KR840001931B1 - Process for preparing substituted 3-amino-sydnone-imines - Google Patents

Abstract

A method for the preparation of substituted 3-amino- sydnone imines of formula I≮R1 = H, halogen; R2=H, -NO, -COR3, or -SO2R4;A=:S(O) n(n=0,1,2) or :NSO2R5; R3 = H, C1-6 aliphatic residue, C5-8 aliphatic residue, C6-12 aryl, C1-4 alkyl or alkoxy, C1-6 alkoxy, C6-12 aryloxy; R4=R5=C1-6 aliphatic residue, C6-12 aryl! and their pharamcologically acceptable acid-addition salts was developed. The title compds. are used as cardiovascular agents.

Description

Method for preparing substituted 3-amino-sidone-imines

The present invention relates to a method for preparing substituted 3-amino-sidone-imines and their pharmaceutically acceptable acid addition salts of general formula (I), which have a useful pharmacological action on the cardiovascular system.

Wherein R ¹ is hydrogen, or halogen, R ² is hydrogen, —NO, —COR ³ or —SO ₂ R ⁴ group, A is group> S (O) _m , where m is 0,1 or 2 Or group> N-SO ₂ R ⁵ , R ³ is hydrogen, an aliphatic radical having 1 to 6 carbon atoms (which may be substituted by alkoxy having 1 to 6 carbon atoms or aryloxy having 6 to 12 carbon atoms), Alicyclic radicals of 5 to 8 carbon atoms, aryl radicals of 6 to 12 carbon atoms (which may be mono-, di- or tri-substituted by halogen and / or alkyl of 1 to 4 carbon atoms and / or alkoxy of 1 to 4 carbon atoms). ), Araliphatic radicals of 7 to 13 carbon atoms, alkoxy radicals of 1 to 6 carbon atoms, aryloxy radicals of 6 to 12 carbon atoms, 5- or 6-membered hetero-aromatic radicals, or alkoxycarbonyls of 2 to 7 carbon atoms in total R ⁴ and R ⁵ are each independently an aliphatic radical having 1 to 6 carbon atoms or 6 to 6 carbon atoms. Aryl radicals of 12 (which may be substituted with methyl or chlorine) or alkylalkyl radicals having 1 to 4 carbon atoms.

It is preferred that R ¹ is hydrogen, and when R ¹ is halogen, chlorine or bromine is preferred. Preferred aliphatic radicals representing R ³ are alkyl radicals, in particular alkyl radicals of 1 to 4 carbon atoms, and when the aliphatic radicals representing R ³ , in particular alkyl radicals, are substituted by alkoxy radicals, these alkoxy radicals have 1 to 1 carbon atoms. It is preferable to contain about four. The cycloaliphatic radical representing R ³ is preferably cyclohexyl or cyclopentyl, and the aryl radicals representing R ³ are especially mono-, di- or tri-substituted by chlorine, methyl and / or methoxy or ethoxy. Phenyl radical which may be sufficient is preferable. As the araliphatic radical representing R ³ , benzyl, phenethyl or styryl are preferable, especially when R ¹ is hydrogen and / or A is> SO ₂ , R ² is hydrogen, and R ³ has 1 carbon atom. Preference is given to alkoxy having 2 to 2 or alkoxycarbonyl having 2 to 3 carbon atoms in total. The aliphatic radicals representing R ⁴ and / or R ⁵ are in particular alkyl radicals, preferably methyl radicals, and the aryl radicals representing R ⁴ and / or R ⁵ may be substituted with methyl or chlorine at the 4 position. Dialkylaminoradicals, in which there are phenyl radicals and also represent R ⁴ and / or R ⁵ , are in particular radicals having 1 or 2 carbon atoms in each alkyl group.

Examples of suitable hetero-aromatic radicals representing R ³ include pyrrole, imidazole, pyrazole, pyrazine, pyrimidine and pyridazine radicals and the like, but pyridine radicals are particularly preferred.

Compounds of the general formula (I) and acid addition salts thereof, by ring-closing the compounds of the general formula (II) to obtain a compound of the general formula (Ia) (which may be in the form of an acid addition salt) or acyl compound Acylating with the agent to introduce the radical-COR ³ or SO ₂ R ⁴ , nitrating with nitrous acid, and / or reacting with the halogen or halogenating agent to introduce halogen, and then the resulting compound is optionally It can be prepared by conversion to acid addition salt.

In the above general formula, A is as defined above.

The ring-closure reaction in which the compound of formula (II) is closed to prepare the compound of formula (Ia) is water, alkanols having 1 to 4 carbon atoms, carboxylic acid alkyl esters or mixtures of these solvents (e.g., water / ethanol, or Preferably in a suitable inorganic or organic solvent, such as a mixture of ethyl acetate / methanol), by addition of a ring closure agent at a temperature of from 0 to 40 ° C., preferably from 0 to 20 ° C. in general. As the pH in the inside is 3 or less, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, and strong organic acids such as trifluoroacetic acid. During ring closure, the corresponding acid addition salts of compounds of formula (Ia) are prepared.

The compound of general formula (Ia) is a compound according to the present invention wherein R ¹ and R ² in hydrogen in formula (I). In order to introduce a -NO group representing R ² , the compound of general formula (Ia) is nitrated, and to introduce a -COR ³ or -SO ₂ R ⁴ group representing R ² , the following general formula (III) or the following general Acylating with an appropriate acylating agent of formula (IV).

X-COR ³ (III) X-SO ₂ R ₄

Wherein X is halogen, in particular chlorine, -OCOR ³ , or -O-aryl in particular tolyloxy, nitrophenyl oxy or dinitro phenyloxy, and R ³ and R ⁴ are as defined above.

The nitrification reaction is carried out in a suitable solvent, preferably in water, at a temperature of from 0 to 10 ° C. Since nitrous acid is usually prepared from alkali metal nitrite and hydrochloric acid, the pH of the compound is adjusted to pH 1 to 3 by adding hydrochloric acid to an aqueous solution of the compound of general formula (Ia), and then the alkali metal nitrite is dissolved in an aqueous solution form. It is appropriate to drop it. Acylation using the compound of the general formula (III) or the compound of the general formula (IV), which is an acylating agent, may be carried out in a suitable solvent such as water; Polar organic solvents such as dimethylformamide, dimethyl sulfoxide or pyridine; Or in an excess of acylating agent, optionally in the presence of an acid binder such as pyridine or sodium bicarbonate, by stirring at a temperature between the boiling point of the solvent or acylating agent, preferably at a temperature of 0 to 20 ° C. The halogen atom representing R ¹ is introduced by reacting a compound of formula (Ia) or preferably a compound of formula (Ib) with an appropriate halogenating agent.

In the general formula, R ⁶ is -NO, -COR ³ or -SO ₂ R ⁴ , A is as defined above.

This reaction is carried out in a conventional manner in a suitable solvent such as chlorinated hydrocarbon or glacial acetic acid at a temperature of 0 to 20 ° C. Examples of halogenating agents used are halogeno succinimides or halogen atoms. If necessary, the -COR ³ or -SO ₂ R ⁴ radical representing R ⁶ can be hydrolyzed from the compound obtained by halogenation of the compound of formula (lb) in acidic medium according to known methods. Compounds of the general formula (I) according to the invention wherein R ¹ is halogen and R ² is hydrogen are prepared in this manner.

The compound of formula (Ib) is a compound according to the invention in which R ¹ is hydrogen and R ² is R ⁶ in formula (I).

Substituted 3-amino-sidone-imines of formula (I) form acid addition salts with inorganic or organic acids. Examples of these acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, lactic acid, tartaric acid, acetic acid, salicylic acid, benzoic acid, citric acid, ascorbic acid, adipic acid or naphthalene-disulfonic acid. Often acid addition salts of compounds of formula (I), in particular hydrochloride, are prepared directly from the synthesis of compounds of formula (I). If necessary, the free compound of general formula (I) is dissolved in a conventional manner, i.e., by dissolving or suspending the acid addition salt of the compound in water, and then alkalizing the solution or suspension with, for example, sodium hydroxide solution, By the method of separating free acid, it can be prepared from acid addition salts. Preference is given to pharmaceutically acceptable salts.

Compounds of the general formula (II), which is a necessary starting material, can be prepared by the method of streptor aminonitrile synthesis in which the compound of the general formula (V) is reacted with formaldehyde and hydrocyanic acid in a suitable solvent such as water. .

In the above general formula, A is as defined above.

In this reaction, the compound of the following general formula (VI) is first produced, and then converted into the compound of the general formula (II) by nitrosation reaction.

In the general formula, A is as defined above.

The nitrification reaction is carried out in a conventional manner at a temperature of 0 to 10 ° C. in a suitable solvent, preferably water, and nitrous acid is generally produced from alkali metal nitrite and hydrochloric acid. The pH of the aqueous solution of the compound of formula (VI) is preferably adjusted to 1 to 3 using hydrochloric acid, and an alkali metal nitrite is added dropwise to the stirring and cooling solution of the compound in the form of an aqueous solution.

The resulting solution of the general formula (II) compound can be directly ring-closed. Generally, however, it is appropriate to first dissolve the nitroso compound of the general formula (II) in a suitable organic solvent, and then optionally further add a solvent, and then ring-close the compound of the general formula (I) in this solvent.

Compounds of formula (V) are known compounds or may be prepared by the following methods, for example 1-amino-4-methanesulfonyl-piperazine wherein A is group > N-SO ₂ R ⁵ , wherein R ⁵ Is methyl radical) is prepared by first reacting piperazine of the following general formula (IV) with potassium cyanate to produce urea of the following general formula (IV), and then reacting this compound by Hoffmann's decomposition reaction. (This method is described in the examples).

The compound of the following general formula (Ic) according to the present invention can also be produced by oxidizing the compound of the following general formula (Id) and acid addition salt thereof.

In the general formula, R ¹ and R ² are as defined above.

내지 60℃)에서 빙아세트산과 같은 적절한 용매내에서, 과산화수소를 사용하여 수행된다.This oxidation reaction can be performed at room temperature or slightly elevated temperature (about 50

To 60 ° C.), in a suitable solvent such as glacial acetic acid, using hydrogen peroxide.

Formula (I) compounds and their pharmaceutically acceptable acid addition salts have useful pharmacological properties.

The compounds according to the invention show a particularly good effect on the cardiovascular system. Compared to the commercially available compound molsidominin having a similar structure to the present compound or isosorbide dinitrate which is a commercially available compound exhibiting a similar action to the present compound, the compound of the present invention is potent in several properties. Exhibits and / or lasts a long time. For example, the compound lowers blood pressure, pulmonary artery pressure, and left ventricular terminal diastolic pressure, thus reducing cardiac action without causing reflex pulsation in terms of anti-anginal action.

The anti-eye group and the action of the compound according to the present invention can be measured using the following method.

Pentobarbital anesthesia (intravenously in an amount of 30 to 40 mg / kg) or urethane-chloral anesthesia (injection of a urethane / chloralose in an amount of 3 ml / kg) or 20 mg / kg Is administered intravenously with chloralose and 250 mg / kg urethane). Animals are ventilated using a Bird Mark 7 respirator. The amount of exhaled carbon dioxide (measured using urea) is 4.5 to 5% by volume. To ensure a certain depth of anesthesia, animals that had pentobarbital anesthesia continued to be injected intravenously with pentobarbital at an amount of 4 mg / kg / 6ml / hour during the entire experiment, and none to animals that had urethane / chloral anesthesia. Do not inject. After the test animals are made, settle for about 1 hour until all variables related to blood dynamics become constant, and then start the appropriate experiment.

Blood pressure in systolic and diastolic cells is periodically measured in the femoral artery using a statam pressure recorder. Signals for LVEDP (left ventricular diastolic pressure) and heart rate were measured by a Millar tip catheter inserted through the carotid artery into the left ventricle and averaged in the pulmonary artery by a second tip catheter inserted through the jugular vein. Measure your blood pressure.

By this methodology, the following compounds according to the invention exhibit significant activity at the indicated dosages:

A = 3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine hydrochloride

B = N ⁶ -cyclohexylcarbonyl-3- (tetrahydro-1,4-thiazin-4-yl1,1-dioxide) -sidone-imine

C = 3 (4-Methanesulfonyl-piperazin-1-yl) -sidone-iminehydrochloride

D = N ⁶ -ethoxycarbonylcarbonyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone imine

E = N ⁶ -benzoyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine

F = 3- (4-Dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine hydrochloride

G = N ^6- (4-chlorobenzoyl) -3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine

H = 3- (thiomorpholino) -sidone-imine hydrochloride and

I = N ⁶ -propionyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine hydrochloride.

PAP = mean pulmonary artery pressure

LVEDP = terminal dilatation pressure of the left ventricle

BPm = mean peripheral blood pressure

HR = heart rate

t / min = duration of activity (average)

ISDN = isosorbide dinitrate (control)

Mol = Molcidomin (Control)

For use in therapy, pharmaceutically acceptable acid addition salts or free compounds of the novel compounds may be prepared by conventional pharmaceutical fillers or excipients, tableting agents, disintegrants, binders, suspending agents, extenders or diluents, solvents or solubilizers, Or an agent used to obtain an accumulation effect, an additive suitably used for rectal administration or parenteral administration, and the like. Examples of suitable pharmaceutical formulations include tablets, dragees, pills, capsules, solutions, suspensions or emulsions, and include, in addition to novel active compounds, preservatives, stabilizers, emulsifiers, buffers and one or more therapeutically effective substances. It can also be added. Examples of therapeutically effective substances of this type include (β) -receptor blockers such as propranolol, pindorol and metoprolol; Vasodilators such as carbochromen; Mental stabilizers such as barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; Diuretics such as chlorothiazide; Drugs which induce cardiac muscle stiffness such as digitalis preparations; Hypotensive agents such as hydralazine, dihydralazine, prazosin, clonidine and laupulpia alkyloids; Agents that reduce the concentration of fatty acids in the blood, such as bezafibrate and fenofibrate; Thrombosis prevention agents such as phenprocomon.

Pharmaceutical formulations generally contain from 0.1 to 50 mg, preferably from 0.5 to 10 mg in a single dose.

In further detail the invention in the following examples, the percentages in these examples are percentages by weight unless otherwise indicated.

Example 1

17.7 g of aminothiomorpholine is dissolved in 100 g of water. The pH value of this solution was adjusted to 4 by dropwise addition of concentrated hydrochloric acid, the solution was cooled to 0 to 5 ° C, and then a solution of 7.4 g of sodium cyanide dissolved in 15 g of water was added dropwise. After 12.4 g of 40% strength formalin was added and left overnight (pH = 7 to 7.5), pH was adjusted to 2 by adding concentrated hydrochloric acid, the solution was cooled to 0 ° C, and 10.4 g of sodium nitrite was added to 30 g of water. The dissolved solution is slowly added dropwise. The resulting mixture was stirred for 1 hour at 0-5 ° C., then extracted twice with 50 ml of ethyl acetate and the organic phase was dehydrated over sodium sulfate. The solution is diluted with 150 ml of methanol and then passed through 15 g of hydrogen chloride while cooling in a water bath and then stirred for 1 hour. The solid product thus produced is filtered off, the mother liquor is concentrated and the product is recrystallized from ethanol. Melting point: 181 to 183 ° C. (decomposition). Yield: 18.5 g (83% of theory)

Similar to this example, 4-amino-tetrahydro-1,4-thiazine dioxide, 4-amino-tetrahydro-1,4-thiazine oxide, 1-amino-methanesulfonyl-pipepe, respectively, as starting materials The following compounds according to the invention are prepared, respectively, using lazine, 1-amino-1-dimethylamino-sulfonyl-piperazine and 1-amino-4-p-toluenesulfonyl-piperazine.

3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine hydrochloride, melting point 206 to 208 ° C. (decomposition); 3- (tetrahydro-1,4-thiazin-4-yl 1-oxide) -sidone-imine hydrochloride, Melting point: 200 to 201 ° C. (decomposition); 3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine hydrochloride, melting point: 226 ° C. (decomposition); 3- [4- (p-Toluenesulfonyl) -piperazin-1-yl] -sidone-imine hydrochloride, melting point 193-194 ° C. (decomposition)

The 1-anino-4-methanesulfonyl-piperazine used as starting material can be prepared as follows.

After dissolving 10 g of methanesulfonyl-piperazine in 50 ml of water, 6.2 ml of concentrated hydrochloric acid was added, followed by dropwise addition of a solution of 5.4 g of potassium cyanate dissolved in 20 ml of water, and the mixture was stirred at room temperature. Stir for time. The separated precipitate is filtered off and dried. 11 g of yield, 10 g of the dried precipitate having a melting point of 254 ° C. and 4 g of sodium hydroxide were added to 80 ml of water and cooled to 0 ° C., followed by addition of 0.052 mol of sodium hypochlorite precooled to 0 ° C. The mixture is stirred at room temperature until no hypochlorite salts are detected anymore. The aqueous 1-amino-methanesulfonyl-piperazine solution thus obtained can be used directly for the next reaction.

Piperazine, another starting material, can be similarly prepared.

Example 2

After dissolving 17.5 g of 3-thiomorpholino-sidone-imine hydrochloride in 100 ml of glacial acetic acid, a mixture of 9.0 g of 30% strength aqueous hydrogen peroxide solution was added dropwise to the solution and stirred for 1 hour at room temperature. . After it is concentrated in vacuo, the product is recrystallized from ethanol.

Melting Point: 200 ~ 201 ℃ (Decomposition)

Yield: 15.3% (86% of theory)

3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine hydrochloride also uses a very high concentration of 30% hydrogen peroxide and uses much more stringent reaction conditions than above. It can be prepared by a method similar to the above.

Example 3

6.0 g of 3-thiomorpholino-sidone-imine-hydrochloride is suspended in 50 ml of acetic anhydride, then 10 ml of anhydrous pyridine is added and stirred overnight. The colorless crystals thus formed are filtered and recrystallized from methanol.

Melting point: 197 ° C (decomposition), yield: 6.3% (89% of theory)

The following compounds according to the present invention can also be prepared by a method similar to the above examples.

N ⁶ -acetyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, melting point; 212 to 214 ° C (decomposition);

N ⁶ -methoxyacetyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, Melting point: 188 to 192 ° C. (decomposition);

N ⁶ -acetyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine hydrochloride, Melting point: 185 ° C. (decomposition);

N ⁶ -Atyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine, melting point; 176 ~ 177 ℃ (decomposition)

N ⁶ -acetyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine hydrochloride, Melting point: 204 ° C. (decomposition);

N ⁶ -acetyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 236 ° C. (decomposition);

N ⁶ -propionyl-3- (4-dimethylamino sulfonyl-piperazin-1-yl) -sidone-imine hydrochloride, Melting point: 179 ° C. (decomposition); And N ⁶ -formyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, melting point: 213 ° C. (decomposition)

Example 4

28.3 g of 3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine hydrochloride is dissolved in 200 ml of water, cooled to 0 ° C., and 28 g of sodium bicarbonate is added with stirring. To this was added dropwise 24 g of pivaloyl chloride, the solution was stirred overnight at room temperature, and then the resulting solid compound was filtered and recrystallized from ethanol.

Melting point: 94-95 ° C, yield 25.8g (78% of theory)

After dissolving this compound in methanol, methanolic hydrochloric acid may be added to convert it into hydrochloride having a melting point of 178 ° C (decomposition).

Example 5

5.6 g of 3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine hydrochloride and 2.8 g of benzoyl chloride were added to 50 ml of anhydrous pyridine and stirred at room temperature for 1 day, followed by fine crystals The adult precipitate is filtered off and recrystallized from ethanol.

Melting Point: 225 ° C (Decomposition) Yield: 6.0 g (85% of theory)

The following compounds according to the invention can also be prepared in a similar manner to Examples 4 and 5:

N ⁶ -ethoxycarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, melting point: 208 to 210 ° C. (decomposition);

N ⁶ -cyclohexylcarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, Melting point: 160-163 degreeC;

N ⁶ -ethoxycarbonyl-3-thiomorpholino-sidone-imine, Melting point: 166 to 168 ° C;

N ⁶ -ethoxycarbonyl-3- (tetrahydro-1,4-thiazin-4yl 1-oxide) -sidone-imine, melting point 135 ° C;

N ^6- (p-chlorobenzoyl) -3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, Melting point: 248-249 ° C. (decomposition);

N ⁶ -phenoxycarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) sidone-imine, Melting point: 213 to 215 ° C. (decomposition);

N ⁶ -cinnamoyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 190 to 192 ° C;

N ⁶ -benzoyl-3- (tetrahydro-1,4-thiazin-4-yl1,1-dioxide) -sidone-imine, melting point: 245 to 247 ° C. (decomposition);

N ⁶ -ethoxycarbonyl-3- [4- (p-toluenesulfonyl) -piperazin-1-yl] sidone-imine, Melting point: 190 to 192 ° C;

N ⁶ -cyclohexylcarbonyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine, Melting Point: 171 to 172 ° C. (decomposition);

N ⁶ -phenoxyacetyl-3- [4- (p-toluenesulfonyl) -piperazin-1-yl] -sidone-imine, Melting point: 150 ° C. (decomposition)

N ⁶ -pivaloyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, Melting point: 183 ° C. (decomposition);

N ^6- (3,4,5-trimethoxy-benzoyl) -3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, Melting point: 180 ° C .;

N ⁶ -ethoxycarbonyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 194 ° C (decomposition);

N ⁶ -ethoxycarbonylcarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,2-dioxide) -sidone-imine, Melting point: 179 to 181 ° C;

N ⁶ -neopentylcarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) sidone-imine, Melting point: 168 to 171 ° C;

N ⁶ -ethoxycarbonyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 167 to 168 ° C;

N ⁶ -nicotinoyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine Melting Point: 206 to 207 ° C;

N ⁶ -nicotinoyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, melting point: 235 ° C. (decomposition);

N ^6- (2,4-dichlorobenzoyl) -3- (4-dimethylamino-sulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 194-196 ° C .;

N ⁶ -ethoxycarbonylmethanesulfonyl-3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine, melting point: 182 ° C (decomposition)

N ⁶ -benzoyl-3- (4-dimethylaminosulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 205 to 207 ° C;

N ⁶ -phenylacetyl-3- [4- (p-toluenesulfonyl) -piperazin-1-yl] -sidone-imine, Melting point: 160 ° C .;

N ⁶ -butoxyacetyl-3- [4- (p-toluene-sulfonyl) -piperazin-1-yl] -sidone-imine, Melting point: 119 to 121 ° C;

N ^6- (p-toluenesulfonyl) -3- (4-methanesulfonyl-piperazin-1-yl) -sidone-imine, Melting point: 250 ° C. (decomposition); And N ^6- (p-toluenesulfonyl) -3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine, mp: 167-169 ° C.

Example 6

5.1 g of 3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -sidone-imine hydrochloride are dissolved in 30 ml of water and cooled to 0-5 ° C., followed by 1.4 g of A solution of sodium nitrite dissolved in 15 ml of water is added dropwise, and then the mixture is stirred at 5 ° C. for 1 hour, and then the product is filtered off.

Melting point: 128 to 130 ° C. (decomposition), yield: 3.9 g (78% of theory)

Example 7

3.2 g of N ⁶ -ethoxycarbonyl-3- (4-methanesulfonylpiperazin-1-yl) -sidone-imine is suspended in 40 ml of carbon tetrachloride, followed by 3.2 g of N-bromosuccinimide Is added in small portions, and the mixture is heated at 50 to 60 ° C. and vigorously stirred for 30 minutes. After cooling with ice water, the colorless crystals are filtered and recrystallized from methanol.

Melting Point: 120 ~ 122 ℃ (Decomposition)

Yield: 3.0 g (63% of theory)

N ⁶ -ethoxycarbonyl-3- (tetrahydro-1,4-thiazin-4-yl 1,1-dioxide) -4-bromo-sidone-imine having a melting point of 160 to 164 ° C (decomposition) Is prepared in a similar manner to this embodiment.

Claims (1)

The compound of formula (II) is closed to obtain a compound of formula (Ia) (which may be present in the form of an acid addition salt), or the compound of formula (Ia) or an acid addition salt thereof is acylated, nitro A process for preparing substituted 3-amino-sidone-imines and their pharmaceutically acceptable acid addition salts of the general formula (I), characterized by digestion or halogenation.

Wherein R ¹ is hydrogen or halogen, R ² is hydrogen, —NO, —COR ³ or —SO ₂ R ⁴ group, A is group> S (O) m where m is 0, 1 or 2 Or group> N-SO ₂ R ⁵ , R ³ is hydrogen, an aliphatic radical having 1 to 6 carbon atoms (which may be substituted by alkoxy having 1 to 6 carbon atoms or aryloxy having 6 to 12 carbon atoms), 5 carbon atoms Alicyclic radicals of 8 to 8, aryl radicals of 6 to 12 carbon atoms (which may be mono-, di- or tri-substituted by halogen and / or alkyl of 1 to 4 carbon atoms and / or alkoxy of 1 to 4 carbon atoms) , Araliphatic radicals of 7 to 13 carbon atoms, alkoxy radicals of 1 to 6 carbon atoms, aryloxy radicals of 6 to 12 carbon atoms, 5- or 6-membered hetero-aromatic radicals, or alkoxycarbonyl radicals of 2 to 7 carbon atoms in total , R ⁴ and R ⁵ are each independently an aliphatic radical of 1 to 6 carbon atoms, 6 to 6 carbon atoms An aryl radical of 12 (which may be substituted with methyl or chlorine), or a dialkylamino group having 1 to 4 carbon atoms of an alkyl radical.