Derivatives of piperidine and pharmaceutical drugs based on them

 

(57) Abstract:

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate. The compounds of formula I possess antipsychotic activity and can find application in medicine. 2 S. and 6 C.p. f-crystals, 2 PL.

The invention relates to certain new derivatives of piperidine derivatives, to processes for their preparation, to their containing pharmaceutical preparations and to their use in medical therapy, particularly in the treatment of mental disorders.

In U.S. patent 2739968 described derivatives substituted piperidine having antihistaminic, antispasmodic, antiacetylcholine and pain-soothing activity.

In the British patent GB P> Effective antipsychotic (neuroleptic) agents include tricyclic phenothiazines, tioksantena and dibenzazepine and benzamide and butyrophenones. These compounds block the dopamine receptors D2 and inactivate the transfer of dopamine. As a result, these compounds cause characteristic neurological side effects in humans, such as extrapyramidal side effects such as dystonia and dyskinesia (R. J. Baldessarini, 1996, Goodman, Gilman's, The Pharmacological Basis of Therapeutics, 9-th ed. eds. J. G. Hardman et. al). In tests on animals such side effects were manifested in the form of catalepsy. Thus, there is a need for the development of a number of antipsychotic agents that do not have such negative side effects.

The present invention offers some derivatives of piperidine, which have a strong antipsychotic activity, but do not show cataleptic action, and, therefore, may not cause extrapyramidal side effects when used in therapeutic doses.

Thus, the present invention provides compounds of formula (I):

< / BR>
where substituent R1represents benzothiazol, benzofuranyl or naphthyl (where benzothiazolin what teli, choose from a halogen atom, a C1-6-alkoxygroup, C1-6-alkyl, C3-6-cycloalkyl and C1-6-alkenyl), substituted thienyl or substituted furanyl (where thienyl or farnily fragment substituted by one or more substituents selected from a halogen atom, a C1-6-alkyl, C3-6-cycloalkyl and C1-6-alkenyl);

Deputy R2represents a halogen atom, and

Deputy R3represents a C1-6-alkyl or C3-6-cycloalkenyl;

or their pharmaceutically acceptable salt or solvate.

The present invention includes derivatives of piperidine derivatives of the formula (I), where the substituent R1represents benzothiazol, benzofuranyl, naphthyl (where sensationally, benzofuranyl or nattily fragment can be optionally substituted by one or more substituents selected from a halogen atom or C1-6-alkoxygroup), substituted thienyl or substituted furanyl (where thienyl or farnily fragment substituted by one or more substituents selected from a halogen atom or C1-6-alkyl); Deputy R2represents a halogen atom and the substituent R3represents a C1-61represents benzothiazol, benzofuranyl (where sensationally or benzofuranyl fragment can be optionally substituted by one or more substituents selected from a halogen atom or C1-6-alkoxygroup), substituted thienyl or substituted furanyl (where thienyl or farnily fragment substituted by one or more substituents selected from a halogen atom or C1-6-alkyl); Deputy R2represents a halogen atom and the substituent R3represents a C1-6-alkyl.

Examples of the above compounds of formula (I) include derivatives of piperidine, as described in Examples 1-7.

As used in this description, the term "alkyl" means a linear or branched alkyl group. Such groups include methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and neohexyl. Such alkyl groups preferably represent FROM1-4is an alkyl group. To cycloalkenyl groups include cyclopropyl and cyclopentyl. WITH3-6-cycloalkylation group include cyclopropylmethyl and cyclopentylmethyl.

Examples alkenyl groups allawa least three carbon atoms. Such alkeneamine group preferably represents a C1-4-alkeline group. Examples of such alkenyl groups are vinyl, allyl, Isopropenyl, butenyl, Isobutanol, pentanol, isopentanol, hexanol, isohexanol and neohexene.

Definition alkoxygroup is understandable for a person skilled in the field of value and includes linear and branched groups. Examples of alkoxygroup are methoxy and ethoxypropan. The preferred alkoxygroup are1-4-alkoxygroup.

The term "halogen" includes chlorine atoms, bromine, fluorine and iodine.

Sensationally, benzofuranyl, nattily, substituted thienyl and substituted farnily fragments include 2 - and 3-benzothiazol, 2 - and 3-benzofuranyl, 2 - and 3-naphthyl, substituted 2-thienyl, substituted 3-thienyl, substituted 2-furanyl and substituted 3-furanyl. Deputy(s) in sensationalism, benzofuranyl, naftalina, thienyl and TuranAlem rings can be in any of the available positions. Specific examples of such substituents are fluorine atoms and chlorine and methoxy group.

A preferred example of the substituent R1is substituted thienyl, most before is the subject of atoms of halogen, preferably chlorine atoms, and C1-6-alkyl, preferably methyl and ethyl, most preferably methyl.

A preferred example of the substituent R2is a fluorine atom, most preferably 4-fluoro. Deputy R3preferably is the stands.

Preferred compounds in accordance with the present invention are the compounds of formula (I), where the substituent R1represents a substituted thienyl where the thienyl residue substituted by one or more substituents selected from a halogen atom and C1-6-alkyl; Deputy R2represents a halogen atom; and the substituent R3represents a C1-6-alkyl; or pharmaceutically acceptable salt or solvate.

Other preferred compounds of formula (I) are compounds where the substituent R1represents a substituted 2-thienyl where the thienyl residue substituted by one or more substituents selected from a chlorine atom and a methyl group; preferably 4-chloro and 4-methyl; Deputy R2represents a fluorine atom, preferably 4-fluoro; and the substituent R3represents methyl; or farmatsevticheskii invention, which, as installed, can be used in the treatment of mental illness are:

1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)]methyleneimine

1-methyl-4-[(4-methyl-2-thienyl)-(4-forfinal)]methyleneimine, as well as their pharmaceutically acceptable salt or solvate.

For therapeutic use of salts of compounds of formula (I) are salts in which the counterion is pharmaceutically acceptable. However, salts and acids, which are not pharmaceutically acceptable may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Examples of pharmaceutically acceptable acid additive salts are salts derived from mineral acids such as hydrochloric, Hydrobromic, uudistoodetena, phosphoric, metaphosphoric, nitric and sulfuric acid; and organic salts, such as tartaric, acetic, triperoxonane, citric, maleic, lactic, malonic, fumaric, benzoic, ascorbic, propionic, glycolic, gluconic, succinic acid, and methanesulfonanilide in accordance with the present invention are the acid additive salts of hydrochloric, maleic, succinic and fumaric acids.

The solvate of the present invention are hydrates. In accordance with another aspect of the present invention provides compounds of formula (I) and their pharmaceutically acceptable salt and solvate for therapeutic applications, more specifically, for the treatment or prevention of mental illness, such as schizophrenia, mania, increased activity, abuse of chemical substances, vomiting and the like schizophrenia disease.

The present invention also includes a method of treating animals such as mammals, including humans, suffering from or susceptible to mental illness, including the above-mentioned diseases, and this method includes the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES.

Another object of the present invention is the use of compounds of formula (I) or its pharmaceutically acceptable salt or MES in the production of pharmaceuticals for the treatment or prevention of any of these diseases.

The amount of the compounds of formula (I) or its pharmaceutically acceptable salts Electa, of course, will vary depending on the particular compound, its mode of administration, the age and condition of the patient, and the particular disorder or disease being treated.

Acceptable daily intake for each of these diseases will lie in the range of from 0.001 to 25 mg per kg of body weight of the patient (e.g., human) per day, preferably in the range from 0.1 to 10 mg/kg of body weight per day and most preferably in the range of from 0.25 to 5 mg/kg of body weight per day. The desired dose may be presented as one, two, three, four, five or more sub-doses prescribed at appropriate intervals throughout the day.

Although the active ingredient can be entered separately, it is preferable to prepare it in the form of a pharmaceutical preparation. Thus, the present invention also provides a pharmaceutical preparation containing the compound of formula (I) or its pharmaceutically acceptable salt or MES and a pharmaceutically acceptable carrier and optionally other therapeutic agents. The media is considered acceptable if it is combined with other ingredients and has no negative effects on patsie the material (including transdermal, transbukkalno and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal) introduction. Drugs can be obtained by any method known in the pharmaceutical field, for example, using methods described in Gennaro and other Remington''s Pharmaceutical Sciences (18th-th ed. Mack Publishing Company, 1990, see especially part 8 - "Pharmaceuticals and their acquisition"). These include the stage of combining the active ingredient with the carrier which consists of one or more accessory ingredients. To these auxiliary ingredients are common in this area ingredients, such as fillers, binders, diluents, dezintegriruetsja agents, lubricants, dyes, corrective taste and aroma additives and wetting.

Drugs, acceptable for oral administration, can be prepared as a separate standard dosage forms, such as pills, tablets or capsules that contain a predetermined amount of the active ingredient; in the form of powders or granules; as solutions or suspensions. The active ingredient can also be present in the form of a ball is ut to be received in the form of a suppository or enema. For parenteral use acceptable formulations are aqueous and non-aqueous sterile injectable preparations. These drugs can be presented in the form of a container containing a single dose or multiple doses, such as sealed vials or ampoules. They can be stored as dried by freezing (lyophilization) of the product to which the application should only add sterile liquid carrier, for example water.

Preparations suitable for inhalation through the nose, are finely chopped dusty or aerosols, which can be obtained by using under high pressure metered dose aerosol, spray or poroshkovaya.

The compounds of formula (I) can be obtained in various ways, which are generally known in organic chemistry. The original materials or known, or readily available from various sources or may be obtained by conventional methods. For example, the compounds can be synthesized using the methods described in "The Chemistry of Heterocyclic Compounds", Vol. 44, "Thiophene and its derivatives", part 1-5, Ed. S. Gronowitz, J. Wiley and Son; A. R. Katritsky and C. W. Rees, "Comprehensive Heterocyclic Chemistry", Part 4, Ed. C. W. Bird and G. H. Cheesman, Pergamon Press.).

In the following description, unless otherwise stated, the symbols R1, r2and r3have the meanings specified for them when considering the formula (I).

The compounds of formula (I) can be obtained by the reaction of compounds of formula (II)

< / BR>
where substituent R4represents a group R3the meanings of which are defined above in the description of formula (I), with acceptable dehydrating agent, for example with a mineral acid, such as hydrochloric acid, or phosphorus oxychloride. The reaction can be conducted under conditions that are standard for dehydration of alcohol. For example, using phosphorus oxychloride in the presence of a suitable solvent, such as pyridine, at a temperature in the range from 80 to 120oC.

For dehumidification can be used in other ways, well-known qualified or described in the chemical literature, including the use of sulfuric acid, 4-methylbenzenesulfonate, triperoxonane acid, methanesulfonate, reformersglossary, thionyl chloride, or by using sulfureuse dehydrating agent Martin, and using, if necessary, a suitable solvent is the Rupp, protecting the nitrogen atom, for example trityloxy group, using methods known qualified or described in the literature, can be either simultaneously or sequentially subjected to a dehydration reaction and remove protection from obtaining the compounds of formula (III):

< / BR>
The alkylation of compounds of formula (III) gives compounds of the present invention.

Suitable alkylating agents are alkylhalogenide, such as alkylidene, such as ethyliodide or n-butyl bromide. The reaction is usually carried out in the presence of a base, for example potassium acetate and triethylamine, in a suitable solvent, such as acetone, at a temperature in the range from 0 to 50oWith, or in an inert solvent, such as toluene or xylene, at a temperature in the range of 80-120oC.

The compounds of formula (III) can also be etilirovany using the appropriate carboxylic acid in the presence of pyridine followed by reduction to the compounds of formula (I) using methods well known to restore amides. For example, the recovery may be carried out using lithium aluminum hydride.

If necessary or desirable, after one islennyh stages:

(I) transforming pharmaceutically acceptable salt or MES the compounds of formula (I) in the compound of formula (I).

(II) the transformation pharmaceutically acceptable salt or MES the compounds of formula (I) into another pharmaceutically acceptable salt or MES formula (I).

(III) the conversion of compounds of formula (I) into a pharmaceutically acceptable salt or MES the compounds of formula (I).

The compounds of formula (II), where the substituent R4represents a group R3whose values defined above for the formula (I) can be obtained by addition of a suitable ORGANOMETALLIC reagent such as a Grignard reagent obtained, for example, of 1-methyl-4-chloro-piperidine, to the compound of formula (IV)

< / BR>
The reaction is usually carried out in the presence of non-polar aprotic solvent, such as ether or tetrahydrofuran, at temperatures from -30 to 67oC.

The compound of formula (II) can also be obtained by treating compounds of formula (V)

< / BR>
where substituent R4represents a group R3whose values defined above for the formula (I), or a group protecting the nitrogen atom, with a suitable ORGANOMETALLIC, Reagan the appropriate halogen atom, such as a bromine atom or a chlorine atom, or a lithium reagent derived from activated aryl hydrogen atom. The reaction is usually carried out in the presence of an aprotic non-polar solvent, such as ether or tetrahydrofuran, at a temperature in the range from -60 67oC.

On the other hand, the compounds of formula (II) can be obtained by treating the compounds of formula (VI)

< / BR>
where substituent R4represents a group R3whose values defined above for the formula (I), or a group protecting the nitrogen atom, with a suitable ORGANOMETALLIC reagent such as a Grignard reagent or a lithium reagent derived from substituted by the halogen atom of the benzene. For example, the compounds of formula (II), where the phenyl group substituted by halogen atom, can be obtained by treating compounds of formula (VI) with the appropriate substituted by a halogen atom by phenylalkylamines using standard reaction conditions.

The compounds of formula (IV) can be obtained by methods known from the chemical literature. For example, compounds where the substituent R1represents 4-chloro - or 2,3-dichlorethyl can be obtained by the method of Example 1, potemski available or get them by known methods, for example, the benzoylation by Friedel-Crafts of thiophene or other groups represented by the substituent R1.

In accordance with another method, compounds of formula (IV) can be obtained by acylation according to the Friedel-Crafts or by benzoylation of 3-chloro-2-bromo-thiophene in the presence of a catalyst, such as ferric chloride or aluminum chloride, in a non-polar solvent, such as dichloromethane, at a temperature in the range of 10-25oC. Recovery dibromononane received first product gives the desired connection. Such recovery can be carried out by catalytic hydrogenation using a suitable catalyst such as palladium on charcoal, in a suitable solvent, such as ethanol or acetic acid, at a temperature in the range from 15 to 25oC and at a pressure of from 1 to 50 pounds per square inch (3,51 kg/cm2), or by using activated zinc in the above mentioned solvents at a temperature of 20-65oC.

Compounds of formulas (V) and (VI) can be obtained, for example, adding the appropriate Grignard reagent to ethyl-N-methyl - or N-tritylodontidae. The latter compound is commercially available compound or can the another hand, the compounds of formula (V), where the substituent R4represents methyl or hydrogen atom, and the substituent R2is a 4-fluorine can be obtained by the techniques described in the article J. Med. Chem., 1970, 13, 1. The compounds of formula (V), where the substituent R4represents trityl, can be obtained from compounds of formula (V), where the substituent R4represents a hydrogen atom, for example, when interacting with trityl-bromide by the method described below in Example 4.

The compounds of formula (III) (see above) can be obtained by transformation of a compound of formula (I), where the substituent R3represents methyl, in its urethane derivative. The reaction may be carried out with CHLOROFORMATES, such as ethyl-, benzyl - or trichlorethyl-chloroformiate (see Baldwin S. W., Jeffs, P. W. , Natarajan, S., Gross, P. M., Synthetic. Commun. 1977, 7, 79; Kraiss G., Nader K. Tetrahedron Letters, 1971, 57). The hydrolysis of these urethane derivatives, for example, mineral acid, such as hydrochloric acid, or by treatment in appropriate cases, zinc, lead to compounds of the formula (III).

Salt in accordance with the present invention can be obtained by treating the compounds of formula (I) with a suitable base, such as hydroxide of alkali metal, selna, fumaric or maleic acid.

The present invention also includes all new intermediate compounds described above, and in particular the compounds of formula (II). Examples of intermediate compounds in accordance with the present invention are:

-(4-forfinal)--(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(4-methyl-2-thienyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(4,5-dichloro-2-thienyl)-1-methyl-4-Piperi-inmethanol;

-(4-forfinal)--(5-ethyl-2-thienyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(4-ethyl-2-thienyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(2-benzothiazyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(5-fluoro-2-benzothiazyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(6-methoxy-2-benzothiazyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(2-benzofuranyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(4, 5-dimethyl-2-furanyl)-1-methyl-4-piperidinemethanol;

-(4-forfinal)--(4-methyl-2-thienyl)-1-triphenylmethyl-4-piperidinemethanol.

The following examples are intended only to illustrate the invention and in no way limit the invention.

Example 1

1. Getting 2-chloro-4-(4-perbenzoic)-thiophene

Crushed chloride is) at approximately 5oFrom and after 1 hour added dropwise a solution of chlorine (5,16 g in carbon tetrachloride (26,3 ml), maintaining the temperature at about 5oC. Upon completion of addition the temperature of the reaction mixture is allowed to rise to approximately 12oC for 1.5 hours and stirred at this temperature for 1 hour. The solution is again cooled to approximately 5oWith and add more chlorine solution (1.3 g) in carbon tetrachloride (6.8 ml). The resulting solution was stirred at this temperature for a further 1 hour and then incubated overnight at approximately the 20oC. the Solution is again cooled to 5oTo add an additional amount of chlorine (2.6 g) in carbon tetrachloride (13 ml), the temperature was raised to approximately the 20oC and the mixture is stirred for 2 hours. The mixture is cooled in an ice bath, add water (200 ml) and then ether (400 ml) and the layers separated. The ether layer is washed until neutral with water, dried with Na2SO4and evaporated, get a brown resin (18,9 g), which crystallized from a mixture of ether/hexane. Get 2-chloro-4-(4-perbenzoic)thiophene (10.3 g), the output 77,6% (GC).

2. Obtain 2,3-dichloro-4-(4-perbenzoic)-thiophene

Mataco (4:1) receive a fraction, which is evaporated, the residue is crystallized from a mixture of ether/hexane and get a named connection (1.9 grams), so pl. 104-105oC.

Example 2

A. 1-Methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)]methyleneimine(fumarate salt)

4-Chloro-1-methylpiperidin model HC1 (18.7 g) alkalinized water ammonium hydroxide and the solution extracted with ether, the extract washed with brine, dried (Na2SO4) and evaporated, to obtain 4-chloro-1-methylpiperidine (14,7 g) as an almost colourless oil.

To a suspension of magnesium shavings (2,32 g) in distilled tetrahydrofuran (THF) (10.0 g) was added with stirring a crystal of iodine, then add ethylbromide (0.16 ml) and after the disappearance of the iodine staining (approximately 5 min) dropwise within about 30 minutes add 4-chloro-1-methylpiperidine (14.4 g) in THF (96 ml). The reaction mixture was slightly heated so that it is gently boiling. At the end of the addition the mixture is refluxed for another 1.5 hours, then cooled to approximately 0oC. To the solution is added dropwise within 40 minutes, add a solution of 2-chloro-4-(4-perbenzoic)thiophene (10.3 g, example 1) in THF (25 ml) and the mixture refluxed for 2.5 hours.

To the cooled mixture is added nait, the layers are separated. The ether layer is washed with water, dried (Na2SO4) and evaporated. Get a brown resin (18.2 g).

A mixture of hydrochloric acid (5 N., 60 ml) and hydrochloric acid

(2 N., 60 ml) are added to a brown resin (10.8 g) and stirring the mixture refluxed for 0.75 hour. After complete dissolution, the reaction mixture is cooled to approximately 5oAnd alkalinized with an aqueous solution of ammonium hydroxide. The product is extracted with dichloromethane, the extract washed with water, dried (Na2SO4) and evaporated. Get a brown resin (8,2 g), which chromatographic on silicon dioxide. When elution with a mixture of dichloromethane/methanol (elution with a gradient of 1-10% methanol) release fraction, which is evaporated, and receive -(4-forfinal)--(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol (1.07 g), contains a number of impurities pereplanirovannogo product.

To a suspension of the crude product (0,78 g) in sodium hydroxide solution (4 N., and 7.8 ml) add powder dust (1.56 g) and the mixture refluxed for 2.5 hours. The mixture is cooled, water is added (15 ml) and the product extracted with dichloromethane (30 ml). The extract was washed with water (330 ml), dried (Na2oC.

B. Succinate 1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)] methyleneimine receive the same; so pl. 161-169oC.

C. in a Similar manner, but without the need to remove pereplanirovannogo material, 2,3-dichloro-4-(4-perbenzoic)-thiophene converted into the fumarate of 1-methyl-4-[(4,5-dichloro-2-thienyl)-(4-forfinal)]-methyleneimine: so LP 220oC.

, Methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)]methyleneimine (alternative production method)

I. 2-Bromo-3-chlorothiophene

A solution of N-bromosuccinimide (221,7 g) in dimethylformamide (550 ml) under stirring for 75 minutes added dropwise to a solution of 3-chlorothiophene (143,4 g) and perchloro acid (70%, 5.8 ml), cooled in an ice-water bath until the 15oC. the Temperature of the reaction mixture gradually over 30 minutes increase to 40oC and then cooled to the 11oC. the Cooling is removed and the reaction mixture is stirred for a further 2 hours. The reaction mixture was poured into water and extracted with methyl tert-butyl ether. The organic extract is washed sequentially with water, aqueous solution hydroslim on an oil bath with a temperature of 80-90oC. Obtain 2-bromo-3-chlorothiophene in the form of oil (202 g, yield 97%); so bales. 42o(1 mm RT. Art.).

II. 2-Bromo-3-chloro-5-(4-perbenzoic)thiophene

To a solution of 2-bromo-3-chlorothiophene (148,5 g) and 4-tormentilla (169,7 g) in dichloromethane (2230 ml), cooled to 18oC in a water bath with ice, add with stirring chloride iron (301,2 g). The temperature of the reaction mixture increased to 22oC and then cooled to 12oC. the Cooling is removed and the reaction mixture is stirred for a further 50 minutes, during which the temperature of the reaction mixture rises to 16oC. the Reaction mixture is again cooled to 10oWith carefully add water (700 ml), maintaining the temperature of the mixture below 15oC, and the resulting mixture is stirred for 1 hour. The dichloromethane layer is separated, the aqueous layer washed with dichloromethane. The combined dichloromethane layer was washed with water and saturated sodium bicarbonate solution. Dichloromethane was separated, the aqueous layer was filtered through dicalite and extracted with dichloromethane. The extract is washed with water, dried (Na2S04) and evaporated to dryness. Get 2-bromo-3-chloro-5-(4-perbenzoic)-thiophene in the form of solids (233,3 g).

III. 4-Chloro-2-(4-perbenzoic)thiophene

RA is of 77.0 g), in an atmosphere of nitrogen was added a suspension of 5% palladium on coal (20 g) in ethanol (100 ml) and the resulting mixture hydronaut for 3 hours at room temperature and room pressure (total absorption of hydrogen is 22,994 ml). The reaction mixture was filtered through a layer dicalite, and this layer washed with ethanol (2200 ml). The filtrate is evaporated to reduce the volume (approximately 2 l) and add water (17 l). The precipitate is filtered off and the wet dissolved in dichloromethane (1 l), then the volume of solution is reduced to approximately 500 ml Add methanol (500 ml) and the residue dichloromethane is distilled off. The resulting crystals are filtered and dried, to obtain 4-chloro-2-(4-perbenzoic)thiophene as a white solid (169 g). Allocate a second portion (19,2 g) product and recrystallized from a mixture of dichloromethane/methanol, getting more pure product (12.9 g). Selected portions used in the next stage.

IV. -(4-Forfinal)--(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol

A suspension of magnesium turnings (36,7 g) in tetrahydrofuran (470 ml) is heated under nitrogen atmosphere to 55oAnd add an aliquot (20,0 ml) solution of N-methyl-4-chloropyridine (221,6 g) in tetrahydrofuran (1400 ml), and then a crystal of iodine and ethylbromide (14,0 ml). Almost SRAS the military iodine, and the beginning of the boil. Then within 75 minutes add the rest of the solution of N-methyl-4-chloropyridine, maintaining a gentle boil. At the end of the addition the mixture was stirred at 64oC for 90 minutes after which the reaction mixture remains only a few grains of magnesium. The solution is cooled in a water bath with ice to the 20oWith and then for 60 minutes served by the pump at high pressure nitrogen into a solution of 4-chloro-2-(4-perbenzoic)thiophene (140.0 g) in tetrahydrofuran (1.4 l), which is pre-cooled to 0oWith in a bath of ice and salt; the temperature of the mixture at the same time supporting below the 8oC. the Solution within 40 minutes added to a cold (5o(C) saturated solution of ammonium chloride (4.6 liters), keeping the temperature below 15oC. the Mixture is extracted with ethyl acetate, the extract washed with water, dried (Na2SO4) and evaporated to dryness. Get a brown resin (202 g). The resin is crystallized from a mixture of dichloromethane/methyl tert-butyl ether, get a solid product, which is filtered and washed with cold methyl tert-butyl ether. The solid product is filtered and dried. The resulting product (79,2 g) is recrystallized from a mixture of dichloromethane/methyl tert-butyl ether. Receive -(4-forfinal)--ridin

The above alcohol (73,8 g) in 50 minutes refluxed in a mixture of 2 N. hydrochloric acid (440 ml) and 5 G. hydrochloric acid (440 ml). The reaction mixture is cooled in a water bath with ice, the obtained white precipitate is filtered off and washed with water, get a white shiny crystals. The wet crystals are suspended in a mixture of ethyl acetate (300 ml) and water (300 ml) and with stirring alkalinized using 4 n sodium hydroxide solution (200 ml). An ethyl acetate layer is separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts washed with water, dried (Na2SO4) and evaporated. Get 1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)]-methyleneimine in the form of a brown oil (66,8 g), 98% (GC).

VI. Succinate 1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)]methyleneimine

The above amine (64,6 g) dissolved in methanol (640 ml), add succinic acid (are 24.88 g), the solution evaporated to dryness and the resulting solid residue (89,4 g) dissolved in hot ethanol (1.1 l). The volume of solution is reduced (200 ml), cooled in a water bath with ice, the resulting solid product is filtered and washed with ethanol (200 ml). The solid product is dried in vacuum at 50oTo get succinate 1-methyl-4-[(4-chloro-2-thienyl)2">

Example 3

A. Obtain hydrochloride of 1-methyl-4-[(4-methyl-2-thienyl)-(4-forfinal)] methyleneimine

To a solution of n-utility in hexane (1,6 N., 20 ml) add a solution of 3-methylthiophene (3.5 g) in dry THF (40 ml). The resulting solution was refluxed for 2 hours. The solution is cooled to 0oWith and within 10 minutes, add a solution of 1-methyl-4-(4-perbenzoic)piperidine (2.1 g) in dry THF (40 ml), maintaining the temperature at approximately 0oC. the Solution is allowed to warm to room temperature, carefully add water (20 ml) and the mixture extracted with ethyl acetate. The extract is again extracted with hydrochloric acid (1 ad ), an aqueous extract of alkalinized water ammonium hydroxide and the product extracted with ethyl acetate. The extract is washed with water, dried (Na2SO4), evaporated, get an oil (2.6 g). The solution of this oil (1.7 g) in pyridine (17 ml) containing phosphorus oxychloride (0.1 ml), heated at 115-120oWith over 8.5 hours. The solution is cooled, water is added, the mixture is alkalinized water ammonium hydroxide and extracted with ethyl acetate. The extract is washed with water, dried (Na2SO4) and evaporated, get the crude product in the form of free base, which was purified by filtration n the print product, which is crystallized from methanol/ether. Get 1-methyl-4-[(4-methyl-2-thienyl-(4-forfinal)] methyleneimine model HC1 (1.45 g); so pl. 235oC.

B. the Following connections get the same methodology:

- 2-ethylthiophene get maleate of 1-methyl-4-[(5-ethyl-2-thienyl)-(4-forfinal)]methyleneimine; so pl. 175-176oC.

- 3-ethylthiophene get maleate of 1-methyl-4-[(4-ethyl-2-thienyl)-(4-forfinal)]methyleneimine; so pl. 76,8oC.

from benzothiophene get maleate of 1-methyl-4-(2-benzothiazyl)-(4-forfinal)] methyleneimine: so pl. 197-214oC.

- 5-ferbenstein get maleate of 1-methyl-4-[(5-fluoro-2-benzothiazyl)-(4-forfinal)]methyleneimine; so pl. 152-155oC.

- 6-methoxybenzamide get maleate of 1-methyl-4-[(6-methoxy-2-benzothiazyl)-(4-forfinal)]methyleneimine; so pl. 150-153oC.

from benzofuran get maleate of 1-methyl-4-[(2-benzofuranyl)-(4-forfinal)]methyleneimine: so pl. 196,2oC.

from 2,3-dimethylfuran get maleate of 1-methyl-4-[(4,5-dimethyl-2-furanyl)-(4-forfinal)]methyleneimine; so pl. 197-200oC.

Example 4

Hydrochloride 4-[(4-Forfinal)-2-(4-methylthieno)methyleneimine

To a solution of 4-(1-acetylpiperidine add powdered aluminium chloride (71 g), then for 17 minutes a solution of 2-bromo-3-methylthiophene (50 g) in dichloromethane (300 ml). After 30 minutes the reaction mixture was added dropwise water (240 ml), allowing the temperature of the reaction mixture to rise to approximately +20oC. After stirring for another 30 minutes inorganic components is filtered through a layer dicalite. The layers separated, the organic layer washed twice with water, dried (Na2SO4) and evaporated under reduced pressure. The crude product (73 g) purified by chromatography, to obtain 2-(5-bromo-4-methylthieno)-4-(1-acetylpiperidine)methanon (62,2 g); so pl. 105-108,5oC (decomp.).

A suspension of powdered zinc (22 g), sodium iodide (11 g), triphenylphosphine (16.5 g) and uranyl chloride Nickel (2,56 g) in purified oxygen from methanol (340 ml) (produced by boiling of methanol in a flow of nitrogen for 2 hours) was stirred in nitrogen atmosphere at 60oC for 15 minutes. To this mixture add a solution obtained above prosteradlo connection (62,2 g) in purified oxygen from methanol (150 ml) and the reaction mixture refluxed under nitrogen atmosphere for 22 hours. The reaction mixture is cooled and the inorganic components is filtered through a layer dicalite. The filtrate mpariwa neutral, dried (Na2SO4) and evaporated to dryness under reduced pressure. The crude product (61,3 g) purified by rapid chromatography, crystallized from a mixture of dichloromethane/ether and receive two portions of 2-(4-methylthieno)-4-(1-acetylpiperidine)methanon (41,2 g); so pl. 120-125oC. the Solution obtained methanone (41,2 g) 5 N. aqueous solution of hydrochloric acid (140 ml) is refluxed for 16 hours and then evaporated under reduced pressure, the remaining water is removed by azeotropic distillation with toluene. After trituration of the residue with diethyl ether to obtain the crude product (38,8 g), which is marked by filtration. After recrystallization from methanol/diethyl ether to obtain the hydrochloride of 2-(4-methylthieno)-4-piperidinemethanol in two portions (29,5 g); so pl. 217,5-218,5o(Changes in crystalline form start at temperatures above 200oC).

The solution obtained above hydrochloride (28 g) in water and alkalinized solution of the base (24,1 g) in dichloromethane (240 ml) and triethylamine (48 ml) was stirred at 0oC in nitrogen atmosphere. The portions add triphenylmethylchloride (33,7 g) with such a rate as to maintain the reaction temperature 02oC. After 30 minutes the mixture carefully add water (240 ml) and extrano replacing dichloromethane heptane, and left to crystallize. The crystals are filtered and washed with a mixture of heptane and dichloromethane, 4:1, get 2-(4-methylthieno)-4-(1-triphenylethylene)-methanon (46,9 g): so pl. 219-221oC (decomp.).

To a suspension of magnesium turnings (6.4 g) in dry diethyl ether (100 ml) containing a crystal of iodine was added with stirring bromatan (1.5 ml). The temperature of the exothermic reaction support in the range of 32-36oWith throughout the reaction, while carefully add a solution of 4-bromptonville (29 ml) in dry diethyl ether (170 ml). The resulting mixture was gently refluxed for 30 minutes and then cooled to 0oC.

To this mixture for 15 minutes and added dropwise to the solution obtained above methanone (23,5 g) in dry diethyl ether (280 ml), keeping the temperature at 0-5oC. Then the reaction mixture is allowed to warm to room temperature over 30 minutes and the product extracted with ethyl acetate. The extracts washed with water, dried (Na2SO4) and evaporated under reduced pressure to obtain resin (32,4 g) which is dissolved in a mixture of acetic acid (261 ml) and water (130 ml). The resulting solution was refluxed for 18 hours. Add the initial alcohol) is filtered off, and the filtrate evaporated under reduced pressure to small volume. The residue is alkalinized with concentrated ammonium hydroxide solution and the product extracted with ethyl acetate. The extracts are washed with aqueous solution of sodium chloride, dried (Na2SO4) and evaporated to dryness under reduced pressure, get a resinous residue (15.0 g). To a solution of this product in diethyl ether is added a solution of hydrochloric acid in methanol, and the solution is kept for crystallization, receive hydrochloride 4-[(4-forfinal)-2-(4-methylthieno)-methyleneimine (9.0 g); so pl. 191-206oC (decomp.).

Example 5

Fumarate of 1-butyl-4-[(5-chloro-2-thienyl)-(4-forfinal)]-methyleneimine

A solution of 4-[(5-chloro-2-thienyl)-(4-forfinal)] methyleneimine (0,69 g), 1-bromobutane (0,48 ml) and triethylamine (1,56 ml) in toluene (20 ml) with stirring and refluxed for 24 hours. The reaction mixture is allowed to cool, transferred into a separating funnel and washed with toluene (30 ml) and water (30 ml). Shake mixture, the toluene layer was separated, washed with water, dried (Na2SO4) and evaporated, to obtain a viscous oil (0.71 g), which chromatographic on silicon dioxide. After elution with a mixture of dichloromethane/methanol, 24:1, get fracc the oru add a solution of fumaric acid (0.16 g) in methanol (5 ml). The solution is evaporated to a small volume. Add ether and the resulting crystals filtered off, get the named compound (0.51 g); so pl. 167-172oC.

Example 6

According to the method described in example 5, but using (methyl bromide)cyclopropane as an alkylating agent, get the fumarate of 1-cyclopropylmethyl-4-[(5-chloro-2-thienyl)-(4-forfinal)]methyleneimine: so pl. 171-172oC.

Example 7

Fumarate 4-(4-forfinal-2-nardil)-1-methylpiperidine

In a nitrogen atmosphere to a suspension of magnesium turnings (0,37 g) in dry distilled tetrahydrofuran (10 ml) containing a crystal of iodine was added with stirring a solution of 2-bromonaphthalene (3.13 g) in dry tetrahydrofuran (10 ml). The reaction mixture is heated to 55oC in a water bath, and the heating stops after 3 minutes after start of the reaction. Adding the last portions of the temperature of the reaction mixture is maintained within the range of 50-55oUsing the water bath. After 15 minutes the reaction mixture is cooled to 5oAnd then add a solution of 4-(4-perbenzoic)-N-methylpiperidine (0,81 g) in dry tetrahydrofuran (4 ml), maintaining the temperature in the range from 5 to 10oC. the Mixture is heated at 50oC for 1 hour and then o, the extracts washed with water, dried (Na2SO4) and evaporated, to obtain white solid (2,41 g), which chromatographic on silica gel. After elution with a mixture of dichloromethane/methanol (95:5, vol/about.) receive - (4-forfinal) -- (2-naphthyl)-1-(methyl)-4-piperidinemethanol which crystallized from dichloromethane by adding ether (0.27 g); so pl. 164-169oC.

The suspension obtained above alcohol (0,81 g) 3.5 G. hydrochloric acid (10 ml) is refluxed for 2.5 hours, cooled to 20oAnd then alkalinized with an aqueous solution of ammonia (5 ml). The product is extracted with dichloromethane (50 ml), the extract washed with water, dried (Na2SO4) and evaporated to dryness, to obtain 4-(4-forfinal-2-naphthyl)-1-methylpiperidin in the form of a pale yellow resin (0,81 g). This connection is transferred to fumarate by the above method and crystallized from methanol by adding ether, get a named connection (0,89 g); so pl. 214-218oC.

Example 8

Test on apomorphine-induced reflex climbing in mice

The ability of antagonists of dopamine receptors to inhibit behavioral reflexes in rodents induced by dopamine agonists, such as apomorphine, is a well-isoken the example W. C. Bowman, M. J. Rand, Textbook of Pharmacology, 2nd ed., 1980, 15, 6). Particularly suitable in this case, the test is a test on apomorphine-induced reflex climbing in mice (ATC apomorphine cliving test), which measures the ability of antagonists to inhibit the reflex climbing in mice induced by subcutaneous or oral administration of apomorphine. The activity identified in this test and manifested after systemic or oral administration, is widely used as an indicator of antipsychotic activity, that is, antihistaminics activity (see, for example, J. T. Strupczewski et al., J. Med.Chem., 1995, 38, 1119). Mice treated with apomorphine hydrochloride, have a tendency to take a vertical position along the wall of the cylinder of wire with holes, while remaining stationary or messing around on the wall. This lasagna, it is believed, is the result mediated by apomorphine stimulation of dopamine receptors. A large number of drugs causing the behavior, manifested in the lasagna, but antagonists of dopamine in doses that do not affect spontaneous motor activity and/or motor coordination in mice that normally inhibit such behavior. Test compounds that modulate specified the hypoxia treatment options. Each experience includes 1+n groups of subjects: group 1 represents a control group of 12 mice, which is administered apomorphine and the solvent subcutaneously; or represents a control group of 12 mice, which is injected subcutaneous apomorphine and oral solvent; n-group (usually 4) is a group for the test compounds, consisting of 12 mice, which is administered apomorphine and test compound subcutaneously, or group for the test compounds of the 12 mice, which is injected subcutaneous apomorphine and oral test connection.

Experiments are performed in 3 sets of 20 mice each. Mice mark and weighed. The test compounds and the solvent is injected subcutaneously, and mice are placed in small cells of Makrolon (HH cm), 5 mice in a cage. Or the test compound and the solvent is administered orally, and the mice are placed in cells of Makrolon (HH cm), 5 mice in a cage. After 30 minutes subcutaneously injected with 0.75 mg/kg of apomorphine hydrochloride mice treated subcutaneously with a solvent or the test compound, or 0.75 mg/kg of apomorphine hydrochloride is injected subcutaneously to mice treated orally with a solvent or the test compound, the mice are placed individually in the om assess the manifestation of reflex climbing for each mouse and expressed his points in accordance with the following scale;

4 paws on the floor - 0 points

1 or 2 feet are on the wall - 1 point

3 or 4 legs on the wall - 2 points

20 minutes after treatment with apomorphine again appreciate reflex climbing in points. For each of the treated groups determine the average value. The score for the control group must be equal to at least 1,0; if not, the test is reject. The final results for the group are expressed in percent relative to the control group.

Obtained in this experiment the results for the tested compounds are presented in Table I (after subcutaneous and oral administration of the test compounds).

Connection Example 2,1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)] methyleneimine, and Example 3, 1-methyl-4-[(4-methyl-2-thienyl)-(4-forfinal)]methyleneimine, compared with 1-methyl-4-[(2-thienyl)-(4-forfinal)]etilenpieperazina (Compound A), which falls under the scope of the claims of U.S. patent 2739968, 1-methyl-4-(2-thienyl)phenylethylenediamine (Compound B) in accordance with U.S. patent 2739968 and 1-methyl-4-[(5-chloro-2-thienyl)-phenyl]etilenpieperazina (Connection). Compounds in accordance with the present invention have a high activity, particularly high oral activity by CPA is male Wistar rats (100-125 g, Olac UK). Catalepsy is evaluated according to previously described methods (Broekkamp et al., Naunyn-Schmiedeberg''s Arch. Pharmacol. 338, 191, 1988). Rats have 6 different experiments in which animals are placed in abnormal postures and assess reliably from one point saving imposed position for 10 seconds. Imposed by the provisions were: vertical clinging to the bars, vertical stand with a high support for the front paws, stretching of the hind legs, on his back, with a spatula in his mouth and rotation of the wire in the cylinder.

Theoretically can be obtained the maximum score of 6. Catalepsy determined after 60 and 120 minutes after drug administration. The results were evaluated using 2-way analysis of variants ANOVAR, followed by Newman Kools post hoc test, and expect ED50(Table II).

1. Derivatives of piperidine derivatives of the formula I

< / BR>
where substituent R1represents benzothiazol, benzofuranyl, naphthyl (where sensationally, benzofuranyl or nattily fragment can be optionally substituted by one or more substituents selected from a halogen atom, a C1-6-alkoxygroup, C1-6-alkyl and C1-6-alkenyl), substituted thienyl or substituted furanyl (where dianiline is -6
-alkyl, C3-6-cycloalkyl and C1-6-alkenyl);

Deputy R2represents a halogen atom;

Deputy R3represents a C1-6-alkyl or C3-6-cyclooctylmethyl,

or their pharmaceutically acceptable salt, or solvate.

2. Connection on p. 1, where the substituent R1represents benzothiazol, benzofuranyl, naphthyl (where sensationally, benzofuranyl or nattily fragment can be optionally substituted by one or more substituents selected from a halogen atom or C1-6-alkoxygroup), substituted thienyl or substituted furanyl (where thienyl or farnily fragment substituted by one or more substituents selected from a halogen atom or C1-6-alkyl); Deputy R2represents a halogen atom and the substituent R3represents a C1-6-alkyl, or its pharmaceutically acceptable salt, or MES.

3. Connection under item 1 or 2, where the substituent R1is thienyl substituted by one or more substituents selected from a halogen atom and a1-6-alkyl; Deputy R2represents a halogen atom and the substituent R3predstavljamo of PP.1-3, where substituent R1represents a 2 - or 3-thienyl substituted by one or more substituents selected from a chlorine atom and methyl, preferably 4-chloro and 4-methyl; Deputy R2represents a fluorine atom, and the substituent R3represents methyl, or its pharmaceutically acceptable salt, or MES.

5. Connection to any PP.1-4, selected from 1-methyl-4-[(4-chloro-2-thienyl)-(4-forfinal)] methyleneimine and 1-methyl-4-[(4-methyl-2-thienyl)-(4-forfinal)] methyleneimine, or their pharmaceutically acceptable salts, or MES.

6. The compound of formula I, or its pharmaceutically acceptable salt, or MES according to any one of paragraphs.1-5, having antipsychotic activity.

7. The compound of formula I, or its pharmaceutically acceptable salt, or MES according to any one of paragraphs.1-5, suitable for the manufacture of a pharmaceutical preparation having antipsychotic activity.

8. Pharmaceutical drug, possess antipsychotic activity and containing as active ingredient a compound according to PP.1-5, or its pharmaceutically acceptable salt, or MES, and a pharmaceutically acceptable carrier.

 

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-(5'-nitro-2'-furyl)vinyl]-6,7,8,9 - tetrahydropyrimido[4,5-b] quinoline-4-one and 1-metalorganic-2- [-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6n-pyrimido[4 ,5-b] -pyrindine-4-one, exhibiting antimicrobial activity" target="_blank">

The invention relates to the field of organic chemistry, a class pyrimido[4,5-b] quinoline, pyrimido[4,5 - b]pyrindine, namely to new biologically active 1-phenyl-2- [-(5'-nitro-2'-furyl)vinyl]-6,7,8,9-tetrahydropyrimido[4,5-b]quinoline-4-ONU(I)I1-metalorganic-2-[-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6H-pyrimido[4,5-b]pyrindine-4-ONU (II), formula

< / BR>
< / BR>
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