Method for preparation of 1-arylsulfonyl-2-pyrrolidinone derivatives

专利摘要:
The invention relates to the compounds of formula (I): …<IMAGE>… in which R represents …<IMAGE>… where R1 is either (C1-8) alkyl, or denotes …<IMAGE>… where R2 and R3 are hydrogen, (C1-8) alkyl or, together with N, represent a heterocycle optionally containing another hetero atom, or denotes NO2, or OR' where R' is hydrogen, (C1-8) alkyl or aryl, or denotes SR4 or S(O)R5 where R4 and R5 are (C1-8) alkyl, or alternatively R represents a naphthyl optionally substituted with R'1, R'1 having the meanings stated for R1, to a process for their preparation, to their use as medicaments which are useful in the treatment of various spasmodic disorders and to pharmaceutical compositions containing them.
公开号:SU1657055A3
申请号:SU894613797
申请日:1989-02-24
公开日:1991-06-15
发明作者:Галлиани Джулио；Барцаджи Фернандо；Фортэн Мишель；Горини Карло；Тоя Эмилио
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to the field of the preparation of new derivatives of 1-arylsulfonyl-2-pyrrolidinone of the general formula:
.N-s02-r
 one
where R is either a radical is
in which RJ in position 4 means trgt-butyl, isopropyloxy, methyls or isopropylthio, cyclopentyl or cyclohexyl, or group / R2
N, where Ru and R are the same and oe- R,
one-
start C-C alkyl, or R (in position 3 means a methoxy group, or R - unsubstituted naphthyl, with valuable pharmacological properties, in particular, specific and selective anti-muscarinic activity.
Os
ate xj ate

with
The purpose of the invention is to develop, on the basis of known methods, a method for the preparation of new pyrrolidinone derivatives with pharmacological advantages over compounds of a similar effect.
Example. 1- (4-tert-butylbenzenesulphonyl) -2-pyrrolidinone.
1, 65 g of 2-pyrrolidinone in 75 cm of tetrahydrofuran is cooled to -5 ° C. To this was added 12.1 cm of a 1.6 M solution of n-butyl lithium in hexane. The temperature is maintained at (-5) - (0) C. The product is stirred for 25 minutes at -5 ° C and cooled to -20 ° C. To this is added 4,5 g of 4-tert-butylphenylsulfonyl. The temperature is raised to room temperature. The tetrahydrofuran is evaporated under reduced pressure. The residue is diluted in water, filtered and P-ethanol crystallized.
Obtain 2.75 g of the desired product, so pl. 131-133 HP.
Calculated,%: C 59.76; H 6.81; N 4.98.
C, 4H 9NOjS (281.376). Found,%: C 59.62; H 6.78; N 4.79.
PRI mme R 2. 1 - 0-4- (Diethylamino) benzenesulfonyl -2-pyrrolidinone.
0.69 g of 2-pyrrolidinone in 25 cm-tetrahydrofuran is cooled to -10 ° C. 4.89 cm3 of a 1.6 M solution of butyl lithium in hexane were added to it at a temperature below 5 ° C. The product is stirred for 20 minutes and cooled to -25 ° C. A solution of 2 g of diethylaminobuchzolsulfonyl chloride in 15 cm of tetrahydrofuran is poured into it drop by drop, keeping the temperature below -20 ° C. The temperature is allowed to rise to room temperature. Stirring is carried out for 2 hours. The solvent is removed under reduced pressure. The residue is chromatographed on silica (eluant: ethyl acetate - 1: 1 n-hexane) and diluted in isopropyl ether. Obtain 0.74 g of the target product, so pl. 128-.
Calculated,%: C 56.73; H 6.8; N 9.45.
CHH 20N-2. ° 3S (296.392). Found,%: C 56.59; H 6.73; N 9.38 /
I
Example 3. 1 (Dimethylamino) benzenesulfonyl -2-pyrrolidinone.
To a solution containing 6.11 g of 2-pyrrolidinone and 200 cm3 of dioxane,
0
five
0
five
four
0
five
0
0
3.44 g of sodium hydride (55-60% in oil) is added. The product is stirred at room temperature. 15.76 cm -1 of 4-dimethylaminobenzenesulfonyl chloride in 250 cm dioxane is added dropwise to it. Stirring / conduct 1 h at room temperature. Sodium chloride is filtered on celite. Dioxane is evaporated under reduced pressure. The residue is crystallized with P acetone.
3.90 g of the expected product are obtained, m.p. 202-204 0.
Calculated,%: C 53.71; H 6.01; N 10.44.
C uH4bNa03S (268.340).
Found,%: C 53.92; H 5.97; N 10.50; .
The product is soluble in chloroform, slightly soluble in acetone, benzene and alcohol (95%), insoluble in ethyl ether, water, 2n. a solution of hydrochloric acid and 2n. caustic soda solution.
PRI me R 4. 1 - - (Methylthio) - benzenesulfonyl-2-pyrrolidinone,
To 2.29 g of 2-pyrrolidinone in 160 cm of tetrahydrofuran cooled to -30 ° C, 16.95 cm3 of a solution of 1.6 M n-butyl lithium in n-hexane are added dropwise, maintaining the temperature of -30 ° C . The product is stirred for 30 minutes. A solution containing 6 g of 4-methylthiobenzene sulphonyl chloride in 10. cm of tetrahydrofuran is poured into it dropwise at (-30) - (- 25) ° C. The temperature is raised to room temperature. The solvent is evaporated under reduced pressure. The residue is diluted with water. The solid is filtered off and crystallized in isopropanol.
Obtain 3.80 g of the target product, so pl. 123-125 C.
Calculated,%: C 48.69; H 4.83; N 5.16.
C ,, H / aNOftR, j (271.36).
Found,%: C 48.91; H 4.69; N 5.22.
Example 5. 1- (4-Isopropyl-hydroxybenzenesulfonyl) -2-pyrrolidinone.
To 1.3 g of 2-pyrrolidinone in 90 cm of tetrahydrofuran, cooled to -30 ° C, was added 9.6 cm 1} b of a M solution of n-butyl lithium in n-hexane, maintaining the temperature ((-30) ° C. The product is stirred 1 hour at -30 ° C .; 4 g of 4-isopropyloxy-benoenesulfonyl chloride in 6 cm tetragldro5, 1 is poured into it dropwise at this temperature.
Furana. Stirring is carried out for 1 h at -30 tC The temperature is raised to room temperature. The solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluant: cyclohexane – ethyl acetate 7: 3) and crystallized in isopropanol.
Obtain 1, 5 g of the target product, so pl. 88-90 C.
C 55.10; H 6.05;
(283.35).
C 55.07; H 5.98;
Calculated N 4.94.
.S
Found,% N 4.90.
PRI me R 6. 1- (4- (Methylsulfonyl) -benzenesulfon1-2-pyrrolidinone
To the prepared according to example 4 1- (4-methylthiobenzene sulfonyl) -2-pyrrolidinone (3.4 g), dissolved in 34 cm of methylene chloride, was added a solution containing 2.41 g of m-chloro benzoic acid in 48 cm of chloride methylene, at a temperature not exceeding. At room temperature, the product is stirred for 30 minutes. Then the reaction medium is treated with a 10% aqueous solution of sodium sulfite. The organic layer is separated, washed with a 5% aqueous solution of sodium bicarbonate and water, and dried. The solvent is distilled off under reduced pressure. The residue is crystallized p. 95% ethanol.
1.70 g of the expected product are obtained. Mp. 127-129 ° C.
Calculated,%: C 45.98; H 4.56; N 4.87.
, eN04Se. (287.36).
Found,%: C 45.87; H 4.60; N 4.81.
Example. 1- (3-Methoxybeneol sulfonyl) -2-pyrrolidinone.
To 2.22 g of 2-pyrrolidinone in 80 cm of tetrahydrofuran, cooled to -25 ° C, 15.76 cm of a 1.6 M solution of n-butyl lithium in hexane was added, maintaining the temperature (-25) - (20) ° C. The product is stirred for 30 minutes at -25 C. A solution of 5.40 g of 3-methoxybenzene sulyl chloride in 40 cm of tetrahydrofuran is added dropwise to it at (-25) - (-20) ° C. Stirring is carried out for 30 min at -25 ° C. The temperature is raised to room temperature. The solvent is distilled off under reduced pressure. The residue is diluted in water, filtered and crystallized with E isopropanol.


0
0
Obtain 3.5 g of the target product, h so pl. 108-109 C.
Calculated,%: C, 51.75; H 5.13; N 5.49.
C "H4, N04S (255.298).
Found,%: C 51, 84; H 5.12; N 5.54.
Try on I- (2-Naphthylsulfonyl) -2-pyrrolidinone.
To 2.13 g of 2-pyrrolidinone in 80 cm3 of tetrahydrofuran, cooled to H ° C, 15.6 cm of a 1.6 M solution of butyl lithium in hexanone is added, maintaining the temperature (-5) - (+ 5) ° WITH. The product is stirred for 75 minutes at. Then 6.12 g of L-naphthalene sulfonyl is added to it at a temperature not exceeding 0 ° C. The temperature is raised to room temperature. The solvent is distilled off under reduced pressure. The residue is diluted in ethyl acetate with acetic acid, lithium chloride is filtered off from it, evaporated to dryness under reduced pressure, taken ode,
filtered and crystallized in isopropanol.
4 g of the expected product are obtained, m.p. 118-120 0.
 Calculated,%: C 61.07; H 4.76; N 5.09.
C 4H 3N03S
Found,%; N 4.99.
PRI me R 9. 1-H4-Cyclopentyl) - phenylsulfonyl -2-pyrrolidinone.
To a solution containing 1.02 g or 0.9 cm of 2-pyrrolidinone in 50 cm of tetrahydrofuran, cooled to -70 ° C, pour 8 cm of a 1.5 M solution of n-butyl lithium in n-hexane. The temperature should not exceed -60 ° C. After 15 minutes, 3 g of 4-cyclopentylbenzenesulfonyl chloride, dissolved in 12 cm of tetrahydrofuran, are added, keeping the temperature (-65) - (-70) ° C. The temperature was raised to room temperature over 2 hours. The residue was evaporated to dryness and chromatographed on silica (eluant: ethyl acetate - n-hexane 1: 3).
Obtain 2.6 g of the target product, so pl. 105-106 ° C, from which, after recrystallization in isopropanol, 2 g of the product can be obtained, melting at los-ioe c.
Calculated,%: C, 61.41; H 6.53;
(275.3).
C, 60.91; H 4.72;
five
0
five
0
five
N 4.77.
 (293.40).
Found,%: C 6i, 22; H 6.71; N 5.06;
PRI me R 10. 1 - / 4-Cyclohexyl-Phenylsulfones-2-pyrrolidinone.
The process is conducted according to example 9, but using I, 97 g of 2-pyrrolidine in 100 p. 1L of tetrahydrofuran, 15.5
1.5 M solution of n-butyl lithium in hexane, 6 g of (4-cyclohexyl) -ben- Q chloride of zolsulfonyl in 24 cm 5 of tetrahydrofuran.
Obtain 3 g of the target product, so pl. 91-92 C. After crystallization in isopropanol, 2 g of product are obtained, melting at 91-92 ° C.
Calculated,%: C 62.51; H 6.88; N 4.56.
16570558
Example 13. 1 - Ј (4-Diisopropyl-; amino) -phenylsulfonyl-3-pyrrolidinone.
The process is carried out according to example 9, but using 2.76 g of 2-pyrrolidinone in 81 cm of tetrahydrofuran, 21.7 cm of 1, 5 M solution of butyl lithium in n-hexane at (-20) - (- 1 5) C, and then 9 g chloride (4-diisopropylamine) -benzenesulfonyl in 45 cm of tetrahydrofuran.
After chromatography (eluant: ethyl acetate - n-hexane 1: 2), 3.4 g of the expected product are obtained, mp. 1 40-1 451. After crystallization in isopropanol, a product is obtained which melts at 142-145 ° C.
(307.42). C 62.29; H
C 59.23; H 7.46;
6.74;
N
Found,% 4.69.
Example 11.1- (4-Dipropyl-amine) -phenylsulfonyl J. -2-pyrrolidinone.
The process is carried out according to example 9, but using 1.39 g of 2-pyrrolidinone in 42 cm of tetrahydrofuran, 10.8 cm3 of a 1, 5 M solution of n-butyl lithium in n-hexane, 4.5 g
20
25
and then at (-20) - (-10) C chloride (4-dipropylamino) -ben (324.45). C, 59.09;
H 7.38;
 Calculated N 8,63.
with y / n% oe
Found,%: N 8.57.
Example 14. 1- (4-Isopropylthio-h phenylsulfonyl) -2-pyrrolidinone.
The process is carried out according to Example 9, but using 1, 7 g of 2-pyrrolidinone in 51 cm of tetrahydrofuran, 13.3 cm of a 1.5 M solution of n-butyllna in n-hexane and 5 g of 4-isop chloride; 5 cm -2 tetrahydrofuran. The temperature is raised to room temperature. The residue is evaporated to dryness, diluted in water. The precipitate is filtered off and dried.
zolsulfonil in the wound.
Get 2
25 cm tetrahydrofu
(324,454).
C 59.13; H 7.53;
g of the target product, so pl. 88-90 ° C. After crystallization in isopropanol, I, 5 g of product is obtained, melting at 92-93 ° C.
Calculated,%: C 59.23; H 7.46; N 8.63.
C / faH-MN S
Found,%: N 8.44.
Example 12. 1- (4-Dibutyla but) -phenylsulfonyl 2-pyrrolidinone.
The process is conducted according to example 9, but using 1.76 g of pyrrolidinone in 51 cm of tetrahydrofuran, 13.8, 5 M solution of n-butyllna in n-hexane at (-20) - (- 15) C, and then 6.3 g 4-dibutylaminobenzenesulfonyl chloride in 35 cm3 of tetrahydrofuran.
After chromatography on silica (eluant: ethyl acetate - 1: 1 n-hexane) and crystallization in isopropanol, 3 g of the expected product are obtained, mp. 73-74 ° C
Calculated,%: C, 61.33; H 8.01; N 7.95.
C | 6HMNep3S (352.51).
Found,%: C 61.14; H 8.03; N 7.86.
In isopropanol, products are obtained melting at 142-145 ° C.
C 59.23; H 7.46;
0
five
0
five
(324.45). C, 59.09;
H 7.38;
 Calculated N 8,63.
with y / n% oe
Found,%: N 8.57.
Example 14. 1- (4-Isopropylthio-h phenylsulfonyl) -2-pyrrolidinone.
The process is carried out according to Example 9, but using 1, 7 g of 2-pyrrolidinone in 51 cm of tetrahydrofuran, 13.3 cm of a 1.5 M solution of n-butyllna in n-hexane and 5 g of 4-isop chloride; 5 cm -2 tetrahydrofuran. The temperature is raised to room temperature. The residue is evaporated to dryness, diluted in water. The precipitate is filtered off and dried.
Obtain 3.1 g of the target product, so pl. 62-66 ° C, which is recrystallized from P isopropanol, and 2.4 g of product are obtained, melting at 68-70 ° C.
C 52.15; H 5.72;
N
N
C 51, 86; H 5.63;
Calculated% 4.68. C HjrNOjSfc.
Found,%: 4.57.
Biochemical and pharmacological studies.
Link to various brain receptors.
Muscarinic receptor 1 (M,) was obtained from the cortical substance of the brains of a male rat (weighing 150-200 g), crushed by a polytron in a Na / K 10 mM buffer solution, pH 7.4. After incubation (multiples of 0.5 ml of the homogeneous mixture) for 60 minutes at 25 HP in the presence of 0.25 nm N pirenzepin, either alone or with the product under test, or with an excess of pyrenchepin at 10 M (to determine non-specific fixed radioactivity) incubation cooled and about 20
25
filtered on Whatman GF / C filters, prewashed in 0.05% polyethyleneimine solution. The filters were rinsed with ml of 10 mM 5 buffer solution of phosphate Na / K, pH 7.4, and then measured by liquid scintillation.
Muscarinic receptor 2 (Mr) was obtained from the brains of a male rat (weighing 150-200 g). Brains were ground (Teflon-glass) in a solution of 0.32 M sucrose. The homogeneous mixture was centrifuged for 10 minutes at 1000 g (0-4 ° C). The resulting floating part was collected and centrifuged at 30000 g for 15 minutes (). The bottom part was again suspended in Tris 50 mM buffer, pH 7.5, and the new homogeneous mixture was centrifuged again at 30,000 g for 15 minutes (0-4 ° C).
After removal of the floating part, the bottom parts can be immediately consumed or stored for up to 1 month at -30 ° C.
For testing, the bottom parts were first thawed, if necessary, to room temperature, and then suspended with Duns in Tris 50 mM pH 7.5 buffer solution. Multiples in 2 ml were allowed to incubate for 60 min at 25 ° C in the presence of 0.3 nm H quinuclidinyl benzoate, either alone or with the product under test, or with benzatropine to determine 35 35 nonspecific fixed radioactivity.
At the end of the incubation, the tubes with the incubation results were cooled to 4 ° C and quickly filtered on Whatman GF / C filters. The filters were rinsed with 3x5 ml of Tris 50 mM buffer, pH 7.5, and then measured by liquid scintillation.
Results are expressed in Clgo (concentration, needed for 50% inhibition of specific fixed radioactivity).
The data are summarized in table 1.
The compounds of examples 1 and 2 showed affinity for muscarinic receptors, in particular, the M | receptor type. The same compounds showed a weak affinity (C1d-0 5000-10000) for other studied receptors, including dopamine receptors, serotonin (5 NT and 5 NT), benzodiazepines, CABA receptors, adrenergic receptors ( Re) opioid receptors (M, € 9).
thirty
40
45
50
55
20
25
five
yu 15
35
57055Y
The interaction and affinity with various intestinal receptors.
The interaction of the compounds with different receptors was evaluated in the guinea-pig ileum by the following method.
Segments of the guinea pig iluem in 2 cm were washed and immediately suspended in a bath containing 10 ml of thyroid solution at 37 ° C and a ventilated mixture of oxygen (95 /) and carbon dioxide (5/0). After a period of stabilization of at least 30 minutes - reduce the contraction by holding the drug at a constant voltage of 1 g using a sensor connected to a polygraph. The agonistic effect was evaluated by contacting the compound with the selected tissue for the time required to express the maximum concentration, and then washed with a solution rum of tyrode. The next dose was introduced into the bath only after the drug came back to its main line. Arecoline was used as a reference product. Antagonistic effect was evaluated by reductions caused by acetylcholine (), gistemin (), serotonin () and barium chloride (2x10 M). Atropine, diphenidramine, methisergin, and papaverine were used as control products. The contact time before agonist addition was 1 min.
For each product, the dose-response curves were obtained with 4-6 different concentrations and 3-5 independent tests. Agonist activity is expressed in terms of pDg (negative logarithm of the dose, which produces 50% of the maximum effect). Antagonistic activity is expressed in terms of CIgj (concentration, inhibiting the maximum response by 50%).
The results obtained during the tests in examples 1 and 2 are given in table 2.
thirty
40
45
- -
In vitro studies on isolated guinea pig ileum have shown that the compounds proposed are strong antimuscarinic agents. They show antagonism of contractions caused by acetylcholine, but do not show antagonism of contractions caused by histamine, serotonin. These compounds produced antago.
Nistic activity is slightly lower (7 times) than that produced by atropine.
A good antagonistic effect of the proposed compounds was confirmed on the colon (isolated) rats.
The segments of the colon of the ratyl-2.5 cm were washed and suspended in a bath containing 10 ml of De Zhalon solution having the following composition, mM: NaCl 154; KC1 5.7; , 27; NaHCO 5.9 and glucose 2.5. Bath temperature
value 1 (table 3). From these data and from the obtained pA m values (Table 3), it can be concluded that the proposed compounds are competitive antagonists for muscarinic receptors involved in acetylcholine-induced rat colon contractions, and they show a potency of approximately 4 to 10 times lower than the power of atropine.
Anticholinergic action in a living body.
The anticholinergic effect of the compounds was determined by evaluating the
32 ° C. Under these conditions, withstanding pre-15 ° ° bn °. ™ retard cholinomimetic
effects caused by carbacholine. Atropine sulfate was used as a control.
Parameters under a voltage of 1 g, the spontaneous activity of the intestine is at its minimum. After a stabilization period of at least 30 minutes, voltage variations are measured using an isothermal converter connected to a recorder. A series of experiments was carried out to measure the antagonistic activity against
effects caused by carbacholine. Atropine sulfate was used as a control.
Eat male washes. SP / (weighing 25-30 g). They are divided into groups of 5 animals and treated intraperitoneally by using scalar doses or 0.25% of metocell for controls. "10 animals for every 30
35
30 minutes after administration of the compounds, mice are injected subcutaneously with 1 mg / kg of carbacholine dissolved in physiological saline solution.
Each animal was examined 30 minutes after the injection of carbachol to determine diarrhea, salivation and tearing, and body temperature was taken using a thermocouple inserted 1.5 cm into the rectum.
Carbachol induced diarrhea, drooling and lacrimation in all control mice and a decrease in temperature in the rectum by approximately 2.5 C.
For each compound, determine
After a dose of 40 ° C cat has been able to slow down
, in 50% of animals, the appearance of peripheral cholinomimetic symptoms caused by carbachol and to increase by 1 ° C the hypothermic effect introduced by the cholinergic agent.
The results are shown in table 4.
The results show that the proposed compounds show anticholinergic in the living body. some action (elective) at the level of kik contractions caused by a maximum 25 dose of acetylcholine (M).
The compounds are left in contact for 3 minutes prior to the addition of acetylcholine.
Atropine was used as a control product. For each compound, dose-response curves are obtained with 4-6 different concentrations and 3-5 independent tests.
Antagonistic activity is expressed as CI g-f (concentration, inhibiting 50% of the maximum response entered by acetylcholine).
In the second series of tests, acetylcholine was added to the bath in cumulative doses.
2 identical and consecutive dose – response curves with acetylcholine were found, a third dose – response curve was obtained in the presence of a compound (the time of contact with the compound before acetylcholine was 5 min). Each compound was tested at 3-4 different concentrations.
Antagonistic affinity and type of antagonism (competitive, noncompetitive) for muscarinic receptors were calculated by Schild method.
Both compounds of Examples 1 and 2 and, like atropine, gave a parallel shift to the right of the dose curve — an acetylcholine response without decreasing the maximum contraction.
Direct regression slope in a shield raft corresponds to the theoretical
50
spanner muscles.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 1 - arylsulfonyl-2-pyrrolidinone of the formula
s
S02R
5705512
value 1 (table 3). From these data and from the pA values obtained (Table 3), it can be concluded that the proposed compounds are competitive antagonists for muscarinic receptors involved in acetylcholine-induced rat colon contractions, and they show a potency of approximately 4 to 10 times lower than the power of atropine.
Anticholinergic action in a living body.
The anticholinergic effect of the compounds was determined by evaluating the
s ° bn ° s. ™ retard cholinomimetic
effects caused by carbacholine. Atropine sulfate was used as a control.
Eat male washes. SP / (weighing 25-30 g). They are divided into groups of 5 animals and treated intraperitoneally by using scalar doses or 0.25% of metocell for controls. "10 animals for each results obtained show that the proposed compounds show anticholinergic in a living body. some action (elective) at the level of ki
spanner muscles.
Invention Formula
The method of obtaining derivatives of 1 - arylsulfonyl-2-pyrrolidinone of the formula
s
S02R
where R is either a radical
-ABOUT
in which R - in position 4 means 5 tert-butyl, isopropyloxy, methyl or isopropylthio, cyclopentyl or cyclohexyl or group
14
1657055
about tl and h a y i and with -, p,, 2-pyrrolidinone formula
N N
subjected to the interaction of the general formula
- / R2
-N;
Rrfle R "ЈH R% is the same and means Cf-C-alkyl, or R in position 3 means a methoxy group, or R is an unsubstituted naphthyl,
by that
N N
subjected to interaction with the compound of the General formula
R - S02Hal,
where Hal is a chlorine or bromine atom; R has the indicated values of j in the medium of an organic solvent in the presence of an alkali metal hydride.
Table 1
Connection example
ropin
6.4 6.2
10 10
9,5- 10
To
-AT 9
Connection by example
Affinity for muscarinic receptors M (and M g
l
H quinuclidinyl benzoate
130 98
1300 1300
table 2
yu yu
-four
-41, 6 10 6.0 s
-selected rat intestine
15
1657055
sixteen
TableD

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同族专利:

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公开号 | 公开日

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PT89798B|1994-04-29|

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MX15050A|1993-10-01|

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US5081130A|1992-01-14|

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IT1216461B|1990-03-08|

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US4990531A|1991-02-05|

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MA21499A1|1989-10-01|

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MX173423B|1994-03-03|

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AU3071289A|1989-08-31|

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AU619804B2|1992-02-06|

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EP0335758A3|1990-01-10|

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CA1324605C|1993-11-23|

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ZA891413B|1990-04-25|

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JPH01287070A|1989-11-17|

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PT89798A|1989-10-04|

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HUT50764A|1990-03-28|

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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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IT8819560A|IT1216461B|1988-02-26|1988-02-26|DERIVATIVES OF 1_ARIL SOLFONIL2_PIRROLIDINONE THEIR PROCESSES OF PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS.|

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