Derivative tetrahydroimidazo [2,1-a]isoquinoline and pharmaceutical drugs based on them

 

The invention relates to a derivative of tetrahydroimidazo[2,1-a]isoquinoline of the formula (I), where X represents a group (A) or (B), R1, R2and R3are hydrogen, C1-6by alkyl or halogen, a R4, R5, R6and R7are hydrogen. Also described is a pharmaceutical preparation for inhibiting re-uptake of serotonin, dopamine and noradrenaline on the basis of these compounds. Technical result: received new compounds having valuable biological properties. The invention can be used in medicine as a drug for the treatment of depression. 4 C. and 5 C.p. f-crystals, 3 PL.

The invention relates to certain derivatives of tetrahydroimidazo [2,l-a] isoquinoline, methods for their preparation, containing pharmaceutical preparations, and to their use in the treatment of drugs, in particular in the treatment of depression.

Depression is a common ceresnie threatening disease, and its effects are persistent and debilitating.

Older first generation antidepressants, including the which can cause serious toxicity in overdose, and poor patient compliance with the regimen and the regimen. More new drugs of the second generation, which became available since the mid 70-ies, such as atypical antidepressants and inhibitors of reuptake of serotonin (thirty-two, an SSRI), have their own side effect profile, which includes sleep disturbances, gastrointestinal symptoms, the appearance of sexual problems and fear. Lithium is characterized by a number of negative side effects, which often lead to poor patient compliance with the regimen and the regimen and subsequent relapse. Modern alternatives to lithium, carbamazepine and valproate, are not more effective than lithium, and carry additional cargo hematological and hepatic toxicity, respectively.

Due to the short history of antidepressant drugs, the search for new agents continues. Found a new group of medicines, which in addition to inhibiting re-uptake of serotonin also inhibit the re-uptake of norepinephrine and dopamine.

Inhibition of re-uptake of dopamine is believed, causes rapid improvement in mood, making such compounds acceptable to a sharp weakening of the symptoms of depression. It is reputed to be the only means such as blockers of re-absorption of serotonin and norepinephrine, which are the beginning of an action delayed for two weeks or more.

In addition, these compounds because of their ability to block the re-uptake of dopamine have less sedative effect than compounds of the prior art, and, therefore, more suitable for the treatment of patients with psychomotor retardation. Thus, a broader pharmacological profile of the compounds of the present invention provide receiving antidepressants, which are characterized by rapid onset of effect, a broader spectrum of activity and reduced side effects. Also suppose that these compounds are, in particular, is effective in the treatment of elderly people, treatment resistant bipolar oppressed patients.

Compounds of the present invention can also be used to treat Parkinson's disease, obesity, anxiety, major pain, addiction and negative symptoms in patients with schizophrenia, and other diseases referred to herein.

Thus, in accordance with one aspect of the present invention provides compounds of formula (I)where X represents a group (A) or (B)coboy one or more substituents, choose from a hydrogen atom, a C1-6-alkyl, C3-6-cycloalkyl,1-6-allylthiourea, C4-6-cycloalkenyl,2-6-alkenylphenol, C2-6-alkenylphenol groups and halogen; each of the substituents R4, R5, R6and R7that may be the same or different, is selected from hydrogen, C1-6-alkoxy-C1-6-alkyl, C4-6-cycloalkenyl, C2-6-alkenylphenol, C2-6-alkenylphenol,3-6-cycloalkyl and C1-6-alkyl groups; n takes on the values 1 or 2, or its pharmaceutically acceptable salt or MES for use in the treatment drugs.

In accordance with another aspect of the invention provides compounds of formula (I) and their pharmaceutically acceptable salt and solvate for use in the treatment or prevention of depression or any of the diseases or disorders mentioned here.

The term alkyl used in this case as a group or part of a group, means an alkyl group with a linear or branched chain. The number of carbon atoms in the alkyl group (or any other groups defined below) is indicated by a prefix, for example, C1-6-alkyl means alkyl group containing-butyl, tert-butyl, n-pentyl, out-of pencil, neopentyl, n-hexyl, ISO-hexyl and neohexyl. The concept of a1-6-allylthiourea includes methylthio, ethylthio and PropertyGroup.

Alkeneamine groups are groups that can have the E - or Z-form or can be a mixture of these forms, when they contain at least three carbon atoms, may be branched. Specific examples alkenyl groups are vinyl, allyl, bucinellina, ISO-bucinellina, penttila, ISO-penttila, hexeline, ISO-examilia, neoessarily and 1-methyl-2-protanilla group. The concept of alkoxy - and Alchemilla groups have values that are understandable to the skilled in this field specialist, and can have linear and branched chains. Examples of alkoxygroup are methoxy and ethoxypropan, and examples etkinlik groups are etinilnoy, proponila and Butyrina group.

Used in this description of the concepts cycloalkyl and cycloalkenyl groups have values that are understandable to the skilled in this field specialist, and include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyls, cyclohexyl is.

The substituent in the ring R1when it is present in the phenyl group (a) may be in any one or more of positions 2, 3, 4, 5 or 6. Specific examples of the only Deputy in the ring is 4-chloro or 4-fluoro. A few examples of the substituents are 3-chloro, 4-fluoro and 3,4-dichloro.

The substituent in the ring R1when it is present in naftilos group (B) can be in any one or more of positions 1, 3, or 4.

The substituents in the ring R2and R3can be in any one or more available positions.

It should be noted that some compounds of formula (I), their salts and solvate may contain one or more chiral centers and may exist as stereoisomers, including diastereomers and enantiomers. The present invention includes in its scope called stereoisomers, as well as each individual (R) and (S) enantiomer of the compounds of formula (I) and their salts and solvate. Individual enantiomer may be almost pure, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, or a mixture of such enantiomers in any ratio, including racemenu salts of the compounds of formula (I) are the acid additive salt, where the acid is a pharmaceutically acceptable. However, acid salts that are not pharmaceutically acceptable may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, such as pharmaceutically acceptable and pharmaceutically unacceptable, covered by the present invention.

In accordance with the present invention to salts include pharmaceutically acceptable acid additive salts derived from mineral acids such as hydrochloric, Hydrobromic, iodine, hydrogen, phosphoric, metaphosphoric, nitric and sulfuric acid as well as salts derived from organic acids, such as tartaric, acetic, triperoxonane, citric, malic, lactic, maleic (CIS-Buendia acid), malonic, fumaric, benzoic, ascorbic, propionic, glycolic, gluconic, succinic, methansulfonate and arylsulfonate, for example p-toluensulfonate, acid. The preferred salts according to the present invention are the acid additive salts of hydrochloric, oxalic, fumaric and maleic acids.

The solvate in accordance with the present invention are hydrates.

Compound (racemate the Institute, presented in J. Org. Chem. 35, (4), 1178-1180 (1970). Therefore, by itself, this connection is not protected.

Thus, in accordance with another aspect of the present invention is the compounds of formula (I) described above, provided that this connection is not (racemate)-6-phenyl-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline.

The following compounds of formula (I), or with or without conditions, are preferred compounds in accordance with the present invention: (i) X is a (A); (ii) R1represents one or more substituents chosen from a hydrogen atom, a C1-6-alkyl and halogen atom, preferably the substituent R1is in the 4th position (when X represents (A));
(iii) each of the substituents R3, R4, R5, R6and R7represents a hydrogen atom;
(iv) n is 1;
(v) the substituents X, R1, R3, R4, R5, R6and R7defined above in items (i) to (iv);
or their pharmaceutically acceptable salt or solvate.

Particularly preferred compounds in accordance with the present invention, which, as installed, can be used n arvanil)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline;
(+)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline;
(racemate)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline;
(-)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline;
(+)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline;
as well as their pharmaceutically acceptable salt and solvate.

The present invention also includes a method of treating an animal, such as a mammal, including man, suffering from depression or prone, or any of the above-mentioned diseases, which includes the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES.

In accordance with another aspect 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 depression or any of the above diseases or disorders.

Depression, the treatment of which can be used the compounds of formula (I) and their pharmaceutically acceptable salt and solvate represent the state classified edition of the "Diagnostic and Statistical Manual of Mental Disorders" (Fourth Edition-Revised, America is E. affective disorder and bipolar and depressive disorders, not some other way.

Another use of the compounds of formula (I) or their pharmaceutically acceptable salts or solvate in human therapy includes the treatment of the following conditions:
- anxiety, including anxiety neurosis, panic and nervousness, neurosis, fear, disease, post traumatic stress disorder and acute stress;
- diseases associated with attention deficit;
- eating disorders, including obesity, anorexia and bulimia;
diseases associated with changes in personality, including the border state personality changes;
- schizophrenia and other psychotic disorders, including schizoaffective disorder, disorder of view, separated psychotic disorder, brief psychotic disorder, and psychotic disorder;
syndrome narcolepsy-catalepsy;
- related disorders substance;
- disorders of sexual function;
- sleep disorders.

The amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, referred to in this description is also the active ingredient needed to achieve a therapeutic effect will, of course, vary depending on the specific coodinator should be treated.

Acceptable daily dose for the treatment of any of these diseases is in the range from 0.01 to 125 mg per kg of body weight of the patient (e.g., human) per day, preferably in the range from 0.1 to 50 mg per kg of body weight per day and most preferably in the range from 0.25 to 25 mg per kg of body weight per day. Necessary the dose may be presented as one, two, three, four, five or more subds used during the day at certain intervals of time.

Although you can enter one active ingredient, it is preferable to present it as a pharmaceutical preparation. Thus, the present invention additionally provides a pharmaceutical preparation containing the compound of formula (I) or its pharmaceutically acceptable salt or MES, together with a pharmaceutically acceptable carrier and optionally other therapeutic agents. The carrier must be "acceptable", i.e. compatible with the other ingredients and harmless for the patient.

Drugs are medications for oral, rectal, nasal, local (including transdermal, transbukkalno or sublingual), vaginal or parenteral (including subcutaneous, vannoy region, for example, using methods described in Gennaro et al., Remington''s Pharmaceutical Sciences (18tned. , Mack Publishing company, 1990, Part 8: Pharmaceutical Preparations and their Manufacture). These include the stage of mixing the active ingredient with the carrier which consists of one or more accessory ingredients. Such auxiliary ingredients are ingredients that are well known in this field, such as fillers, binders, diluents, dispersing agents, lubricants, colorants, flavoring additives and wetting agents.

Preparations intended for oral administration may constitute discrete units such as pills, tablets or capsules, each containing a predetermined amount of the active ingredient; a powder or granules; solutions or suspensions. The active ingredient may also be presented in the form of a ball or paste, or may be in liposomes, or other formulations that provide a slow release of active ingredient.

Formulations for rectal application may constitute a suppository or an enema.

For parenteral use acceptable formulations are aqueous and non-aqueous formulations for sterile is a, for example in sealed vials and vials, and can be stored in a dried state before application requires the addition of sterile liquid carrier, for example water.

Preparations suitable for application by inhalation through the nose, include dusty or aerosols, which can be obtained using a metered dose of the compressed under pressure of aerosols, aerosol nebulizer or poroshkovaya.

The present invention also includes the following methods for obtaining compounds of formula (I).

In the following description, the symbols X, R1R2, R3In4, R5, R6and R7unless otherwise stated, take the values defined for formula (I).

In accordance with the first method And the compounds of formula (I) can be obtained by the reaction of compounds of General formula (II)

with Ethylenediamine or its derivatives or chemical equivalents. For example, can be used monosol Ethylenediamine with various organic and inorganic acids, preferably p-toluensulfonate Ethylenediamine (1: 1). The reaction can be carried out in the presence of a solvent and at elevated temperature or melt temperature of the education of the lactone in the interaction of the compounds of formula (III)

with an appropriate ORGANOMETALLIC reagent such as a compound of lithium or zinc, and preferably with a Grignard reagent obtained, for example, from Snz-L1where L1represents a suitable leaving group such as halogen atom such as chlorine atom or bromine. Preferably used methylaniline or bromide in the presence of a nonpolar solvent such as hexane, diethyl ether or tetrahydrofuran, at a temperature of from about -40oWith up to 120oUsually at the boiling point under reflux.

The compounds of formula (III) can be synthesized by the methods described in the chemical literature, or obtained commercially.

In accordance with the second General way In compounds of General formula (I) can be synthesized by cyclization of the intermediate compounds of formula (IV) in the presence of a dehydrating agent or an acid catalyst, preferably in the presence of concentrated sulfuric acid, at elevated temperatures, for example at 50oC.


Intermediate compounds of formula (IV) can be conveniently obtained by recovery of the ketone of formula (V)osstanavlivayuschie agents are hydrides, such as allivalite lithium, alumoweld lithium or borane or a substituted boron. The reaction can be carried out in an aprotic solvent such as diethyl ether and/or tetrahydrofuran. Other acceptable hydride is sodium borohydride in a polar solvent, such as alcohol, using temperatures from -30oWith up to 100oC.


Compounds of General formula (V) can be obtained by the reaction of intermediate compounds (VI) with ventillation, preferably after protection using triphenylmethylchloride to the reaction, obtaining monoalkylation products (V).


Intermediate compound (VI) is readily available or can be obtained by the reaction of appropriately substituted benzonitrile with Ethylenediamine or its derivatives or its chemical equivalent in the presence of a solvent or without solvent at elevated temperatures.

Individual enantiomers of compounds of formula (I) can be obtained from a mixture of stereoisomers obtained by using one of the above sequence of reactions, using any of the methods well known in the field. Naprimet obtained by conversion of diastereomers ways, as getting a salt with an optically active acid followed by separation of the components of the diastereomers by fractional crystallization or by differential absorption using columns filled with a chiral material, for example by means of preparative chiral liquid or gas chromatography.

When one of the enantiomers is preferred, the fraction remaining after fractional crystallization and containing predominantly the other enantiomer, or other selected enantiomer can be ramisovna using a suitable base type potassium hydroxide in a suitable solvent, such as dimethylsulfoxide, at different temperatures, typically at room temperature, and the resulting racemate can be separated again for higher output.

The final 6-aryl-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinolines can be isolated as such or they can be converted to the desired acid additive salt or desired derivative. Usually the most preferred additive salts derived from pharmaceutically acceptable acids, such as hydrochloric acid, oxalic acid or fumaric acid.

If necessary or desirable, after one or neskolkih stages:
1. Removing any remaining protective group (or groups).

2. The transformation of compounds of formula (I) or a protected form into another compound of formula (I) or a protected form.

3. The transformation of compounds of formula (I) or a protected form in a pharmaceutically acceptable salt or MES the compounds of formula (I) or a protected form.

4. Turning pharmaceutically acceptable salt or MES the compounds of formula (I) or a protected form in the compound of formula (I) or a protected form.

5. Turning pharmaceutically acceptable salt or MES the compounds of formula (I) or a protected form into another pharmaceutically acceptable salt or MES formula (I).

6. When the compound of formula (I) are obtained in the form of a mixture of (R) and (S) enantiomers, the resolution of the mixture to give the desired enantiomer.

The present invention also includes all new intermediate compounds and, in particular, the compounds of formula (II), (IV) and (V). Specific intermediate compounds in accordance with the present invention are:
3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone;
3-(4-forfinal)-3-methyl-1(3H)-isobenzofuranone; and
3-(4-were)-3-methyl-1(3H)-isobenzofuranone.

The following examples serve only the N-isobenzofuranone
In nitrogen atmosphere for 30 minutes to 900 ml of 3 M solution of methylmagnesium in anhydrous tetrahydrofuran with stirring, add dropwise a solution of 130 g of 2-(4-chlorobenzoyl)benzoic acid in 300 ml of anhydrous tetrahydrofuran. After the addition was finished the reaction mixture was refluxed for 1 hour. Then the reaction mixture was cooled in an ice bath to room temperature and slowly add 1 l 2 N. aqueous solution of sulfuric acid, and then 600 ml of toluene. The organic layer is separated and washed with brine, dried and evaporated in vacuum. After distillation of the flask into the flask (0.1 mm, RT. senior/160oC) get 60 grams of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone in the form of a yellow oil.

Mass spectrum (chem. ionisation) (M/Z ): 260 [M+H]+.

Similarly receive:
3-(4-forfinal)-3-methyl-1(3H)-isobenzofuranone, mass spectrum (chem. ionisation) (M/Z: 243 (M+N)+when using as a starting compound 2-(4-perbenzoic)benzoic acid;
3-(4-were)-3-methyl-1(3H)-isobenzofuranone, mass spectrum (chem. ionisation)(M/Z): 239 [M+H]+when using as a starting compound 2-(4-methylbenzoyl)benzoic acid;
3-(2-naphthyl)-3-methyl-1(3H)-isobenzofuranone, mass spectrum (chem. ionization 2
Hydrochloride (racemate)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-b] of isoquinoline
A mixture of 60 g of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone and 257 g of p-toluensulfonate Ethylenediamine (166 ml Ethylenediamine treated with 470 g of p-toluenesulfonic acid and recrystallized from 2-propanol) is heated to 200oC and maintained at this temperature throughout the night. The reaction mixture is allowed to cool and add 850 ml of 1 N. aqueous solution of hydrogen chloride. The resulting mixture is extracted with 600 ml of chloroform. The organic layer was washed with 700 ml of 1 N. aqueous solution of potassium hydroxide, dried and evaporated in vacuum. The resulting residue is crystallized from a mixture of diethyl ether and hexane, 1: 3, at -20oTo get 46 grams (racemate)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline as a yellow solid. Adding hydrochloric acid in methanol receive hydrochloride (racemate)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a]isoquinoline, so pl. 230oC.

Similarly receive:
salt (racemate)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline and (Z)-2-butandiol acid (1:1), so pl. 164oSince, when using as the starting compound 3-(4-forfinal)-3-methyl-1(3H)-isobenzofuranone;152oSince, when using as the starting compound 3-(4-were)-3-methyl-1(3H)-isobenzofuranone;
salt (racemate)-2,3,5,6-tetrahydro-6-(2-naphthyl)imidazo [2,1 - a] isoquinoline and (E)-2-butandiol acid (1:1), so pl. 216oSince, when using as the starting compound 3-(2-naphthyl)-3-methyl-1(3H)-isobenzofuranone.

EXAMPLE 3
Salt of (-)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline and (E)-2-butandiol acid (1:1)
To 40 g of 6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline add 300 ml of ethanol and 30 ml of water together with 77 g of (+)-2-hydroxy-4-(2 - methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-oxide. The mixture is heated and get a clear solution. Then the solution is cooled to room temperature and stirred for another hour. The resulting solid product is filtered off and recrystallized from a mixture of 200 ml of ethanol and 20 ml of water, obtain 31 g of product, which process 1 N. aqueous solution of potassium hydroxide and extracted with diethyl ether. The ether solution is dried, evaporated and the resulting residue crystallized from hexane, to obtain 9 g of (-)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline as a white solid with an enantiomeric excess higher than 99%. In 100 ml of hot 2-propane is Toru allowed to cool to room temperature. Allocate filtering of 10.9 g of salt (-)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline and (E)-2-butandiol acid (1:1), so pl. 184oC.

EXAMPLE 4
Salt (+)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline and (E)-2-butandiol acid (1:1)
The remaining mother liquid obtained in Example 3, evaporated in vacuum and heated in a mixture of 1 N. aqueous solution of potassium hydroxide and toluene. Toluene layer is separated and evaporated in vacuum, get 25 grams of enriched (+)-enantiomer of 6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline. This quantity is dissolved in 200 ml of ethanol and 20 ml of water together with 45 g of (-)-2-hydroxy-4-(2 - methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-oxide. The mixture is heated and get a clear solution. After cooling to room temperature a white solid precipitates, which is filtered off and recrystallized from a mixture of ethanol/water, 10:1. The obtained solid product is distributed between 1 N. aqueous solution of potassium hydroxide and diethyl ether. The ether solution is evaporated and the resulting residue crystallized from hexane, to obtain 7 g of (+)-6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline as a white solid with an enantiomeric excess higher than 99%. Salt (E)-2-butandiol the Nile)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline
In 100 ml of anhydrous dimethyl sulfoxide was dissolved 14 g of enriched (+)-enantiomer of 6-(4-chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline with enantiomer excess of 87%. To the resulting solution was added 6 g of powdered potassium hydroxide and the mixture is stirred over night at room temperature. Then the reaction mixture was partitioned between water and diethyl ether and the organic layer washed with brine, dried and evaporated. Get 12 g (racemate)-6-(4 - chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline.

EXAMPLE 6
Salt of (-)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a]isoquinoline and (E)-2-butandiol acid (1:1)
The entire quantity (racemate)-6-(4-forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline (1.5 g) separated using chiral HPLC using a mixture of hexane: ethanol, 95:5 containing 0.2% diethylamine, and column ChiracelTMOJ h cm, at a temperature of 52oC and a flow rate of 10 ml/min Approximately every 18 minutes enter 120 ml (h Ál). Faction coming out of 29.6 minutes are pooled and evaporated to dryness under reduced pressure to obtain 600 mg of the compound that is transformed into salt (E)-2-butandiol acid (1:1) by adding the equivalent of (E)-2-butandiol acid in methanol. Get a salt of (-)-6-(4-forfinal)-2p>oC.

EXAMPLE 7
Salt (+)-6-(4-Forfinal)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline and (E)-2-butandiol acid (1:1)
The second fraction obtained in the process of chiral HPLC as described in Example 6 (face 38 minutes), combined and evaporated to dryness under reduced pressure. Obtain 590 mg of the compound that is transformed into salt (E)-2-butandiol acid (1: 1) by adding the equivalent of (E)-2-butandiol acid in methanol. Receive 600 mg of salt (+)-6-(4 - forfinal)-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinoline and (E)-2-butandiol acid (1:1), the enantiomeric purity of > 99.5% pure, so pl. 205oC.

EXAMPLE 8
Activity in vitro
Using the methods described in Neuropharmacology, Vol. 27, 3, pp. 251-260, 1988, conduct measurements blockade of reuptake of dopamine (DUP), serotonin (SUP) and noradrenaline (NUP). The results obtained are presented in table 1.

Annex 1.

Research activity in vivo to compounds in accordance with this invention was carried out on two techniques described in the literature.

Method 1: Ruight et al. // Computer-based prediction of psychotropic drug classes on a discriminant analysis of drug effect on rat sleep. Neuropsichology. Vol. 28 (1993). Pp. 138-153.

Method 2: Wieringa et al. // Monoamine reuptake inhibiting 1-[2-[(phenoxyphenyl)methoxy] ethyl] piperazines as potential antidepressants. Rel. Trav. Chim. Pays-Bas. Vol. 112 (one data below, characterize the antidepressant activity (method 1) and inhibition of re-uptake of dopamine (method 2) (see table 2).

EXAMPLE 9
Tablets (see table 3)
Using any of the suitable methods for the manufacture of tablets, well-known specialist in the field of pharmaceutics, get a tablet weighing 500 (A) or 1000 mg (In), respectively, containing 1 or 150 mg of the active component, the receipt of which is described in EXAMPLE 3.


Claims

1. Tetrahydroimidazo [2, 1-a] isoquinoline of the formula (I)

where X represents a group (A) or (B)

each of the substituents R1, R2and R3that may be the same or different, represents one or more substituents chosen from a hydrogen atom, a C1-6the alkyl or halogen atom;
each of the substituents R4, R5, R6and R7selected from a hydrogen atom
or its pharmaceutically acceptable salt or solvate provided that this connection is not (racemate)-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline, for use in the treatment of.

2. Connection on p. 1 to note is the yubom of PP. 1-3, where the substituent R represents one or more substituents chosen from a hydrogen atom, a C1-6of alkyl and halogen atom, and preferably the substituent R1is in the 4th position.

5. The compound according to any one of paragraphs. 1-4, where each of the substituents R4, R5, R6and R7represents a hydrogen atom.

6. The compound according to any one of paragraphs. 1-5, where n takes a value of 1.

7. Pharmaceutical preparation for inhibiting re-uptake of serotonin, dopamine and noradrenaline-containing compound of the formula (I) or its pharmaceutically acceptable salt or MES according to any one of paragraphs. 1-6 together with a pharmaceutically acceptable carrier.

8. Application (racemate)-6-phenyl-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline or its pharmaceutically acceptable salt or MES in the production of pharmaceuticals for the treatment or prevention of depression.

9. Compound selected from (racemate)-6-(4-Chlorophenyl)-2,3,5,6-tetrahydroimidazo [2,1-a] isoquinoline; (-)-6-(4-Chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline; (+)-6-(4-Chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline; (racemate)-6-(4-Forfinal)-2,3,5,6-tetrahydroimidazo[2,1-a] isoquinoline; (-)-6-(4-Forfinal)-2,3,5,6-tetrahydroimidazo[2,1-a] from the her and the solvate.

 

Same patents:

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

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is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to new derivatives of imidazo[1,2-a] pyridine f-ly I or its pharmaceutically acceptable salts, where R1is CH3or CH2HE, R2and R3is lower alkyl, R4Is h or halogen, R5Is h, halogen or lower alkyl, X is NH or O

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to new derivatives of 6-arrepiado[2,3-d]pyrimidine and-naphthiridine, their pharmaceutically acceptable salts, pharmaceutical composition having inhibitory effect of cell proliferation caused by protein tyrosinekinase, and to a method of inhibiting cell proliferation

The invention relates to the field of medicine and related antidepressant based on amitriptyline

The invention relates to novel 2,4-dioxo-5-arylidene-1,3-pyrimidines of General formula I, where R is independently selected from the group: H, HE, lowest alkoxyl, halogen, nitro, di(lower)alkylamino, n = 1-3, or two adjacent R along the benzene ring to which they are attached, when n = 2, 4 form a benzo, and dibenzo when n = 2 form a 3,4-dioxolane ring

The invention relates to derivatives of 16-hydroxy-11-(substituted phenyl)-÷stra-4,9-diene corresponding to the formula I, where R1- C1-6- alkyl, triflate or phenyl, where the phenyl group is optionally substituted by one or more substituents selected from cyano, halogen and C1-4-alkyl, R2is hydrogen or carboxy-1-oxo-C1-6-alkyl; R3is hydrogen, halogen or1-6- alkyl, optionally substituted by one or more1-6-alkoxy, R4is hydrogen or C1-6-alkyl, and X, O or NOH; or their pharmaceutically acceptable salts or MES; describes the methods for their preparation and the pharmaceutical composition is intended for use in medical therapy particularly for the treatment or prevention glucocorticoidavoid diseases or symptoms

The invention relates to the chemistry of heterocyclic sulfur compounds and concerns diabeticheskih derivatives of the formula I, having antidepressant activity, where R= H, Na, Me, CH2=CHCH2CH2Ph or CH3CH2CH2CH2X=CONH2; NH2HCl; NHBoc; CH2NH2or C(OEt)2NH2HCl

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to the field of medicine and relates to a combination of the first component (a), which is an inhibitor of re-uptake of 5-HT with the second component (b), which is a selective 5-HT1Aantagonist of formula (I), where R1represents n-propyl or cyclobutyl; R2represents isopropyl, tert-butyl, cyclobutyl, cyclopentyl or cyclohexyl; R3represents a hydrogen atom; R4represents a hydrogen atom or methyl; in the form of (R)-enantiomer in the form of free base or its pharmaceutically acceptable salts, to receive his blessing, to pharmaceutical preparations for the treatment of affective disorders, containing the specified combination

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims
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