NOVEL 2,3-THIOMORPHOLINEDIONE-2-OXIME DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The present invention relates to novel compounds of general formula (I), wherein R1 stands for hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or nitro group; R2 means a C1-7 alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4 alkoxy, cyano, amino, C1-4 alkylamino, or diakylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R2 means an aryl-C1-7 alkyl group optionally bearing the substituents defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C1-4 alkyl or alkoxy group in the benzene ring; or R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4 alkyl group in the benzene ring; or R2 stands for a carbamoyl group substituted by one or two C1-4 alkyl group(s) or phenyl group on the nitrogen atom. The compounds according to the invention show a cytoprotective and acid secretion-inhibiting action and are effective against gastric and duodenal ulcers.

Description: 0 NOVEL 2,3-THI0M0RPH0LINEDI0N£-2-0XIME DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING Th'EM AND PROCESS FOR PREPARING SAME This invention relates to novel 2 ,3-thiomαrpoline- dione-2-oxime-derivatives of the general formula (I), w erein R-, stands for hydrogen, halogen, C, _*alkyl, C-,_ 4 alkoxy or nitro group; R. eaπs a C, 7 alkyl group optionally substituted by: hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C, .alkoxy. cyano, amino, C^alkylamiπo, or dialkylamiπo group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C, -,alkyl group optionally bearing the substitueπts defined above for R in the alkyl chain and optionally substituted by halogen, nitro, C, .alkyl or alkoxy group in the benzene ring; or R represents an allyl, pheπylallyl or pheπylsulfon.yl group, both latter groups optionally being substituted by halogen or a C, .alkyl group in the benzene ring; or R 2 stands for a carbamoyl group substituted by one or two C, -alkyl group(s) or phenyl group on the nitrogen atom as well as the pharmaceutical compositions containing these compounds. The compounds of the general formula (I) have - interesting cytαprotective and gastric acid secretion- -inhibiting properties and are effective against gastric and duodenal ulcers. The therapeutic importance of the above new compounds is very high since the number of patients suffering from gastric and duodenal ulcer is continuously increasing both in the absolute and relative sense as well. Although a number of drugs are known which are useful for the ulcer therapy, no similar effect has up to the present been described for 2,3-thiomorpholinedione-2-o imes. According to the literature, several patents (United States patent specifications Nos. 3,790,566, 3,883,510, 3,894,150, 3,930,002, 4,003,895 and 4,003,897) describing 2,3-thiomorpholinedione-2-oxime derivatives .as pesticides were granted for the Union Carbide and the du Pont companies; however, no benzyl group substituted by R-, was bound to the ring nitrogen in the compounds of these patents. Thus, the aim of the present invention was to find novel, therapeutically useful compounds which can be prepared economically on an industrial scale, too. Accordingly the invention relates also to a process for the preparation of the new compounds of general formula (I), wherein R-, stands for hydrogen, halogen, C, ^alkyl, C-, .alkoxy or nitro group; R 2 means a C-,_ 7 alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C-, .alkoxy, cyano, amino, C, , : alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C,_ 7 alkyl group optionally bearing the substituents defined above for R 2 in the alkyl chain and optionally substituted by halogen, nitro, C, .alkyl or alkoxy group in the benzene ring; or R 2 represents an allyl, phenylallyl or phenylsul onyl group, both latter groups optionally being substituted by halogen or a C, .alkyl group in the benzene ring; or R 2 stands for a carbamoyl group substituted by one or two C, .alkyl group(s) or pheπyl group on the nitrogen atom which comprises a) to obtain compounds of the general formula (I) containing as R ? a substituent different from an N- -substituted carbamoyl group reacting a compound of the general formula (II), wherein R-, is solvent in the presence of an inorganic or organic base with a compound of the general formula (III), wherein R-, has the same meaning as R 2 , except the N-substituted carbamoyl group and X is halogen or, when the meaning of R-, is different from an acylatable group, X may be also a mesyloxy or tosyloxy group; or b) to obtain compounds of the general formula (I) containing an N-substituted cabamoyl group as R 2 , reacting a compound of the general formula (II), wherein R, is as defined above, in an inert organic solvent in the presence of an organic tertiary amine, preferably triethylamiπe with a compound of the general formula (IV), p NCO (IV) wherein R. stands for a pheπyl or C-, .alkyl group. The preparation of the 2,3-thiomorpholinediαπe-2- -oxi e derivatives of general formula (II) used as starting substances has been described in our patent application simultaneously filed. According to those reported in that patent application, the compounds of the general formula (II) can be prepared e.g. by reacting an appropriately substituted 2-πitromethylene- -3-(phenylmethyl)thiazolidine with a basic reagent in an aqueous and/or alcoholic medium. From the 2,3-thiomorpholinedione-2-oxime derivatives of the general formula (II), the compounds according to the present invention can be prepared by the methods discussed hereinafter: a) a substitution alkylatioπ or acylatioπ is carried out the using a compound of the general formula (III), wherein R-, is the same as R 2 , except any N- -substituted cabamoyl group; and b) an addition acylatioπ is performed by using a compound of the general formula (IV); in this case R 2 stands for an N-substituted cabamoyl group. In the process variant a) of the present invention, the reaction is usually carried out in an organic solvent, preferably in methanol, ethanol, acetone or in an ether-type solvent, such as dioxaπe; or in aceto- πitrile, dimethylforma ide or dimethylsulfoxide. Alkaline metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines may be used as acid binding agents. The reaction is usually carried out at a temperature corresponding to the boiling point of the solvent used. After filtering off the precipitated salt, the product is isolated by evaporating the reaction mixture and then purified by a method known per se. When using process variant b) of the invention, the reaction is accomplished in the presence of a solvent and a catalyst. Depending on the solubility conditions of the reactaπts used, C-,_ 6 ketoπes, C 2 _cethers, dimethylformamide, dimethylsulfoxide, ~ - _ l ^hydrocarbons or chlorinated hydrocarbons may preferebly be employed as solvents. Suitable catalysts are organic tertiary amiπe bases, preferably triethylamine. The reaction temperature may be varied between 0 °C and 100 °C. Out of the compounds of the general formula (I), 4-phenylmethyl-0-methyl-2,3-thiomorpholinedioπe-2-oxime exerts a particularly advantageous effect based on the pharmacological iπventigations. This compound shows a gastric acid secretion-inhibiting action with an oral EDrg value of 20 g/kg in the so-called Shay's rats, is effective also against stress-induced ulcers with an oral ED 5Q value of 71 mg/kg and against acidic ethaπol-induced gastric ulcers with an oral value of 7 mg/kg. The invention is illustrated in detail by the following non-limiting Examples. Example 1 General Example for the substitution alkylation or acylatioπ, respectively After weighing 100 mmol of a compound of the general formula (II), 20 ml of acetone, 10 mmol of a compound of the general formula (III), 10 mmol of potassium carbonate and 1 mmol of potassium iodide in a round-bottom flask, the reaction mixture is refluxed until the substance of general formula (II) as detected by thin layer chcmatograhy (TLC) diappears, then the inorganic precipitate is filtered off and the filtrate is evaporated. The residue is purified after having been solidified by adding ether by recrystallisation or by column chomatography. The data of compounds obtained by this method are summarized in Table I. Chemical names of the compounds listed in Table I: 1. 4-Pheπylmethyl-0-pheπylmethyl-2,3-thio- mαrpholiπedioπe-2-oxime 2. 4-Phenylmethyl-0-ethoxycarboπylmethyl-2,3- -thiomorpholiπedioπe-2-oxime . 4-Pheπylmethyl-0-methyl-2,3-thiomorpholiπedioπe- -2-oxime 4. 4-Pheπylmethyl-Q-ethyl-2,3-thiomorpholinedione- -2-oxime 5. 4-Pheπylmethyl-0-n-propyl-2,3-thiomorphαliπe- -dioπe-2-oxime 6 . 4-Pheπylmethyl-0-(3-pheπyl-l-propyl)-2,3- thiomorpholinedioπe-2-oxime 7. 4-Pheπylmethyl-Q-cyaπome hyl-2,3-thiomorpholiπe- dioπe-2-oxime 8. 4-(2-Chloropheπylmethyl)-0-methyl-2,3-thio- morpholiπedioπe-2-oxime 9. 4-(4-Methoxyphenylmethyl)-0-methyl-2,3-thio- morpholiπedione-2-oxime 10. 4-(3-Chloropheπyl ethyl)-0-methyl-2,3-thio- morpholiπedione-2-oxime 11. 4-(4-Methylpheπylmethyl)-0-methyl-2,3-thio- morpholiπedione-2-o ime 12. 4-Phenylmethyl-0-cinnamyl-2,3-thiomorpholine- dione-2-oxime 13. 4-Phenylmethyl-0-tαsyl-2,3-thiomorpholinedione- -2-oxime 14. 4-Phenylmethy1-0-phenylsulfony1-2,3-thio- morpholiπedione-2-oxime 15. 4-Pheπylmethyl-0-(4-fluorpheπylsulfoπyl)-2,3- thio orpholinedione-2-oxime 16. 4-Pheπylmethyl-0-dimethylcarbamoyl-2,3-thio- morpholiπedione-2-oxime 17. 4-Phenylmethyl-0-(3-hydroxy-l-propyl)-2,3-thio- morpholiπedioπe-2-oxime - Example 2 General Example for the addition acylation After weighing 10 mmol of the compound of general formula (I), 20 ml of acetone, 15 mmol of triethylamine and 11 mmol of the substance of general formula (IV) in a round-bottom flask, the reaction mixture is stirred at room temperature for 24 hours, then the uπreacted compound of the general formula (II) is filtered off and the filtrate is evaporated. The residue is purified after having been solidified by adding ether and then by recrystallisation or by direct chromatography. The data of compounds obtained by this method are summarized in Table II. Chemical names of the compounds listed in Table 1. 4-Pheπylmethyl-0-n-butylcarbamoyl-2,3-thio- morpholiπedione-2-oxime 2. 4-Pheπylmethyl-0-phenylcarbamoyl-2,3-thio- morpholinedioπe-2-oxime 3. 4-Pheπylmethyl-0-ethylcarbamoyl-2,3-thio- morpholiπedioπe-2-oxime Example 3 Preparation of 4-phenylmethyl-2,3-thiomorpholiπe- dione-2-oxime 2,36 g (0.01 mol) of 3-phenylmethyl-2-nitromethyleπe- thiazolidiπe are boiled under reflux in the mixture of 50 ml of IN sodium hydroxide solution and 25 ml of ethaπol until the dissolution of the starting substance (when, based on the TLC examination, no starting substance is detected in a sample taken from the reaction mixture). Then, the mixture is cooled, acidified by adding hydrochloric acid diluted to 1:1 with water (to a pH value of 1), the precipitated product is filtered off, washed with water and dried to give the title compound in a yield of 2,15 g (91%), m.p.: 225-227 °C. The purity of this product is 99.7% when measured by titratioπ with alkaline metal hydroxide in pyridine, in the presence of silver nitrate. Table I No. Reactant R, R-, Reaction time Yield Melting point IR spectrum NMR spectrum 1 ^ hour % °C Benzyl bromide H Ph-CH 2 - 59.2 103 1657 2.8/m,2H,CH 2 / /EtOH/ 1015 3.6/m,2H,CH 2 / 4.6/s,2H,CH 2 / 5.3/s,2H,CH 2 / 7.2/2xs,20H,ArH/ 2 Ethyl bro oacetate H -CH 2 -C0 2 Et 45 109-110 1750 1.3/t,3H,CH 3 / /EtOH/ 1660 2.9/m,2H,CH 2 / 1220 3.7/m,2H,CH 2 / 3 Methyl iodide H -CH, Table I /cont./ No . Reactant Reaction time Yield Melting point IR spectrum NMR spectrum hour % °C 7 Chloroaceto- nitrile /" CN 41.4 77-79 /i-PrOH/ 8 Methyl iodide 2-C1 CH, 70.2 128-129 /i-PrOH/ 9 Methyl iodide 4-0CH, CH, 46.7 107-110 /i-PrOH/ 4.2/s,3H,CH 3 / 4.6/s,3H,CH 3 / 7.0/q,4H,ArH/ I Table I /cont./ Table I /cont./

Claims: Claims 1 , 2 , 3-Thiomorpholinedioπe-2-oxime derivatives of the general f ormula (I ) , N 0 wherein Ur<2 R-, stands for hydrogen, halogen, C,_.alkyl, C, .alkoxy or nitro group; R 2 means a C, ^alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C- j ^alkoxy, cyano, amino, C-,_ 4 alkylamino, or dialkyla iπo group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C,_ 7 alkyl group optionally bearing the substitueπts defined above for 2 in the alkyl chain and optionally substituted by halogen, nitro, C-J Λ alkyl or alkoxy group in the benzene ring; or R 2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C, alkyl group in the benzene ring; or R 2 stands for a carbamoyl group substituted by one or two C-._ 4 alkyl group(s) or pheπyl group on the nitrogen atom. 2. 4-Phenylmethyl-0-methyl-2,3-thiomorpholinedioπe- -2-oxime. 3. A process for the preparation of 2,3-thio- morpholiπedioπe-2-oxime derivatives of the general formula (I), wherein R, stands for hydrogen, halogen, C-,_ z ,alkyl, C,_ * alkoxy or nitro group; R 2 means a C, -,alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C,_ 4 alkoxy, cyano, amino, C, _ 4 alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C,_-,alkyl group optionally bearing the substitueπts defined above for R 2 in the alkyl chain and optionally substituted by halogen, nitro, C-, ^ alkyl or alkoxy group in the benzene ring; or R 2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C, ^alkyl group in the benzene ring; or R stands for a carbamoyl group substituted by one or two C, * alkyl group(s) or phenyl group on the nitrogen atom which comprises a) to obtain compounds of the general formula (I) containing as R~ a substitueπt different from an N- -substituted carbamoyl group, reacting a compound of the general formula (II), wherein R, is as defined above, in an inert organic solvent in the presence of an inorganic or organic base with a compound of the general formula (III), R 3 -X (III) wherein R has the same meaning as R 2 , except the N-substituted carbamoyl group and X is halogen or, when the meaning of R-, is different from an acylatable group, X may be also a mesyloxy or tosyloxy group; or b) to obtain compounds of the general formula (I) containing an N-substituted cabamoyl group as R 2 ,- reacting a compound of the general formula (II), wherein R, is as defined above, in an inert organic solvent in the presence of an organic tertiary amine, preferebly triethylamine with a compound of the general formula (IV), - NCO (IV) wherein R ή stands for a phenyl or C, alkyl group. 4. A process as claimed in claim 3 a) which comprises carrying out the reaction at about a temperature of the boiling point of the solvent use 5. A process as claimed in claim 3 a), which comprises using an alkaline metal hydroxide, carbonate or alkαxide or a C, ^alkylamiπe, preferably a tertiery amine as an inorganic or organic base, respectively. 6. A process as claimed in claim 3 b), which comprises carrying out the reaction at a temperature between 0 °C and 100 * °C. 7. A process as claimed in claim 3 a) which comprises using a C, .alcohol, ~ - _ , ketoπe, C 2 _ ether or acetonitrile, dimethylsulfoxide or dimethylformamide as an inert organic solvent. 8. A process as claimed in claim 3 b), which comprises using a ~ - _ ketoπe, C 2 _ 5 ether, acetonitrile, dimethylsulfoxide , dimethylformamide, C 5 _, η hydrocarbon or chlorinated hydrocarbon as an inert organic solvent. 9. A pharmaceutical composition, which comprises as active ingredient a 2,3-thiomorpholiπedioπe-2-oxime derivative of the general formula (I), R, stands for hydrogen, halogen C, .alkyl, C, .alkoxy or nitro group; R 2 means a C ^ ^alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a ~ - _ A alkoxy, cyano, amino, C, .alkylamino, or dialkyl- amino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or means an aryl-C, 7 alkyl group optionally bearing the substitueπts defined above for R 2 in the alkyl chain and optionally substituted by halogen, nitro, C-, .alkyl or alkoxy group in the benzene ring; or R 2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C,_.alkyl group in the benzene ring; or R 2 stands for a carbamoyl group substituted by one or two C, .alkyl group(s) or pheπyl group on the nitrogen atom in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 10. A process for the preparation of a pharma¬ ceutical composition, which comprises mixing as active ingredient a 2,3-thiomorpholiπedione-2-oxime derivative of the general formula (I), wherein R-, and R 2 are as defined in claim 3, prepared by using -a process according to claim" 3 with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

Inventors: DOMANY GYOERGY, EZER ELEMER, HAJOS GYOERGY, HARSANYI KALMAN, HEGEDUES BELA, LAMPERT AGNES, MATUZ JUDIT, SAGHY KATALIN, SZABADKAI ISTVAN, SZEKELY KRISZTINA, SZPORNY LASZLO, DOMANY, GYOERGY, EZER, ELEMER, HAJOS, GYOERGY, HARSANYI, KALMAN, HEGEDUES, BELA, LAMPERT, AGNES, MATUZ, JUDIT, SAGHY, KATALIN, SZABADKAI, ISTVAN, SZEKELY, KRISZTINA, SZPORNY, LASZLO
Applicants: RICHTER GEDEON VEGYESZET, RICHTER GEDEON VEGYESZETI GYAR RT.
Application year: 1988
Main classification: C07D279
IPC codes: A61K31, A61P1, C07D279