Method for preparation of 3-piperazinylbenzazol derivatives or theirs pharmaceutically acceptable ad

专利摘要:
Novel 3-piperazinyl-1,2-benzazoles of formula <CHEM> wherein Q is a radical of formula <CHEM> R is hydrogen or C1-6alkyl; R<1> and R<2> are hydrogen, halo, hydroxy, C1-6alkyloxy or C1-6alkyl; X is O, S or NR<3>; the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are antipsychotic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1687030A3
申请号:SU894614564
申请日:1989-07-26
公开日:1991-10-23
发明作者:Эдмонд Жозефин Кеннис Людо；Ванденбек Ян；Каролус Мертенс Жозефус
申请人:Жансен Фармасетика Н.В.(Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of novel heterocyclic compounds, in particular to novel 3-piperazinyl benzazoles, which are effective antagonists of neurotransmitters.
The purpose of the invention is to obtain new 3-piperazinylbenzazole derivatives, which show a higher dopamine-antagonistic activity compared with this activity of a known structural analogue of risperidone.
A. Preparation of intermediate products
a) To a stirred mixture of 114 May including 1,2-benzisoxazole-3-ol and 230 wt.h. phosphoryl chloride is added dropwise to 160 mash, N.N-diethylethylamine (exothermic reaction). After the addition, the reaction mixture is stirred overnight at 135 ° C. The mixture is poured onto crushed ice and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is boiled in 2,2-oxybis propane. The solvent is decanted (this procedure is repeated twice), and the residue is purified by capillary chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3 volume) as eluent. Pure fractions are collected and the eluent is evaporated. Get 60 wt.h. (51.1%) 3-chloro-7-methyl-1,2-benzisoxazole as a residue (intermediate 1).
b) To a stirred and heated (90 ° C) mixture of May 120, h, piperazm and 400 wt.h. 1-butanol was added dropwise 60 parts by weight of 3-chloro-7-methyl-1,2-benzisoxazole. After the addition is complete, stirring is continued for 6 hours at reflux temperature. After cooling, the reaction mixture is filtered and the filtrate is evaporated. The residue is added to water and the product is extracted with trichloromethane. The extract is dehydrated, filtered and evaporated. The residue was purified by capillary chromatography on silica gel using a mixture of trichloromegan and methanol (volume 95: 5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue upon settling hardens, which gives 56 wt.h. (71.50%) 7-methyl-3- (1-piperazinyl) -1,2-benzisoxazole in the residue form (intermediate 2).
Example 2
a) A mixture of 32 wt.h. ethyl 1-piperazine carboxylate, 17 wt.h. 3-chloro-1,2-benzisothiazole and 45 May; M, M-dimethylacetamide is stirred for 0.5 h at 150 ° C. After cooling to 50 ° C, the reaction mixture is poured onto ice. The aqueous layer was decanted and the oily layer was stirred with water. The product from the oily layer is extracted with trichloromethane, the product from the oily layer is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by capillary chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected, the eluent was evaporated and 13 wt.h, (44%) of ethyl 4- (1,2-benzisothiazol-3-yl) -1-piperated carboxylate was obtained as a residue (intermediate compound 3).
b) A mixture of 12.5 ma.ch. ethyl 4- {1,2-benzisothiazol-3-yl) -1-piperazinecarboxylate and 187.5 wt.h. Hydrobromic acid in the form of a 48% aqueous solution is stirred for 1.5 hours at reflux temperature. After evaporation, the residue is taken up in 2-propanol, and the solvent is again evaporated. The residue is dissolved in methanol.
0 is evaporated and stirred in 2-propanol. The product is filtered, dried. Obtain 11.5 wt.h, (73%) 3- (1-piperazinyl) - 1,2-benzisothiazole dihydrobromide (intermediate compound 4),
5 Example 3. a) To a stirred and cooled mixture (10 ° C) of 64 wt.h. 1- {phenyl-methyl) piperazine and 360 wt.h. tetrahydrofuran added 32.5 wt.h. 2,4-difluorobenzoyl chloride. After the addition was complete, the stirring was continued to room temperature, the reaction mixture was cooled, the resulting salt was filtered and the filtrate was evaporated in vacuo. The residue was purified by capillary chromatography on silica gel using a mixture of chloroform and methanol (95: 5 by volume) as eluent. Collect pure fractions, the eluent is evaporated and receive 50 wt.h. (8.3%) 1- (2,4-difluorobenzoyl) -4CHPe0 nylmethyl) -piperazine, (intermediate 5).
b) A mixture of May 30, h, 1- (2,4-difluorobenzoyl) -4- (phenylmethyl) piperazine, 19 wt.h. 2,4-bis (4-methoxyphenyl) -2,4-disulfide-1,3
5, 2,4-dithiaphosphetan and 174 wt.h. benzene is stirred and distilled for 3 hours. The reaction mixture is evaporated, the residue is dissolved in trichloromethane and purified by capillary chromatography on silica gel,
0 using chloroform as eluent. The pure fractions are collected, the eluent is evaporated in vacuo, and the residue is left to stand for 2 days at room temperature. The product is filtered off, dried and 5% by weight are obtained. (79.2%) H (2,4-difluorophenyl) thioxomethyl-4- (phenyl methyl) piperazine (intermediate compound 6),
c) A mixture of 40 wt.h. 1 - {(2,4-difluorophenyl) thioxomethyl-4- (phenylmethyl) piperazi
0 on, 144 wt.h. 1-butanol, 13 wt.h. hydrazine monohydrate and 24 wt.h. acetic acid is stirred overnight at reflux temperature. After cooling, 50 wt.h. sodium carbonate and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled to room temperature and water and methylbenzene are added. After stirring for 15 minutes, the separated organic phase is dried, filtered and evaporated. using a mixture of trichloromethane and methanol (volume 92: 8) as a solvent. The pure fractions are collected and the eluent is evaporated. Get 12 wt.h. (32.2% -) 6-fluoro-3- 4- (phenylmethyl) piperazinyl-1H-indazole, mp, 162.0 ° C from acetonitrile (intermediate compound 7).
g) A mixture of 12 wt.h. 6-fluoro-3- 4- {phenylmethyl piperazinyl TH-indazole, 1 wt.h. Nickel catalyst Reiney and 200 wt.h, methanol is subjected to hydrogenation apparatus Parr under normal pressure and at 50 ° C with 2 wt.h. 10% Fd / C. After separation of the calculated amount of hydrogen, the catalyst is filtered on infusorial earth, and the filtrate is evaporated in vacuo. After recrystallization from acetonitrile, 7.7 wt.h. (92.0%) 6-fluoro-3- (1-piperazinide) -1 H-indazole (intermediate 8).
Example 4
a) To a stirred mixture of 12.5 wt.h. piperazine, 3.6 wt.h. N. N-diethylamine and 75 wt.h. trichloromethane was added a solution of 9 m.ch, 2-fluoro-M-phenylbenzo-carboxyhydrazsoyl chloride and 75 wt.h. chloroform. The whole is stirred for 2 hours at room temperature. After addition of 5 parts by weight of potassium carbonate, the reaction mixture is stirred for 30 minutes at reflux temperature. The mixture is cooled, washed with 100 wt.h. water and layers are separated from each other. The organic layer is dried, filtered off and, after evaporation as a residue, 6 wt.h. (55.8%) 1- (2-fluoro-&amp; enzoyl) -piperazine, 2-phenylhydrazine (intermediate 9).
b) A mixture of 4.5 May, h, 3- (2-chloroethyl) -2-methyl-1H-pyrido- (1,2-a) -pyrimidin-4-one, 6 wt.h. 1- (2-fluorobenzoyl) piperazine, 2-phenylhydrazine, 5.04 wt.h. sodium carbonate, 0.1 wt.h. potassium iodide and 120 wt.h. 4-methyl-2-pentanone is stirred overnight at reflux temperature. Inorganic salts are filtered, the filtrate is evaporated. The residue was purified by column chromatography on silica gel, using a mixture of chloroform in methanol (volume 95: 5) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, Get 2.5 wt.h. (25.8%) 3- (2- {4- (2-fluorophenyl) (2-phenylhydrazono) methyl -1-piperazinyl} -ethyl / -2-methyl-1 H-pyrido (1.2 -a) pyrimidin-4-one, mp 180 ° C (intermediate compound 10).
B. Preparation of the final compounds Example 5. A mixture of 5 wt.h. 3 - (2 chloroethyl) -b, 7,8.9-tetrahydro-2-methyl - 4H-pyr ido {1,2-a) pyrimidin-4-onz Monshydrochloride, 5 wt.h. 3- (1-piperazine l) -1,2-benzisothiazole dihydrochloride, 8 wt.h. sodium carbonate, 0.2 wt.h. potassium iodide and 200 wt.h. 4-methyl-2-pentanone is stirred for 20 hours at reflux temperature.
the fridge. The reaction mixture is filtered and the filtrate is evaporated. The residue was purified by capillary chromatography on silica gel using a mixture of chloroform and methanol (volume 95: 5) as eluent.
The pure fractions are collected and the eluent is evaporated. The residue is converted to (E) -2-bundioate salt in 2-propanol. The salt is filtered and crystallized from ethanol. The product is filtered, dried and
get 7.4 wt.h. (85%) 3- {2- {4- (1,2-benzisothiazol-3-yl) -1-piperazinyl ethyl} -6,7,8,9- -tetramdro-2-methyl-4H-pyrido (1,2-a) pyri midin-4-one (E) -2-butanedioate (1: 1), so pl. 186.0 ° (compound 1).
PRI me R 6. A mixture of 7.4 wt.h. 7- (2bromstil) -3,4-dihydro-8-methyl-2H, 6H-pyr-imidoCH M-b) (1,3) thiazin-6-one monohydrobromome. 4.4 wt.h. 7-methyl-3- (1-piperazinyl) -1,2-ben x a sol, 10 wt.h.
sodium carbonate and 94 wt.h. M, H-dimethylformamid stirred overnight at 90 ° C. After cooling, the reaction mixture is poured into water and the product is extracted with 4-methyl-2-pentanone. The extract is dried. filtered and evaporated. The residue is purified by capillary chromatography on silica gel. using a mixture of trichloromethane and methanol (volume 95: 5) as eluents. Pure fractions are collected and eluent
evaporated, and the residue is crystallized from 4methyl-2-pentanone. The product is filtered and
dried to obtain 3.8 wt.h. (44.6%) 3,4-dihydro-8-methyl-7- (2) 4- (7-methyl-1,2-benzieoxazol-3-yl) -1-piperazinyl (ethyl) -2H, bN- pyrimido (2,1-LH1,3) thiazin-6-one, so pl. 170.0 ° C (compound 2).
Tables 1 and 2 list the compounds obtained in accordance with the preparation method described in examples 5 and 6.
C. Pharmacological testing.
The activity of the target compounds as antipsychotic agents is evident from the experimental data obtained
as a result of at least two different tests visually: mixed apormorphin, tryptamine and norepinephrine tests on rats and apormorphine test on dogs. The tests are carried out in accordance with the described procedures, and the experimental data are summarized in Table 3.
Mixed testing of apomorphine (APO), tryptamine (HA) and norepinephrine (NOR) in rats. Adult Wistar male rats (weight 240 ± 10 g) are taken as experimental animals. After exposure overnight without food, animals are subcutaneously or orally administered. an aqueous solution of the test compound (1 ml / 100 g body weight) and placed in a separate cage for viewing. After thirty minutes (30 minutes), 1.25 mg / kg of apomorphine hydrochloride was intravenously administered, and the rats were monitored for 1 hour to determine whether or not apomorphine caused the chewing and characteristic chewing. At the end of this hour (time 90 min), tryptamine was administered intravenously to the same animal in an amount of 40 mg / kg, and typical tryptamine-induced bilateral tonic convulsions and ear hyperemia were noted. Two hours after the pretreatment (time 120 min), finally, 1.25 mg / kg intravenous norepinephrine was administered to the same animals and possible death was observed 60 minutes later.
Table 3 shows the EDBO values, representing the dose that protected 50% of the animals from the symptoms caused by the action of apomorphine, tryptamine and norepinephrine.
Testing apomorphine on dogs (dog aros).
The compounds listed in Table 3 were administered subcutaneously or orally to beagle dogs at various doses, and then one hour later the standard dose of 0.31 kg / kg (subcutaneously) apomorphine was administered to the animals.
Table 3 summarizes the eDb values for a number of compounds 1. In the glue value used here, the edu value is the dose that protects 50% of the animals from vomiting.
By inhibiting apormorphin-induced effects (rat ARP / canine ARP) by introducing compounds obtained in accordance with the claimed method, it can be concluded that the dopamine-antagonistic activity is generally higher than in this method. risperidone activity. In addition, the serotonergic properties of the proposed compounds exhibit a better balance between the central nervous system and peripheral activity. In general, the compounds of formula 1 inhibit tryptamine-induced phenomena in the central nervous system (convulsions) as well as risperidone, but have a less pronounced effect on the periphery (hyperemia), thus showing increased central activity.

权利要求:
Claims (1)
[1]
The toxicity of the compounds of formula (I) was tested in rats by intraperitoneal dosing equal to 40 mg of the test compound per kg of body weight. None of the compounds caused a fatal outcome at this dosage. The invention The method of obtaining derivatives of 3-piperizinylbenzazole of the formula
and,
Q-AlK-K jN
/ -L; 41
Yes
where RI is hydrogen, halogen or Ci-Cb-alkyl; X is O, S or NH; Alk - (Ci-CO-alkanediyl; Q -radical of formula
25
n
(a) and / and
L (}
where Ra is Ci-Sb-alkyl; 2 - S- or. moreover, said Ra and R4 each independently designate hydrogen or Ci-Sb-alkyl, or Z - -CH2-, where one hydrogen atom
may be substituted with hydroxyl or Ci-Cb-alkyl; A denotes a bivalent radical —CH2 — CH2 - or —CH2 — CH2 — CH2—, in which one or two hydrogen atoms can be replaced by Ci-Ce-alkyl, or A is a divalent radical, where RS and Re each independently represents hydrogen, halogen or Ci-Sb-alkyl, or when Z stands for, then A may also be -0-, or their pharmaceutically
acceptable acid addition salts, characterized in that the compound of formula
50
nO
RI
l ")
where X and Ri are as defined, they are reacted with an alkylating reagent of the formula
Q-AIK-W.
where Q and Aik have the indicated meanings; W denotes a leaving group, in an inert solvent with respect to the reaction medium, with stirring at the boiling point in the presence of a base, if necessary in the presence of an alkali metal iodide, with the release
of the desired product in free form or, if necessary, convert the compound of formula (f) into a therapeutically active non-toxic acid addition salt by treatment with an acid or, conversely, convert an acid additive salt into a free base by treatment with alkali.
Table 1
H
i
iA i
ABOUT .
I-A1K-NQN
Table 2
Continuation of table 2
229.9 ESD
 3- {2- {4- {6-fluoro-1,2-benzoxazol-3-yl) -1-piperidinyl ethyl} -6,7,8,9-tetrahydro-2-methyl-4H-pyrido (1, 2-a) pyrimidin-4-one of the formula
Table 3
 X
° o
t

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DK383689D0|1989-08-04|

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HU206341B|1992-10-28|

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CA1331609C|1994-08-23|

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PT91364B|1995-03-31|

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IL91194A|1994-04-12|

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EP0353821A3|1991-07-17|

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PH26550A|1992-08-19|

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FI893701A0|1989-08-04|

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DE68922537D1|1995-06-14|

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IL91194D0|1990-03-19|

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法律状态:
2007-12-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20060727 |

优先权:

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申请号 | 申请日 | 专利标题

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US22841788A| true| 1988-08-05|1988-08-05|

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