Piperazine derivatives

 

(57) Abstract:

The present invention relates to piperazine derivatives of the formula (a), where a represents a heterocyclic group of 5 to 6 atoms in the ring, where there are 1-2 heteroatoms from the group O and N, R1is hydrogen, R2is1-4-alkyl, C1-4-alkoxy or oxoprop and p = 0,1 or 2, Z represents nitrogen and the dotted line represents a single bond, R3and R4represent hydrogen, n = 1, R5represents 2-pyridyl, 3-pyridyl or 4-pyridyl. Connections can be used for the treatment of schizophrenia and other psychotic disorders. Also described intermediate compounds used in the synthesis. 2 S. and 3 C.p. f-crystals, 2 PL.

This invention relates to new compounds of the number of piperazine having useful pharmacological properties.

It was found that the compounds of formula (a):

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where a represents a heterocyclic group with 5-7 atoms in the ring, where there are 1-3 heteroatoms from the group O, N and S,

R1represents hydrogen or fluorine,

R2is1-4-alkyl, C1-4-alkoxy or oxoprop and p is 0, 1 or 2,

Z to depict the full or double bond, when Z represents carbon,

R3and R4independently represent hydrogen or C1-4-alkyl,

n has the value 1 or 2,

R5represents 2-pyridyl, 3-pyridyl or 4-pyridyl substituted in the meta position relative to the methylene bridge group Y, and optionally substituted (R6)q,

Y represents phenyl, furanyl or thienyl, and these groups may be substituted by 1-3 substituents from the group comprising hydroxy group, halogen, CF3WITH1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono - or di-C1-4-alkylaminocarbonyl,

R6is halogen, hydroxy, C1-4-alkoxy or C1-4alkyl and q is 0, 1, 2 or 3, and their salts, possess useful pharmacological properties.

Preferred compounds according to this invention are the compounds of formula (a), which together with the phenyl group represents a group of formula a, b, C, d, e, f or g:

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and R1, (R2)p, R3, R4, R5, (R6)q, Y and Z have the abovementioned meanings and n is 1, and their salts.

Especially preferred compounds of formula (a) are compounds where a together with the phenyl group decomposes be substituted, as indicated above, and where R2has the above significance, p = 0 or 1, n is 1, R3and R4represent hydrogen, R6represents hydroxy, methoxy or halogen, q is 0 or 1, Z is nitrogen, and their salts.

A specific preferred compound is a compound having the formula (a), which together with the phenyl group represents a group of formula (d), R1, (R2)p, R3and R4represent hydrogen, n is 1, Z is nitrogen and R5represents a group of 5-(4-forfinal)-pyrid-3-yl, and the salts thereof.

From European patent 0650964 it is known that compounds of the formula:

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where R0is1-14-alkyl, and compounds may be substituted in the phenyl group and/or heterocyclic group, and/or piperazino group, have an effect on the Central nervous system by binding to 5-HT receptors (5-HT denotes 5-hydroxytryptamine, or serotonin). Particularly, these compounds are associated with subtypes of 5-HT-receptor, i.e. 5-HT1Aand 5-HT1D-receptors.

Now it has been unexpectedly found that the compounds according to this invention show affinity for D2-dopamine receptor (range PKi7-9,5) and D1Athe serotonin receptors (range PKi7-9,5). This combination of affinity to dopamine receptors and serotonin can be used for the treatment of schizophrenia and other psychotic disorders, and can allow for a more complete treatment of all symptoms of such diseases (e.g., positive symptoms, negative symptoms and deficits in cognitive abilities).

The compounds exhibit variable activity as either partial agonists or antagonists against D2-, D3and D4-dopamine receptors. Some compounds exhibit actions such as a agonist of dopamine receptors, however, they have a strong antagonistic effect on apomorphine-induced climbing behavior in mice (size ED50<1 mg/kg by oral administration). The compounds exhibit varying activity as agonists 5-HT1Areceptors and induce aspects of the serotonin behavioral syndrome to various intensities.

These compounds are active in therapeutic models that are sensitive to clinically relevant antipsychotic agents (for example, obul the e strengthening slow reaction van Hest et al., Psychopharmacologe, 1992, 107: 474-479) and anxiolytics (e.g., suppression induced stress loud sounds; van der Poel et al., Psychopharmacology, 1989, 97: 147-148).

In contrast to the clinically relevant antagonists D2-dopamine receptor compounds described herein have a low propensity to induce catalepsy in rodents and as such, will likely induce more weak extrapyramidal side effects than existing antipsychotics.

Agonism to 5-HT1A-receptor inherent in these compounds may be responsible for a reduced tendency to induce extrapyramidal action and therapeutic effect observed in behavioral models that are sensitive to either antidepressants or anxiolytics.

The data connection seems valuable for the treatment of lesions or diseases of the Central nervous system, caused by a disorder in dopaminergic and serotoninergicheskoi systems, for example: Parkinson's disease, aggression, disorders, manifested in alarming condition, autism, vertigo, depression, disorders of cognitive ability or memory, and especially schizophrenia and other psychotica acceptable acid additive salt, are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluensulfonate acid, methanesulfonate acid and naphthalenesulfonate acid.

Compounds of the invention can be converted into a form for injection by conventional methods with the use of auxiliary substances, such as liquid or solid materials carriers.

Compounds of the invention can be obtained by methods (a and b), which are described below. Piperazines used in these methods are referred to as I-N. to III-N, where I-III represent the following groups:

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The synthesis of these piperazines from I-N. to III-N is described in European patent 0189612.

N-atom part of N-N compounds from 1 to III-N can be replaced by a group Q in two different chemical routes (a and b), ultimately leading to the compounds of the invention. Group values from Q1 to Q9 following:

Group Q

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Synthetic path AND

The compounds listed in table a, was obtained by synthesis depicted in Shamim as a base; in some cases, it was added KI (or NaI). Instead of Et(i-Pr)2N you can use Et3N

Synthetic path IN

The compounds listed in table V, were obtained through the synthesis depicted in scheme B1 (see at the end of the description); piperazine was subjected to reaction with 3-bromo-5-chloromethylpyridine, receiving the intermediate product b1 (scheme B2), which combined with the derived Bronevoy acid by means of the so-called reaction cross combination Suzuki.

Obtaining compounds of formula (a) and a number of intermediate compounds will now be described in detail in the following examples are not limiting, however, the present invention.

Example 1.

Method A1 (scheme A1):

To a suspension of monohydrochloride 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine, III-l (1.1 g, of 4.25 mmol) in CH3JV (40 ml) was added Q4-C1 (1.0 g, a 3.87 mmol) and diisopropylethylamine (2,45 g, 19 mmol). The mixture was stirred while boiling under reflux for 3 hours. After cooling and evaporation of the solvent in vacuo the residue was dissolved in CH2Cl2off , washed with 5% solution of NaHCO3, saturated NaCl, dried (Na2SO4), filtered and evaporated in vacuum. The resulting dark matte oil. The product was converted into its monohydrochloride Sol: the residue was dissolved in Et2O and treated with 1 EQ. HCl in ethanol. The product was precipitated as a white solid. Solid 8l was collected by filtration and dried: I. pl. 233-5oWith decomposition;

1H NMR (400 MHz, DMSO/CDCl3, 4/1) (ppm) 3.1-3.6 (cluster, 8H), 4.24 (m, 4H), 4.58 (s, 2H), 6.49 (d, 1H, J = 8 Hz), 6.55 (d, 1H, J = 8 Hz), 6.74 (t, 1H, J = 8 Hz), 7.34 (m, 2H), 7.91 (m, 2H), 8.77 (m, 1H), 8.9 (m, 1H), 9.10 (m, 1H), 11.8 (brs, 1H, NH+).

Example 2.

Method Al (figure Al):

A suspension of 2-(p-chlorophenyl)-4-pommerellen, Q5-Br, (0.71 g, to 2.67 mmol) and 1-(2-benzoxazolinone-4-yl)piperazine 1-l (0,58 g of 2.27 mmol) in DMF (20 ml) together with 2.1 equivalents Et3N was stirred at room temperature for 2 hours. Get bright, the solution was concentrated, receiving a red oil, which was purified flash chromatography (SiO2the elution CH2Cl2/MeOH/NH4OH, 92/7, 5/0,5), receiving the A9 (0.28 g, 26%) as a yellow solid: so pl. 213-4o;1H-NMR (400 MHz, DMSO/Dl3, 4/1) (ppm) 2.62 (m, 4H), 3.24 (m, 4H), 3.64 (s, 2H), 6.59 (d, 1H, J = 8 Hz), 6.63 (d, 1H, J = 8 Hz), 7.01 (t, 1H, J = 8 Hz), 7.27 (m, 2H), 7.32 (m, 1H), 7.85 (m, 1H), 8.13 (m, 2H), 8.6 (m, 1H), 11.5 (s, 1H).

According to the above syntheses, other compounds A1-A12 was obtained in a similar way (see table A).

PR is (5 ml) was stirred at room temperature for 10 minutes in an atmosphere of N2. Then successively added 2-tiefenbronn acid (0.39 g, 3.0 mmol) and an aqueous solution of Na2CO3(2,75 ml of 2 M solution) and the mixture was allowed to react at a temperature of phlegmy for 1 hour. The solution was cooled, diluted with H2O and was extracted with CH2Cl2. The organic phase is evaporated to dryness in vacuum to give crude product B1, which was purified flash chromatography (CH2Cl2/MeOH, 98/2) and then turned in monohydrochloride salt to obtain 1l (0.8 g, 74%) as a white solid: so pl. 160oWith the decomposition, the material becomes sticky;

1H-NMR (400 MHz, Dl3) (ppm) 3.0-3.8 (brb, 8H, NH+N2Oh), 4.25 (m, 4H), 4.63 (brs, 2H), 6.54 (d, 1H, J = 8 Hz), 6.64 (d, 1H, J = 8 Hz), 6.75 (t, 1H, J = 8 Hz), 7.14 (m, 1H), 7.43 (d, 1H, J = 5 Hz), 7.74 (m, 1H).

According to the above syntheses, other compounds B2 B3 was obtained in a similar way (see table B).

INTERMEDIATE PRODUCTS USED IN THE PATH AND

Intermediate products Q-X

Q1-C1:

This intermediate product was synthesized as described in scheme A2:

Stage i (scheme A2):

This stage was carried out according to the method similar to that described in J. Het. Chem., 12, (1975), 443.

Stage ii (scheme A2):

Under stirring at room Tempe is the PR of 7.8 g of 75% m-SRV (33,9 mmol) in 75 ml of chloroform. The reaction mixture showed only a weak temperature rise. After stirring for 1.5 hours the reaction mixture was shaken twice with 5% aqueous solution of NaHCO3and twice with an aqueous solution of Na2S2O3to remove excess msrwa, after which the reaction mixture gave a negative reaction on damp paper KI/starch. The organic layer was dried over MgSO4. Removal of the desiccant by filtration and the solvent by evaporation in vacuum gave an oil, which crystallized upon scratching the walls of the vessel, giving 5.5 g (105%) of crude N-oxide 2-phenyl-6-methylpyridine, which was used in the next stage without further purification.

Stage iii (scheme A2):

Mix a solution of crude N-oxide 2-phenyl-6-methyl-pyridine (5.2 g, 28.5 mmol) in AU2O (25 ml) was heated at a temperature of phlegmy within 2 hours. AU2About removed using an oil pump (10 mm) at 40oWith getting a red oil, which was purified flash chromatography on silica gel using as eluent a mixture of Et2O/petroleum ether = 1:1, receiving 2-phenyl-6-(acetoxymethyl)pyridine (4.6 g, 70%) as oil.

Stage iv (scheme A2):

4.5 g 2-phenyl-6-(acetoxymethyl)pyridine (20 mmol) was treated with the mixture was concentrated using an oil pump (10 mm) at 40oWith added CH3CN and the mixture is evaporated to dryness in vacuum, obtaining 2-phenyl-6-(hydroxymethyl)pyridine (3.0 g, 80%) as oil.

Stage v (scheme A2):

To a stirred solution of 2-phenyl-6-(hydroxymethyl)pyridine (1.0 g, 5.4 mmol) in l3(7 ml) at room temperature was added dropwise SOCl2(1.22 g, 10.2 mmol) and the mixture was heated at 60oC for 20 minutes. After evaporation of the solvent in vacuo the residue was purified by rubbing with Et2O. the resulting precipitate was collected by filtration and dried, obtaining the chloride 2-phenyl-6-(chloromethyl)pyridinium, Q1-C1 (1.2 g, 92%) as a white solid product.

Q2-C1:

Q2-C1 was obtained analogously to the synthesis of Q1-C1.

Q3-C1:

Q3-C1 was obtained analogously to synthesis Q4-C1 (see below).

Q4-C1:

This intermediate product was synthesized as shown in scheme A3.

Stage i (figure A3):

Stir a mixture of 3-bromo-5-pyridineboronic acid (10.1 g, 50 mmol) and H2SO4(1.5 ml) in Et (150 ml) was boiled under reflux for 6 hours. After cooling, the solvent was removed by evaporation in a vacuum. The residue was diluted with H2O (100 ml) was podslushivaet 5% solution (water) NaHCO3and was extracted with ether (4 x 100 ml). United is the in vacuo of the filtrate gave the ethyl ester of 3-bromo-5-pyridineboronic acid in the form of oil, which was aterials when standing (9,8 g, 85%).

Stage ii (figure A3):

To a stirred solution of ethyl ester of 3-bromo-5-pyridineboronic acid (9.5 g, a 41.3 mmol) in EtOH (96%, 220 ml) was slowly added NaBH4(14.4 g, 380 mmol) at 25oC. the Reaction was weakly endothermic. The mixture was stirred in nitrogen atmosphere at room temperature for 6 hours. The resulting milky mixture was diluted with H2O (150 ml), EtOH evaporated in vacuum and the residue was extracted with CH2CL2(3 times). The combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum, obtaining 9 g of a crude oil which was purified flash chromatography on silica gel (eluent: Et2O) to give 3-bromo-5-hydroxymethyluracil (3.5 g, 45%).

Stage iii (figure A3):

To a solution of 3-bromo-5-hydroxymethylbilane (3,3 g, 17.5 mmol) in toluene (35 ml) was added Pd(PPh3)4(0.6 g, 0.52 mmol), an aqueous solution of Na2CO3(17,5 ml of 2 M solution) and p-ftorhinolonovy acid (2.65 g, 19 mmol, dissolved in 8.5 ml of EtOH). The mixture was heated at 80-90oC for 1 hour and vigorously stirred. After completion of the reaction two-phase reaction mixture was cooled, the organic layer was collected and washed out the dryer was removed by filtration and the solvent evaporated in vacuum, getting dark oil, which was purified flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH, 95/4, 5/0,5) to give 3-(p-forfinal)-5-hydroxymethyluracil (3.0 g, 84%). The product was converted into its monohydrochloride Sol: the residue was dissolved in Et2O and treated with 16.5 EQ. HCl in ethanol. Product, the hydrochloride of 3-(p-forfinal)-5-hydroxymethylpropane, Q4-OHHCl, was deposited in the form of a white solid, which was collected by filtration and then dried.

Stage iv (scheme A3)

Hydrochloride 3-(p-forfinal)-5-hydroxymethylpropane Q4-l (3.5 g, 14.7 mmol) was added to excess SOCl2(20 ml) and the mixture was heated at 60oTo start with reaction (generation of Hcl). After complete conversion of starting material (45 min) the reaction mixture was cooled and the excess SOCl2was removed in vacuo, leaving a dry residue. Crystallization of Et2O gave the hydrochloride of 3-(p-forfinal)-5-chloromethylpyridine Q4-1l (2.5 g, 66%).

Q5-VG:

Synthesis Q5-Br shown in figure A4.

Stage i (figure A4):

A solution of 2-bromo-4-methylpyridine (10 g, 58 mmol) and Pd(PPh3)4(1.5 g, 1.3 mmol) in toluene (110 ml) was stirred at room temperature under nitrogen atmosphere. Sequentially added water reali to react at 90-100oC for 4 hours. The mixture was cooled, the aqueous layer was separated and was extracted with EtOAc (2 times). Combined fractions EtOAc and toluene were dried over MgSO4. The separation of the desiccant by filtration and removal of solvent in vacuo gave a pink oil (28 g). Distillation gave pure 2-(p-forfinal)-4-methylpyridin (6,10 g, 56%); so bales. 110-116o(6-7 mbar) as a colorless oil.

Stage ii (figure A4):

A mixture of 2-(p-forfinal)-4-methylpyridine (0.5 g, to 2.67 mmol), N-bromosuccinimide (0,48 g, 2,69 mmol) and catalytic amount of benzoyl peroxide in CCL4(50 ml) was stirred at a temperature of phlegmy and were irradiated using a standard UV lamp 250 watts for 4 hours. Then the reaction mixture was cooled and then rubbed with a mixture of E2O/petroleum ether. The precipitate was removed by filtration, the filtrate was concentrated in vacuum, obtaining 2-(p-forfinal)-4-bromomethylphenyl (0,63 g, 88%, unstable) as a dark yellow oil.

Q6-S1:

The intermediate product Q6-C1 was synthesized according to the following scheme (scheme A5):

Stage i (figure A5):

4-(p-forfinal)pyridine (13 g, 75 mmol) was dissolved in glacial acetic acid (100%; 50 ml) at 70-80oC. Then with stirring was added N2ABOUT2(35%; 8 ml). After 4 hours of relax the Wali to dryness in a vacuum, leaving a yellow solid, which was diluted in N2O (150 ml), was podslushivaet aqueous solution of NaOH (150 ml, 2 M solution) and was extracted with CH2Cl2(100 ml). The organic layer was separated and dried over Na2SO4. After removal of the desiccant by filtration and removal of solvent in vacuo was allocated 13 g (91%) of the desired product, N-oxide 4-(p-forfinal)pyridine.

Stage ii (figure A5):

To 13 g of N-oxide of 4-(p-forfinal)pyridine (68,7 mmol) in an atmosphere of N2when 80oWith added Me2SO4(8.6 g, 68 mmol), after which the mixture was stirred at 100-110oC for 2 hours. The mixture was cooled and the reaction mixture is poured into 70% solution of dioxane/water. The obtained dark brown solution was added dropwise to a stirred solution of NaCN (10 g, 0.20 mol) in N2About (85 ml) at 15-20oC. the Mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, the residue washed with CH2CL2which was added to the two-phase filtrate. The organic layer of the filtrate was dried over Na2SO4. Removal of the desiccant by filtration and evaporation of solvent in vacuo gave the target compound as a pale brown solid, which was purified Krista is Diya iii (diagram A5):

Mix a solution of 2-cyano-4-(p-forfinal)pyridine (8.6 g, to 46.7 mmol) in a saturated solution of HCl-MeOH (200 ml) was allowed to react at the boiling point under reflux for 6 hours. The resulting pink solution was concentrated in vacuo to approximately 50 ml, after which it was diluted with 250 ml of water. The last solution was podslushivaet aqueous solution of NH4OH (25%) and was extracted with CH2CL2. The organic layer was dried over Na2SO4. The destruction was carried out by filtration and evaporation of solvent in vacuo gave the desired product, methyl ester 4-(p-forfinal)pyridine-2-carboxylic acid, in the form of a pink solid (5.0 g, 46%): so pl. 97-8oC.

Stage iv (figure A5):

NaBH4(8,2 g, 0.2 mol) was added in portions to a stirred solution of methyl ester 4-(p-forfinal)pyridine-2-carboxylic acid (5.0 g, 21.6 mmol) in EtOH (96%, 100 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, then added water. Then extraction was performed with EtOAc. The organic layer was dried over MgSO4. Removal of the desiccant and evaporation of the solvent in vacuo gave an oil which was dissolved in the second foam (4,47 g, 87%).

Stage v (figure A5):

This reaction was similar to stage iv in scheme A3:

Intermediate products used in the way IN

Intermediate b1:

This intermediate product was synthesized as depicted in scheme B2.

Stage i (figure E2):

To a suspension of monohydrochloride 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (5.4 g, 21 mmol) in CH2CN (125 mmol) was added 3-bromo-5-chloromethylpyridine (4.6 g, 19 mmol) and diisopropylethylamine (12.3 g, 95 mmol). The mixture was stirred at a temperature of phlegmy within 30 minutes After cooling of the mixture and evaporation of the solvent in vacuo the residue was dissolved in CH2Cl2off , washed with 5% aqueous solution of NaHCO3, saturated aqueous NaCl, and then the organic portion was dried over Na2SO4. After removal of the desiccant by filtration and the solvent by evaporation in vacuo the residue was purified flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 97, 25/2, 5/0, 25), receiving b1 (7.2 g, 97%) as oil.

1. Derivatives of piperazine of General formula (a)

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where a represents a heterocyclic group of 5 to 6 atoms in the ring, where there are 1-2 heteroatoms from the group O and N;

R1represents hydrogen;

R3and R4represent hydrogen;

n = 1;

R5represents 2-pyridyl, 3-pyridyl or 4-pyridyl substituted in metaprogram relative to the methylene bridge group Y, and optionally substituted by substituent (R6)q;

Y represents phenyl, furanyl or thienyl, and phenyl may be substituted by 1-3 substituents from the group comprising halogen;

R6is1-4alkyl;

q = 0 or 1,

and their salts.

2. Connection on p. 1, which together with the phenyl group represents a group of formula b, C, d:

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n = 1;

R1and (R2)p, R3, R4, R5, (R6)q, Y and Z have the values given in paragraph 1,

and its salts.

3. Connection on p. 2, which together with the phenyl group represents a group of formula (C) or (d), where R5has the values given in paragraph 1, Y is phenyl, R3and R4represent hydrogen, Z is nitrogen, and salts thereof.

4. Connection on p. 3, which together with the phenyl group represents a group of formula (d), R1, (R2)p, R3and R4represent hydrogen, n = 1, Z is nitrogen and R5represents a group of 5-(4-forfinal)-pyrid-3-yl, and shall have the value this in paragraph 1;

R'5represents 2-pyridyl, 3-pyridyl or 4-pyridyl, optionally substituted by group (R6)qwhere R6and q have the meanings specified in paragraph 1, and the bromine atom is in metaprogram relative to the methylene group.

 

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