Method of producing derivatives of 1-phenylculfonyl-2-piperidinone

专利摘要:
Use: as a substance with selective anti-masin activity. The essence of the invention: Product: 1-phenylsulfonyl-2-piperidinone derivatives of the general formula C5N S02-O R1 where RI is the group - in which Ri R2 and RS are the same and mean C1 C4-alkyl or together with the nitrogen atom with which they bound, form piperidinyl, hexahydro-aeepinyl, azacyclooctyl radical. Reagent 1: 1-phenylsulfonyl halide derivatives of the general formula RI -O 502-Na1, Hal - chlorine or bromine. Reagent 2: 5-aminovaleric acid. Reaction conditions: in the presence of a base in an organic solvent medium, followed by cyclization of the obtained compound with acetic anhydride. 3 tab. WITH
公开号:SU1757463A3
申请号:SU904743117
申请日:1990-02-21
公开日:1992-08-23
发明作者:Тойя Эмилио；Барцаджи Фернандо；Галлиани Джулио
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to the field of the preparation of new 1-phenylsulfonyl-2-piperidinone derivatives of the general formula
VI
d
N-S02 where RI means group - N
N
./,
in which R2 and Ra are the same and mean
Ci-Cd alkyl, or together with the nitrogen atom, with
to which they are bonded form a piperidinyl, hexahydroazepinyl, azacyclooctyl radical,
exhibiting selective antimuscarinic activity.
The aim of the invention is to develop, on the basis of known methods, a method of producing new compounds with valuable pharmacological properties.
The invention is illustrated by the following examples.
Example 1.1 / 4- / Dimethylamino / benzenesulfonyl / -2-piperidinone.
Stage A. 5- / 4-dimethylaminobenzenesulfonylamino / valeric acid.
To a solution containing 2.34 g of 5-aminovaleric acid and 2.4 g of sodium hydroxide in 24 cm3 of water, 4.4 g of 4-dimethylaminobenzoylsulfonyl chloride was added, and then 24 cm3 of tetrahydrofuran to obtain a solution. The temperature rises to 36 ° C. Incubated for 4 hours.
2
gk s

SA)
NII, tetrahydrofuran is evaporated, the reaction medium is acidified with acetic acid, extracted with chloroform, the organic layer is dried and the solvents are removed under reduced pressure. 3.7 g of the expected product are obtained. T, pl. 105-110 ° C. After crystallization in an isopropanol-water mixture (1-1), the product is obtained melting at 118-120 ° C.
Analysis:
Calculated,%: C, 51.98; H 6.71; N 9.33
C13H20N204S
Found,%: C, 51.85; H 6.77; N 9.28
Stage B. 1-4-dimethylamino (benzosulfonyl) -2-piperidinone.
3.8 g of the product obtained in stage A is heated with reflux for 3 hours with 4.8 g of sodium acetate in 48 cm3 of acetic anhydride. It is cooled to room temperature, evaporated to dryness, the residue is taken up in 50 cm 3 of water, filtered off and dried, and 3.7 g of crude target product are obtained. T, mp. 165-170 ° C. After crystallization in ethanol, 2.9 g of pure product are obtained. T. pl. 169-171 ° C.
Analysis:
Calculated,%: C 55.30; H 6.43; N 9.92
Ci3HisN203S
Found,%: C 55.5; H 6.5; N 9,8
PRI mme R 2. (Diethylamino) benzosulfonyl -2-piperidinone,
To a solution containing 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide in 12 cm3 of water was added 2.5 g of 4-diethylaminobenzenesulfonyl chloride, and then 12 cm3 of tetrahydrofuran to form a solution. The mixture is kept under stirring for 2 hours at room temperature, the tetrahydrofuran is distilled off, the reaction medium is acidified with acetic acid, extracted with chloroform, the organic layer is dried and the solvents are removed under reduced pressure. 2.2 g of the expected product are obtained. T. pl. 106-108 ° C.
After crystallization in a mixture of isopropanol-water (1-1), a product is obtained which melts at 109-110 ° C.
Analysis:
Calculated,%: C 54.86; H 7.36; N 8.53
C15H24N2CUS
Found,%: C 54.63; H 7.28; N 8.65 Stage B. 1- (4-Diethylamino) benzenesulfPHylla {2-piperidinone.
2 hours 2 hours 2 g of the product I received with 2 g sodium acetate 20 cm3 of acetic anhydride. The mixture is cooled to room temperature, evaporated, the residue is taken up in a mixture of x / scar and water, the organic layer is separated, dried and, after removal of the solvents, 1.8 g of crude desired product are obtained. Mp, 118-120 ° C. After crystallization in isopropanol, 1.2 g of pure product are obtained. T. pl. 122-123 ° C Analysis1
Calculated,%: C 58.04; H 7.14; N 9.02
SbN22№Oz5
Found,%: C 58.28; H 7.34; N 9.09
Example 3. 1- (Dipropylamino) ben-0 zolsulfonyl 2-piperidinone.
Stage A, 5- (4-Dipropylaminobenzenesulfonylamino) valeric acid.
6.5 g of 4-dipropylaminobenzene sulfonyl chloride in solution and then 28 cm of tetrahydrofuran are added to a solution containing 2.76 g of 5-minerineric acid and 2.82 g of sodium hydroxide 5 in 28 cm3 of water. The mixture is kept for 2 hours with stirring, the tetrahydrofuran is evaporated, the reaction medium is acidified with acetic acid, the solid formed is filtered off, washed with water and dried. 6 g of the expected product are obtained. T. pl. 95-98 ° C. After crystallization in a mixture of iso-5 propanol-water (1-1), 5 g of product are obtained, melting at 98-99 ° C.
Analysis:
Calculated,%: C 57.28; H 7.92; N 7.86
C17H28№CMS
0Found. %: C 57.34; H 8.0; N 7.91
Stage B. 1 (4-Dipropylamino) benzene sulphonyl 2-piperidinone.
2 g of the product obtained in stage A with 5 g of sodium acetate 5 in 50 cm3 of acetic anhydride are heated with reflux for 2 hours. It is cooled to room temperature, evaporated to dryness, the residue is taken up in 50 cm 3 of water, dried, and 4.4 g of the expected product are obtained. After chromatography on silica 0 silica (eluant: ethyl acetate / n-hexa 1-1) M.p. 105-108 ° C. After crystallization in isopropanol, 3.2 g of pure product are obtained. T. pl. 110-111 ° C. 5 Analysis:
Calculated,%: C 60,32; H 7.74; N 8.28
ScN2b№Oz
Found,%: C 60.48; H 7.81; N 8.36
4-Dipropylaminobenzenesulfonyl chloride 0 was obtained as follows.
At a temperature between n-5 ° C + 10 ° C, 10.2 g of NN-dilropananiline (Annalen der Chemle 2D4., 168) are added to a solution containing 10.86 g (or 8.86 cm3 ) 5 chloromerionate of trimethylsilyl and 50 cm of dichloromethane. The temperature is allowed to rise to room temperature, evaporated to dryness, the residue is taken up with acetone, the solid product is filtered off and dried. 4.9 g of acid are obtained, which are taken up in 100 cm3 of dichloromethane and 3.63 g of phosphorus pentachloride are added and heated to reflux for 4 hours. The mixture is cooled to room temperature, evaporated to dryness, the residual oil is taken up in benzene and water. The organic layer is separated, dried and the solvents are distilled off. 4.5 g of oil are obtained, which is taken up in this form in the next step.
Example 4. (1-Piperidinyl) benzenesulfonyl 2-piperidinone.
Stage A. 5- (4-Piperidinylbenzenesulfonylamino) valeric acid.
To a solution containing 3.51 g of 5-amino-valeric acid and 3.6 g of sodium hydroxide in 35 cm3 of water, 7.8 g of 4-piperidine benzene sulfonyl chloride are added, and then 35 cm of tetrahydrofuran to obtain a solution. The temperature rises to 35 ° C. Stand for 4 hours with stirring at room temperature, distilled
tetrahydrofuran, acidify the reaction medium with acetic acid, dilute with 100 cm3 of water, extract with chloroform, dry the organic layer, and remove solvents under reduced pressure. 5.8 g of the expected product are obtained. T. pl. 115-120 ° C. After crystallization in an isopropanol-water mixture (1-1), the product is obtained, melting at 120-122 ° C.
Analysis:
Calculated. %: With 56.45; H 7.10; N 8.25
C16H24N2O4S
Found,%: C 56.19; H 7.05; N 8.06 Stadi B. (1-Piperidinyl) benzene sulfonyl 2-piperidinone
With reflux, for 4 hours, 3 g of the product obtained in Stage A is heated with 5 g of sodium acetate in 50 cm of acetic anhydride. The mixture is cooled to room temperature, evaporated to dryness, the residue is taken up in 50 cm of water, filtered off and dried, and 4.4 g of crude desired product are obtained. T. pl. 140-145 ° C. After crystallization in ethanol, 3.4 g of pure product is obtained. T. pl. 145-146 ° C.
Analysis:
Calculated,%: C 59.60; H 6.88; N 8.69
C16H22N203S
Found,%: C 59.51; H 6.97; N 8.63.
4-Piperidinylaminobenzene sulfohl orid was obtained as follows.
To a solution containing 8.46 g of sulfuric anhydride c. 45 cm of methylene chloride, cooled to 0 ° C -5 ° C, 9.3 g of dioxane are added dropwise to the drop, and then 17.1 g of N-phenylpiperidine dissolved in 45 cm of methylene chloride. The temperature is allowed to rise to room temperature, and then heated with reflux for 1 hour, evaporated to dryness, neutralized with 10% sodium carbonate solution, the aqueous layer is concentrated and the residue is dried, which is treated with 200 cm of phosphorous chloride and 21.8 g of phosphorus pentachloride 12 h at room temperature. It is evaporated to dryness, the residue is taken up in chloroform with a small amount of water, the organic layer is separated, dried on sodium sulfate, filtered and the solvent is evaporated. 19 g of the expected product are obtained, which is taken up in this form in the next stage.
Example 5. (1-Hexahydroazepinyl) benzenesulfonyl 2-piperidinone.
Stage A. (1-Hexahydroazepinyl) benzenesulfonylamino valeric acid.
6 g of 4-hexahydroazepine benzene sulfonyl chloride and then 60 cm of tetrahydrofuran are added to a solution containing 2.56 g of 5-amino-valeric acid and 2.6 g of sodium hydroxide in 60 cm of water, and then 60 cm of tetrahydrofuran. The mixture is kept under stirring for 2 hours at room temperature, the tetrahydrofuran is distilled off, the reaction medium is acidified with acetic acid, the precipitate is filtered off, washed with water and dried, and 4.65 g of the expected product are obtained. T. pl. 135-140 ° C. After crystallization in isopropanol, a product is obtained melting at 139-140 ° C.
Analysis:
Calculated,%: C 57.60; H 7.39; N 7.90
С17Н2б№045
Found,%: C 57.46; H 7.37; N 7.98
Stage B. (1-Hexahydroazepinyl) benzenesulfonyl 2-piperidinone.
1 g is heated with reflux 4 g of the product obtained in stage A with 4 g of sodium acetate in 80 cm3 of acetic anhydride. It is cooled to room temperature, evaporated to dryness, the residue is taken up in 60 cm3 of water, filtered and dried, and 3.5 g of the desired product are obtained. After crystallization in isopropanol, 2.3 g of product are obtained. T. pl. 164-165.
Analysis:
Calculated,%: C 60.69; H 7.19; N 8.33
Ci7H24N203S - Found,%: p. 60.75 ;. H 7.09; N 8.41.
4-Hexahydroazepinylbenzene sulfochloride was prepared as follows:
To a solution containing 2.64 g of sulfuric anhydride in 78 cm of methylene chloride and cooled to + 5 ° C - + 10 ° C, 2.91 g of dioxane are added dropwise to the drop, and then 5.26 g of 1-phenylhexahydroazepine (Tetrahedron 41) (1985) p. 101-106) in 53 cm3 of methylene chloride. The temperature is allowed to rise to room temperature, and then heated with reflux for 2 hours, cooled again to room temperature, 200 cm 3 of ethyl ether are added to the suspension, the precipitate is filtered off, washed with ether, dried, and 7.2 g of acid are obtained (m.p. 235 ° C decomposition.) Which are treated with 36 cm3 of phosphoryl chloride in 36 cm3 of methylene chloride and 5.87 g of phosphorus pentachloride for 4 hours at room temperature. It is evaporated to dryness, the residue is taken up with 100 cm3 of water and 150 cm3 of chloroform, the organic layer is separated, dried on sodium sulfate, filtered and the solvents are distilled off. 6.6 g of the expected product are obtained. T. pl. 85-88 ° C.
Example 6. (1-Azacyclooctyl) benzenesulfonyl 2-piperidinone.
Stage A. 5- {4- (1-Azacyclooctyl) benzene sulfonylamino-valeric acid.
4.5 g of 4-azacyclo-octylbenzenesulfonyl chloride and then 45 cm3 of tetrahydrofuran are added to a solution containing 1.82 g of 5-aminovaleric acid and 1.87 g of sodium hydroxide in 45 cm3 of water, and then 45 cm3 of tetrahydrofuran. The mixture is kept under stirring at room temperature for 2 hours, tetrahydrofuran is evaporated, the reaction medium is acidified with acetic acid, the precipitate is filtered off, washed with water and dried, and 3.6 g of the expected product are obtained. T. pl. 149-150 ° C. After crystallization in a mixture of isopropanol-water (1-1). a product is obtained melting at 153-154 ° C.
Analysis:
Calculated,%: C 58.65; H 7.66; N 7.60
C18H28N204S
Found,%: C 58.76; H 7.56; N 7.74
Stage B. 1- (1-Azacyclooctyl) benzene sulfonyl 2-piperidinone.
3.4 g of the product obtained in Stage A with 3.4 sodium acetate in 68 cm3 of acetic anhydride are heated with reflux. The mixture is cooled to room temperature, evaporated to dryness, the residue is taken up in 50 cm of water, filtered off and dried, and 2.87 g of the expected product are obtained. So pl, 150-152 ° C. After crystallization in isopropanol, 1.9 g of pure product is obtained. T. pl. 152-153 ° C.
Analysis:
Calculated,%: C, 61.68; H 7.48; N 7.99
Cl8H26N20sS
Found,%: C 61.50; H 7.50; N 7.86.
4-Azacyclooctylbenzenesulfonyl chloride was obtained as follows.
Stage A. 1-Azacyclooctylbenzene.
4.3 g of 50% sodium amide in toluene, suspended in 18.9 cm (i.e., 16.9 g) heptamethyleneamine, are heated at 100 ° C for 20 minutes and then added dropwise to drop by drop 7.85 g (i.e. 5.03 cm3) of bromobenzene. The reaction medium is heated with reflux for 18 hours, cooled to room temperature,
50 cm3 of water are added. 100 cm of benzene is added, the organic layer is separated, extracted with a 5% aqueous solution of hydrochloric acid, alkalinized with a 20% aqueous solution of sodium hydroxide, the oily layer is separated, extracted with ethyl ether, dried and distilling off the solvent. After distillation of the residue (kip. 118-120 ° C under 0.5 mm Nd, 9.4 g of the expected product are obtained.
5 Analysis:
Calculated,%: C 82.48; H 10.12; N 7.40
Ci3HigN
Found %: C 82.28; H 9.95; N 7.52
Stage B. 4-Azacyclooctylbenzenesul0 fochloride.
To a solution containing 3.97 g of sulfuric anhydride in 40 cm of methylene chloride and cooled to between + 5 ° C and + 10 ° C, 4.36 g of dioxane is added dropwise, and for 5 9.4 g of 1-azacyclooctyl benzene . The temperature is allowed to rise to room temperature and then heated with reflux for 1 hour. It is cooled again to room temperature, diluted with 200 cm of ethyl ether,
0 is filtered and after drying, 13.3 g of acid are obtained, which are treated with 10.34 g of phosphorus pentachloride in 50 cm of phosphoryl chloride and 40 cm of methylene chloride for 3 hours at room temperature, evaporated to dryness, the residue is taken in water and chloroform, separated the organic layer is dried on sodium sulfate, filtered and evaporated. This gives 13 g of the desired product.
0 Biochemical and pharmacological studies.
1) Linked to various brain receptors.
a) Muscarinic receptor 1.
5 Its preparation was made on the basis of Cortex, taken from the brains of male rats weighing 150-200 g (Iffa Credo) ground with a Polytron in a Na / K mM pH 7.4 buffer solution. After incubation (aliquot parts of 0.5 ml of homogeneous composition) for 60 min at 25 ° C in the presence of 0.25 nm H of pirenzepine, either alone, or with the product under test, or with an excess of pirenzepine M (to determine the non-specific, fixed radioactivity), the incubation product is cooled and filtered.
Filtration is carried out on Whatman GF / C filters, previously washed with a solution of 0.05% polyethyleneimine. Filters
rinsed three times with 5 ml of Na / K phosphate buffer 10 mM pH 7.4, and then measured using liquid scintillator,
b) Muscarinic receptor 2.
The preparation is made from the brains of male rats weighing 150-200 g.
Brains are ground (Teflon glass) in a sucrose solution of 0.32 M The homogeneous composition is centrifuged for 10 minutes at 1000 g (0-4 ° C).
The floating part is collected and centrifuged from 30,000 g for 15 minutes (0-4 ° C).
The precipitate is suspended in Tris buffer solution 50 mM pH 7.5 and the new homogenization product is re-centrifuged at ZOOOOg 15 min (0-4 ° C).
After removal of the surface layer, precipitates can be consumed immediately or stored up to one month at -30 ° C.
For the experiments, the precipitates are first thawed, if necessary, to room temperature and suspended with Duns in Tris 50 mM pH 7.5 buffer solution. 2 ml aliquots were incubated for 60 minutes at 25 ° C in the presence of 0.3 nm benzylate 3H quinuclidinyl, either alone or with the test product or benzatropine M to determine non-specific fixed radioactivity.
At the end of the incubation, the tubes containing the incubation products are cooled to 4 ° C and quickly filtered on Whatman GF / C filters. The filters are rinsed three times with 5 ml of Tris buffer 50 mM pH 7.5, and then measured with the help of a liquid scintillator.
Results are expressed in (concentration is necessary to inhibit fixed specific radioactivity by 50%).
The compounds of Examples 2.4, 5 show a remarkable and interesting affinity for muscarinic Mi-type receptors (see Table 1). Therefore, the same compounds showed a slight affinity (Clso 5000-10000) in relation to other studied formulations, among which dopamine, histamine, serotonin (5 HTi and 5 HT2), benzodiazepines, adrenoreceptors (alpha 1, alpha 2, beta 1, beta 2) or even opiate receptors (Mic, carr).
2) Interaction and affinity with various intestinal receptors.
The interaction of compounds with various receptors was evaluated on ileum, which was removed from the guinea pig by the following method.
Segments of ileum guinea pigs in 2.5-3 cm are washed and immediately suspended in a bath containing 10 ml of Tyroid solution at 37 ° C and aerated with a mixture of oxygen
5 (95%) and carbon dioxide (5%). After a period of stabilization of 30 minutes, at least, the contractions are recorded by holding the drug at a constant voltage of 1 g, using a sensor connected to a graph. Agonistic activity is assessed by leaving the compound in contact with the isolated tissue for the time necessary to express the maximum concentration, then washed with Tyrode's solution. The next dose was added to the bath after the drug came back to the main line. Arecoline was used as the ethanol product. Antagonistic effect on
0 contractions induced by acetylcholine (1
five
0
0
five
0
five
v6
x 10 M), ohm oppressions (1 x 10 M), and barium chloride (2 x M) are measured. Atropine, diphenidramine and paraverin were used as standards products. The contact time to agonist increase was one minute.
For each compound, dose-response curves were obtained with 4 6 different concentrations and 3-5 independent samples. Agonist activity is expressed as p02 (negative dose logarithm, which produces 50% of the maximum effect). Antagonistic activity is expressed as CLso) (concentration, brake - 5 times 50% of the maximum response).
The results obtained with the compounds of examples 2, 4 and 5 are given in Table. 2
In vitro studies on ileum taken from a guinea pig revealed that the compounds of the invention are anti-muscari-new agents. They exhibit the opposite effect of contractions induced by acetylcholine, but do not exhibit this effect to contacts induced by histamine and barium chloride.
3) Anticholin action in a living body.
The anti-choline effect of the compounds was determined by assessing the ability to inhibit the cholinomimetic effects imposed by carbacholine. Atropine sulfate was used as a product, ethanol.
Male CDi mice weighing 25-30 g are consumed. They are distributed in groups of animals in a group and treated intraperitoneally with scalar doses of products or 0.25% of Method for control samples. 12 animals are used for each dose. 30 minutes after administration of the compounds, subcutaneous injection of 1 mg / kg of carbacholine dissolved in physiological saline solution was injected into mice.
Each animal was examined 30 minutes after the carbacholine injection, in order to assess the presence of diarrhea, salivation and tearing, and body temperature was also measured using a thermocouple inserted 1.5 cm into the rectum.
Carbacholine (1 mg / kg, subcutaneous) produced diarrhea, drooling and lacrimation in all control mice and a decrease in rectal temperature of about 2.5 ° C.
For each compound, the dose, which is able to slow down in 50% of the animals, the occurrence of cholinomimetic symptoms induced by carbacholine and increase by 1 ° C the hypothermic effect induced by the choline agent is determined.
The results are summarized in table. 3
The results show that, in contrast to atropine, compounds exhibit selective anticholine activity in the living body at the level of the intestinal muscles.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 1-phenylsulfonyl-2-piperidinone of the general formula Q
0
where RI is the group N / Rj
X where R2 and Yaz are the same,
C1 C4-alkyl, or together with the nitrogen atom to which they are bound, form a piperidinyl, hexahydroazepinyl, azocyclochloride,
characterized in that the compound of the general formula
where Hal is chlorine or bromine;
RI has the indicated meanings; 5-aminovaleric acid of the formula xx.
k COO
20
NH,
and the resulting compound of general formulaA
sleep
NH S02
but
subjected to cyclization.
35
Table 1
Table 2
Ta lb and c and 3

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DE69430483D1|1993-07-16|2002-05-29|Merck & Co Inc|Benzoxazinone and benzopyrimidinone piperidinyl compounds as tocolytic oxytocin receptor antagonists|

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WO1995002587A1|1993-07-16|1995-01-26|Merck & Co., Inc.|Substituted piperazinylcamphor derivatives as oxytocin antagonists|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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IT8919524A|IT1228454B|1989-02-22|1989-02-22|DERIVATIVES OF 1-ARILSOLFONIL 2 PIPERIDONE, THEIR PREPARATION PROCEDURE AND THEIR USE AS DRUGS.|

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