Method of prepation arylpiperazinylalkylenphenylheterocyclic compund or their acid=additive salts su

专利摘要:
An arylpiperazinyl-alkylenephenyl-p-heterocyclic compound, useful in the treatment of psychotic disorders, of the formula- <CHEM> or a pharmaceutically-acceptable acid-addition salt thereof, wherein:- Ar is phenyl, 3-trifluoromethylphenyl, 3-cyanopyridyl, naphthyl, or a five- or six-membered aromatic heterocyclic ring, said ring being attached to the N atom of the adjacent piperazinyl group by a carbon atom and having one nitrogen, oxygen or sulfur, or two nitrogens one of which may be replaced by oxygen or sulfur, or said heterocyclic ring is condensed with benzo, said naphthyl, heterocyclic and benzoheterocyclic rings being optionally substituted by one fluoro, chloro or trifluoromethyl substituent, said substitution in the case of said naphthyl and benzoheterocyclic rings being in the ring not attached to the piperazinyl group; n is 2, 3 or 4; and "Het" is a group of the formula:- <CHEM> in which R is H or C1-C3 alkyl, and Y is -H, -OH, -SH, -NH2, C1-C3 alkyl or C1-C3 alkylamino.
公开号:SU1634136A3
申请号:SU4355194
申请日:1988-02-16
公开日:1991-03-07
发明作者:Эдамс Лоу Ш Джон
申请人:Пфайзер Инк (Фирма)；
IPC主号:

专利说明:

This invention relates to organic chemistry, in particular, to the sposbbu of obtaining arylpiperazinylalkylenephenylheterocyclic compounds of the general formula
.S 7-v (D
Ar-NCN- (CH2) n-O-; z-Y
where Ag. is phenyl, 1-naphthyl, 1- (6-fluoro-naphthyl), 1- (6-chloro-naphthyl), 3-benzisothiaolol; n 2-4;
Z-Y - С-ОН, C-NHU, С- (С, -С3:) - alkyl, or nitrogen,
which can be used as major components of pharmaceutical compositions for the treatment of mental illness.
The aim of the invention is to develop a method for producing new derivatives of aromatic heterocyclic compounds with increased neuroleptic activity.
In accordance with the proposed method, compounds of formula (I) are obtained by the reaction of piperazines of formula (II) with compounds of formula (III)
about with
4SO O}
 WITH
lll
AL
(SNL 1 Ha) 1H (
where Ar is phenyl, naphthyl, 1- (6-6 volon naphthyl), 1- (6-chloronaphthyl), 3-benzisothiazolyl; n 2-4; Z-Y - C-OH, C-HH2, C- (C1-C,) - alkyl or nitrogen,
or then pharmaceutically acceptable salts thereof.
The said coupling reaction is carried out in a polar solvent. For example, ethanol, dimethylformamide or methyl ethylbenzoyl ketone, and in the presence of a weak base, a tertiary amine, such as triethylamine or diisopropylethylamine. The reaction is also carried out in the presence of a catalytic amount of sodium iodide and a neutralizing agent for the hydrochloride, such as sodium carbonate or sodium bicarbonate. The reaction is carried out at reflux temperature.
Pharmaceutically acceptable salts — adducts of acids of compounds of formula (I) —are prepared by standard methods by treating the solution in suspension of the free base (I) with about one chemical equivalent of a pharmaceutically acceptable acid. Standard concentration and recrystallization methods are used to separate the salts.
Example 1. 4- (4- {2- 4- (3-Ben-eisothiazolyl) piperazinyl ethyl 1-fe
Nile) -2-aminothiazole.
2.4 g (7.53 mmol) of (2-chloroethyl) -phenyl) -2-aminothiazole hydrobromide, 1.65 g (7.53 mmol) of H- ( 3-benzisothiazolyl) piperaein (prepared according to a known method), 1.3 ml (7.53 mmol) of diieopropylethylamine, 1.6 g (15.1 mmol) of sodium carbonate, 2 mg of sodium iodide and 25 ml of methylisobutyl ketone. The reaction mass is heated under reflux for five days, cooled, evaporated and dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was passed through a silica gel column using ethyl acetate in a
Ar-NON (CH2V-C
five
0
five
0
five
0
five
-
0
eluting solvent, and get a solid. The substance is dissolved in hot ethyl acetate, precipitated by the addition of gaseous HC1, the precipitate is filtered off, washed with ether and dried to give a beige solid. 1,536 g (330) with m.p. above 300 ° C (decomposition).
NMR spectrum n (in deuterated dimethyl sulfoxide-dg): Ј, ppm: 3.2-3.8 (m, YN); 4.1 (m, 2H); 7.25 (s, 1H); 7.4-3.2 (m., 3N); 11.5 (bs, 2H).
Example 2. 4- (4- {4- 4- (3-Benziisothiazolyl) piperazinyl butyl-phenyl) -2-aminothiazole.
In a 100 ml round bottom flask equipped with a condenser and nitrogen inlet, 1.22 g (3.52 mmol) of (4-chlorobutyl) phenyl) -2-aminothiazole, 0.90 g (3.52 mmol) of 3- piperazinylbenezothiazole, 1.34 ml (10.57 mmol) of diisopropylethylamine, 0.75 g (7.04 mmol) of sodium carbonate, 2 mg of sodium iodide and 35 ml of methyl isobutyl ketone. The reaction mixture is heated under reflux for 6 days, cooled and evaporated. The residue is passed through a silica gel column chromatography using methylene chloride-ethyl acetate as an eluting carrier, and portions of the product are dissolved in dichloromethane / methanol and precipitated by the addition of dichloromethane, saturated with IS1. The precipitate is filtered off and dried, and 242 mg (13% yield) of a solid product is obtained with a mp. 258-261 ° C.
NMR H spectrum (in deuterated dimethyl sulfoxide-d); , ppm: 1.6-1.8 (m, 4H); 2.7 (t, 2H); 3.2-3.6 (m, 8H); 4.1 (m, 2H); 7.20 (s, 1H); 7.3-8.2 (m., 8H).
Example 4- (4- {2- 4- (3-Benzisotriazolyl) piperazinyl ethyl thiazolone-2.
A 100 ml round bottom flask equipped with a condenser and nitrogen inlet was charged with 1.0 g (4.57 mmol) of 3-piperazinyl-benzisotriazole, 1, 46 g (4.57 mmol) of (2-chloroethyl) phenyl-thiazolone -2 Bromhydrate, 970 mg (9.13 mmol) sodium carbonate, 600 mg
(4.57 mmol) of diisopropylethylamine, 2 mg of sodium iodide and 35 ml of methylisobutyl ketone. The reaction was heated to reflux for 24 hours, cooled and evaporated. The residue is mixed with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. The newly obtained residue is passed through a chromatography column with silica gel using dichloromethane-ethyl acetate as eluting medium. Portions of the product were dissolved in dichloromethane / ethyl acetate and precipitated with gaseous hydrogen chloride. The precipitate was filtered off and a solid was obtained with mp. 190 ° C.
The product yield is 455 mg (21.9%).
Example 4. 4-Ј4- (4-Chlorobutyl) phenyl -1,2,3-thiadiazole.
In a 125 ml round-bottomed flask, equipped with a condenser and nitrogen inlet, 6.25 g (29.65 mmol) of a pair of (4-chlorobutyl) acetophenone, 5.57 g (29.65 mmol) of tosyl hydrazine and 50 ml of ethanol are charged. The reaction mixture is heated under reflux for 3.5 hours, cooled and evaporated. The residue is mixed with 23.4 ml (326 mmol) of thionyl chloride and stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is passed through a chromatographic silica gel column using hexane-dichloromethane as an eluting support. An oil is obtained.
Yield 6.1 g (81.5%).
Nuclear Magnetic Resonance Spectrum (CDC1,), ppm: 1.84 (m, 4H); 2.73 (m, 2H); 3.58 (m, 2H); 7.3 and 7.95 (m, 4H); 8.59 (s., 1H).
4- (4 -. (3-Benzisothiazolyl) piperazinyl butyl-phenyl) -1,2,3-thiadiazole.
In a 65 ml round-bottomed flask, equipped with a condenser and a nitrogen inlet, 1.43 g (5.66 mmol) of 4-gh- (4-chlorobutyl) phenagg -1,2,3-thiadiazole, 0.90 g (4 , 11 mmol) of N-benz eizothiazolyl piperazine-, 1.43 g (8.22 mmol) of diisopropylethylamine, 0.87 g (8.22 mmol) of sodium carbonate, 2 mg of sodium iodide and 30 ml of methyl isobutyl ketone. The reaction mixture was heated under reflux for 24 hours, cooled, filtered, and the filtrate was evaporated. The residue is passed through a silica column, using as eluting medium
five
0
five
ethyl acetate-dichloroshesan, and an oil is obtained which is mixed with ethyl acetate-1 and precipitated by the addition of ethyl acetate saturated with hydrogen chloride.
The solid product is filtered, washed with ethyl acetate and dried to obtain 1.70 g (87.6%) of a white product with mp. 246-247 ° C.
PRI me R 5. 4-Chlorobutylacetophenone.
5.0 g (29.65 mmol) of 4-chlorophenylbutane and 10 ml of 1,2-dichloroethane are charged to a 250 ml round bottom flask. A solution of 4.35 g (32.62 mmol) of aluminum chloride and 4.22 ml (59.31 mmol) of acetyl chloride in 50 ml of 1,2-dichloroethane is added to the stirred solution. The solution is stirred at room temperature for 1 hour, and hydrogen chloride is released. The reaction mass is poured into water, the layers are separated, and the organic layer is washed with 1N. hydrochloric acid, an aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and evaporated to an oil, yield 6.7 g (100 g).
Nuclear Magnetic Resonance Spectrum (SOSTS), ppm: 1.76 (m, 4H); 2.54 (m., ZN); 2.66 (m, 2H); 3.50 (m, 2H); 7.2 and 7.85 (m, 4H).
IR spectrum -}, 1678 ().
4- (4-Chlorobutyl) phenyl-2-methylthiazole bromohydrate.
The oil obtained above is loaded into a 100 ml round bottom flask equipped with a nitrogen inlet, together with 15 ml of acetic acid, and bromine (1.53 ml, 29.65 mmol) is added dropwise. The solution is stirred at room temperature for 15 minutes (provision takes place within about 7 minutes). The solution is carefully added to ethyl acetate, washed with water, an aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and evaporated to an oil, yield 8.9 g (approximately 100% yield).
The oil is dissolved in 70 ml of acetone, treated with 2.23 g (29.65 mmol) of thioacetamide and refluxed for 15 hours. The reaction mass is cooled, evaporated to a volume of 10 ml to obtain a precipitate. After filtration, the precipitate is washed with 10 ml of acetone, then thoroughly washed with ethyl ether and dried, yielding 6.3 g
0
five
0
five
five
(66.2% yield) of a white solid with m.p. 128-129 ° C.
4- (4-HA- 4- (3-Benzisothiazolyl) pepe 5azinyl butyl1-phenyl) -2-methylthiazole.
In a 100 ml round bottom flask equipped with a condenser and a nitrogen inlet, 1.43 g (4.11 mmol) of 4- (4-chlorobutyl) phenyl) -2-methylthiazole hydrobromide, 0.90 g (4.11 mmol) H are charged. benzisothiazolylpiperazine, 0.72 g (4.11 mmol) diieopropylethylamine, 0.37 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methyl isobutyl ketone. The reaction mixture was heated under reflux for 31 hours, cooled, filtered, and the filtrate was evaporated. The resulting precipitate is passed through a silica gel column, using ethyl acetate-dichloromethane as eluting support. An oil is obtained, which is mixed with dichloromethane and a solid is precipitated by the addition of sulfuric ether saturated with HC1. This substance is filtered off, washed with ether, briefly for a short time, then washed with a minimum amount of acetone and dried again to obtain a white solid with mp. 207-212 C.
The output of 1.87 g (37.2%).
Nuclear Magnetic Resonance Spectrum (DMSO-s16), ppm: 1.6-1.3 (m, 4H); 2.64 (t, 2H); 2.72 (s., ZN); 3.1-3.3 (m, 4H); 3.4-3.6 (m, 4H); 4.0 (d, 2H); 7.2-3.1 (m., 3N); 7.85 (s, 1H).
Example 6. 6-Fluoro-1-naphthoic acid.
In a round bottle volume of 1 L,
equipped with a condenser and nitrogen inlet, 345 ml (3.63 mmol) of fluorobeneol and 48 g (0.423 mmol) of furancarboxylic acid are charged. 120 g (0.399 mmol) of aluminum chloride are added to the stirred suspension in separate portions. The reaction mixture is stirred at 95 ° C for 16 hours and then interrupted by adding ice / water / 1N. hydrochloric acid. After stirring for 1 hour, the aqueous layer was decanted and benzene and a saturated sodium bicarbonate aqueous solution were added. After stirring for 1 h, the layers are separated. The aqueous layer is washed with benzene, acidified and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dissolved, dried over sodium sulfate

d

0
five
ri and evaporated to dryness. The solid residue was triturated with isopropyl ether to give 5.0 g (6.1%) of a white solid.
Nuclear Magnetic Resonance Spectrum (DMSO-dg), ppm: 7.0-3.0 (m, 5H); 8.6 (m, 1H).
6-Fluoro-1-amino-naphthalene. A 125 ml round bottom flask equipped with a condenser, an inlet for nitrogen and an addition funnel was charged with 5.0 g (26.3 mmol) of 6-fluoro-1-naphthoic acid and 50 ml of acetone. 6.25 ml (28.9 mmol) of diphenylphosphorylazide and 4 ml (28.9 mmol) of triethylamine are added dropwise to the stirred suspension. The reaction was boiled for 1 h, poured into water / ethyl acetate and filtered. The filtrate is washed with water and brine, dried over sodium sulfate and evaporated. The residue is further treated with HC1 to obtain the chlorohydrate salt and then sodium hydroxide to obtain an oily free base.
The product yield of 1.0 g (24%).
1-Benzyl-4- (6-fluoronaphthyl) -piperazine.
In a 125 ml round-bottomed flask, equipped with a condenser and nitrogen injection, 1.0 g (6.21 mmol) of 6-fluoro-1-amino-naphthalene, 1.3 g (7.76 mmol) N-benzyl bis ( 2-chloroethyl) amine, 3.3 ml (19.2 mmol) of diisopropylethylamine and 50 ml of isopropenol. The reaction mixture is heated under reflux for 24 hours, cooled and evaporated to an oil. The oil is mixed with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated to an oil. This oil is passed through a silica gel chromatography column using dichloromethane as an eluting solvent.
Oil yield 1.5 g (75.5%).
N- (1-6-Fluoro) naphthyl) piperazine.
Into a 125 ml round-bottom flask equipped with a nitrogen feed, 1.5 g (4.69 mmol) of 1-benzyl-4- (6-fluoro-naphthyl) piperazine, 1.2 ml (31.3 mmol) of formic acid are charged, 3.0 g of 5% palladium on carbon and 50 ml of ethanol. The reaction mass is stirred at room temperature for 16 hours, the catalyst is filtered off under nitrogen and the solvent is evaporated. The oil is used directly in the next stage.
The product yield 0,420-g, (/ 39%). 4- (4- {2-Ј4- (b-Fluoro-naphthyl-1) piperizinyl E1 yl-phenyl) -2-aminothiaol.
3 100 ml round-bottom flask equipped with a condenser and nitrogen feed was charged with 500 mg (2.17 mmol) LiP- (6-fluoro) naphthyl lypiperazine, 700 mg (2.17 mmol) 4-14- ( 2-chloro-ethyl) phenyl -2-aminothiazole hydrobromide, 460 mg (4.35 mmol) of sodium carbonate, 0.37 ml (2.17 mmol of diisopropylethylamine and 25 ml of methyl eobutyl ketone. The reaction mixture is heated under reflux condenser 24 The mixture is cooled and evaporated. The residue is mixed with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. The new residue is passed through silica gel, using as el dichloromethane-ethyl acetate carrier. The product fractions are combined, dissolved in dichloromethane / methanol, treated with ethyl acetate, saturated with HCl, and the precipitate is collected and dried. A white solid is obtained with a mp of 220-225 ° C .
Yield 297 g (25.3%).
Nuclear Magnetic Resonance Spectrum (DCSD-d 6), ppm: 3.3–3.6 (m, YUN); 3.7-3.8 (m, 2H); 7.2-3.3 (m, 11H); 11.6 (bs, 2H).
The neuroleptic activity of the present compounds can be illustrated by methods based on standard procedures. In accordance with one of the methods, the corresponding doses of the test compound were precutaneously injected subcutaneously into adult male rats with Sprague-Dawley. After 30 min, 1 mg / kg of hydrochloric acid apomorphine dissolved in 0.1% ascorbate was intraperitoneally administered. The condition of the rats was assessed by the effective dose (FD) at which a 50% blockade of amphetamine-induced hypermobility was observed.
The neuroleptic activity of the proposed compounds is given in the table.
The compounds are classified as low toxic.
Comparison of the neuroleptic activity of the compounds obtained by the proposed method was performed with a known compound of the formula
Fj NOHCH2yO)

The effective dose (KD50) at which there is a 50% reduction in the orientational hypermobility of animals treated with placebo in known example 13 is 20.5 mg / kg.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining arylpiperazinyl alkylenephenylheterocyclic compounds of the general formula
 S
 V. /
Ar-N (
/
where Ar is phenyl, 1-naphthyl, 1- (6-fluoro-naphthyl), 1- (6-chloro-naphthyl), 3-benzisothiazolyl; n 2 - 4; Z-Y - C-OH, C-NHfc, C- (C1-C3) alkyl
or nitrogen
or a pharmaceutically acceptable acid addition salt thereof, characterized in that the piperazine of the general formula
Ag-CCh
where Ar has the specified value, is subjected to interaction with the compound of the General formula
i
HQlCTzVO-yz-Y
where HA1 is halogen;
Ar and Z-Y have the indicated meanings.
45
40
That blitz
Af-NGN (
50
55

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法律状态:
2005-05-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040217 |

优先权:

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申请号 | 申请日 | 专利标题

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US8700340|1987-02-17|

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