2,3,4,5,6,7-hexahydro- 1-[4-[1-[4-(2-methoxyphenyl) piperazinil]]-2-phenylbutyl]-1h-azepin and how to obtain it


(57) Abstract:

Usage: in medicine for binding of the receptor 5-HTJA. The inventive Product: 2,3,4,5,6,7-hexahydro-1-[4-[L-[4-(2-methoxyphenyl) piperazinil]]-2-phenylbutyl]-1H-azepin, so pl. 175-178oC. Reagent 1: 2,3,4,5,6,7-hexahydro-1H-azepin. Reagent 2: compound of formula I. reaction Conditions: in a medium of an organic solvent. 2 s and 5 C.p. f-crystals.

The invention relates to piperazinone derivatives, to processes for their production, to their use and to contain their pharmaceutical compositions. New connections act on the Central nervous system, linking 5-HT receptors, and, consequently, can be used as drugs for treatment of humans and other mammals.

The new compounds of the invention are compounds of the formula

< / BR>
and their pharmaceutically acceptable salts.

The compound (A) is a 2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinil]-2-phenylbutyl)-1H-azepin.

Our thoroughly review the application form UK N 9008925.1 describes compounds having the General formula:

< / BR>
and farmatsevticheskii acceptable acid additive salt.

is an aryl or nitrogen containing heteroaryl radical;

R2represents hydrogen or lower alkyl;

R3is aryl radical, alkyl radical containing from 4 to 8 carbon atoms or aryl(lower)alkyl radical;

X represents a-OCOR10, -CO2R6, -OCNR5R9, -OCO2R6, -NR4COR6, OCNHR11, -NHCO2R6, -NR4CONHR6,-CONHNHR6, -CONHOR6;


R4and R5each represents hydrogen or lower alkyl, R6is-CHR7R8, cycloalkyl or aryl(lower)alkyl containing from 3 to 12 carbon atoms (in which R7and R8each represents hydrogen or lower alkyl), R9is hydrogen, alkyl group sizes from 1 to 8 carbon atoms, but not tertiary alkyl group, cycloalkyl containing from 3 to 12 carbon atoms, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl or 8 azaspiro[4,5] DECA-7,9-Dion-8-yl-(lower)alkyl (with the proviso that when R3is aryl or arylalkyl, R9not a phenyl group substituted in ortho-position with halogen, nitrogen, triptorelin, cyano, sulfonic acid, sulfonamide, carboxy, carbalkoxy, orthoxylene Il the l(lower)alkyl, R5is hydrogen or-CHR7R8)

or R5and R9together with the nitrogen atom to which they are attached, represent azetidinone, pyrolidine, piperidine, hexahydroazepin, morpholino or pieperazinove ring which may be substituted by lower alkyl, aryl or aryl(lower)alkyl;

R10is cycloalkyl from 3-12 carbon atoms or a 2,3-dihydro[1,4] benzodioxin, not necessarily substituted lower alkyl, lower alkoxy or halogen, or, when R is an alkyl radical containing from 4 to 8 carbon atoms, R10can also be aryl;

R11is cycloalkyl containing from 3 to 12 carbon atoms, aryl or aryl(lower)alkyl;

R12and R13each is lower alkyl or together with the carbon atom to which they are both attached, represent a C4-6-cycloalkyl,

R14represents hydrogen, halogen, lower alkyl or lower aryl;

Y represents CO or SO2.

The General formula of the compounds of the application of UK subject the compound of the present invention. However, in the description of this earlier application is not specifically a description of the formula (I) application great Britain, where the values of R, R1, R2, R3, x and n are in a certain combination. Formula (I) covers a large number of possible compounds, whereas in this application is considered a single connection (optionally in the form of its salts or its enantiomers). This is the only connection is not described in the application great Britain, and the description of this application absolutely does not imply a particular combination of values of the substituents R, R1and so on, In particular, the connection of this application not only has a specific combination of substituents R, R1and so on, but in this case n has the value 2. Description of the proposal the UK contains 58 examples, and each example n is 1 and indicates that the preferred compounds have a value of n equal to 1. Therefore, the person skilled in the art would seek to avoid obtaining compounds where n is 2. Unexpectedly, the applicant has found that only one in particular, compound with n equal to 2, is the most active. The new compound of the present invention, the compound (A) or its enantiomer compound (C) has a much higher activity than the compound of example 34 applications in the UK, i.e. the compound (B). Connection B is connected is equal to the compound (A), except that n is 1.

Thus, the data of this application illustrate that a new connection has a much higher activity than the closest known compound (3-9 times the efficiency of binding of 5-HTIA-receptor according to the test results in 10 times the efficiency of binding of 5-HTIA-receptor against the antagonist according to the test results, and 33 times tranquilidade activity). Thus, a new connection is much more active not only in comparison with the nearest known connection, it is also more active than all compounds described in this application in the UK.

The compound of the invention of formula (A) can be obtained by the coupling of compounds of formula


in which X represents a removable group, such as halogen, amide anion of formula

< / BR>
or acylation of amine of the formula

< / BR>
acid formula


or alkylation of the piperazine of the formula

< / BR>
alkylating agent, giving the group

< / BR>
If any of these methods, the resulting product is a base, not necessarily make it a pharmaceutically receiving base and, if necessary, turn the racemic form of the compounds obtained in optically active.

The anion can be obtained by the interaction of the amide with a strong base, such as diisopropylamide lithium.

The implementation of the methods described above leads to the production of compounds of the invention in free base form or acid-salt additive. If the compound of the invention obtained in the form of an acid additive salt, the free base can be obtained by alkalization of the solution of acid additive salt. On the contrary, if the reaction product is the free base, an acid additive salt, in particular pharmaceutically acceptable acid additive salt, can be obtained by dissolving the free base in a suitable organic solvent and the acid solution in accordance with the standard methods of obtaining the acid additive salts of the basic compounds.

Examples of the acid additive salts are salts formed with inorganic and organic acids, such as sulfuric, hydrochloric, Hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulfonate, p-toluensulfonate, oxalic and succinic.

Compounds of the invention contain an asymmetric carbon atom and therefore the mi or in optically active form. Optically active forms can be obtained by re-dissolving the racemate or asymmetric synthesis. For example, it may be repeated dissolution with formation of diastereoisomeric salts racemic base with an optically active acid (e.g., Dibenzoyl-L-tartaric acid), allocation diastereoisomeric salts and turning them into optically active base or other salts.

The compounds of this invention possess pharmacological activity. In particular, they affect the Central nervous system, binding of 5-HT receptors. Pharmacological tests showed that the compounds, in particular, join receptor type 5-HTIA. Compounds selectively connected with the receptor type 5-HTIAto a much greater extent than with other receptors, such as receptors1. They are active as of anatagonists 5-HTIAin pharmacological tests. Pharmacological testing of compounds shows that they can be used for the treatment of CNS disorders such as anxiety in mammals, particularly in humans. They can also be useful as antidepressants, antihypertensive agents and agents for regularmente was tested for activity in binding to 5-HT1A-receptor in the membrane homogenate in the hippocampus of rats according to the method of B. S. Alexander and M. D. Wood (J. Pharm. Pharmacol. 1988, 40, 888-891).

The results show that the compounds of the invention are more potent than other compounds of formula (I), including the related connection 2,3,4,5,6,7-hexahydro-1-[3-[1-[4-(2-methoxyphenyl)piperazinil] -2-phenylpropionyl]-1H-azepine (compound (B) described in example 34 together our pending application). The compound (B) was one of the most potent compounds, disclosed in co-pending application. Below are the results, in which the compound (C) is the isomer described in example 2(a) below: - 1C50(nm)

Connection (A) 3

The compound (B) 9

The compound (C) 1

Compounds were also tested for antagonistic activity against 5-HT1A- receptor in the test, including antagonistic syndrome in relation to 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) in rats. The results are given below: MED minimum effective dose (mg/kg; subcutaneously)

The compound (A) 0,03

The compound (B) 0.3 TO

Compounds were also tested for potential activity as tranquilizing means using the method of evaluation ) and J. N. Crawley and others (Pharmac. Biochem. Behav. 1980, 13, 167-170). The results are given below: MED - minimum effective dose (mg/kg; subcutaneously)

The compound (A) 0,03

Connection (B) 1

The invention also includes a pharmaceutical composition comprising a compound of formula (A) or its pharmaceutically acceptable acid additive salt in combination with a pharmaceutically acceptable carrier. For the preparation of pharmaceutical compositions may be used any suitable carrier known in this field. In such compositions, the carrier is typically a solid or a liquid, or a mixture of solid and liquid.

The composition in solid form include powders, granules, tablets, capsules (for example, solid or liquid gelatin capsules), suppositories or pessaries. Solid media can consist of one or more substances that can act as aromatic agents, lubricants, solubilizers agents, suspendida agents, fillers, substances, improve slip, substances that improve pressing, binding, or agents that promote decomposition of tablets; it may also be a kapsulirujushchej substance. In powders, the carrier is a thin the om. In tablets, the active ingredient is mixed with carrier having the necessary compression statistics, in appropriate proportions and compacted to the desired shape and size. The powders and tablets preferably contain up to 99% for example from 0.03 to 99%, preferably from 1 to 80% of the active ingredient. Appropriate solid media includes, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, nikopensius waxes and ion exchange resins.

The term "composition" involves the preparation of formulations of the active component with kapsulirujushchej material with the formation of capsules in which the active component (with other carriers or without them) is surrounded by carrier, which is thus associated with this component. Similarly prepared starch capsules.

Compositions in liquid form include, for example, solutions, suspensions, emulsions, syrups, elixirs and tight composition. For example, the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of these components or in pharmaceutical preparations is key, such as solubilizing agents, emulsifiers, buffering agents, preservatives, sweeteners, flavouring agents, suspendresume agents, thickeners, tinted substances, substances that regulate the viscosity stabilizers or substances that regulate the smell.

Examples of liquid carriers for oral and parenteral intake include water (particularly containing the above-mentioned additives such as cellulose derivatives, preferably natrocarbonatite solution), alcohols (such as glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter). For parenteral receiving media may represent an oily ester such as ethyl oleate and isopropylmyristate. In sterile liquid form compositions for parenteral intake used sterile liquid media.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be used for intravenous administration. In that case the th, or solid composition.

The preferred pharmaceutical composition is a standard dosage form, for example, in the form of tablets or capsules. In this form, the composition is divided into standard doses containing appropriate quantities of the active component; standard dosage form can be a packaged powders, vials, ampoules, prefilled syringes or sachets filled with liquid. Standard dosage form can be, for example, capsules or tablets, or it may be any number of compositions in package form. The number of active component in a standard dosage form of the composition may be varied or adjusted from 0.5 mg or less to about 750 mg or more in accordance with the particular need and the activity of the active component.

Example 1. 2 2,3,4,5,6,7-Hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinil]-2-phenylbutyl]-1H-Sapin

Utility (1.5 M in hexane: 5 ml, 7.5 mmol) was added dropwise over 5 minutes while maintaining the temperature below 8oC to stir the solution 2,3,4,5,6,7-hexahydro-1-phenylacetyl-1H-azepine (1.48 g, 6.8 mmol) and Diisopropylamine (2.0 ml, 1.4 g, 14 mmol) in dry toluene (16 ml) in an atmosphere of ar is a mere method of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (1.73 g, 6.8 mmol) in dried toluene (4 ml). The mixture is stirred for 18 hours at a temperature of from 0 to 20oC, and water was added (50 ml). Spent the separation of the layers, and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were concentrated in vacuo. The crude product was subjected to chromatographicaliy (2,92 g) using silica and ethyl acetate as eluent with the formation of the connection specified in the header in the form of the free base (0.15 g). By recrystallization from diisopropyl ether obtained free base in the form of white crystals. So pl. 91-92oC. the Free base was dissolved in ethyl acetate (30 ml) and the solution was pagkilala complex ether hydrochloric acid. The product was collected, forming the connection specified in the header, in the form of three-Quaternary dihydrochloride hydrate (0.36 g), so pl. 175-178oC (Found: C 62,05; H 7,8; N 7,75.

C27H37N3O22HCl 0,75 H2O requires C to 62.1; H 7,8; N 8,05%).

Example 2. Division 2,3,4,5,6,7-hexahydro-1-[4-[4-[4-(2-methoxyphenyl)piperazinil]-2-phenylbutyl]-1H-azepine

(a) 2,3,4,5,6,7-Hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinil]-2-phenylbutyl] -1H-azepin (12.1 g) was dissolved in ethyl acetate (2.5 volume, i.e., 30 ml), and the resulting oil was dissolved again by adding a minimum amount of acetonitrile (3.6 ml). After the third filtration gave crystals (6.2 g), which had an optical purity of 28% as judged on the basis of method of chiral HPLC. The first recrystallization from a mixture of ethyl acetate-acetonitrile (3:10, 13 volumes) gave the sample optical purity of 84% and repeated recrystallization from methanol (7.5 volumes) gave enantiomer (isomer I) product in the form of Dibenzoyl-L-tartrate (2.1 g), so pl. 147-150oC []2D2-26o(1% CH3OH) (Found: C 66,7; H 6,7; N 5,1; C27H37N3O2C18H14O8H2O requires C of 66.6; H 6,6; N 5,2%) with an optical purity of 97.4% of the Sample was converted to the free base of the isomer (I) (1.1 g, so pl. 83-86oC) [] 2D3+53o(1% in CHCl3) and in hydrochloric salt in the standard manner with the formation of a colourless powder (0.65 g), so pl. 181-184oC. []2D3+35o(1% CH3OH) (Found C to 63.1; H 7,8; N 7,9; C27H37N3O22HCl 0,25 H2O requires C to 63.2; H 7,7; N 8,2%) with an optical purity of 97.6%

(b) a Second enantiomer (isomer II)was obtained similarly from the racemate of example 1 and monohydrate Dibenzoyl-D-tartaric acid. Isomer II Dibenzoyl-D-tartrate, so pl. 141-142oC []2D0,25 H2O requires C to 67.3; H, 6.5; the N 5,2%).

Isomer II the base was obtained by crystallization from diisopropyl ether as white: crystals, so pl. 81-82oC []2D6-62o(1% solution in CHCl3).

Isomer II hydrochloride, T. pl. 181-184oC. []2D6-36o(1% CH3OH) (Found: C a 60.2; H 7,7; N 7,75; C27H37N3O22HCl 1,75 H2O requires C 60,05; H 7,9; N 7,8%) with an optical purity of 98.2%

Example 3. 2 2,3,4,5,6,7-Hexahydro-1-[4-[1- [4-(2-methoxyphenyl)piperazinil]-2-phenylbutyl]-1H-asutin

Dicyclohexylcarbodiimide (5.0 mmol), 4-(1-(4-(2-methoxy)phenyl)piperazinil)-2-phenylalanyl acid (5.0 mmol), CH2Cl2(20 ml) and hexamethyleneimine (7,60 mmol) is stirred in the air tube at 20oC for 24 hours. The reaction mass is filtered and evaporated in vacuum. Orange oil is treated with water (25 ml) and concentrated hydrochloric acid (2 ml), the solution washed with ether (2.25 ml), alkalinized with 5 n NaOH solution (6 ml) and extracted with CH2Cl2(2.25 ml). The extracts are dried (Na2SO4), evaporated in vacuum and azeotropic distillation with CH3OH get a free base as a pale yellow resin, which in turn 3/4 guy who yl] -2-phenylbutyl]-1H-asutin

In the atmosphere of argon, 1-(2-methoxyphenyl)piperazine (6.42 per mmol), Diisopropylamine (7.5 mmol) and potassium iodide (6.42 per mmol) in dry dimethylformamide (10 ml) is treated with a solution of 1-(4-chloro-2-phenyl)butyryl-2,3,4,5,6,7-hexahydro-1H-azepine (of 6.75 mmol) in dry dimethylformamide (10 ml), maintained at 110oC for 3 hours, cooled to room temperature, treated with water (150 ml) and extracted with ether (2,50 ml). The extracts are dried (Na2SO4), evaporated in vacuo, chromatographic [SiO2CH3COOC2H5] and receive free base as a brown oil, which in turn 3/4 hydrate of the dihydrochloride, so pl. 175-178oC.

1. 2, 3, 4, 5, 6, 7-Hexahydro-1-[4-[1-[4-(2-methoxyphenyl) piperazinil] -2-phenylbutyl]-1H-azepin formula


or its pharmaceutically acceptable acid additive salt.

2. Connection on p. 1 of formula I, which represents an enantiomer, the angle of rotation of which is []2D6approximately +53o(1% in CHCl3), or its pharmaceutically acceptable salt.

3. Connection on p. 1 of formula I, which represents an enantiomer, the angle of rotation of which is []2D6approximately minus 62o(1% in CHCl3or in pharmaceutical preparations the formula acelerou acid formula

< / BR>
or allermuir derivative and, optionally, if the target product is a base, it turns into a pharmaceutically acceptable acid additive salt or turn pharmaceutically acceptable acid additive salt of a free base and, if necessary, turn the racemic form of the target product in optically active.

5. The method of obtaining the compounds of formula I on p. 1, wherein the piperazine derivative of the formula

< / BR>
subjected to interaction with an alkylating agent containing the group

< / BR>
and, if necessary, if the target product is a base, turn it into a pharmaceutically acceptable acid additive salt or turn pharmaceutically acceptable acid additive salt of a free base and, if necessary, turn the racemic form of the target product in optically active.

6. The method of obtaining the compounds of formula I on p. 1, wherein the piperazine derivative of General formula

< / BR>
where X tsepliaeva group,

subjected to interaction with the amide anion of formula

< / BR>
and, if necessary, if the target product is a basis is acceptable acid additive salt of a free base and if necessary, turn the racemic form of the target product in optically active.

7. The compound according to any one of paragraphs. 1 to 3, has the property to bind the receptor 5-HTIA.


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where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

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9 cl, 10 ex, 1 tbl

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58 ex

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EFFECT: valuable medicinal properties of salts and drug.

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