Title of Invention

DITHIOCARBAMATE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS .

Abstract

The invention relates to the use of dithiocarbamate derivatives for the therapeutic or prophylactic treatment of infectious diseases in mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and lepra caused by mycobacteria and infectious diseases caused by staphylococci. The invention further relates to novel dithiocarbamate derivatives of the formula (I), wherein X is a bivalent residue selected from the group consisting of formulae (1, 2, 3, 4) having excellent antibacterial activities, and to pharmaceutical preparations containing the same.

Full Text

Dithiocarbamate derivatives and their use as antibacterial agents The invention relates to the use of dithiocarbamate derivatives, including novel dithiocarbamate derivatives, as antibacterial agents in infectious diseases of mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and lepra caused by mycobacteria and infectious diseases caused by staphylococci. The invention further relates to novel dithiocarbamate derivatives as such and pharmaceutical preparations containing the same. As known, there is a threadful worldwide increase in tuberculosis infections with mycobacteria which developed resistance against the available therapeutics (B.R.Bloom, J.L.Murray, tuberculosis: commentary on a reemergent killer. Science 257, 1992, 1055- 1064). Extremely dangerous is the development of multidrug resistant (MDR) mycobacteria. These are mycobacteria, resistant at least against two of the most active tuberculosis drugs, isoniazid and rifampicin, but also against streptomycin, pyranzinamid and ethambutol. The proportion of MDR-TB in some countries is already more than 20%. In Germany resistance against a single tuberculosis drug raised since 1996 for 50%. Together with the increased number of diseases generally, worldwide tuberculosis causes a number of 3.000.000 deaths annually. Another growing problem is the therapy of infections with multiresistant staphylococci (M. Kresken, Bundesgesundheitsblatt 38, 1996, 170-178). For the treatment of such diseases there is an urgent need for new drugs with new mechanisms of actions, especially to overcome drug resistance and to overcome the known dramatic side effects of the available drugs. The present invention aims at the generation of new compounds with activity against mycobacteria as potential new tuberculosis drugs and with activity against other Gram-positive pathogens like staphylococci to overcome problems concerning resistance and drug intolerance. According to the present invention, it was surprisingly discovered that dithiocarbamate derivatives exhibit strong antibacterial activity, especially, against mycobacteria The aim is thus solved by the use of compounds of the general formula I wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4 CONHNR3R4; R2 is H, NO2, CN, CONR3R4, CONHNR3R4,COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, linear or branched alkanol radical having 1-8 chain member, OR5, SR5, NR3R4, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 are, independently from each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, cycloalkyl having 3-7 carbon atoms; a saturated or unsaturated, linear or branched alkanol radical having 1-8 chain member; benzyl, phenyl or naphthyl substituted by (R5)m wherein m is 0-7; OR5; or NR3R4 is morpholino, a saturated or unsaturated, mono or polyheterocyclic residue with heteroatoms N, S, O and substituted by (R5)m; or R3 and R4 together represent a bivalent radical -(CH2)m- wherein m is 2-7, or a bivalent radical -(CH2CH2)NR6(CH2CH2)-; or R3 and R4 together represent a bivalent radical R5 is H, or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, trifluoromethyl, benzyl or phenyl; or halogen, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, linear or branched alkanol radical having 1-8 chain members, benzyl, phenyl, stiryl or naphtyl, each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; R6 is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, halogetated or unhalogenated linear or branched alkanol radical having 1-8 chain member, trifluoromethyl, benzyl, phenyl, stiryl or naphtyl, each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; R7 is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, OR5, SR5, NR3R4, trifluoromethyl, phenyl, stiryl, each unsubstituted or substituted by (R6)m; for the manufacture of pharmaceutical preparations for the therapeutic or prophylactic treatment of bacterial infections, and pharmaceutical compositions containing the afore-mentioned compounds. According to a particular embodiment, the above-mentioned compounds according to formula I are selected from the group consisting of 1,5-dinitro-3-cyano-6-dimethyldithiocarbamoyl-benzene, 3,5-dinitro-2- dimethyldithio-carbamoyl-pyridine, 3,5-dinitro-6-dimethyl-amino-2-dimethyl- dithiocarbaitnoyl-pyridine, 4-methoxy-6-diemyldimiocarbamoyl-5-nitro-pyrimidine, 4- methoxy-6-dipropyldithiocar-bamoyl-5-nitro-pyrimidine, 4-dimethyl-amino-6- diethyldithiocarbamoyl-5-nitropyrimidine, 4-dimethylamino-6-dipropyldithio-carbamoyl- 5-nitro-pyrimidine, and 4-methyl-amino-6-diethyldithiocarbamoyl-5-nitro-pyrimidine. Specifically, the invention relates to new compounds of the formula I wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4, CONHNR3R4; R2 is H, NO2, CN, CONR3R4, CONHNR3R4, COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by hydroxy; OR5, SR5, NR3R4, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 for X= 1 are, independently from each other, H, an unsaturated, linear or branched aliphatic radical having 1-7 chain members, cycloalkyl having 3-7 carbon atoms; a saturated or unsaturated, linear or branched alkyl radical having 1-8 chain member substituted by hydroxy; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O which is unsubstituted or substituted by (R5)m; R3 and R4 for X= 2-4 are, independently from each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by hydroxy; cycloalkyl having 3-7 carbon atoms; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocycles with heteroatoms N, S, O and substituted by (R5)m; or R and R for X= 1-4 together represent the bivalent radical R5 is H, or halogen, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m wherein m is 1-5; COOH, COOR5, CONR3R4; R is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4: with the exclusion of 3,5-dinitro-2-dimethyldithio-carbamoyl-pyridinc, 3,5-dinitro-6-dimethyl-amino-2- dimethyl-dithiocarbamoyl-pyridine, 4-methoxy-6-diethyldithiocarbamoyl-5-nitro- pyrimidine, 4-methoxy-6-dipropyldithiocar-bamoyl-5-nitro-pyrimidine, 4-dimethyl- amino-6-diethyldithiocarbamoyl-5-nitropyrimi-dine, 4-dimethylamino-6-dipropyldithio- carbamoyl-5-nitro-pyrimidine, and 4-methyl-amino-6-diethyldithiocarbamoyl-5-nitro- pyrimidine (Khim, Getcrotsikl, Soedin., (Rus.) 1994, 10, p. 1420-1423, CA 122:314512), and 4-methylamino-6-diethyldithiocarbamoyl-5-nitro-pyrimidine (Acta Cryst. Section C, 2001, C57, p.72-75), and their use for the manufacture of pharmaceutical preparations for the therapeutic or prophylactic treatment of bacterial infections. In a preferred embodiment, the invention concerns compounds of the formula (I) selected from the group consisting of 3,5-dinitro-2-R3R4-dithiocarbamoyl-benzonitrilesl 3,5-dinitro-2-R3R4-dithiocarbamoyl-benzamides, 3,5-dinitro-2-R3R4-dithiocarbamoyl-pyridines, and 4-R7-2-R5-6-R3R4-dithiocarbamoyl-5-nitro-pyrimidines, wherein R3, R4, R5 and R7 have the above meanings, except 3,5-dinitro-2-dimethyl-dithiocarbamoyl-pyridine, 4-methoxy-6-diethyldithio- carbamoyl-5-nitro-pyrimidine, 4-methoxy-6-dipropyldithiocarbamoyl-5-nitro-pyrimidine, 4-dimethylamino-6-diethyldithiocarbamoyl-5-nitro-pyrimidine, 4-dimethylamino-6- dipropyl-dithiocarbamoyl-5-nitro-pyrimidine and 4-methylamino-6-diethyldithiocarba- moyl-5-nitro-pyrimidine. The present invention is even more particularly concerned with at least one compound selected from the group consisting of 4-cyclopropylarmno-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-methylhydroxyamino-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-ethoxy-2-methyl-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-methylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-dimethylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-ethoxy-2-methyl-6-tetramethylenedithiocarbamoyl-5-mtropyrimidine, 4-propoxy-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-methylamino-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 4-dimemylamino-6-teframethylenedithiocarbamoyl-5-nitropyrirnidine, 4-methoxy-6-dimemyldimiocaAamoyl-5-nitropyrimidine, 4-memoxy-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 3,5-dinitro-2-hexamethylenedithiocarbamoylbenzamide, 3,5-dinitro-2-tetramemylenedithiocarbamoylben2amide, 3,5-dinitro-2-tetramethylenedithiocarbamoylpyridine, 3,5-dinitro-2-hexamethylenedithiocarbamoylbenzonitril,and 4-methylamino-6-heptamethylenedithiocarbamoyl-5-nitropyrimidine, furthermore 3,5-dinitro-2-dimethyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-diethyldithiocarbamoylben2onitril, 3,5-dinitro-2-methylethyldithiocarbamoylbenzonitril, 3,5-dinitro-2-methylpropyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-methylisopropyldithiocarbamoylbenzonitril, 3,5-dinitro-2-methylisobutyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-ethylpropyldithiocarbamoylbenzonitril, 3,5-dinitro-2-ethylisopropyldithiocarbamoylbenzonitrile 3,5-dinitro-2-dimethyldithiocarbamoylbenzoamide, 3,5-dinitro-2-diethyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylethyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylpropyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylisopropyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylisobutyldithiocarbamoylbenzoamide, 3,5-dinitro-2-ethylpropyldithiocarbamoylbenzoamide, 3,5-dinitro-2-ethylisopropyldithiocarbamoylbenzoamide The substituents mentioned hereinbefore or hereinafter have the following meanings: A saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members is, for example, a corresponding alkyl, alkenyl or alkinyl radical having 1- 6 carbon atoms optionally interrupted by one oxygen or sulphur atom or by NR6. A saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O is, for example, a five or six membered ring such as morpholino, thiomorpholino, piperazinyl, pyrrolidinyl or piperinyl. Compounds of the formula I wherein R3 and R4 together represent a bivalent radical are preferably symmetrical with respect to the symmetric axis dividing the central piperazine ring into two equal halves. Surprisingly the compounds of the invention exhibit strong antibacterial activities, especially against mycobacteria with minimal inhibitory concentrations (MIC) in the range of 0,1-50 µg/ml for fast growing mycobacteria and of 3,12-12,5 µg/ml for M. tuberculosis, and against multiresistant staphylococci (MRSA) in a MIC range of. 0,4-50 µg/ml. Thus, the compounds of the invention are useful for the treatment of bacterial infections, especially tuberculosis and other mycobacterial infections, in humans and in animals. Accordingly, the invention concerns pharmaceutical compositions comprising one or more (ie. at least one) of the compounds of the formula I referred to above. The invention relates furthermore to a compound of the formula I wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4, CONHNR3R4; R2 is H, NO2, CN, CONR3R4, CONHNR3R4, COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by hydroxy; OR5, SR5, NR3R4, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 are, independently from each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by hydroxy; cycloalkyl having 3-7 carbon atoms; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O which is unsubstituted or substituted by (R5)m; or R3 and R4 together represent a bivalent radical R5 is H, or halogen, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m wherein m is 1-5; COOH, COOR5, CONR3R4; R6 is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members optionally substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; for use in a method for the therapeutic or prophylactic treatment of bacterial infections in mammals, or for the preparation of a pharmaceutical composition for the therapeutic or prophylactic treatment of bacterial infections in mammals, respectively. Preferred compounds of the formula I for use in such method are those specifically listed above. The above-referenced compounds are formulated for use by preparing a dilute solution or suspension in pharmacautically acceptable aqueous, organic or aqueous- organic medium for topical or parenteral administration by intravenous, subcutaneous or intramuscular injection, or for intranasal application; or are prepared in tablet, capsule or aqueous suspension form with conventional excipients for oral administration or as suppositorium. The compounds can be used in dosages from 0,1 - 1000 mg/kg body weight. The examples which follow in the subsequent experimental part serve to illustrate the invention but should not be construed as a limitation thereof. The structures of the compounds of the invention were established by modes of synthesis and elementary analysis, and by nuclear magnetic resonance and/or mass spectra, X-ray analysis. Experimental Part Starting materials Starting chloroaryles are commercial available or were synthesized: 4-chloro-6-R-5- nitropyrimidines were synthesized according to Chesney J.D., Gonzales-Sierra M., Pharm. Res., 1985, p.145-147 and Clark J., Parvizi B., Colmam R., J.Chem.Soc, Perkin Trans 1,1976, p. 1004-1007; 3,5-dinitro-2-chlorobenzonitrile and 3,5-dinitro-2- chlorobenzamide were synthesized according to Thiel W., Mayer R., J.Prakt. Chemie, B328,1986, p.497-514. Sodim dithiocarbamates were synthesized by classic reaction between carbone disulfide, sodium hydroxide and different amines, and purified by crystallization from ethanol or acetone. Some sodim dithiocarbamates are commercial available. Example 1 4-isopropylamino-6-diethyldithiocarbamoyl-5-nitropyrimidine (1) A mixture of 4-isopropylamino-6-chloro-5-nitropyrimidine (0.94 g, 4.3 mmol), sodium diethyldithiocarbamate trihydrate (1.05 g, 4.6 mmol) and ethanol (25 mL) was mixed for 24 hours at room temperature. Reaction mixture was diluted by water (50 mL), yellow solid was filtered and purified by crystallization from ethanol to give 0.8 g of pure title compound as an yellow crystalline solid, m.p. 165-167°C Example 2 4-cyclopropylamino-6-diethyldithiocarbamoyl-5-nitropyrimidine(2) Following the procedure of Example 1. Yellow crystalline solid, m.p. 143-145°C. Example 3 3,5-dinitro-2-diethyldithiocarbamoylbenzonitril (3) A mixture of 3,5-dinitro-2-chlorobenzonitrile (1.5 g, 6.6 mmol), sodium diethyldithiocarbamate trihydrate (1.6 g, 7.1 mmol) and ethanol (40 mL) was mixed for 2 hours at room temperature. Reaction mixture was treated by active charcoal, filtered off. Mother liquid was diluted by water (80 mL), yellow solid was filtered and purified by consecutive crystallization from i-propanol and acetone/water to give 1.2 g of pure title compound as an light yellow crystalline solid, m.p. 151-153°C. Example 4 4-methylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine(7) A mixture of 4-methylamino-6-chloro-5-nitropyrimidine (0.7 g, 3.7 mmol), sodium dimethyldithiocarbamate dihydrate (0.7 g, 3.9 mmol), ethanol (15 mL) and acetone (15 mL) was mixed for 4 hours at room temperature. Reaction mixture was diluted by water (60 mL), yellow solid was filtered and purified by crystallization from ethanol to give 0.5 g of pure title compound as an yellow crystalline solid, m.p. 136-137°C. Example 5 4-methylamino-6-heptamethylenedithiocarbamoyl-5-nitropyrimidine(20) Following the procedure of Example 4. Yellow crystalline solid, m.p. 180-182°C. Example 6 4-methylamino-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine (12) Following the procedure of Example 4. Yellow crystalline solid, m.p. 213-215°C. Example 7 4-methylhydroxyamino-6-diethyldithiocarbamoyl-5-nitropyrimidine(5) Following the procedure of Example 4. Yellow crystalline solid, m.p.92-94°C. Example 8 4-dimemylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine(8) Following the procedure of Example 4. Yellow crystalline solid, m.p. 135-137°C. Example 9 4-dimethylamino-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine (13) Following the procedure of Example 4. Yellow crystalline solid, m.p. 130-132°C. Example 10 3,5-dinitro-2-tetramethylendithiocarbamoylthiophene, (28) A mixture of 3,5-dinitro-2-chlorothiophene (0.5 g, 2.4 mmol), sodium tetramethylendithiocarbamate dihydrate (0.6 g, 2.9 mmol) and ethanol (40 mL) was mixed for 5 hours at room temperature. Reaction mixture was diluted by water (100 mL), light tan yellow solid was filtered and purified by crystallization from mixture EtOH/H2O to give 0.4 g of pure title compound as an yellow crystalline solid, m.p. 178-180°C. Example 11 3,5-dinitro-2-dimethyldithiocarbamoylbenzonitrile(9) A mixture of 3,5-dinitro-2-chlorobenzonitrile (2.0 g, 8.8 mmol), sodium dimethyldithiocarbamate dihydrate (1.7 g, 9.5 mmol) and ethanol (50 mL) was mixed for 0,5 hour at room temperature. Reaction mixture was diluted by water (100 mL), yellow solid was filtered and purified by consecutive crystallization from ethanol with addition of active charcoal to give 1.4 g of pure title compound as an orange solid, m.p. 147- 149°C. Example 12 3,5-dinitro-2-hexamethylenedithiocarbamoylbenzomtrile(19) Following the procedure of Example 11. Yellow crystalline solid, m.p. 148-150°C. Example 13 3,5-dinitro-2 -tetramethylenedithiocarbamoylbenzonitrile, (22) Following the procedure of Example 11. Yellow crystalline solid, m.p. 131 -134°C. Example 14 3,5-dinitro-2-methylethyldithiocarbamoylbenzonitrile, (23) Following the procedure of Example 11. Oranje crystalline solid, m.p. 112-114°C. Anal. Calcd. for C11H10N4O4S2: C, 42.34; H, 3.55; N, 16.46; S, 18.84 Found: C, 42.49; H, 3.62; N, 16.34; S, 18.73 Example 15 3,5-dinitro-2-methylethyldithiocarbamoylbenzonitrile, (24) Following the procedure of Example 11. Yellow crystalline solid, m.p. 167-169°C. Example 16 4-methoxy-6-dimethyldithiocarbamoyl-5-nitropyrimidine(14) A solution of 4-methoxy-6-chloro-5-nitropyrimidine (0.5 g, 2.6 mmol), sodium dimethyldithiocarbamate dihydrate (0.6 g, 3.3 mmol) and ethanol (40 mL) was mixed for 1 hour at room temperature. Reaction mixture was diluted by water (80 mL), light yellow solid was filtered and purified by crystallization from methanol to give 0.4 g of pure title compound as an bright yellow crystalline solid, m.p. 122-125°C. Example 17 4-methoxy-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine (15) Following the procedure of Example 16. Yellow crystalline solid, m.p. 147-149°C. Example 18 4-methylamino-6-diethyldithiocarbamoyl-5-nitropyrimidine(4) Following the procedure of Example 12. Yellow crystalline solid, m.p. 147-150°C. Example 19 4-memoxy-6-methylethyldithiocarbamoyl-5-mtropyrimidine,(25) Following the procedure of Example 16. Yellow crystalline solid, m.p. 154-156°C. Example 20 4-ethoxy-2-methyl-6-diethyldithiocarbamoyl-5 -nitropyrimidine (6) Following the procedure of Example 16. Yellow crystalline solid, m.p. 108-110°C. Example 21 4-ethoxy-2-methyl-6-tetramethylenedithiocarbarnoyl-5-nitropyrimidine (10) Following the procedure of Example 16. Yellow crystalline solid, m.p. 100-102°C. Example 22 4-propoxy-6-dimethyldithiocarbamoyl-5-nitropyrimidine (11) Following the procedure of Example 16. Yellow crystalline solid, m.p. 107-109°C. Example 23 3,5-dinitro-2-hexamethylenedithiocarbamoylbenzamide (16) A solution of 3,5-dinitro-2-chlorobenzamide (0.7 g, 2.9 mmol), sodium hexamethylenedithiocarbamate dihydrate (0.7 g, 3.0 mmol) and ethanol (50 mL) was mixed for 0,5 hour at room temperature. Reaction mixture was partitioned between water (100 mL) and ethyl acetate (50 mL). The aqueous layer was extracted twice with 30 mL portions of ethyl acetate. The combined organic extracts were washed with water, brine, dried (Na2SO4), and concentrated in vacuo to provide brown oil. Its treatment by water provide yellow solid was filtered and purified by consecutive crystallization from ethanol to give 0.6 g of pure title compound as an yellow solid, m.p. 187-189°C. Example 24 3,5-dinitro-2-tetramethylcnedithiocarbamoylbenzamide (17) A solution of 3,5-dinitro-2-chlorobenzamide (1.0 g, 4.0 mmol), sodium tetramethylenedithiocarbamate dihydrate (0.9 g, 4.4 mmol) and acetone (40 mL) was mixed for 0.5 hour at room temperature. Reaction mixture was diluted by water (80 mL), yellow solid was filtered and purified by crystallization from i-propanol to give 0.9 g of pure title compound as an light yellow crystalline solid, m.p. 116-118°C. Example 25 3,5-dinitro-2-(1 ,4-dioxa-8-azaspiro[4,5]decane)dithiocarbamoylbenzamide, (26) Following the procedure of Example 23. Yellow crystalline solid, m.p. 144-146°C. Example 26 3,5-dinitro-2(1 ,4-thiazolan)dithiocarbamoylbenzamide, (27) Following the procedure of Example 23. Yellow crystalline solid, m.p. 123-126°C. Example 27 3,5-dinitro-2-tetramethylenedithiocarbamoylpyridine (18) A mixture of 3,5-dinitro-2-chloropyridine (0.5 g, 2.4 mmol), sodium tetramethylenedithiocarbamate dihydrate (0.6 g, 2.9 mmol) and ethanol (40 mL) was mixed for 3 hours at room temperature. Reaction mixture was diluted by water (80 mL), light tan yellow solid was filtered and purified by crystallization from mixture EtOH/DMF to give 0.5 g of pure title compound as an yellow crystalline solid, m.p. 157- 159°C. Example 28 3,5-dinitro-2-dimethyldithiocarbamatethiophene, (29) Following the procedure of Example 27. Light yellow crystalline solid, m.p. 169-171°C. Anal. Calcd. for C7H7N3O4S3: C, 28.66; H, 2.41; N, 14.32; S, 32.79 Found: C, 28.54; H, 2.33; N, 14.29; S, 32.90 Example 29 3-nitro-5-methylaminosulfonyl-2-tetramethylendithiocarbamoylbenzamide, (30) Following the procedure of Example 27. Yellow crystalline solid, m.p. 136-138°C. Example 30 2-methyl-4-methylamino-5-nitro-6-methylethyldithiocarbamoylpyrimidine, (21) Following the procedure of Example 27. Yellow crystalline solid, m.p. 172-174°C. Example 31 Determination of the inhibitory activity of the compounds of the invention against staphylococci and mycobacteria. The antibacterial activities of the compounds against multiresistent staphylococci (MRSA) strains 134/93 and 994/93 as well as against Mycobacterium smegmatls SG 987, M. aureum SB66, M. vaccae MET 1010670 and M. fortuitum B were tested by determination of minimal inhibitory concentrations (MIC) by the micro broth dilution method in Mueller-Hinton broth (Difco) according to the NCCLS guidelines [National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; 4th Ed.; Villanova, Ed.; Approved standard Document M7-A4. NCCLS, (1997)]. The results are presented in Table 1. Activity against M. tuberculosis H37Rv and two drug-resistant clinical isolates was tested by the following method for determination of minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC): Strains were inoculated onto solid Lowenstein-Jensen medium. After 21 days, the cultures grown were used to prepare an inoculum suspension corresponding to 5 x 108 microbial cells/ml). With 0,2 ml of that suspension tubes with 2 ml liquid Shkolnikova medium containing corresponding concentrations of compounds under study- from 100,0 to 0,195 µg/ml. were inoculated. After 14 days of incubation at 37 °C the tubes with liquid medium were centrifuged for 15min. at 3000 RPM. After discarding the supernatant, the sediment was resuspended in 0,8 ml of sterile 0,9% NaCl. 0,1 ml of the suspension was used to prepare smears subsequently stained by the Ziehl-Neelsen method. The remaining sediment was inoculated in 0,2 ml volumes into three tubes with solid drug free Lowenstein-Jensen medium to determine minimal bactericidal concentrations (MBC). The results were read after 21-28 days of cultivation at 37 °C. Controls were tubes cultured with test-strains not treated with the studied agents. Minimal bactericidal concentration of drugs (MBC) was considered as the drug concentration completely inhibiting the growth of mycobacteria on the solid medium. The bacteriostatic effect (MIC) was characterized by the presence of only individual mycobacteria in the smear and a strong decrease in the number of colonies grown on solid media compared to the controls. The results are presented in Table 2 as mean values of the three strains. Table 2: Antimicrobial activity of compounds of the formula I against Mycobacterium tuberculosis as determined by minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) Subst.Nr. MIC (µg/ml) MBC (µg/ml) 1 31,3 100,0 2 20,8 29,1 3 5,37 7,29 4 6,25 12,5 5 9,38 12,5 6 20,8 41,7 7 7,78 10,42 8 7,81 12,5 9 4,78 6,25 10 5,21 8,33 11 9,37 12,5 12 3,64 8,33 13 3,12 6,25 WE CLAIM: 1 A compound of the formula I wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4, CONHNR3R4; R2 is H, NO;, CN, CONR3R4, CONHNR3R4, COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by hydroxy; OR5, SR5, NRV, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 mentioned in formula (I), when X is a bivalent residue, represented by group (1), as aforesaid, are, independently from each other, H, an unsaturated, linear or branched aliphatic radical having 1-7 chain members; cycloalkyl having 3-7 carbon atoms; a saturated or unsaturated, linear or branched alkyl radical having 1-8 chain member substituted by hydroxy; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O which is unsubstituted or substituted by (R5)m; R3 and R4 mentioned in formula (I), when X is a bivalent residue, selected from the group consisting of (2), (3) and (4), as aforesaid, are, independently from each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by hydroxy; cycloalkyl having 3-7 carbon atoms; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1 -5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocycles with heteroatoms N, S, O and substituted by (R5)m: or R and R for X= 1-4 together represent a bivalent radical; R" is H, or halogen, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m wherein m is 1-5; COOH, COOR5, CONR3R4; R is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; with the exclusion of 3,5-dinitro-2-dimethyldithio-carbamoyl-pyridine, 3,5-dinitro-6-dimethyl-amino-2- dimethyl-dithiocarbamoyl-pyridine, 4-methoxy-6-diethyldithiocarbamoyl-5-nitxo- pyrimidine, 4-methoxy-6Hlipropyldithiocar-bamoyl-5-nitro-pyrimidine, 4-dimethyl- amino-6-diethyldithiocarbamoyl-5-nitropyrimi-dine, 4-dimethylamino-6-dipropyldithio- carbamoyl-5-nitro-pyrimidine, and 4-mediyl-axnino-6-diethy]dithiocarbamoyl-5-nitro- pyrimidine. 2. A 3,5-dinitro-2-R3R4-dithiocarbamoyl-benzonitrile of the formula (I) as claimed in claim 1, wherein X is the residue represented by the group (1), as aforesaid, R' represents CN, R2 is NO2, n is 1, and R3 and R4 as defined in claim 1. 3. A 3,5-dinitro-2-R3R4-dithiocarbamoyl-benzamide of the formula (I) as claimed in claim 1, wherein X is the residue represented by the group (1), as aforesaid. R1 represents CONR3R4, R2 is NO2, n is 1, and R3 and R4 as defined in claim I. 4. A 3,5-dinitro-2-R3R4-dithiocarbamoyl-pyridine of the formula (I) as claimed in claim 1, wherein X is the residue represented by the group (2), as aforesaid, R2 is NO2, n is 1,and R3 and R4 as defined in claim 1, except 3,5-dinitro-2-dithiocarbamoyl-pyridine 5 A 4-R7-2-R5-6-R3R4-dithiocarbamoyl-5-nitro-pyrimidine of the formula (I) as claimed in claim 2, wherein X is the residue represented by group (3), as aforesaid, R3, R4, R5 and R7 as defined in claim 1 except 4-methoxy-6-diethyldithio-carbamoyl-5-nitro- pyrimidine, 4-methoxy-6-dipropyldithiocarbamoyl-5-nitro-pyrimidine, 4-dimethylamino- 6-diethyldithiocarbamoyl-5-nitro-pyrimidine, 4-dimethylamino-6-dipropyl-dithio-carba- moyl-5-nitro-pyrimidine and 4-methylamino-6-diethyldithiocarbamoyl-5-nitro-pyrimi- dine 6. A compound of formula I as claimed in claim 1, selected from the group consisting of 3,5-dinitro-2-dimethyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-diethyldithiocarbamoylbenzonitril, 3,5-dinitro-2-methylethyldithiocarbamoylbenzonitril, 3,5-dinitro-2-methylpropyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-methylisopropyldithiocarbamoylbenzonitril, 3,5-dinitro-2-methylisobutyldithiocarbamoylbenzonitrile, 3,5-dinitro-2-ethylpropyldithiocarbamoylbenzonitril, 3,5-dinitro-2-ethylisopropyldithiocarbamoylbenzonitrile 7. A compound of formula I as claimed in claim 1 selected from the group consisting of 3,5-dinitro-2-dimethyldithiocarbamoylbenzoarnide, 3,5-dinitro-2-diethyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylethyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylpropyldithiocarbamoylbenzoamide, 3,5-dinitro-2-methylisopropyldithiocarbamoylbenzoamide, 3,5-dintro-2-methylisobutyldithiocarbamoylbenzoamide, 3,5-dinitro-2-ethylpropyldithiocarbamoylbenzoamide, 3,5-dinitro-2-ethylisopropyldithiocarbamoylbenzoamide 8. A compound of the formula I as claimed in claim 1, in which R3 and R4 together represent a bivalent radical of 2,5-dihydropyrrole, 1,2,3,6-tetrahydropyridine, 1,3- thiazolane, 1,4-dioxa-8-azaspiro[4.5]decane 9. A compound of formula I as claimed in claim 1, selected from the group consisting of 4-cyclopropylamino-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-methylhydroxyamino-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-ethoxy-2-methyl-6-diethyldithiocarbamoyl-5-nitropyrimidine, 4-methylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-dimethylamino-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-ethoxy-2-methyl-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 4-propoxy-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-methylamine)-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 4-dimethylamino-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 4-methoxy-6-dimethyldithiocarbamoyl-5-nitropyrimidine, 4-methoxy-6-tetramethylenedithiocarbamoyl-5-nitropyrimidine, 3,5-dinitro-2-hexamethylenedithiocarbamoylbenzamide, 3,5-dinitro-2-tetramethylenedithiocarbamoylbenzamide, 3,5-dinitro-2-tetramethylenecdithiocarbamcylpyridine, 3,5-dirurro-2-hexamethylenedithiocarbamoylbenzonitril, and 4-methylamino-6-heptamethylenedithiocarbamoyl-5-nitropyrimidine. 10. A pharmaceutical composition comprising a compound of the formula I as claimed in claim 1, and pharmaceutically acceptable excepients, such as herein described. 11. A compound of the formula I as claimed in claim 1. wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4, CONHNR3R4; ' R2 is H, NO2, CN, CONR3R4, CONHNR3R4, COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1 -7 chain members unsubstituted or substituted by hydroxy; OR5, SR5, NR3R4, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 mentioned in formula (I), when X is a bivalent residue, represented by group (1), as aforesaid, are, independently from each other, H, an unsaturated, linear or branched aliphatic radical having 1-7 chain members; cycloalkyl having 3-7 carbon atoms; a saturated or unsaturated, linear or branched alkyl radical having 1-8 chain member substituted by hydroxy; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O which is unsubstituted or substituted by (R5)m; R3 and R4 mentioned in formula (I), when X is a bivalent residue, selected from the group consisting of (2), (3) and (4), as aforesaid, are, independently from each other, H, a saturated' or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by hydroxy; cycloalkyl having 3-7 carbon atoms; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR3; or NR3R4 is a saturated or unsaturated, mono or polyheterocycles with heteroatoms N, S, O and substituted by (R5)m; or R3 and R4 together represent a bivalent radical. R5 is H, or halogen, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by halogen or hydroxy; benzyl, phenyl, styryl or naphthyl each unsubstituted or substituted by (R )m wherein m is 1-5; COOH, COOR5, CONR3R4; R is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by halogen or hydroxy; benzyl, phenyl, styiyl or naphthy] each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; for use in a method for the therapeutic or prophylactic treatment of bacterial infections in mammals. 12. A pharmaceutical composition comprising a compound of the formula I wherein X is a bivalent residue selected from the group consisting of wherein R1 is CN, CONR3R4, CONHNR3R4; R2 is H, NO2, CN, CONR3R4, CONHNR3R4,COOR5, CHO, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, linear or branched alkanol radical having 1-8 chain member, OR5, SR5, NR3R4, SO2NR3R4, trifluoromethyl, phenyl; n is 0-3; R3 and R4 mentioned in formula (1), when X is a bivalent residue, represented by group (1), as aforesaid, are, independently from each other, H, an unsaturated, linear or branched aliphatic radical having 1-7 chain members; cycloalkyl having 3-7 carbon atoms; a saturated or unsaturated, linear or branched alky! radical having 1-8 chain member substituted by hydroxy; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR3; or NR3R4 is a saturated or unsaturated, mono or polyheterocyclic ring with heteroatoms N, S, O which is unsubstituted or substituted by (R5)m; R3 and R4 mentioned in formula (I), when X is a bivalent residue, selected from the group consisting of (2), (3) and (4), as aforesaid, are, independently from each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members unsubstituted or substituted by hydroxy; cycloalkyl having 3-7 carbon atoms; benzyl, phenyl or naphthyl each unsubstituted or substituted by (R5)m wherein m is 1-5; OR5; or NR3R4 is a saturated or unsaturated, mono or polyheterocycles with heteroatoms N, S, O and substituted by (R5)m: or R3 and R4 together represent a bivalent radical R is H, or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, trifluoromethyl, benzyl or phenyl; or halogen, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, linear or branched alkanol radical having 1-8 chain members, benzyl, phenyl, stiryl or naphtyl, each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; R6 is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, a saturated or unsaturated, halogetated or unhalogenated linear or branched alkanol radical having 1-8 chain member, trifluoromethyl, benzyl, phenyl, stiryl or naphtyl, each unsubstituted or substituted by (R6)m; COOH, COOR5, CONR3R4; R7 is H, halogen or a saturated or unsaturated, linear or branched aliphatic radical having 1-7 chain members, OR5, SR5, NR3R4, trifluoromethyl, phenyl, stiryl, each unsubstituted or substituted by (R6)m, and pharmaceutically acceptable excepients, such as herein described. 13. A pharmaceutical composition as claimed in claim 12, wherein the compound according to formula I is l,5-dinitro-3-cyano-6- dimethyldithiocarbamoyl-benzene, 3,5-dinitro-2-dimethyldithio-carbamoyl-pyridine, 3,5-dinirro-6-dimethyl-amino-2-dimemyl-dithiocarbamoyl-pyridine, 4-methoxy-6- diethyldithiocarbamoyl-5-nitro-pyrimidine, 4-methoxy-6-dipropyldithiocarbamoyl-5- nitro-pyrimidine, 4-dimemyl-amino-6-diethyldithiocarbamoyl-5-nitropyrimi-dine, 4- dimethylamino-6-dipropyldithio-carbamoyl-5-nitro-pyrimidine, and/or 4-methyl- arnino-6-diethyldithiocarbamoyl-5-nitro-pyrimidine. The invention relates to the use of dithiocarbamate derivatives for the therapeutic or prophylactic treatment of infectious diseases in mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and lepra caused by mycobacteria and infectious diseases caused by staphylococci. The invention further relates to novel dithiocarbamate derivatives of the formula (I), wherein X is a bivalent residue selected from the group consisting of formulae (1, 2, 3, 4) having excellent antibacterial activities, and to pharmaceutical preparations containing the same.

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