KR820001993B1 - Process for preparing nitro compounds - Google Patents

Abstract

The title compds.(I; Het = atoms required to complete 5-6 membered ring; Z + CH2, O, S; m = 0-2; n = 2-3; B = lower alkylene), useful as histaminic H2 receptor antagonists, were prepd. by the reaction of II(X = QO, QS, HS(CH2)nNH-; Q = lower alkyl, aryl, aralkyl) and Het-(CH2)my (Y = -Z(CH2)nNH2). Thus, 0.51 g 2-(5-methyl-4-imidazolylmethylthio) -ethylamine and 0.49 g 2-methylthio-3-nitro-1,4,5,6-tetrahydro-pyridine were refluxed in EtOH for 6 hr to give 0.66 g 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino -3-nitro -1,4,5,6-tetrahydro pyridine(m.p. 205.5-206.5≰C).

Description

[Name of invention]

Method for preparing nitro compound with histamine H ₂ receptor antagonism

Detailed description of the invention

The present invention relates to a process for the preparation of nitro compounds having histamine H ₂ receptor antagonism. Many physiologically active substances exhibit their biological action by interaction with specific sites called receptors. Histamine is just such a substance, and it has several biological actions. This biological action, inhibited by drugs such as mepyramine, diphenhydramine and chloropheniramine, commonly referred to as "antihistamine", is transmitted by histamine H, -receptors. However, this type of action, in which histamine's other biological actions are not inhibited by antihistamine but inhibited by burimamide, is transmitted through a receptor called histamine H ₂ -receptor and H ₂ -receptor is not inhibited by mepyramine but It is defined as the histamine receptor that is inhibited by.

Referred to as receptor antagonists - Histamine H ₂ - a compound to block histamine H ₂ receptors.

Blocking of the histamine H ₂ -receptor is valuable for inhibiting the biological action of histamine that is not inhibited by antihistamines.

Histamine H ₂ receptor antagonists are therefore effective as agents acting on the cardiovascular system such as, for example, gastric acid secretion, anti-inflammatory agents, and inhibition of histamine effects on blood pressure.

The compound produced by the present invention is a compound of formula (I)

In the above formula

Het is a 5 or 6 membered fully unsaturated heterocycle containing at least one nitrogen atom and optionally substituted with lower alkyl, trifluoromethyl, hydroxymethyl, halogen, hydroxy, lower alkoxy or amino, or a hetero ring alone. Containing one oxygen or sulfur atom and R ¹ R ² NA-group, where R ¹ and R ² are the same or different and each is hydrogen, lower alkyl, C ₃ -C ₆ cycloalkyl, lower alkenyl, arylalkyl, lower Lower alkyl substituted by alkoxy, (lower alkyl) aminonadi (lower alkyl) amino, or R ¹ and R ² together with the adjacent nitrogen atom form a saturated 5- or 6-membered heterocycle and A is straight or branched A five-membered fully unsaturated heterocycle substituted with a chain (C ₁ -C ₆ alkanediyl group), z is sulfur, methylene or oxygen, m is 0, 1 or 2 and n is m + n is 3 4 is 2 or 3.

B is a 1, 2-ethanediyl- (CH ₂ -CH ₂ ), 1, 3-propanediyl (CH ₂ CH ₂ CH ₂ ) or 1, 4-butanediyl (CH ₂ CH ₂ CH ₂ CH ₂ ) group This group is optionally substituted with one or more alkyl, aryl, arylalkyl, heteroaryl alkyl or B is a 2-aza-1, 3-propanediyl group (CH ₂ NR ³ CH _2- , where R ³ is lower alkyl, aryl or Arylalkyl or hetero arylalkyl).

Lower alkyl or lower alkoxy as used herein refers to alkyl or alkoxy groups having 1 to 4 carbon atoms which are straight or branched chains and lower alkenyl means alkenyl groups having 3 to 6 carbon atoms in straight or branched chains. Examples of nitrogen-containing heterocycle Het groups include imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, 1, 2, 4-triazole, 1, 2, 5-thiadiazole and 1 , 3, 4-thiadiazole. The (CH ₂ ) m group is usually bonded to a carbon atom of a heterocycle adjacent to a nitrogen atom, and a heterocyclic phosphorus is preferably imidazole. In particular, Het may be 2- or 4-imidazole optionally substituted with lower alkyl (particularly methyl), halogen (particularly chlorine bromine), trifluoromethyl or hydroxymethyl.

Other suitable Het groups include 2-pyridyl optionally substituted with lower alkyl (particularly methyl), lower alkoxy (particularly methoxy), halogen (particularly chlorine bromide), amino or hydroxy; 2-thiazolyl; 3-isothiazolyl optionally substituted with chlorine nabrom; 3- (1, 2, 5-thiadiazolyl) optionally substituted with chlorine nabrom; And 2- (5-amino-1, 3, 4-thiadiazolyl).

Specific examples of the Het group include 5-methyl-4-imidazolyl, 5-brofhmo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl, 3-meth Oxy-2-pyridyl and 3-hydroxy-2-hydroxypyridyl.

When Het is a hetero atom and a 5-atom containing one oxygen as a single hetero atom, the (CH ₂ ) m group is preferably bound to a heterocyclic carbon atom adjacent to the oxygen atom.

The R ¹ R ² NA-group is preferably bonded to another carbon atom of a heterocycle adjacent to the hetero atom. R ¹ and R ² are preferably hydrogen, lower alkyl (especially methyl) phenyl (lower alkyl) where phenyl is optionally substituted by lower alkyl, lower alkoxy halogen, di (lower alkyl) or amino (lower alkyl).

A is preferably α, ω- straight chain alkylene having 1 to 3 carbon atoms, especially methylene. Particular examples of such Het groups are 5- (4-dimethylamino) butyl-2-furyl, 5-((dimethylamino) methyl) -2-furyl and 5- (methylaminomethyl) -2-furyl. z is good sulfur, m is good 1, n is good. It is preferable that each carbon atom of B is secondary or tertiary and that the carbon atom of B adjacent to the nitrogen atom in sulfur of the formula (I) is not substituted.

Examples of aryl groups and aryl substituents of the arylalkyl substituents of B include phenyl groups optionally substituted with one or more lower alkyl, lower alkoxy or halogen, in particular 3-methylphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl and 3-chlorophenyl Or 5- or 6- (2, 3-dihydro-1, 4-benzodioxyyl) and 4- or 5- (1, 3-benzodioxolyl). Examples of heteroaryl substituents of B include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, which groups are optionally substituted with one or more alkyl or lower alkoxy groups, especially 3- Pyridyl, 6-methyl-3-pyridyl and 6-methoxy-3-pyridyl are preferred.

Examples of specific compounds of the present invention are as follows.

2- [2- (5methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-1, 4, 5, 6-tetrahydropyridine

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-1,4, 5,6-tetrahydropyridine

2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropizol and

4- [2- (5-methyl-4-imidazolylmethylthio) ethylamino-5-nitro-1-benzyl-1, 2, 3, 6-tetrahydropyrimidine.

The compound of formula (I) is prepared according to the present invention by reacting the compound Het- (CH ₂ ) mY with the compound of formula (II).

Wherein Y is -Z (CH ₂ ) n NH ₂ or m is 1 or 2, e.g. halogen, trisubstituted phosphonium (e.g. triphenylphosphonium) or substituted sulfonyloxy (e.g. p- Free groups which may be substituted by mercaptans such as toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy). X is halogen, QO- or QS, where Y is lower alkyl, aryl or arylalkyl, or other free group which may be substituted by amine when Y is -Z (CH ₂ ) n and Y may be substituted by mercaptan X is an HS (CH ₂ ) n NH- group when the free radical is present. This reaction is preferably carried out in the presence of a solvent such as lower alkanol or pyridine. The temperature is carried out at an elevated temperature, such as the boiling point of the reaction mixture and the reaction can be carried out without solvent. X is preferably QS, in particular methylthio or benzylthio.

When R ¹ and (or) R ² is a lower alkyl group substituted with hydrogen or (lower alkyl) amino, it is necessary to protect the amino group in the R ¹ R ² NA substituent of the structural Het- (CH ₂ ) mY compound to prevent side reactions. Will understand that there is. Intermediate compounds of formula (II) wherein X is QS- and B is substituted or unsubstituted 1, 2-ethanediyl, 1, 3-propanediyl or 1, 4-butanediyl can be prepared according to the following schemes.

Compound (III) is prepared by reacting a compound of formula (III), wherein X ¹ is QS- or QSO-, with H ₂ NB-Hal, where Hal is chlorine, bromine or iodine. This reaction is preferably carried out in a solvent, for example lower alkanol. Hal is good for bromine or iodine. The compound of formula (IV) can be converted to the compound of formula (V) by reacting with a strong base such as, for example, sodium hydride or potassium t-butoxide. This reaction is preferably carried out in an inert polar solvent such as tetrahydrofran or dimethylformamide. The temperature is generally good at elevated temperatures, for example the boiling point of the reaction mixture.

Another method for preparing intermediates of formula (II), wherein X is QS- and B is 1, 2-ethanediyl or 1, 3-propanediyl, is used to prepare a compound of formula (III) with aziridine or azeridine or its-substituted derivatives. Reaction produces a compound of formula (VI) and heats the compound in the presence of a catalyst such as potassium iodide to produce a compound of formula (V).

This latter reaction is preferably carried out in anhydrous polar solvents such as acetone or 2-butane.

Intermediate compounds of formula (III) wherein X is QS and B is 2-aza-1, 3-propanediyl can be prepared by reacting a compound of formula (VII) with formaldehyde and an amine.

The formula (VII) compound can be prepared by reacting the compound of formula (IV) with ammonia.

Intermediates of X is HS (CH ₂₎ mNH- breakfast population (II) is formula (II) compound (where X is a suitable free radical that may be substituted with an amine), the structure HS (CH ₂₎ nNH ₂ is reacted with the amine prepared Can be.

Structural formula (I) compounds block histamine H ₂ -receptors. That is, they inhibit the biological action of histamine, which is not inhibited by antihistamines such as mepyramine but inhibited by burimamide.

For example, when intravenously administered at doses of 0.5 to 256 micromoles per kilogram, they also inhibit uric acid secretion due to histamine excitement from the stomach in the urinated rat luman-perfuse.

Their activity as histamine H ₂ -receptor antagonists is also demonstrated by their ability to inhibit other actions of histamine that are not delivered to the histamine H ₁ -receptor. For example, they inhibit the action of histamine on isolated guinea pig atriums and isolated mouse uterus.

They also inhibit the basic secretion of gastric acid and gastric acid promoted by pancreatine or food. Vascular relaxation of histamine was inhibited in conventional trials, such as measuring blood pressure in anesthetized cats when semen administered 0.5-256 micromoles per kg. The effect of this compound is explained by an effective dose (10 ⁻⁴ mol or less) that inhibits gastric acid secretion by 50% in anesthetized rats and inhibits 50% of tachycardia caused by histamine in isolated guinea pig atrium. As a therapeutic agent, this pharmacologically active compound is usually administered as a pharmaceutical composition comprising this compound in at least one free base or its pharmaceutically acceptable acid salts and a pharmaceutical diluent or carrier. Such addition salts include those such as hydrochloric acid, bromic acid iodide, sulfuric acid and maleic acid, which salts can be reacted with acids in lower alkanols or directly from bases or other addition salts using ion exchange resins. It can be readily formed from the corresponding base according to standard procedures for forming the desired salts. Pharmaceutical carriers used may be solid or liquid, examples of which are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, There is olive oil and water. When a solid carrier is used, the composition may be prepared in the form of tablets, capsules, troches or lozenges and the amount of solid carrier in unit dosage form is usually 25 to 300 mg.

When liquid carriers are used, the compositions may be in the form of syrups, emulsions, soft gelatin capsules, sterile injections, such as in ampoules, or aqueous or non-aqueous liquid suspensions. Pharmaceutical compositions can be prepared by conventional processes, as appropriate, by mixing, granulating, compacting or dissolving the components in the form of the desired composition.

The composition preferably contains a sufficient amount of the active ingredient in the unit dosage form to inhibit the histamine H ₂ -receptor. Each unit dosage form preferably contains about 50-250 mg of active ingredient.

Histamine receptors can be blocked by administering the active ingredient of formula (I) or a pharmaceutical composition containing the same. This active ingredient is preferably administered 1 to 6 times a day, and the daily dosage range is usually 150 to 1500 mg.

The route of administration is oral or parenteral.

The invention is explained in detail in accordance with the following examples. The temperatures used here are all Celsius.

Example 1

(a) A solution containing 0.09 g (0.004 mol) of sodium in 10 ml of methanol was added to 0.5 ml (0.003 mol) of 1-nitro-2-methylthio-2methylsulfinyl-ethylene mol and 3-bromopropylamine bromate in 30 ml of methanol. 0.9 g (2.004 mol) was added dropwise to the stirred solution, and the mixture was stirred for 5 hours, and then the solvent was removed in vacuo. The residue was dissolved in 20 ml of water, extracted with 2 x 30 ml of chloroform, the extracts were combined, dried and concentrated in vacuo. The solid residue was recrystallized with propan-2-ol to obtain 0.3 g (43%) of 1-nitro-2-methylthiob-2- (3-romopropylamino) ethylene having mp92-92.5 ° C. Found; C28.2; H4.3; N10.9; S12.5; Br31.3; Calculated value; C28.2; H4.35; N11.0 S12.5; Br31.3%.

(b) 3.2 g (0.012 mol) of 1-nitro-2-methylthio-2- (3-bromopropylamine) ethylene and sodium hydride

(50% in oil, 0.9 g, 0.019 mol) The mixture was refluxed in 50 ml of anhydrous tetrahydrofuran for 18 hours, the mixture was filtered and the filtrate was evaporated to dryness.

This residue was chromatographed on a silica gel column and the product was eluted with ethyl acetate. The product was recrystallized from methanol / propan-2-ol to give 0.6 g (29%) of 2-methylthio-3-nitro-1, 4, 5, 6-tetrahydropyridine at mp230.5-231.5 ° C.

Found; C 41.5; H 5.7; N 16.1; S 18.25; C ₆ H ₁₀ N ₂ O ₂ S

Calculated value; C41.4; H5.8; N16.1; S18.4%

(c) 0.51 g (0.003 mol) of 2- (5-methyl-4-imidazolylmethylthio) ethylamine in 50 ml of ethanol and 2-methylthio-3-nitro-1, 4, 5, 6-tetrahydropyridine A solution containing 0.49 g (0.003) of molar was refluxed for 6 hours and the mixture was cooled and the solvent was evaporated off. The residue was dissolved in hot propan-2-ol and the product was cooled to crystallize. The product was recrystallized from propan-2-ol / methanol to give 2- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -3-nitro-1, 4, having an mp205.5-206.5 °. 0.66 g (82%) of 5, 6-tetrahydropyridine was obtained.

Found; C 48.6; H 6.5; N 23.6; S 10.8; C ₁₂ H ₁₉ N ₂ O ₂ S calculated; C 48.5; H 6.4; N 23.55; S10.8%.

Example 2

(a) (i) A solution containing 2 g (0.011 mol) of 1-nitro-2-methylthio-2-methylsulfinyl ethylene and 0.5 g (0.0116 mol) of aziridine in 20 mol of methanol was stirred at room temperature for 1 hour. . The crystallized product was filtered to give 1.3 g (74%) of 1-nitro-2-methylthio-2-aziridineethylene at mp107.5-110 °. ¹ HNMR (CDCl ₃ ) δ; 2.4 (S, 4H, -CH ₂ CH _2- ) 2.56 (S, 3H, CH _3- ) 7. 5 (S, 1H, H =)

(a) (ii) Nitrogen gas was passed through a solution containing 0.5 g (0.003 mol) of 1-nitro-2-methylthio-2-aziridino ethylene in 15 ml of anhydrous acetone for about 15 minutes, and the solution was warmed to 35 °. . 2.5 g (0.015 mol) of potassium iodide is added to this solution to form a dark yellow precipitate immediately. The solid was filtered, washed with water and washed with acetone again to give 0.17 (34%) of 2-methylthio-3-nitro-4, 5-dihydropy at m × p207-209 °. Found; C 37.3; H4.9; N17.3; S19.75; C ₅ H ₈ N ₂ 0 ₂ S calculated; C37.5; H5.0; N 17.5; S20.0%.

(b) (i) A solution of sodium methoxide (0.3 g, 0.013 mol) in 10 ml of methanol was added to 2 ml (0.011 mol) of 1-nitro-2-methylthio-2-methylsulfinylethylene in 25 ml of methanol. 2.7 g (0.013 mol) of bromo ethylamine bromate was added dropwise to the stirred mixture for 10 minutes and cooled to 0 °. The solution was further stirred at 0 ° for 15 minutes and left at room temperature. After 1 hour, the solvent was removed in vacuo and the semi-solid residue was extracted with 2 × 25 ml of hot chloroform, the extracts were combined and concentrated in vacuo. This solid was recrystallized from propane-2-ol to give 1.85 g (71%) of 1-nitro-2-methylthio-2- (2-bromoethylamino) ethylene which was mp123-126 degrees.

Found; C 25.1; H 3.7; N 11.8; S 13.6; Br 33.3; C ₅ H ₉ BrN ₂ O ₂ S

Calculated value; C 24.9; H 3.8; N 11.6; S 13.3; Br 33.1%

(b) (ii) 3 g (0.012 mol) of 1-nitro-2-methylthio-2- (2-bromoethylamino) ethylene and 100 g of sodium hydride (0.62 g of 50% in oil) in 100 ml of anhydrous tetrahydrofuran. Molar) was refluxed for 7 hours, the reaction mixture was cooled and the solvent was removed in vacuo. The residue was extracted with 2 × 50 ml of boiling ethyl acetate, the extract was decolorized with charcoal, the extract was concentrated in vacuo, and cooled to give 0.5 g (26%) of 2-methylthio-3-nitro-4 and 5-dihydropyrrole. Get

(c) 1.3 (0.0076 mol) of 2- (5-methyl-4-imidazolylmethylthio) ethylamine and 1.2 (0.0075 mol) of 2-methylthio-3-nitro-4, 5-dihydropyrrole in 50 ml of ethanol. The solution was refluxed for 1 1/2 hours, the mixture was cooled and the solid was filtered and recrystallized from tetanol / water to give 2- [2- (5-methyl-4-imidazolylmethyl, mp 207.5-208 °). Thio) ethylamino] -3-nitro-4, 5-dihydropyrrole 1.4g (66%) was obtained.

Found; C 46.65; H 6.15; N 24.6; S 11.5; C ₁₁ H ₁₇ N ₅ O ₂ S

Calculated value; C 46.6; H 6.05; N 24.7; S 11.3%.

Example 3

(i) Aqueous ammonia solution (30% W / W, 9ml, 0.16mol) was added dropwise to 80ml of methahydrofuran in 20g (0.11mol) of 1-nitro-2-methylsulfinyl-2-methylthioethylene. The mixture was stirred at 50 ° for 1 hour. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column. This product was eluted with petroleum ether (b.p60-80 °) / ethyl acetate (10: 3) and recrystallized with ethyl acetate-petroleum ether to give 1-nitro-2-amino-2-methylthio, mp 109-110.5 °. Ethylene 1.5 (10%) was obtained.

Found; C 27.1; H 4.5; N 20.7; S 23.7; C ₃ H ₆ N ₂ O ₂ S

Calculated value; C 26.9; H 4.5; N 20.9; S 23.9%.

(ii) Formaldehyde (40% W / V, 2ml, 0.03mol) and benzylamine (3ml, 0.03mol) were added 1g (0.007mol) of 1-nitro-2-amino-2-methylthioethylene in 20ml of methanol. Continued addition to the stirred solution, after 5 minutes the solid was filtered and recrystallized with methanol 1.3 g of 1-benzyl-4-methylthio-5-nitro-1, 2, 3, 6-tetrahydro pyrimidine at mp 173-173.5 ° (70%) was obtained.

Found; C 54.0; H 5.6; N 15.8; S 11.8; C ₁₂ H ₁₅ N ₃ O ₂ S

Calculated value; C 54.3; H 5.7; N 15.8; S 12.1%.

(iii) 1 g (0.004 mol) of 1-benzyl-4-methylthio-5-nitro-1, 2, 3, 6-tetrahydropyrimidine and 2- (5-methyl-4-imidazolyl methyl in 40 ml of methanol A solution containing 0.7 g (0.004 mol) of thio) ethylamine was warmed for 10 hours while stirring at 60 °. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column. Elution with ethyl acetate / propan-2-ol (30%) and the product was recrystallized from methanol-propan-2-ol to give m. p. 177-180 ° 1-benzyl-4- [2- (5-methyl-4-imidazolylmethylthio) ethylamino] -5nitro-1, 2, 3, 6-tetra hydropyrimidine 0.5 g ( 32%).

Found; C 55.5; H 6.3; N 21.4; S 8.0; C ₁₈ H ₂₄ N ₆ O ₂ S

Calculated value; C 55.65; H 6.2; N 21.6: S 8.25%

Example 27

In Example 2, Example 4-27 compound was obtained using the same equivalent of the following (a)-(x) compound instead of 2- (5-methyl-4-imidazolylmethylthio) ethylamine.

(a) 2- (2-imidazolylmethylthio) ethylamine

(b) 2- (4-imidazolylmethylthio) ethylamine

(c) 2- (5-bromo-4-imidazolylmethylthio) ethylamine

(d) 2- (5-trifluoromethyl-4-imidazolylmethylthio) ethylamine

(e) 2- (5-hydroxymethyl-4-imidazolylmethylthio) ethylamine

(f) 2- (2-pyridylmethylthio) ethylamine

(g) 2- (3-methyl-2-pyridylmethylthio) ethylamine

(h) 2- (3-methoxy-2-cipyridylmethylthio) ethyl amine

(i) 2- (3-chloro-2-pyridylmethylthio) ethylamine

(j) 2- (3-amino-2-pyridylmethylthio) ethylamine

(k) 2- (3-hydroxy-2-pyridylmethylthio) ethylamine

(L) 2- (3-isothiazolemethylthio) ethylamine

(m) 2- (4-bromo-3-isothiazolylmethylthio) ethylamine

(n) 2- (3- (1, 2, 5) -thiadiazolylmethylthio) -ethylamine

(o) 2- (4-chloro-3- (1, 2, 5) -thiadiazolylmethylthio) -ethylamine

(p) 2- (4-amino-2- (1, 2, 4) -thiadiazolylmethylthio) -ethylamine

(q) 2-((5- (dimethylaminomethyl) 2-furyl) methylthio) ethylamine

(r) 2-((5- (methylaminomethyl) -2-furyl) methylthio) ethylamine

(s) -2-((5- (1-pyrrolidinomethyl) -2-furyl) methylthio) ethylamine

(t) 2-((5-methylethylaminomethyl) -2-furyl) -methylthio) ethylamine

(u) 2-((5-dimethylaminomethyl) -2-thienyl) methylthioethylamine

(v) 2-((5-methylaminomethyl) -2-thienyl (methylthio) ethylamine

(w) 2-((5- (1-phyloterdinomethyl) -2-thienyl) ethylthio) ethylamine

(x) 2-((5-methylethylaminomethyl) 2-thienyl) methylthio) ethylamine

Example Number

4. 2- [2- (imidazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

5. 2- [2- (4-imidazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

6. 2- [2- (5-bromo-4-imidazolylmethylthio) methylamino] -3-nitro-4, 5-dihydropyrrole

7. 2- [2- (5-trifluoromethyl-4-imidazolylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

8. 2- [2- (5-hydroxymethyl-4-imidazolylmethylthio (-ethylamino] -3-nitro-4, 5-dihydropyrrole

9. 2- [2- (2-pyridylmethylthio) ethylamino] -3-nitro-4, 5-hydropyrrole

10. 2- [2- (3-methyl-2-pyridylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

11. 2- [2- (3-methoxy-2-pyridylmethylthio) ethylamino-3-nitro-4, 5-dihydropyrrole

12. 2- [2- (3-chloro-2-pyridylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

13. 2- [2- (3-amino-2-pyridylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

14. 2- [2- (3-hydroxy-2-pyridylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

15. 2- [2- (3-isothiazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydrodropyrrole

16. 2- [2- (4-bromo-3-isothiazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

17. 2- [2- (3- (1, 2, 5) -thiadiazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

18. 2- [2- (chloro-3- (1, 2, 5) -thiadiazolylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

19. 2- [2- (5-amino-2- (1, 3, 4) -thiadiazolylmethylthio) ethylamino] -3-nitro-4, 5-dihydropyrrole

20. 2- [2- (5- (dimethylaminomethyl) -2-furylmethylthio) ethylamino] -3-nitro-4, 5-dihydro and rolls

21. 2- [2- (5- (methylaminomethyl) -2-furylmethylthio) -ethylamino-3-nitro-4, 5-dihydropyrrole

22. 2- [2- (5- (1-phyllolidinomethyl) -2-furylmethylthio-ethylamino] -3-nitro-4, 5-dihydropyrrole

23. 2- [2- (5-methylethylaminomethyl) -2-furylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

24. 2- [2- (5- (dimethylaminomethyl) -2-dienylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

25. 2- [2- (5- (1-methylaminomethyl) -2-thienylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

26. 2- [2- (5- (1-phyllolidinomethyl) -2-thienylmethylthio) -ethylamino] -3-nitro-4, 5-dihydropyrrole

27. 2- [2- (5- (methylethylaminoethyl) -2-dienylmethylthio} -ethylamino] -3-nitro-4, 5-dihydropyrrole

Using the equivalents of the above-described amines in place of 2- (5-methyl-4-imidazolylmethylthio) ethylamine in Examples 1 and 3, respectively, the corresponding 2- [2-heterocyclylmethylthio) ethylamino ] -3-nitro-1, 4, 5, 6-tetrahydropyridines and 1-benzyl-4- [2- (heterocyclylmethylthio) ethylamino] -5-nitro-1, 2, 3, 6-tetrahydropyridines are obtained.

Claims (1)

A process for preparing the following compound of formula (I) or a pharmaceutically acceptable acid titerate thereof by reacting the structure Het- (CH ₂ ) mY compound with the following compound of formula (II).

In the above formula Het is a 5- or 6-membered fully unsaturated heterocycle containing at least one nitrogen atom and optionally substituted with lower alkyl, trifluoromethyl, hydroxy methyl, halogen, hydroxy, lower alkoxynaamino, or a single A hetero atom containing one oxygen or sulfur atom group, wherein R ¹ R ² NA groups (where R ¹ and R ² are the same or different and each is hydrogen, lower alkyl, cycloalkyl of C ₃ -C ₆ , lower alkenyl, arylalkyl, Or lower alkyl substituted by lower alkoxy, (lower alkyl) -aminonadi (lower alkyl) amino, or R ¹ and R ² together with the adjacent nitrogen atom form a saturated 5- or 6-membered heterocycle, and A Is a 5-membered fully unsaturated heterocycle substituted by a straight or branched C ₁ -C ₆ alkanediyl group, Z is sulfur, methylene or oxygen, m is 0.1 or 2 and m + n is If 3 or 4, n is 2 or 3, and B is 1, 2-ethanediyl (-CH ₂ -CH _2- ), 1, 3-propanediyl (-(CH ₂ CH ₂ CH _2- ) or 1, 4-butanediyl (-CH ₂ CH ₂ CH ₂ CH ₂ ) group, which is optionally one or more alkyl, aryl Is substituted with an arylalkyl or hetero arylalkyl group or B is a 2-aza-1, 3-propanediyl group (-CH ₂ NR ₃ CH _2- , where R ³ is lower alkyl, aryl, arylalkyl or heteroaryl arylalkyl Y is -Z (CH ₂ ) n NH ₂ or optionally m is 1 or 2, e.g. halogen, trisubstituted phosphonium (e.g. tridenylphosphonium) or substituted sulfonyloxy ( For example, P-toluenesulfonyloxy, methanesulfonyloxynatrifluoro methanesulfonyloxy) is a free group which can be substituted by betcaptan, and X is when Y is -Z (CH ₂ ) n CH ₂ X is H when QO or QS (where Q is lower alkyl, aryl or arylalkyl or another free group which may be substituted by an amine) and Y is a free group which may be substituted by mercaptan S (CH ₂ ) n NH—.