formula (IV) Reduction was carried out according to the standard procedure of introducing aroyl alkyl into the general formula (XV) N- (2-nitrophenyl) -4-piperidineamine and then reducing the nitro group of (XVI) obtained to the above-mentioned nitro to amine. Prepared by reduction according to standard processes of reducing to amines.

The starting materials of the general formula (III) represented by the following general formula and their preparation methods are listed in the following documents.

a) US Patent 3,238,216

b) US Patent 3,161,645

Belgium Patent 830,403

c) US Patent 3,518,276

U.S. Patent 3,575,990

The starting materials of general formula (III) represented by the following general formulas (III-d) and (III-e) are generally suitable N- (2-aminophenyl) -4-piperidine of general formula (XVII) Prepared starting from amines.

The starting material (III-d) is prepared by cyclizing (XVII) with a suitable cyclizing agent such as carbon wed and then removing the lower alkyloxycarbonyl of (XVIII) obtained by alkali hydrolysis.

The starting material (III-e) is a lower alkyloxycarbo of (XIX) obtained after S-alkylation of (XVIII) as described for the preparation of (1-e) starting from (1-d) Produced by removing the Neal group.

N- (2-aminophenyl) -4-piperidineamine of the general formula (XVII), a known compound, is prepared according to the processes described in US Pat. No. 3,910,930 and Belgian Patent 830,403.

The process is illustrated by the following scheme.

The intermediates of the general formula (III) represented by the following general formula (III-f) are prepared as follows.

The corresponding N- (2-aminophenyl) -1- (phenylmethyl) -4-piperidinamine of the general formula (XX) is subjected to the corresponding 1- by cyclizing it with a suitable cyclic agent such as cyanamide, as is known. (XXI) obtained by converting to 1- (phenylmethyl) -4-piperidinyl-1H-benzimidazol-2-amine (XXI) and acylating agent derived from a suitable lower hydroxyalkyl acid such as halide Acylation with anhydride affords the intermediate of formula (XXII). And the desired (III-f) is obtained by removing the phenylmethyl group of (XXII) by catalytic hydrogenation with a suitable catalyst, such as palladium on charcoal.

Intermediates (XXI) are also suitable cyclic agents such as those known to prepare 2-benzimidazole carbamates starting from 1,2-benzenediamine (XX) such as lower alkyl (iminome) of general formula (XXIII). Lower alkyl 1,3-dihydro-1-1- (phenylmethyl) -4-piperidinyl-2H-benzimidazole-2-iriden carbamate (by cyclizing to methoxymethyl) carbamate XXIV), which is then prepared by decarboxylation by acid hydrolysis.

The reaction is illustrated by the following scheme.

The starting material of the general formula (XX) is, for example, a condensation of 1- (phenylmethyl) -4-piperidineamine with a suitable 2-halo-nitro benzene of general formula (XXV), and then the nitro group of (XXVI) obtained Obtained using known methods such as by reduction by catalytic hydrogenation using a suitable catalyst such as ranei-nickel.

In the above processes are usually known and can be prepared according to known methods.

이 일반식(Ⅲ-c)를 갖이며 R⁵가 메틸인 일반식(1)의 화합물들은 그들의 구조내에 2개의 비대칭 탄소 원자가 존재하므로 상이한 입체화학적 및 광학적 이성체가 존재한다.Food

Compounds of formula (1) having this formula (III-c) and wherein R ⁵ is methyl have two asymmetric carbon atoms in their structure and therefore have different stereochemical and optical isomers.

Depending on the relative position of methyl and hydroxyl groups with respect to the plane of the piperidine nucleus, the compounds have a cis or trans configuration and each of these forms has two optical isomers. Stereochemical and optical isomers of these compounds that fall within the scope of the present invention are prepared according to methods known in the art. It is with the cis obtained compound and these precursors. The obtained compounds and cis and trans isomers of these precursors can be obtained separately by physical methods such as selective crystallization. Regardless of their actual stereochemical configuration, the first separated form is called the A-form and the remainder is called the B-form. Since the compounds involved are basic, their optical isomers are obtained using optically active acids for the resolution of racemic and trans.

The compounds of the present invention may be selected from suitable acids such as hydrochloric acid, halogenated acids such as bromic acid, sulfuric acid, nitric acid, phosphoric acid and the like and vinegar-propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopro Panoic acid, propanedioic acid, butanedioic acid, (Z) -2-butanedioic acid, (E) -2-butenedioic acid, 2-hydroxybutenedioic acid, 2,3-dihydroxybutenedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxybenzeneacetic acid methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, 4-methylbenzenesulfonic acid, Treatment with organic acids such as cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxy benzoic acid can be converted to their pharmaceutically useful acid addition salts and conversely the salt forms are treated with alkali. By the free base form.

Compounds of formula (1) and their pharmaceutically active acid addition salts have potent vomiting inhibitory effects, as is evident by their action of inhibiting apomorphine, which causes vomiting in dogs. The method used was P.A.J. Xansen and C.J.E. Arzneim by Niemegies. Forsch (drug Res), 9 765-767 (1959).

The compounds listed below are injected subcutaneously into Beagle dogs at different dosages and a standard dose of apomorphine at 0.31 mg / kg after 1 hour.

The table below gives the ED ₅₀ values for many compounds. As used herein, the ED ₅₀ value indicates the dose that protected 50% of the animal from vomiting.

The compounds shown in the following table are not listed for the purpose of limiting the present invention but are intended to explain the anti-emetic properties of all compounds within the range of the general formula (1).

TABLE I

TABLE II

TABLE III

Table IV

Compounds of formula (1) are potent neurostabilizers and are therefore useful for the treatment of mental abnormalities such as mental abnormalities and schizophrenia. Neural stabilization of the compound (1) was demonstrated by test data obtained in the apomorphine test in mice exhibiting sedation against the central nervous system. The test was carried out according to the process described below and the test data obtained were summarized in Table 4, wherein the compounds were referenced to the corresponding structural formulas in Tables 1-IV.

The compounds listed in Table V are not given for the purpose of limiting the invention and are intended to illustrate the useful neurostable action of all compounds within the scope of formula (1).

Apomorphine Test in Rats

The test animals used in this study were mature male Wistar rats (240 ± 10 g body weight). After overnight fasting, animals were injected subcutaneously with an aqueous solution of the compound (1 mL / 100 g), placed in a separate observable box, and 30 minutes later, intravenously injected with 1.25 mg / kg of apomorphine hydrochloride, and the rats were apomorphine-containing. Observe over 1 hour for the phenomena causing, ie, the presence or absence of tilting and habitual chewing. Table V is given as the lowest effective dose (LED), or dose level, and their effects are statistically different from those observed in the corresponding untreated comparative animals (fish probability test).

TABLE IV Anti-apomorphine action of Compound (1) on rats

In view of their useful anti-nausea and psychostable effects, the compounds can be formulated into various pharmaceutical forms depending on the purpose of the supplement. To prepare a pharmaceutical composition of the present invention, an effective nausea suppressor or psychostabilizing amount of a specific compound in the form of a base or acid-addition salt as a working ingredient is mixed with a pharmaceutically acceptable carrier and the carrier can be used in a wide range depending on the form suitable for the desired diet. Can take the form. These pharmaceutical compositions are preferably in unit dosage form suitable for feeding by oral or parenteral injection. For example, in the preparation of compositions in oral dosage form, oral liquid products such as suspensions, syrups, essences and solutions, for example, conventional pharmaceutical media such as water, glycol, oils, alcohols and powders, pills, capsules and In the case of tablets, solid carriers such as starch, sugar, talc, lubricants and binder disintegrators are used. Because of ease of feeding, tablets and capsules are the best oral dosage forms, in which case solid pharmaceutical carriers are used. In the case of parenteral compositions, most of it was disinfected water along with other ingredients to increase the solubility of the carrier. Injectable solutions consist of a carrier in saline solution, glucose solution or a mixture of saline and glucose, and injectable suspensions are prepared using suitable liquid carriers, suspending agents and the like. Acid addition salts of the general formula (1) having a higher solubility in water than the corresponding base forms are more suitable for the preparation of the water-soluble composition.

It is particularly suitable to make the above-mentioned pharmaceutical compositions in unit dosage form which is easy to feed and can provide uniformity of dosage.

Unit dosage forms as used herein and in the claims are physically discrete units suited for unit dosage, each unit comprising a predetermined amount of active ingredient calculated to achieve the desired pharmaceutical effect with the desired pharmaceutical carrier. Examples of such unit dosage forms include tablets, capsules, pills, powder packaging, injectable solutions or suspensions, chilled water, filled with sake.

The amount of active ingredient per unit dose for prophylactic or neurostable purposes is 1-200 mg, especially about 5-100 mg.

The following forms are examples of preparing traditional anti-emetic and neuro-stable pharmaceutical compositions in unit dosage forms suitable for systematic feeding to animals and humans.

[Oral drop]

The following form is 5 ml of N {1- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-ylpipet as an active ingredient per ml. A 10 L oral drop solution containing ridinyl] ethyl} -4-fluorobenzamide is prepared.

10 l with pyrogen-free water

Methyl and propyl 4-hydroxy benzoate are dissolved in 5 L of boiling pyrogen-free water, cooled to about 50 ° C., and 2-hydroxy propanoic acid is added with stirring followed by the addition of the active ingredient. The solution is cooled to room temperature and the pyrogen-free water is replenished to a certain volume, then the solution is sterilized by filtration (U.S.P. XVII p.811) and filled into sterilized containers.

[Injection amount]

The oral drop solution described above may be used as an injection solution.

[capsule]

Each capsule contains 20 mg of N {1- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1 as the active ingredient (A, I). 10,000 hard gelatin capsules containing -piperidinyl] ethyl} -4-fluorobenzamide are prepared from the following composition.

A homogeneous mixture of active ingredients and supplements is prepared and filled in a two-sided hard gelatin capsule.

[refine]

Each tablet is 25 mg of N {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-ylpiperidinyl as an active ingredient. 5,000 pressure gauges, including] ethyl} -4-fluorobenzamide, are prepared from the following compositions.

The fine powder components are mixed well into granules with 10% starch paste, the granules are dried and compressed into tablets.

[Oral suspension]

15 mg of N {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimi per 15 mg (5-ml) as tangible ingredient (A, I) in the following form A 5 L oral suspension is prepared comprising dazol-1-yl) -1-piperidinyl] ethyl} -4-pululobenzamide.

Parabens are dissolved in polystyrene glycoside and this solution is added to a solution of sodium cyclomate, sodium saccharin and sugar in half water. Bentonite is suspended in hot (about 85 ° C.) water, stirred for 60 minutes and then added to the solution. The sulfo rosinate is dissolved in a little water, and then the active ingredient is suspended in the obtained solution and mixed well after addition of an antifoam A.F.emulsion diluted to a Roesch form with a minimum amount of water. The suspension of the obtained active ingredient is added to the above solution, mixed well, and then FD C yellow 5 dissolved in a small amount of water is added, orange fragrance is added, the water is filled to a certain volume and stirred until a homogeneous mixture is obtained. The mixture is passed under a colloid and filled into a suitable container.

In view of the anti-vomiting effect of the present invention, the present invention provides an effective anti-vomiting amount of the compound of formula (1) and their pharmaceutically acceptable acid addition salts with a pharmaceutical carrier, and warm blood suffering from vomiting by systematic feeding. An animal is provided with a method of inhibiting vomiting. In addition, in view of the neurostabilizing action of the compound, the present invention provides a method for treating mentally psychiatric disorders by systematically feeding an effective mental disease inhibitory amount of the compound of formula (1) and their pharmaceutically acceptable acid addition salts in combination with a pharmaceutical carrier. Provided are methods for treating abnormal warm blooded animals.

The following examples are intended to illustrate and not limit the scope of the invention and all parts are by weight unless otherwise indicated.

Example 1

To a stirring mixture of 76 parts of 4-fluoro-2-nitrobenzoic acid and 225 parts of benzene were added dropwise 71 parts of sulfinyl chloride, followed by stirring at reflux for 5 hours and at room temperature overnight. Evaporating the reaction mixture, putting the residue into benzene and repeating the evaporation of benzene twice gives 85 parts of 4-fluoro-2-nitrobenbenzoyl chromide as a residue.

Example 2

16 parts of sodium bicarbonate were added to 231 parts of arizine 0.95 m solution in water with stirring at 0 ° C., followed by 36 parts of 4-fluoro-2-methoxy benzoyl chromide in 150 parts of trichloromethane while maintaining at 0 ° C. The solution is added dropwise over 45 minutes and then stirred for 30-45 minutes without cooling. The reaction mixture was adjusted to pH 8 with dilute sodium hydroxide solution, the product was extracted three times with trichromemethane, and the combined extracts were washed three times with water, dried, filtered and evaporated to give 40.5 parts of 1- (4-fluoro-2) as a residue. -Methoxybenzoyl) aziridine is obtained.

Example 3

The following 1- (anyl carbonyl) aziridine is prepared by following the process of formula 2 and using the equivalent arylcarbonyl fluoride equivalents in place of the 4-fluoro-2-methoxybenzoyl fluoride used.

1- (2-hydroxybenzoyl) aziridine: residue

1- (4-Pluoro-2-nitrobenzoyl) aziridine: residue

1- (2-thienylcarbonyl) aziridine: residue

1- (5-Chloro-2-methoxy-4-nitrobenzoyl) aziridine

Example 4

12.94 parts ethyl (2-bromoethyl) carbamate, 13.51 parts 1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-one, 10.1 parts sodium bicarbonate and 160 parts The mixture of ethanol is stirred and refluxed overnight. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is purified by column-chromatography on silica gel using a mixture of trichloromethane, 10% methanol and 1 drop of ammonium hydroxide as eluent. Collecting pure fractions and evaporating the eluate gave 4.4 parts of ethyl 2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethylcarb as a residue. Obtain a barmate.

0.333 parts of ethyl 2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethylcarbamate, 1.65 parts of 48% bromic acid and 0.11 The mixture of portions of water is stirred and refluxed for 2 hours. Bromic acid and water are evaporated, the residue is placed in benzene and evaporated three times and the oily residue is crystallized from 2-propanol. The product was filtered and recrystallized from a small amount of ethanol and 0.27 parts 1- [1- (2-aminoethyl) -4-piperidinyl] -1,3-dihydro-2H-benz having a melting point of + 300 ° C (decomposition) Obtain imidazole-2-one dihydro bromide.

Example 5

To a stirred cooling (ice-bath) mixture of 87 parts 2-chloroethaneamine hydrochloride and 300 parts trichloromethane, 224.2 parts N, N-diethylethanamine is added and 300 parts trichloromethane is added again. After the addition, 96 parts of 2-furancarbonyl chloride solution in 300 parts of trichloromethane was added dropwise over 1.50 hours at a temperature of 5 ° C. or lower, followed by stirring overnight at room temperature. The reaction mixture is poured into water, the layers are separated, the aqueous layer is extracted with trichloromethane, and the combined organic phases are washed with water, diluted hydrochloric acid solution and then twice with water, dried and filtered to evaporate. The residue was purified by column-chromatography on silica gel using a mixture of trichloromethane and 2% methanol as eluent and then pure fractions collected to evaporate the eluent to give 95 parts of N- (2-chloro) as a residue. Ethyl) -2-furancarboxamide is obtained.

Example 6

To a stirring and cooling mixture of 32 parts 2-bromoethanamine hydrobromide in 150 parts water, a solution of 23.5 parts 4-fluluoro-2-nitrobenzoyl chromide in 54 parts benzene was added and maintained at 0-5 ° C. and stirred 13 parts of sodium hydroxide solution in 200 parts of water was added dropwise, followed by stirring at 0-10 ° C. for 2 hours. The precipitated product was filtered off, washed with water and dried to afford 30 parts (93.6%) of N- (2-bromoethyl) -4- pulluro-2-nitrobenzamide.

Example 7

To a stirred solution of 21 parts sodium hydroxide in 75 parts water is added 29 parts 2-chloroethaneamine hydrochloride solution in 75 parts water) and the whole is stirred at 90 ° C. for 10 minutes. After cooling to 0 ° C., 19 parts of sodium bicarbonate was added, and 49 parts of 2.5-dichlorobenzoyl fluoride solution in 75 parts of trichloromethane were added dropwise over 45 minutes at a temperature of 0 ° C. under vigorous stirring. It is then stirred for 30 minutes without cooling. The reaction mixture was warmed to 25 ° C., adjusted to pH 8 using dilute sodium hydroxide, the product was extracted three times with trichloromethane, and the combined extracts were washed three times with water, dried and filtered to evaporate. Obtain (2,5-dichlorobenzoyl) aziridine.

Example 8

A mixture of 72 parts methyl 2-pyridinecarboxylate and 32 parts 2-aminoethanol is stirred and refluxed for 2 hours and the reaction mixture is cooled and poured into water. The product is extracted three times with trichloromethane and the combined extracts are filtered dry and evaporated to yield 49 parts of N- (2hydroxyethyl) -2-pyridinecarboxamide as a residue.

80 parts of sulfinyl chloride are added dropwise to 49 parts of N- (2-hydroxyethyl) -2-pyridinecarboxamide while stirring, followed by stirring for 3 hours at reflux and 2 hours at room temperature. Excess sulfinyl chloride was evaporated, the residue was poured into hot methanol, cooled and the precipitated product was filtered (keeping filtrate) and washed thoroughly with 2,2'-oxybispropane to 14 parts N- (2-chloro Obtain the first fraction of roethyl) -2-pyridinecarboxamide hydrochloride. The filtrate was stirred with 2,2'-oxybis propane and the precipitated product was filtered off and dried to obtain a second fraction of 30 parts of N- (2-chloroethyl) -2-pyridinecarboxamide hydrocoxide. To obtain.

Example 9

A mixture of 5.5 parts methyl 1-methyl-1H-pyrrole-2-carboxylate and 2.4 parts 2-aminoethane is stirred and refluxed for 2 hours. The reaction mixture was evaporated to dryness, added to the residue and then evaporated twice, then the residue was subjected to column-chromatography on silica using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. To purify. Pure fractions are collected, the eluate is evaporated and the residue is placed in petroleum ether and scraped to solidify the product. This is filtered and dried to obtain 1.9 parts of N- (2-hydroxyethyl) -1-methyl-1H-pyrrole-2-carboxamide having a melting point of 78.1 占 폚.

One drop of pyridine is added to a stirring solution of 40 parts of N- (2-hydroxyethyl) -1-methyl-1H-pyrrole-2-carboxamide in 450 parts of trichloromethane, and 28.3 parts of sulfinyl chloride ( Slightly exothermic: temperature rises from 15 ° C. to 25 ° C.) over 30 minutes and then stirred at room temperature overnight. The reaction mixture is evaporated and the residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (96: 4 in volume) as eluent.

Pure fractions were collected to evaporate the eluent and the residue was stirred in 2,2′-oxybispropane and the product was filtered and dried to give 15 parts of N- (2-chloroethyl) -1-methyl-1H-pyrrole- Obtain 2-carboxamide

Example 10

12.94 parts ethyl (2-bromoethyl) carbamate, 15.68 parts 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-one, 10.08 parts A mixture of sodium bicarbonate and 160 parts of ethanol is stirred and refluxed overnight. The precipitate formed is filtered off, washed with trichloromethane, the layers are separated from the filtrate, the organic phase is dried, filtered and evaporated. The residue was stirred in 2-propanol and the unreacted starting material was filtered off and the filtrate was purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 in volume) as eluent. do. Pure fractions were collected to evaporate the eluate, the residue was crystallized from 70% ethanol and the product was filtered and dried to give 6.5 parts of ethyl {2- [4- (5-chloro-2,3-dihydro with a melting point of 187.7 ° C. 2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} carbamate.

6.6 parts of ethyl {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} carbamate, 60 After stirring and refluxing a mixture of 48% bromic acid and 4 parts of water for 2.50 hours, cooling, and the precipitated product was filtered and crystallized from water. 5.5 parts of 1- [1- (2-aminoethyl) -4- Piperidinyl] -5-chloro-1,3-dihydro-2H-benzimidazole-2-onedihydro bromide is obtained.

Example 11

A mixture of several potassium iodide crystals in 38 parts of 1- (phenylmethyl) -4-piperidine amine, 40 parts of 2-chloronitrobenzene, 32 parts of sodium carbonate, and 320 parts of cyclohexane was stirred and refluxed for 22 hours. After cooling, 300 parts of water was added, the organic layer was separated, diluted with 160 parts of benzene, and the whole was washed three times with 150 parts of water. The organic phase is dried over magnesium sulfate, filtered and evaporated and the residue is dissolved in a mixture of 40 parts 2,2'-oxybispropane and 160 parts hexane. After cooling to -15 ° C, the precipitate is filtered and the filtrate is stored. The precipitate was recrystallized from 160 parts of 2,2'-oxybispropane and filtered to give 18.5 parts of N- (2nitrophenyl) -1- (phenylmethyl) -4-piperidinamine having a melting point of 93.4-94.6 ° C. Get

The combined mother liquor was diluted with 2,2'-oxybispropane to introduce a dry hydrogen chloride gas, the precipitated hydrochloride salt was filtered off, washed with 120 parts of water, and the insoluble portion was dried, and the melting point was 206-220 ° C. 18 parts N- (2-nitrophenyl) -1- (phenylmethyl) -4-piperidiamine hydrochloride is obtained.

정도로 농축하면 용융점이 108-109°C인 2,5부의 N-[1-(페닐메틸)-4-피페리디닐]-1,2-벤젠디아민의 둘째 분율을 수득한다.A 31 part N- (2-nitrophenyl) -1- (phenylmethyl) -4-pipedidiamine solution in 160 parts tetrahydrofuran is hydrogenated with 20 parts Lanei-Nickel catalyst at normal pressure and at a temperature of 40 ° C. After taking the calculated amount of hydrogen (3 water) the hydrogenation is stopped, the catalyst is filtered off and the solvent is evaporated from the filtrate. Washing the solid residue with 160 parts 2,2'-oxybispropane yielded 22 parts N- [1- (phenylmethyl) -4-piperidinyl] -1.2-benzenediamine with a melting point of 112-113 ° C. . The filtrate is about its capacity

Concentration to degree yields a second fraction of 2,5 parts N- [1- (phenylmethyl) -4-piperidinyl] -1,2-benzenediamine having a melting point of 108-109 ° C.

5 parts N- [1- (phenylmethyl) -4-piperidinyl] -1,2-benzenediamine 2, 35 parts methyl (iminomethoxymethyl) carbamate, 5 parts vinegar and 75 parts trichloromethane The mixture is stirred and refluxed for 48 hours. The reaction mixture is evaporated, the residue is placed in water and the solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column-chromatography on silica gel with a mixture of methane and methanol (95: 5 in volume) as trichloro as eluent. Collecting pure fractions and evaporating the eluate gave 1.75 parts of methyl {1,3-dihydro-1- [1- (phenylmethyl) -4-piperidinyl] -2H-benzimidazole-2 with a melting point of 169.7 ° C. -Iriden} carbamate.

3.64 parts of methyl {2,3-dihydro-1- [1- (phenylmethyl) -4-piperidinyl] -1H-benzimidazole-2-yriden} carbamate, 24 parts hydrochloric acid solution and 40 parts The mixture of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is dissolved in water and then the solution is alkaline with concentrated ammonium hydroxide solution. The precipitated product was filtered, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. As a residue, 2.1 parts of 1- [1- (phenylmethyl) -4-piperidinyl] -1H-benzimi Obtain dazol-2-amine.

A mixture of 2 parts 1- [1- (phenylmethyl) -4-piperidinyl] -1H-benzimidazol-2-amine, 3 parts vinegar anhydride and 45 parts methylbenzene is stirred and refluxed for 3 hours. The reaction mixture is evaporated and water is added to the residue and the whole is alkaline with concentrated ammonium hydroxide solution. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from 2,2-oxybispropane and dried. 0.8 parts of N- {1,3-dihydro-1- [1- (phenylmethyl) having a melting point of 189.2 ° C ) -4-piperidinyl] -2H-benzimidazole-2-iridene} acetamide.

A mixture of 12 parts N- {1,3-dihydro-1- [1- (phenylmethyl) -4-piperidinyl] -2H-benzimidazole-2-iriden} acetamide and 120 parts methanol is usually Hydrogenate as 5 parts 10% palladium-activated carbon catalyst at pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, and the product was filtered to recrystallize from a mixture of ethanol and 2,2'-oxybispropane. 2.6 parts of N having a melting point of 164.5 ° C. -[1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-iridene] acetamide is obtained.

Example 12

1.68 parts 1- (4-fluorofluoroyl) aziridine, 2.5 parts 1- (4-fluorofluoro) -1,3,8-triazaspiro [4,5] -decane-4-one, 10.8 A mixture of parts benzene and 1.6 parts methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and acidified with 2-propanol previously saturated with hydrogen chloride gas. The hydrochloride salt formed was filtered and crystallized from a mixture of ethanol and water (8: 2 by volume), followed by drying to find 2.4 parts of 4-fluoro-N [2- [1-4-furuo with a melting point of 279.6 ° C. Rophenyl) -4-oxo-1,3,8-triazaspiro [4,5] dec-8-ylethyl} benzamide hydrochloride is obtained.

Example 13

A mixture of 0.74 parts 1- (benzoyl) aziridine, 1.16 parts 1-phenyl-1,3,8-triazaspiro [4,5] decane-4-one, 7.2 parts benzene and 0.8 parts methanol was refluxed for 2 hours and Stir. The reaction mixture is cooled to add 1,1'-oxybisethane and the whole is boiled in ethyl acetate. After cooling, the precipitated product was filtered and crystallized from 70% ethanol and dried in vacuo at 80 ° C. to 0.67 parts of N- [2- (4-oxo-1-phenyl1,3,8- Triazaspiro [4,5] dec-8-yl) ethyl] benzamide-de is obtained.

Example 14

The following compounds are prepared in the form of a base, or in the form of an acid addition salt by reacting the base with a suitable acid, using the process of Example 13 and using an equivalent equivalent starting material.

Example 15

1.2 parts N- (2-bromoethyl) -2-nitrobenzamide, 1.15 parts 1-phenyl-1,3,8-triazaspiro [4,5] decane-4-membered and 45 parts N, N- The mixture of dimethylformamide is stirred and refluxed for 3 hours. After stirring for 1 hour at room temperature and evaporating N, N-dimethylformamide under vacuum at 80 ° C., the residue is boiled in a mixture of 2-propanol and water and the unreacted starting materials are filtered off. The filtrate is concentrated to half of this and 2-propanol is added to the concentrate. The precipitated product was filtered off and dried to 7 parts 2-nitro-N- [2- (4-oxo-1-phenyl-1,3,8-triazaspiro 4,5 deck-8-yl having a melting point of 259.4 ° C. ) Ethyl] benzamide hydrobromide is obtained.

Example 16

6.9 parts N- (2-chloroethyl) -2-furancarboxamide, 0.2 parts 1-phenyl-1,3,8-triazaspiro [4,5] decane-4-one, 6.6 parts potassium iodide and A mixture of 135 parts of N, N-dimethylformamide is first stirred at reflux for 3 hours and at room temperature overnight. The reaction mixture is evaporated, the residue is taken up in water and the whole is alkaline, and then the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated and the residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (96: 4 in volume) as eluent. Collect pure fractions to evaporate the eluate and crystallize the solid residue from 2-propanone. The product was filtered off and dried to give 1.9 parts of N- [2- (4-oxo-1-phenyl 1,3,8-triazaspiro [4,5] deck-8-yl) ethyl] with a melting point of 186.3 ° C. -Furancarboxamide is obtained.

Example 17

Follow the process of Example XVI and replace N- (2-chloroethyl) -2-furancarboxamide with 1- (4- pullophenyl) -1,3,8-triazaspiro [4,5] decane. N- {2- [1- (4- pullophenyl) -4-oxo-1,3,8-triazaspiro [4,5] deck having a melting point of 254.2 ° C. by reaction with a 4-membered -8-yl] ethyl} -2-furancarboxamide hydrochloride is prepared.

Example 18

4.4 parts N- (2-chloroethyl) -2-pyridinecarboxamide, 13.8 parts 1-phenyl-1,3,8-triazaspiro [4,5] decane-4-one, 3,3 parts iodide A mixture of potassium and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is purified by column-chromatography on a silica gel using a mixture of trichloromethane and methanol (98: 2 in volume) as eluent.

Pure fractions were collected to evaporate the eluate, convert the residue to a hydrochloride salt in 2-propanol, and the salt was filtered and crystallized from ethanol to yield 1,1'part of N- [2- (4- Obtain oxo-1-phenyl-1,3,8-triazaspiro [4,5] deck-8 yl) ethyl] -2-pyridinecarboxamide dihydrochloride hydrate.

Example 19

3.75 parts N- (2-chloroethyl) -1-methyl-1H-pyrrole-2-carboxamide, 5 parts 1- (4-fluorophenyl) -1,3,8-triazaspiro 4,5 A mixture of decan-4-one, 1.7 parts sodium bicarbonate, 0.1 parts potassium iodide and 160 parts 4-methyl-2-pentanone is stirred and refluxed for 48 hours. Cool the reaction mixture and evaporate the solvent. The residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. Pure fractions are collected to evaporate the eluate and the residue is converted to the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt was filtered and crystallized from methanol. 0.8 parts of N-2- [1- (4-pulophenyl) -4-oxo-1,3,8-triazaspiro [4,5 having a melting point of 273.4 ° C. Deck-8-yl] ethyl} -1-methyl-1-pyrrole-carboxamide hydrochloride is obtained.

Example 20

8 parts 4-fluoro-2-nitro-N- [2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4,5] deck-8-yl) ethyl] benzamide, A mixture of 40 parts methanol and 90 parts tetrahydrofuran is hydrogenated with 3 parts Lanei-Nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue was converted to the hydrochloride salt in 2-propanol and the salt was filtered off and recrystallized from ethanol to give 1 part 2-amino-4- pullouro-N- [2- (4-oxo having a melting point of 167.3 ° C. -1-phenyl-1,3,8-triazaspiro [4,5] dec-8-yl) ethyl] benzamide hydrochloride is obtained.

Example 21

8 parts 4-Pluoro-N- {2- [1- (4-Pluorophenyl) -4-oxo-1,3,8-triazathro [4,5] dec-8-yl] ethyl } A mixture of 2-nitrobenzamide hydrochloride, 120 parts methanol and 25 parts water is hydrogenated as 5 parts Lanei-Nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue was crystallized from methanol, the product was filtered off and recrystallized from ethanol to give 1 part 2-aminol4-pullouro-N- {2- [1- (4-pululophenyl) -4- with a melting point of 223.5 ° C. Oxo-1,3-8-triazaspiro [4,5] tech-8-yl] ethyl} benzamide hydrochloride hydrate is obtained.

Example 22

6 parts 5-chloro-2-methoxy-4-nitro-N- [2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4,5] deck-8-yl ) A mixture of ethyl benzamide and 50 parts of vinegar acid is hydrogenated with 1 part of Raney-Nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue was poured into water, the whole was alkalized, and the precipitated crude was crystallized twice from ethanol. 1.7 parts of 4-amino-5-chloro-2-methoxy-N- [2 having a melting point of 247.4 ° C. were obtained. -(4-oxo-1-phenyl-1,3,8-triazaspiro [4,5] tech-8-yl) ethyl] to obtain a benzamide.

Example 23

Following the process of Example 22 and as starting material 5-chloro-N- {2- [1- (4-fluorofluoro) -4-oxo-1,3,8-triazaspiro [4,5] Deck-8-yl] ethyl} 2-methoxy-4-nitrobenzamide is used to convert the product obtained to a hydrochloride salt to 4-amino-5-chloro-N- {2 having a melting point of 239.8 ° C. Obtain [-(1- (4-Pluorophenyl) -4-oxo-1,3,8-triazaspiro 4,5 deck-8-yl] ethyl} -2-methoxybenzamide hydrochloride .

Example 24

9 parts N- {2- [1- (4-fluorofluorophenyl) -4-oxo-1,3,8-triazaspiro [4,5] deck-8-yl] ethyl-2-nitrobenzamide The mixture of hydrochloride and 150 parts of vinegar acid is hydrogenated with 2 parts of 10% palladium-activated carbon catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkaline with ammonium hydroxide and the product is extracted twice with trichloromethane. The combined extracts are washed twice with water, dried and filtered to evaporate. The solid residue is boiled in 2-propanol, filtered and left to crystallize from the filtrate. The product was filtered and dried in vacuo to give 5 parts 2-amino-N- {2- [1- (4- pullophenyl) -4-oxo-1,3,8-triazaspiro [1] with a melting point of 194.9 ° C. 4,5] tech-8-yl] ethyl} benzamide.

Example 25

9 parts 2-amino-4 pullo-N- {2- [1- (4 pullophenyl) -4-oxo-1,3,8-traazaspiro [4,5] tech-8-yl] ethyl } -Benzamide, a mixture of 8.5 parts vinegar anhydride and 85 parts water is stirred for 30 minutes in a water bath at 80 ° C. The reaction mixture is cooled to alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane and the combined organic phases are washed three times with water, dried and filtered and evaporated. The residue was crystallized from 2-propanol and the product was filtered and dried. 5.2 parts of 2-amino-4 pullolo-N- {2- [1- (4 pullophenyl) -4-oxo-1 having a melting point of 195.1 ° C. were obtained. , 3,8-traazaspiro [4,5] dec-8-yl] ethyl} benzamide.

Example 26

1.68 parts 1- (4-Pluorobenzoyl) aziridine, 2.5 parts 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-one, 10.8 A mixture of parts benzene and 1.6 parts methanol is stirred and refluxed for 1.50 hours. The precipitated product was filtered off, washed with 2-propanone and crystallized from 2-propanol to give 2.47 parts of N- {2- [4- (5-chloro-2,3-dihydro-2- with a melting point of 239.6 ° C. Oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullobenzamide.

Example XXVII

The acid is added in the form of an acid addition salt by following the process of Example XXVI and using the equivalent starting material to react the following compounds with free base or free base with a suitable acid.

Example XXVIII

Following the process of Example XXVI, (1-aziridinyl) (4- pullophenyl) methanone was replaced with N- [1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole N- [2- {4 (acetylamino) -2,3-dihydro-1H-benzimidazolyl-1-yl] -1 having a melting point of 216.9 ° C. by reacting with 2-iridene] acetamide -Piperidinyl} ethyl] -4- pullobenzamide is prepared.

Example XXIX

1.5 parts N- (2-bromoethyl) -2-nitro-benzamide, 1.55 parts 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2 -A mixture of the original and 27 parts of N, N-dimethylformamide is stirred and refluxed for 5 hours. The reaction mixture was evaporated and the oily residue was crystallized from ethanol to filter the product and dried to give 2.2 parts 671 of N- {2- [4- (5-chloro-2,3-di having a melting point of 273.2 ° C. Hydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -2-nitrobenzamide hydrobromide hemihydrate is obtained.

[Example XXX]

8.7 parts 4-Pluoro-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -2- A mixture of nitrobenzamide and 120 parts of methanol is hydrogenated with 2 parts of Raney-Nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated and the residue is crystallized from a mixture of methanol and 2-propanol. The product was filtered off and dried to give 4.5 parts 2-amino-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- with a melting point of 229.3 ° C. Piperidinyl] ethyl} -4- pullobenzamide is obtained.

[Example XXXI]

N- {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl according to the process of Example XXX ] -4-Pluoro-2-nitrobenzamide is hydrogenated and the resulting product is converted to hydrochloride salt as hydrochloric acid to yield ethyl} -4- pullobenzamide hydrochrom with a melting point of 250 ° C. Obtain a ride.

Example XXXII

16 parts N- {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl in 90 parts of tetrahydrofuran] A mixture of ethyl} -2-nitrobenzamide and 40 parts of methanol is hydrogenated with 3 parts of Raney-Nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen, a methanol solution previously saturated with ammonia gas is added, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in acidified water and washed twice with trichloromethane. The aqueous phase is separated, alkalined with dilute sodium hydroxide solution, the product is extracted twice with trichloromethane, and the combined extracts are washed three times with water, dried and filtered and then evaporated. The residue was triturated in 2,2-oxybispropane and the product was filtered and crystallized from a mixture of ethanol and a small amount of water to give 2 parts 2-amino-N {2- [4- (5-chloro- with a melting point of 226.8 ° C. 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl (-1-piperidinyl] ethyl} benzamide is obtained.

Example XXXIII

The following compounds were prepared from the corresponding nitro compounds according to the procedure of Example XXXII.

4-amino-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzoimidazol-1-yl) -1-piperidinyl] ethyl} -2-methoxybenzamide Hydrate: melting point 220.6 ° C. 2-amino-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} benzamide Hemihydrate: Melting point 219.2 ℃

Example XXXIV

4.2 parts 5-chloro-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -2-meth A mixture of oxy-4-nitrobenzamide and 150 parts of vinegar acid is hydrogenated with 1 part of Raney-Nickel catalyst at normal pressure and room temperature. After taking up the calculated amount of hydrogen, the catalyst is filtered off, the filtrate is evaporated, water is added to the residue and the whole is alkaline with dilute sodium hydroxide solution. The precipitated product was filtrated (the filtrate was stored), crystallized from methanol and then dried to give 0.8 parts of 4-amino-5-chloro-N- {2- [4- (2,3-dihydro) having a melting point of 230.1 ° C. -2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -2-methoxybenzamide.

The stored filtrate was concentrated and filtered to 1.6 parts 4-amino-5-chloro-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazole having a melting point of 232.5 ° C. -1-yl) -1-piperidinyl] ethyl} -2-methoxybenzamide.

Example XXXV

1.68 parts 1- (4-fluorobenzoyl) aziridine, 2.16 parts 1.3-dihydro-1- (3,6-dihydro-1- (2H) pyridinyl) -2H-benzimidazole-2-one , 10.8 parts benzene and 1.6 parts methanol were stirred and refluxed for 1.50 hours. After cooling, the precipitated product was filtered off, washed with 2-propanone and crystallized from ethanol. 1.76 parts of N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimimi having a melting point of 202.7 占 폚 was obtained. Dazol-1-yl) -3,6-dihydro-1- (2H) -pyridinyl] ethyl} -4- pullobenzamide is obtained.

Example XXXVI

1.68 parts 1- (4-Pluorobenzoyl) aziridine, 2.07 parts 2,3-dihydro-2-oxo-3- (4-piperidinyl) -1H-benzimidazole-1-propanenitrile hydrochrome Ride, a mixture of 1.65 parts N, N-diethylethanamine, 10.8 parts benzene and 1.6 parts methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled, poured into water, the product is extracted with trichloromethane, the extract is dried, filtered and evaporated. The residue was crystallized from 2-propanol to filter the product and recrystallized from 2-propanol to give 1 part N- [2- {4- [3- (2-cyanoethyl) -2,3-dihydro with a melting point of 172.2 ° C. -2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullobenzamide.

Example XXXVII

5.6 parts N- (2-chloroethyl) -1-methyl-1H-pyrrole-2-carboxamide, 6.52 parts 1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole A mixture of 2-membered, 2.52 parts sodium bicarbonate, 0.1 parts potassium iodide and 240 parts 4-ethyl-2-pentanone is stirred and refluxed for 62 hours.

The reaction mixture is cooled to evaporate the solvent and the residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. Pure fractions are collected to evaporate the eluate and the residue is converted to hydrochloride salt in ethanol, 2-propanol and 2,2'-oxybispropane. The salts were filtered to crystallize from a mixture of ethanol and 2,2'-oxybispropane, and 0.6 parts of N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimimi having a melting point of 237.7 ° C was obtained. Dazol-1-yl) -1-piperidinyl] ethyl} -1-methyl-1H-pyrrole-2-carboxamide hydrochloride hydrate is obtained.

Example XXXVIII

The following compound was prepared according to the process of Example XXXVII.

Reacts N- (2-chloroethyl) -3-pyridinecarboxamide hydrochloride with 1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-one N- {2- [4- (2,3-dihydro-2-1-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -3 having a melting point of 214.1 ° C. Pyridinecarboxamide dihydrocride hydrate:

N- (2-bromoethyl) -4-fuluro-2-nitrobenzamide to 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole- N- {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] by reaction with a 2-membered Ethyl} -4-Pluoro-2-nitrobenzamide

Example XXXIX

16 parts N- (2-bromoethyl) -4-fuluro-2-nitrobenzamide, 12.6 parts 5-chloro-1,3-dihydro-1- (4-piperidinyl) -2H- A mixture of benzimidazole-2-one and 216 parts N, N-dimethylformamide is stirred and refluxed for 3 hours. N, N-dimethylformamide is evaporated and the residue is purified by column-chromatography on a silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. Pure fractions are collected to evaporate the eluate and convert the residue to a hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered and crystallized from methanol, and 1.5 parts of N- {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) having a melting point of 276.8 ° C. was obtained. -1-piperidinyl] ethyl} -4- pullouro-2-nitro benzamide hydrochloride.

Example XL

2.2 parts N- (2-chloroethyl) -2-pyridinecarboxamide hydrochloride, 6.6 parts 1,3-dihydro-1- (4-piperidinyl) -2H-benzimidazole-2-one , A mixture of 1.66 parts of potassium iodide, and 120 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. After cooling, the precipitated product is filtered, dissolved in water, the solution is alkaline with sodium carbonate, and the product is extracted three times with 4-methyl-2-pentanone. The combined extracts were washed, dried over water, filtered and evaporated, and the residue was purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. Pure fractions were collected to evaporate the eluate and the residue was converted to hydrochloride salts in 2-propanone and 2-propanol and the salts filtered to ethanol and 2,2′-oxybispropane (1: 1 by volume). Crystallization from a mixture of 2 parts N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl having a melting point of 165.7 ° C. } -2-pyridinecarboxamide dihydro chromide dihydrate is obtained.

Example XLI

Following the procedure of Example XL and using N, N-dimethylformamide as the solvent, N- (2-chloroethyl) -2-furancarboxamide was added 1.3-dihydro-1- (4-piperidinyl) N- {2- [4- (2,3-dehydro-2-oxo-1H-benzidazol-1-yl) having a melting point of 231.7 ° C by reacting with -2H-benzimidazole-2-one Prepare piperidinyl] ethyl} -2-furancarboxamide.

Example XLII

1 part 2-amino-N- {2- [4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4-pulolo A mixture of benzamide, 1 part acetic anhydride and 15 parts water is stirred for 30 minutes in a water bath at 80-90 ° C. The reaction mixture is cooled to alkalinize with ammonium hydroxide solution and the product is extracted with trichloromethane. The extract was dried, filtered and evaporated, the residue was crystallized from 4-methyl-2-pentanone and the product was filtered and dried to yield 0.5 parts of 2- (acetylamino) -N- {2- [4 having a melting point of 210 ° C. -(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4-fuluro to obtain benzamide.

Example XLIII

2-amino-N- {2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-pipe according to the process of Example XLII 2- (acetylamino) -N- {2- [4-5-chloro- (2,3-dihydro-2) having a melting point of 196.5 ° C. starting from ridinyl] ethyl} -4-fulurobenzamide -Oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullobenzamide is prepared.

EXAMPLE XLIV

1.68 parts 4-Pluorobenzoyl Chloride, 4.22 parts 1- [1- (2-amino ethyl) -4-piperidinyl-1,3-dihydro-2H-benzimidazole-2-one dihydro bromide , 4.83 parts of potassium carbonate and 18 parts of N, N-dimethylformamide are stirred at 90 DEG C overnight. The reaction mixture is cooled and filtered, the filtrate is washed with a small amount of N, N-dimethylformamide, the N, N-dimethylformamide is removed in vacuo and water is added to the residue. The product was extracted with trichloromethane, the extract was dried, filtered and evaporated and the residue was crystallized from 2-propanol. 2.5 parts of N- {2- [4- (2,3-dihydro- with a melting point of 231 ° C. were obtained. 2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullobenzamide is obtained.

Example XLV

A mixture of 0.74 parts 1- (benzoyl) aziridine, 1.06 parts 4- (4-chlorophenyl) -4-piperidiol, 5.4 parts benzene and 0.4 parts methanol is stirred and refluxed for 2 hours. Cool the reaction mixture and add 1,1'-oxybis ethane to precipitate the product. After stirring for 15 minutes, the product was filtered and dried to give 1,1 'part N- {2- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] ethyl having a melting point of 169 ° C. } Obtain benzamide.

Example XLVI

The following compound is prepared in the form of an acid addition salt by following the process of Example XLV and using an equivalent equivalent starting material by reacting the free base form or base with a suitable acid.

Example XLVII

5.8 parts 2-amino-N- {2- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] ethyl} -4- pullobenzamide, 5.5 parts of acetic anhydride and The mixture of 55 parts of water is stirred for 30 minutes in a water bath at 80 ° C. The reaction mixture is cooled to alkaline with ammonium hydroxide and the product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane and the combined organic phases are washed three times with water, dried and filtered and evaporated. The oily residue was crystallized from 4-methyl-2-pentanone and the product was filtered and dried. 4.5 parts of 2- (acetylamino) -N- {2- [4- (4-chloro with a melting point of 175.1 占 폚 were obtained. Phenyl) -4-hydroxy-1-piperidinyl] ethyl} -4- pullobenzamide.

Example XLVIII

10.6 parts N- (2-bromoethyl) -2-nitrobenzamide, 9.2 parts A (±) -4- (4-chlorophenyl) -3-methyl-4-piperidinol and 270 parts N, N The mixture of dimethylformamide is stirred and refluxed for 4 hours. The reaction mixture is evaporated to dryness and the residue is purified by column-chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 in volume) as eluent. Pure fractions were collected to evaporate the eluate and the residue was converted to a hydrochloride salt in 2-propanol and the salts filtered to crystallize from a mixture of ethanol and 2,2'-oxybispropane (1: 1 in volume). . The product was filtered and dried overnight at 60 DEG C., 4.5 parts of A- (±) -N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl-1 having a melting point of 228 DEG C. -Piperidinyl] ethyl} -2-nitrobenzamide hydrochloride is obtained.

Example IL

Example N- (2-Bromoethyl) -4- pullouro-2-nitrobenzamide was prepared according to the process of Example XLVIII in A- (±) -4- (4-chlorophenyl) -3-methyl-4 -A- (±) -N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl-1-piperidinyl] ethyl} -4 by reaction with piperidinol -Pluoro-2-nitrobenzamide hydrochloride is prepared.

Example L

2.8 parts A- (±) -N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl-1-piperidinyl] ethyl} -4-pulluoro-2- A mixture of nitrobenzamide hydrochloride and 160 parts of methanol is hydrogenated with 2 parts of rani-nickel catalyst at normal pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated and the residue is converted to a hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered to crystallize from 2-propanol to give 1 part A- (±) -2-amino-N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl with a melting point of 185 ° C. -1-piperidinyl] ethyl} -4-pulorobebenzamide dihydrochromide 2-propanoate is obtained.

Example LI

A- (±) -N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl-1-piperidinyl] ethyl} -2-nitro according to the process of example L A- (±) -2-amino-N- {2- [4- (4-chlorophenyl) -4-hydroxy-3-methyl-1-piperidi having a melting point of 190.5 ° C. by hydrogenating benzamide Nil] ethyl} benzamide dihydro chromide.

Example LII

3.5 parts N- {2- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] ethyl} -2-nitrobenzamide, hydrochloride, 90 parts tetrahydrofuran and 40 The mixture of parts methanol is usually hydrogenated with 0.2 parts of platinum oxide at pressure and room temperature. Take the calculated amount of hydrogen and then filter the catalyst to evaporate the filtrate. The residue was converted to a hydrochloride salt in 2-propanol and 2,2'-oxybispropane and the salt filtered off and dried to give 2.6 parts 2-amino-N- {2- [4- (4 having a melting point of 195.7 ° C. -Chrophenyl) -4-hydroxy-1-piperidinyl] ethyl} benzamide dihydrochromide hemihydrate is obtained.

Example LIII

4.5 parts N- {2- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] ethyl} -4-fluoro-2-nitrobenzamide, 40 parts methanol and 90 parts tetra The mixture of hydrofuran is usually hydrogenated with two parts Lanei-Nigel catalyst at pressure and room temperature. After taking the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated and the residue is converted to the hydrochloride salt in 2-propanol. The salt was filtered off and dried to give 2 parts 2-amino-N- {2- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] ethyl} -4-pool having a melting point of 210.7 ° C. Luobenzamide dihydrochloride is obtained.

EXAMPLE LIV

The following compounds are obtained as hydrochloride salts following the process of Example XIV and using an equivalent equivalent starting material

N- {2- [1- (4-Chlorophenyl) -4-oxo-1,3,8-triazaspiro [4,5] deck-8-yl] ethyl} -4- pullobenzamide :

N- {2- [1- (4-Chlorophenyl) -4-oxo-1,3,8-triazaspiro 4,5 deck-8-yl] ethyl} benzamide:

N- {2- [1- (4-bromophenyl) -4-oxo-1,3,8-triazaspiro [4,5] deck-8-yl] ethyl} -4- pullobenzamide ::

2-Chloro-N- {2- [1- (4-chlorophenyl) -4-oxo-1,3,8-triazaspiro [4,5] -deck-8-yl] ethyl} -4 -Fluorobenzamide:

2-amino-N- {2- [1- (4-chlorophenyl) -4-oxo-1,3,8-triazaspiro [4,5] -deck-8-yl] ethyl} -4- Pulluorobesamide:

2-amino-N-2-1- (4-bromophenyl) -4-oxo-1,3,8-triazaspiro [4,5] dec-8-yl] ethyl} -4-pulluo Robbenzamide

Example LV

The following compounds of formula (1) are prepared following the process of Example XXVI and using an equivalent equivalent starting material.

N- {2- [4- {5-bromo-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullobenz Amide:

N- {2- [4- (2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4- pullorobenz Amide:

N- {2- [4- (4,5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl ethyl-4- Pulluorobesamide:

2-Chloro-N- {2- [4- (5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] Ethyl] -4-Pluorobenzamide:

2-amino- {N- [2-4- (5-bromo-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] ethyl} -4 -Fluorobenzamide:

N- {2- [3,5-Dihydro-4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- (2H) -piperidinyl] ethyl } -Benzamide:

2-amino-N- {2- [3,6-dihydro- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- (2H) pyridinyl] ethyl} 4-chlorobenzamide

2-Chloro-N- {2- [3,6-dihydro-4- (2, 3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- (2H) -pyri Diyl] ethyl} -4- pullorobebenzamide:

N- {2- [4- (5-Chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1- (2H) -pyridinyl] ethyl} -4 -Pluorobenzamide:

Example LVI

EXAMPLES The following compounds were prepared following the XLV process and using an equivalent amount of suitable starting material.

N- [2- {4- [4-Chloro-3- (trifuluromethyl) phenyl] -4-hydroxy-1-piperidinyl} ethyl] -4-fulurobenzamide

N-amino [2- {4- [4-chloro-3- (trifuluromethyl) phenyl] -4-hydroxy-1-piperidinyl} methyl] -4-fulurobenzamide

2-Chloro- [2- {4- [4-Chloro-3- (tripulouromethyl) phenyl} -4-hydroxy-1-piperidinyl} ethyl] -4-pululobenzamide

N- [2- {4- (4-bromophenyl) -4-hydroxy-1-piperidinyl] ethyl} -4- pullobenzamide

2-amino-N- [2- {4- (4-bromophenyl) -4-hydroxy-1-piperidinyl} -ethyl} -4- pullobenzamide

Claims (1)

Reaction of the following general formula (II) and the following general formula (III) in an inert organic solvent under the elevated temperature of N-[(I-piperidinyl) alkyl] arylcarboxamide having the following general formula (I) Manufacturing method.

In the food X is a suitable reactive ester group derived from the corresponding alcohol Ar is an aryl group selected from phenyl, substituted phenyl, 2-thienyl, 2-furanyl, pyridinyl and 1-methyl-2-pyrrolyl, wherein the substituted phenyl is halo, lower alkyl, lower alkyloxy, triful Selected from fluoromethyl, nitro, hydroxy, imino, lower alkylcarbonyloxy and lower alkylcarbonylamino and radical

Is selected from the following. a) a radical having the general formula

In the food R ¹ and R 2 are each independently selected from hydrogen, halo, lower alkyl, and trifuluromethyl. b) radicals having the general formula

In the above formula R ³ and R ⁴ are each independently selected from hydrogen, halo, lower alkyl, and trifluomethyl M is selected from hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanoethyl: Y is selected from OS and lower alkylcarbonyl imido and dotted line is a double bond between 3- and 4-carbon atoms of the piperidine nucleus Y is O and M is hydrogen if there is a double bond between 3- and 4-carbon atoms in the phase. c) radicals having the general formula

In the above formula R ³ and R ⁴ are each selected from hydrogen, halo, lower alkyl and trifluomethyl. d) radicals having the general formula

In the above formula R ⁵ is selected from hydrogen and methyl and R ⁶ is selected from hydrogen and halo: R ⁷ is selected from hydrogen halo, lower alkyl and trifluomethyl.