CS221495B1 - Dipyrldyl sulfide derivatives - Google Patents

Abstract

The invention relates to dipyridyl sulfide derivatives of the general formula in which: R represents the groups —CN, —CONHz, —CSNH2, —CONHNHz, —CONHOH, X represents an oxygen atom, n is an integer from 0 to 2, Y represents an oxygen atom, m is an integer from 0 to 1. These new compounds are effective against acid-fast microorganisms, especially against Mycobacterium tuberculosis, so they have the potential for use in the therapy of tuberculosis.

Description

The invention relates to dipyridyl sulfide derivatives of the general formula

R denotes:

R groups —CN, —CONHz, —CSNH2, —CONHNHz, —CONHOH,

X is an oxygen atom, n an integer from 0 to 2,

Y is an oxygen atom, m is an integer from 0 to 1.

These novel compounds are effective against acid-resistant microorganisms, in particular against Mycobacterium tuberculosis, and thus have potential for use in the treatment of tuberculosis.

The present invention relates to dipyridyl sulfide derivatives of the general formula

(Y) _m in which denotes:

R groups —CN, —CONH2, - CSNH2, —CONHNHz, —CONHOH,

X is an oxygen atom, n an integer from 0 to 2,

Y is an oxygen atom, m is an integer from 0 to 1.

These novel compounds are active against acid-resistant microorganisms, in particular against Mycobacterium tuberculosis, as well as against atypical mycobacterium strains.

Interest in this class of substances has been provoked by the practical use of potent antituberculotics from the group of thioamides, such as ethionamide or prothionamide (D. Liberman et al., Compt. Rend. 242, 2409, 1956; British Pat. No. 860,250) and hydrazides, mainly isoniazide (H. H. Fox, J. Org. Chem. 17, 542, 547, 555, 1952; J. Bernstein et al., Am. Rev. Tuberc. 65, 357, 1952; W. Steenken, E. Wolinsky Rev. Tuberc., 65, 365, 1952; HA Offe et al., Naturwiss. 39, 118 (1952). Significant efficacy has also been demonstrated in some functional 4-halopicolinic acid derivatives (M. Celadnik et al., Czechoslovak Pharmacy 25, 181, 1976). Also, some sulfones prepared in the sulfonamide research have been the first synthetic chemotherapeutic agents to have activity against tuberculosis (N. Rist, CR Séances Soc. Biol. Filiales 130, 972, 1939), and especially diaphenylsulfone is still used as one of the most active antileprotics (AM Walter, L. Heilmayer, Antibiotic-Fibel, 3rd ed., G. Thieme Verlag, Stuttgart 1969, p. 648).

The novel dipyridyl sulfide derivatives of the invention were tested in vitro for efficacy against Mycobacterium tuberculosis H37RV, Mycobacterium kansasii PKG 8, Mycobacterium avium d. 225 and Mycobacterium fortuitum on liquid Granite soil by the dilution method compared to practically used standards isoniazide, ethionamide and proth. The results of the evaluation showed that in particular 1,1'-dioxide 4,4'-thiodipyridyl-2,2'-dicarbothiioamide (substance T213) and 4,4'-thiodipyridyl-2,2'-dicarbothioamide (substance T21 &) characterized by high activity compared to standards (see table). The acute toxicity determined by Wagner for these substances is consistently half (DTM 250 mg / kg) than for isioniazide (DTM 125 mg / kg). These substances did not show cross-resistance with isoniazide.

Evaluation of in vivo activity was performed on experimental tuberculosis of mice as compared to isoniazide. Mice weighing up to 18 g were infected i. V. With Mycobacterium tuberculosis "M" (Pasteur Institute, Paris). In the abortive type of experiment, oral agents were administered daily by esophageal gavage in dimethylsulfoxide solution. When evaluated by Fust (B. Fust et al., Schweiz. Z. Tuberk. 12, 468, 1955). Based on histological examination of changes in the organs of infected mice, the highest therapeutic effect was found after application of T216: disappearance of specific granulomatous inflammatory lesion, absence of acid-resistant bacilli. This effect was less pronounced after administration of isoniazide and the weakest after administration of T21.3.

The dipyridyldisulphide derivatives according to the invention were prepared from substances known from the literature or by known methods.

The starting 4-chloro-2-cyanopyridine 1-oxide was obtained by reacting 4-nitro-2-methylpyridine 1-oxide with acetyl chloride (T. Kato, H. Havashi, Yakugaku Zasshi 83, 352, 1963, ref. Chem. Abstr. 59, 7473 (1963). Deoxygenation to 4-chloro-2-cyanopyridine was performed with phosphorus trichloride in anhydrous benzene. 4-Bromo-2-cyanopyridine 1-oxide was prepared from 4-nitro-2-methylpyridine 1-oxide by reaction with acetyl bromide in ethyl acetate. Deoxygenation to 4-bromo-2 cyanopyridine was again carried out with phosphorus trichloride in anhydrous benzene. 4-Bromo-2-cyanopyridine was also obtained from 4-bromopicolinic acid amide by reaction with phosphoryl bromide in anhydrous benzene (M. Celadnik et al., Czechoslovak Pharm. 25, 181, 1976).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The preparation of dipyridyl sulfide derivatives according to the invention is described in more detail in the following examples. Composition and structure of the new compounds were confirmed by elemental analysis and ^X H-NMR- and IR-spectra.

Example 1

Preparation of 4,4'-thiodipyridyl-2,2'-dicarbonitrile Ι, Γ-dioxide (T214) g (0.015 mol) of 4-bromo-2-cyanopyridine-1-oxide or 3 g (0.02 mol) of 4- chloro-2-cyanopyridine-1-oxide were dissolved in 25 ml of anhydrous ethanol while hot and 1.2 g (0.015 mol) or 1.5 g (0.02 mol) of thiourea were added to the solution. The reaction mixture was heated to boiling for 1 hour. The precipitate formed during the reaction was aspirated and dissolved in 60 ml of water. The solution was heated to boiling for 3 hours. The resulting 4,4‘-thiopyridyl-2,2‘-dicarbonitrile Ι, Γ-dioxide precipitate was filtered off with suction, washed with water and recrystallized from dimethylformamide and water with the addition of activated carbon. Mp 285-287 ° C. Yield 2 g, i.e. 98% of theory using 4-bromo derivative or 2.4 g, i.e. 92% of theory, with 4-chloro-2-cyanopyridine-1-oxide as starting material.

Example 2

Preparation Ι, Γ 4,4-dioxide ^{<-thiodipyridyl-2,2'-dikarbothioamidu} (T213 substance)

Method A g (0.065 mol) of 4-chloro-2-cyanopyridine-1-oxide was dissolved in 50 ml of anhydrous pyridine and hydrogen sulfide gas was vigorously introduced into the solution under gentle heating for 1 hour. The reaction mixture was diluted with water. aspirate and dry over phosphorus pentoxide. The 4,4‘-thiodipyridyl-2,2‘-dicarbothioamide dioxide was crystallized from dimethylsulfoxide and water with the addition of activated carbon or ethylene glycol. Mp 205.0-207.5 ° C.

Method B

2.7 g (0.01 mol) of 4,4‘-thiodipyridyl-2,2‘-dicarbonitrile Ι, Γ-dioxide were dissolved hot in a solution of 15 ml of dimethylformamide and 2 ml of pyridine and 0.5-triethylamine was added. Under gentle heating, hydrogen sulfide gas was vigorously introduced into the solution for 30 minutes. The reaction mixture was then diluted with water, the crystalline product was aspirated, dried over phosphorus pentoxide and crystallized from dimethylsulfoxide and water with the addition of activated carbon. Mp 205.0-207.5 ° C.

Example 1 a d 3

Preparation of 4,4‘-sulfinyldipyridyl-2,2‘-dicarboxamide Ι, Γ-dioxide (T211 substances)

0.45 g (0.0017 mol) of 4,4'-thiodipyridyl-2,2'-dicarbonitrile Ι, Γ-dioxide (T214) was suspended in a solution of 15 ml of water and 1.5 ml of 30% peroxide while stirring. of hydrogen, adjusted to pH 9 with sodium hydroxide solution. The reaction mixture was then heated in a water bath at 50-5 ° C for 2.5 hours while maintaining pH 9. The resulting precipitate was filtered off with suction, washed with water, dried and recrystallized from dimethylsulfoxide and water or ethylene glycol. Mp 273-276 ^° C.

Example 4

Preparation of l, l-dioxide 4,4 ^{<-sulfonyldipyridyl-2,2'-dicarboxamide} (compound T210)

0.2 g (0.0006 mol) 4,4‘-thiodipyridyl-2,2‘-dicarbothioamide Ι, Γ-dioxide (T213) was dissolved cold in a solution of 4 ml acetic acid and 8 ml 30% hydrogen peroxide. The reaction mixture was allowed to stand for 12 hours with occasional shaking. After filtering off a small amount of insoluble matter, the filtrate was neutralized with sodium carbonate solution. The resulting precipitate was filtered off with suction, washed several times with water on the filter and dried over phosphorus pentoxide. Crystallization was performed from dimethylsulfoxide and water, or from ethylene glycol. Mp 294.5-296.0 ° C. Yield 0.1 g, i.e. 50% of theory.

Example 5

Preparation of 4,4‘-thiodipyridyl-2,2‘-dicarbonitrile (T215 substances)

Method A g (0.036 mol) of 4-chloro-2-cyanopyriidine was dissolved hot in 50 ml of anhydrous ethanol. Then, 2.8 g (0.036 mol) of thiourea was added and the reaction mixture was heated at reflux for 4 hours. After completion of the reaction, the crystalline precipitate was filtered off and subjected to hydrolysis by heating for 3.5 hours in 50 ml of water. The precipitated yellow-green precipitate was aspirated, washed on the filter with water, dried and crystallized from ethanol with the addition of activated carbon. Mp 179-181 ° C.

Method B

2.8 g (0.02 mol) of 4-chloro-2-cyanopyridine was dissolved while hot in 50 ml of ethanol and a saturated aqueous solution of 36 g (0.015 mol) of sodium sulfide nonahydrate was added. The reaction mixture was heated to boiling for 3 hours. The precipitate was filtered off with suction, washed with water, dried and crystallized from ethanol. Mp 179-180 ° C. Yield 0.6 g, i.e. 25% of theory. Example 1 a d 6

Preparation of 4,4‘-thiopyridyl-2,2‘-dicarbothioamide (T216 substances)

1,2 g (0,005 mol) 4,4'-thiodipyridyl-2,2'-dicarbonitrile (T215) was dissolved hot in 40 ml of anhydrous pyridine, 10 drops of triethylamine were added and the reaction mixture was introduced vigorously into the reaction mixture with gentle heating. min. hydrogen sulfide. The reaction mixture was filtered with the addition of activated carbon, and the filtrate was gradually diluted with 100 ml of distilled water while cooling. The yellow precipitate formed was filtered off with suction and crystallized from ethanol. Mp 210-212 ° C. Yield 1.4 g, i.e. 91% of theory.

Example 7

Acidic hydrolysis of 4,4'-thiodipyridyl-2,2'-dicarbonitrile (T214) and 4,4'-thiodipyridyl-2,2'-dicarbonitrile (T21.5) resulted in Ι, Γ 4,4'-thiodipyridyl-2,2'-dicarboxylic acid dioxide, 4,4'-thiodipyridyl-2,2'-dicarboxylic acid, which were first converted to diesters by reaction with thionyl chloride and ethanol and then to the corresponding diamines (T211 and Tzzi), dihydrazides (T293 and T292) and dihydroxamic acids (T295 and T294).

Preparation of 4,4‘-thiodipyridyl-2,2 ‘-, dicarboxylic acid Ι, Γ-dioxide

7.7 g (0.028 mol) of 4,4‘-thiodipyridyl-2,2‘-dicarbonitrile Ι, Γ-dioxide (T214) were poured over 75 ml of 60% sulfuric acid and the reaction mixture was heated at reflux for 3 hours. After cooling, the reaction mixture was poured into ice-water, the precipitate was filtered off with suction, dried and recrystallized from dimethylsulfoxide and water. Mp 180.0-180.5 ° C. Yield 6.9 g, 79%.

Preparation of 4,4‘-thiodipyridyl-2,2‘-dicarboxylic acid

2.2 g (0.009 mol) of 4,4'-thiodipyridyl-2,2'-dicarbonitrile (T215) were poured into 30 ml of 60% sulfuric acid. The reaction mixture was heated to reflux for 3 h. After cooling (excess sulfuric acid was neutralized with saturated sodium carbonate solution until acidic at which avoid precipitate was filtered off with suction and recrystallized from water. Mp. 237-238 C. Yield of 2 ^e g, ie 78% of theory.

TABLE 1

Minimum inhibitory concentration of pg / ml in Sula's soil

Mycobacterium tuherculosis

H37RV

Mycobacterium kansasii PKG 8

Mycobacterium avium

Mycobacterium fortuitum

T213 3.12 6.25 25.0 200.0 T216 0.78 12.5 50.0 200.0 izoniazid 0.39 25 0 25.0 50.0 ethionamide 1.56 12.5 12.5 200.0 prothionamide 1.78 6.25 6.25 200.0

SUBJECT OF THE INVENTION

Claims (2)

SUBJECT OF THE INVENTION Dipyridyl sulfide derivatives of the general formula: R groups —CN, —CONH2, —CSNH2, —CONHNH2, - CONHOH, X is an oxygen atom, n an integer from 0 to 2, Y an oxygen atom, m an integer from 0 to 1.