Novel antibiotic compounds

Abstract

A compound having the following formula I: wherein-R1 represents O or NH; -R2 represents a linear, branched or cyclic alkyl group comprising from 1 to 8 carbon atoms, which may be intermixed with a group selected from-O-,-S-,-(C = O)-, NH and may be substituted by one or more halogens, an alkylene group comprising from 1 to 8 carbon atoms and may be substituted by one or more halogens, a phenyl group or an arylene group; -R3, R4 and R5 independently represent-H, halogen, a linear or branched alkyl group comprising 1 to 8 carbon atoms, which may be substituted by one or more halogens, CN,-NO2, OX1 (X1 is selected from-H, a linear or branched alkyl group comprising 1 to 8 carbon atoms, which may be substituted by one or more halogens), C00R6, 0C0R6, SO2NR6R7, NR6R7, NR6COR7 or OR6, where R6 and R7 are the same or different, and R6 and R7 represent H or an alkyl group comprising 1 to 8 carbon atoms, CN,-NO2, OX1 (X1 is selected from-H, a linear or branched alkyl group comprising 1 to 8 carbon atoms, which may be substituted by one or more halogens), and its use as a medicament. # imgabs0 #

Description

[0001] The present invention relates to novel compounds and their use as drugs, in particular as antibiotics. The present invention also relates to compounds for treating infectious diseases associated with bacteria, such as acetamide and acetimidamide derivatives, and pharmaceutical compositions containing the compounds, which can be used for the treatment and application of the compounds.

[0002] Antibiotics are one of the most important discoveries in medicine for combating infectious diseases. However, the emergence of multidrug-resistant pathogens to conventional antibiotics has prompted the need for new antimicrobial agents. This is one of the biggest threats to healthcare systems worldwide and could lead to 10 million deaths by 2050 if not addressed. In fact, all of these drugs are currently facing resistance issues due to high selection pressure and misuse / overuse of antibiotics.

[0003] Antibiotic resistance in bacteria can arise from mutations or from the acquisition of resistance genes that confer resistance to one or more antibiotics. According to the World Health Organization (WHO), some pathogens are particularly resistant: strains of Staphylococcus aureus are resistant to a wide range of antibiotics, including methicillin (MRSA), which is derived from the penicillin β-lactam antibiotic, and thus cause serious infections.

[0004] Currently, three main mechanisms of resistance are known: (i) bacterial enzyme inhibition of antibiotics; (ii) a reduction in the amount of antibiotics reaching the target, resulting in reduced membrane permeability, or causing the antibiotic to be expelled from the bacteria, or denaturation; (iii) modification of the antibiotic target

[0005] Therefore, there is a need for new compounds with antibiotic activity that can overcome the problem of bacterial resistance to existing molecules.

[0006] There is also a need for new antimicrobial compounds that are well tolerated and have low cytotoxicity when administered to individuals, particularly mammals. There is also a need for antimicrobial compounds that are active against a wide variety of microorganisms and that may be less susceptible to developing resistance.

[0007] US 3991210 discloses acetamidine derivatives useful as preservatives and their use in a method for combating microorganisms associated with urinary tract infections in mammals.

[0008] GB 1482397 discloses a pharmaceutical composition containing trichloroacetamidine derivatives having a cardiac stimulating effect.

[0009] Kalinin et al. (Heterocycles, 2012, 85, 2515-2522) disclosed the synthesis of heteroaryl-trichloroacetamidines, but did not investigate their activity.

[0010] Grivas et al. (Can. J. Chem. 1961, 39, 761-764) were studying the reaction between halogen-substituted nitriles and amines.

[0011] Hough et al. (J. Heterocyclic Chem., 1984, 21(5), 1377-1380) described the reaction of alkali metal derivatives of heterocyclic amines and proposed 3-heteroaryl-trichloroacetamidine.

[0012] The present inventors have now demonstrated that a new class of acetamidine derivatives exhibits significant antimicrobial activity.

[0013] Therefore, the present invention relates to compounds of formula (I)

[0014]

[0015] in

[0016] -R1 represents O or NH,

[0017] -R2 represents a linear, branched or cyclic alkyl group containing 1 to 8 carbon atoms, which may be interrupted by a group selected from -O-, -S-, -(C=O)-, NH and may be substituted by one or more halogens;

[0018] an alkylene group containing 1 to 8 carbon atoms and which may be substituted by one or more halogens,

[0019] Phenyl or arylene,

[0020] -R3, R4 and R5 independently represent -H, halogen, a straight or branched alkyl group containing 1 to 8 carbon atoms which may be substituted with one or more halogens, CN, -NO 2 OX 1 (Where X 1 is selected from -H, a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens), COOR6, OCOR6, SO2NR6R7, NR6R7, NR6COR7 or OR6, wherein R6 and R7 are the same or different, and R6 and R7 represent H or an alkyl group containing 1 to 8 carbon atoms,

[0021] and its salts or organic complexes,

[0022] Used as medicine.

[0023] Preferably, the use of the compound of the following formula (I) as a medicine is not included in the present invention:

[0024] - a compound wherein in formula (I), R1 represents O, R2 represents CCl3, R3 and R4 represent H, and R5 represents Cl, and

[0025] - a compound wherein in formula (I), R1 represents O, R2 represents CCl3 or CH2Cl, and R3, R4 and R5 each represent H.

[0026] Advantageously, in formula (I), at least one of R3, R4 or R5 represents -H.

[0027] The present invention also relates to compounds of formula (I)

[0028]

[0029] in

[0030] -R1 represents O or NH,

[0031] -R2 represents a linear, branched or cyclic alkyl group containing 1 to 8 carbon atoms, which may be interrupted by a group selected from -O-, -S-, -(C=O)-, NH and may be substituted by one or more halogens;

[0032] or R2 represents an alkylene group containing 1 to 8 carbon atoms and which may be substituted by one or more halogens,

[0033] or R2 represents a phenyl group or an arylene group,

[0034] -R3, R4 and R5 independently represent -H, halogen, a straight or branched alkyl group containing 1 to 8 carbon atoms which may be substituted with one or more halogens, CN, -NO 2 OX 1 (Where X 1 is selected from -H, a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens), COOR6, OCOR6, SO2NR6R7, NR6R7, NR6COR7 or OR6, wherein R6 and R7 are the same or different, and R6 and R7 represent H or an alkyl group containing 1 to 8 carbon atoms,

[0035] and its salt or organometallic complex,

[0036] It is used as an antibiotic,

[0037] Preferably, compounds in which in formula (I) R1 represents O, R2 represents CCl3, R3 and R4 represent H and R5 represents Cl are excluded; and preferably, compounds in which in formula (I) R1 represents O, R2 represents CCl3 or CH2Cl and R3, R4 and R5 each represent H are excluded.

[0038] Advantageously, in formula (I), at least one of R3, R4 or R5 represents -H.

[0039] Compounds of formula (I), their salts or organometallic complexes are also subject of the present invention, preferably except compounds wherein in formula (I) R1 represents O, R2 represents CCl3, R3 and R4 represent H and R5 represents Cl; and preferably except compounds wherein in formula (I) R1 represents O, R2 represents CCl3 or CH2Cl and R3, R4 and R5 each represent H; and further except compounds having the formula

[0040]

[0041] The compounds of formula (I) according to the invention may in particular have the following definitions:

[0042] -R1 represents O or NH,

[0043] -R2 represents a linear, branched or cyclic alkyl group containing 1 to 8 carbon atoms, which may be interrupted by a group selected from -O-, -S-, -(C=O)-, NH and may be substituted by one or more halogens;

[0044] an alkylene group containing 1 to 8 carbon atoms and which may be substituted by one or more halogens,

[0045] Phenyl or arylene,

[0046] -R3, R4 and R5 independently represent -H, halogen, a straight or branched alkyl group containing 1 to 8 carbon atoms which may be substituted with one or more halogens, -NO 2 or OX 1 , where X 1 Selected from -H, linear or branched alkyl containing 1 to 8 carbon atoms which may be substituted by one or more halogens.

[0047] Advantageously, in formula (I), at least one of R3, R4 or R5 represents -H.

[0048] Advantageously, R2 represents a linear or branched alkyl group containing 1 to 5 carbon atoms substituted by at least one halogen. Preferred halogens are selected from Cl, F and Br. According to the invention, R2 may in particular represent a linear or branched alkyl group containing 1 to 5 carbon atoms substituted by 3 halogens.

[0049] Thus, R2 may be selected from the group consisting of C1, C2, C3, C4 and C5 alkyl, in particular C1 or C2 alkyl. R2 may particularly represent C1 alkyl substituted by 1, 2 or 3 halogens. In the latter case, R2 represents C(R'1) 3 , wherein R'1 represents halogen. Preferably, R'1 represents Cl, F or Br, in particular, R'1 represents Cl. Advantageously, in the compounds according to the invention, R2 therefore represents C(Cl) 3 .

[0050] In formula (I) as defined above, at least one of R3 or R5 may in particular be chosen from halogen and a linear or branched alkyl group containing 1 to 6 carbon atoms which may be substituted by one or more halogens, or halogen, and R4 represents H. R3 and R5 may be identical or different; as mentioned above, one of R3 or R5 may also represent H.

[0051] Advantageously, R3 represents halogen or a linear or branched alkyl group containing from 1 to 3 carbon atoms.

[0052] According to one embodiment of the present invention, at least one of R3 or R5 (same or different) represents halogen, in particular a halogen selected from Cl, F and Br, and the other groups in formula (I) are as defined elsewhere in this application. Preferably, R4 represents H. In particular, R3 and R5 may both represent halogen, or at least one of R3 or R5 represents H.

[0053] Such compounds exhibit favorable antimicrobial activity.

[0054] In another embodiment of the invention, at least one of R3 or R5 (same or different) represents a straight or branched alkyl group containing 1 to 6 carbon atoms (especially 1 to 3 carbon atoms), and the other groups in formula (I) are as defined elsewhere in this application. Preferably, R4 represents H. In particular, at least one of R3 or R5 represents a methyl group; therefore, both R3 and R5 may represent a methyl group, or at least one of R3 or R5 represents H.

[0055] Compounds in which, in formula (I) as defined above, R1 represents NH are of particular interest.

[0056] The compounds according to the invention are in particular the following compounds:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] The compounds of formula (I) according to the invention have in particular one of the following formulae:

[0063]

[0064]

[0065] The compound of formula (I) (wherein R represents NH) can be prepared by, for example, adding the corresponding 2-aminobenzothiazole to the nitrile derivative of formula NCR in a suitable solvent. Then, reclaim the desired product by filtering, liquid-liquid extraction or by evaporating volatiles under reduced pressure. The crude product can be recrystallized in a suitable solvent mixture to obtain the pure product.

[0066] In particular, when R2 represents CCl3, the synthesis reaction can be as follows:

[0067]

[0068] The compound of formula (I) (wherein R1 represents O or R2 represents a group different from CCl3) can be prepared as follows:

[0069]

[0070] Compounds of formula (I) (as defined throughout this specification) have been found to be useful as pharmaceuticals.

[0071] As mentioned above, the expression "compound of formula (I)" is intended to also include pharmaceutically acceptable salts and derivatives thereof, in particular complexes of compounds of formula (I) with metals and / or metal ions. These organometallic compounds may have improved properties. The metal may be selected from alkali metals, alkaline earth metals, transition metals, post-transition metals, lanthanides and actinides. The metal ions may be selected in particular from Ag. + 、Co 2+ 、Ni 2+ 、Al 3+ , Pd 2+ , Pd 4+ , Pt 4+ 、Ru 3+ or Fe 3+ .

[0072] In particular, the compound of formula (I) may be in the form of a complex with at least one metal selected from transition metals, for example a metal selected from Cu, Zn and Mo.

[0073] It has been demonstrated that the compounds of formula (I) as defined above exhibit good antibacterial activity while being well tolerated due to low cytotoxicity towards healthy cells. They are stable and can be formulated in compositions for long term use.

[0074] The present invention therefore relates to compounds of formula (I) as defined above and salts, derivatives or metal complexes thereof for use as antibiotics.

[0075] Antibiotics refer to antimicrobial compounds or antimicrobial compositions that are active against bacteria. Antibiotics are able to combat bacterial growth by killing the bacteria or by reducing, decreasing or preventing their growth. Therefore, they can be used as bactericides or bacteriostatics. In certain cases, the same substance can be a bactericidal substance or a bacteriostatic substance, depending on the concentration used.

[0076] The present invention particularly relates to the use of compounds of formula (I) as defined above as fungicides.

[0077] The compounds of formula (I) are particularly useful for treating bacterial infections, ie for preventing, reducing or arresting bacterial infections in a subject in need thereof.

[0078] The subject is advantageously a mammal, and in particular a human. The term "patient" may also be used in this specification to refer to a subject, in particular a human, treated with a compound of formula (I) according to the invention. The term individual may also be used.

[0079] Therefore, the present invention relates to the use of compounds of formula (I) for treating infectious diseases associated with bacteria, in particular infectious diseases associated with at least Gram-positive (Gram+) bacteria or Gram-negative (Gram-) bacteria.

[0080] The compounds of formula (I) may be administered as a preventive measure, for example in at-risk populations, or during surgery to help prevent wound infection, or during dental surgery.

[0081] According to the present invention, the compounds of formula (I) are used to prevent or reduce the development of bacterial infections. The so-called "reduction" is intended to be used to partially or completely limit the development of an infection; therefore, in some embodiments, the compounds of formula (I) will stop the development of an infection at an early stage. Reduction also includes delaying or slowing the development of an infection.

[0082] So-called prophylaxis is intended to be used before an infection starts so that a bacterial infection does not develop.

[0083] Unless otherwise stated, the expression “a compound of formula (I)” is intended to mean “at least one compound of formula (I)”. It thus encompasses the use of only one compound of formula (I) or a mixture of two or more compounds of formula (I).

[0084] As indicated above, the compounds of formula (I) according to the invention are useful for treating infections associated with or induced by bacteria.The compounds of formula (I) as defined in the present application are particularly useful for treating infectious diseases associated with Gram-positive bacteria.

[0085] Gram-positive bacteria can cause a variety of pathologies; they can also exist as resident flora at a location in an organism without causing pathology. Infection can occur in the presence of specific pathogens and can occur when the balance between bacteria present at a location is disturbed.

[0086] The compounds of formula (I) are useful in infectious diseases or conditions associated with Gram-positive bacteria selected from Gram-positive cocci and Gram-positive bacillus (rods).

[0087] Gram-positive bacteria include Staphylococcus and Streptococcus. Gram-positive bacteria include Bacillus and Clostridia (Bacillus), Listeria and Corynebacterium. In addition, Rathybacter, Leifsonia and Clavibacter are three Gram-positive genera that cause plant diseases.

[0088] The compounds of formula (I) according to the present invention can be particularly used for the treatment of Gram-positive bacterial infections or diseases, wherein the bacteria are selected from Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Clostridia tetani, Clostridia botulinum, Clostridia perfringens, Clostridia difficile, Bacillus anthracis, Bacillus cereus, Corynebacterium diphtheriae and Listeria monocytogenes.

[0089] The compounds of formula (I) are particularly useful for treating bacterial diseases associated with Staphylococcus.

[0090] Such diseases include inflammatory diseases, including skin infections, pneumonia, endocarditis, suppurative arthritis, myelitis and abscesses. The compounds of formula (I) may also be used to treat genital or urinary tract infections, otitis media, pneumonia, sinusitis, meningitis, endocarditis, impetigo, erysipelas, glomerulonephritis and rheumatic fever, biliary tract infections or diphtheria.

[0091] For example, compounds of formula (I) may be used in the treatment of skin disorders, such as impetigo.

[0092] The present invention also relates to a pharmaceutical composition comprising at least a compound of formula (I) and at least one physiologically acceptable medium (particularly a pharmaceutically acceptable carrier). It should be understood that all uses and applications of a compound of formula (I) can be carried out in a composition containing the compound or a derivative thereof.

[0093] As mentioned above, the compounds of formula (I) can be used in compositions, especially pharmaceutical compositions, comprising the inhibitors. The compounds of formula (I) are administered to a subject in need thereof by routes suitable for those skilled in the art.

[0094] Various delivery systems are known and can be used to administer the compound of formula (I) of the present invention, including tablets, capsules, injectable solutions, encapsulated in liposomes, microparticles, microcapsules, etc. Methods of administration include but are not limited to epidermal routes, intradermal routes, intramuscular routes, intraperitoneal routes, intralesional routes, intravenous routes, subcutaneous routes, intranasal routes, pulmonary routes, epidural routes, ocular routes and oral routes. The compound of formula (I) of the present invention or its pharmaceutical composition can be administered by any convenient route or other appropriate routes, such as, by infusion or bolus injection, by adsorption of epithelial lining or skin mucosal lining (such as oral cavity, mucosa, rectum and intestinal mucosa, etc.). Administration can be systemic or local. Parenteral administration can be directed to a given tissue of a patient, such as by catheterization. As will be known to those of ordinary skill in the art, in the embodiment in which the compound of formula (I) is administered together with another therapeutic agent, the compound of formula (I) and the therapeutic agent can be administered by the same route (for example, oral) or by different routes (for example, oral and intravenous).

[0095] The compounds of formula (I) may be administered in compositions comprising one or more pharmaceutically acceptable diluents or carriers.

[0096] A "pharmaceutical composition" is defined herein as comprising an effective amount of at least one compound of formula (I) of the present invention or a physiologically tolerable salt or derivative thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0097] The term "pharmaceutically acceptable carrier or excipient" refers to a carrier medium that does not interfere with the effectiveness of the biological and / or therapeutic activity of the active ingredient and is not overly toxic to the host at the concentrations at which it is administered. The term includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is known in the art.

[0098] The present invention can be better understood through the following examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] [ Figure 1 ] represent the results of the antibacterial and bactericidal activities obtained on two Staphylococcus aureus strains RN4220 and S25.

[0100] [ Figure 2 ] represents the results of quantitative evaluation of cytotoxicity by extracellular lactate dehydrogenase (LDH) when the compound was incubated with HEK 293T cells in the same concentration range as MIC and MBC. LDH: positive control, DMEM: negative control. N=3.

[0101] Example 1: Preparation of the compound of formula (I)

[0102] Materials and methods

[0103] All chemicals were purchased from Sigma-Aldrich, Alfa Aesar, Apollo Scientific and Carlo Erba and used directly without further purification. Thin layer chromatography (TLC) was performed on pre-coated Merck 60GF254 silica gel plates and first visualized by ultraviolet light (254nm and 360nm). 1H, 13C and 19F nuclear magnetic resonance spectra were recorded on Bruker Advance 400MHz or Bruker Advance 200MHz spectrometers. Mass spectra (ESI-MS) were recorded on Agilent iQ (Agilent, Santa Clara) single quadrupole mass spectrometers equipped with an electrospray source and coupled to an Agilent 1200HPLC system. HRMS spectra were recorded at m / z 200 with a resolution of 70,000 on a ThermoFisher Q-Exactive Focus mass spectrometer (ESI-MS). The mass spectrometer was coupled to a ThermoFisher Vanquish UHPLC system. The purity of the compounds was further determined by HPLC analysis on a JASCO PU-2089 / AS4050 apparatus with a Supelco analytical column Ascentis Express C18, 100 mm × 46 mm 5 μM, using two flow methods:

[0104] Method 1 : 5% B for 3 minutes; 5% B to 95% B for 12 minutes; 95% B for 5 minutes; then 95% B to 5% B for 2 minutes; 5% B for 3 minutes (total time: 25 minutes). Flow rate: 1 mL / min. Solvent A: Water with 0.1% formic acid. Solvent B: Acetonitrile with 0.1% formic acid.

[0105] Method 2 : 30% B for 2 minutes; 30% B to 95% B for 6 minutes; 95% B for 12 minutes; then 95% B to 30% B for 6 minutes; 30% B for 4 minutes (total time: 30 minutes). Flow rate: 1 mL / min. Solvent A: Water with 0.1% formic acid. Solvent B: Acetonitrile with 0.1% formic acid.

[0106] General process of trichloroacetamimidamide compound

[0107] In the presence of THF (0.5M) or ethanol (0.1M) or pure solvent, trichloroacetonitrile (1.5mmol to 3mmol) is added into the corresponding 2-amino azole (1mmol) in the closed vial. At 20 ℃ to 65 ℃, the mixture is stirred until the reaction is complete (TLC monitoring, 6 hours to 18 hours). Then, the reaction mixture is cooled to ambient temperature, and the desired product is recovered by filtering or by evaporating volatiles under reduced pressure. The crude product is recrystallized in methanol or ethanol or ethanol / water mixture. Finally, the solid is washed with pentane to obtain the pure product.

[0108] 2,2,2-Trichloro-N-(6-nitrobenzo[d]thiazol-2-yl)acetamidine (MTF231)

[0109]

[0110] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-6-nitrobenzothiazole (325 mg, 1.53 mmol) in ethanol. Purified by recrystallization in ethanol to give a yellow solid (460 mg, 89%). 1 HNMR (200 MHz, DMSO-d 6 ): δ9.56 (br.s, 2H, 2NH), 9.01 (s, 1H, CH-Ar), 8.30 (d, J=8.3Hz, 1H, CH-Ar), 8.01 (d, J=9.1Hz, 1H, CH-Ar). 13 C NMR (50 MHz, DMSO-d 6 ): δ175.85, 159.00, 155.08, 143.46, 132.74, 121.74, 121.35, 118.75, 93.71. HRMS-ESI(m / z):C 9 H 6 Cl 3 N 4 O 2 S + [M+H] + Calculated value: 338.9271, found value: 338.9276. HPLC purity (λ 254 ): 99.3%; t R : 12.37 minutes (Method 2).

[0111] 2,2,2-Trichloro-N-(4-chlorobenzo[d]thiazol-2-yl)acetamidine (MTF235)

[0112]

[0113] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4-chlorobenzothiazole (303 mg, 1.66 mmol) in ethanol. Purified by recrystallization in methanol to give a yellow solid (286 mg, 88%). 1 H NMR (200 MHz, DMSO-d 6 ): δ10.02 (br.s, 1H, NH), 9.81 (br.s, 1H, NH), 7.95 (d, J=7.9Hz, 1H, CH-Ar), 7.56 (d, J=7.7Hz, 1H, CH-Ar), 7.35 (t, J=7.9Hz, 1H, CH-Ar). 13 C NMR (50 MHz, DMSO-d 6 ): δ171.80, 158.57, 146.94, 133.26, 126.15, 125.14, 124.71, 120.69, 93.71. HRMS-ESI(m / z):C 9 H 5 Cl 4 N 3 S + [M+H] + Calculated value: 327.9031; Found: 327.9027. HPLC purity (λ 254 ):>99.9%; t R : 13.38 minutes, (Method 2).

[0114] 2,2,2-Trichloro-N-(6-methoxybenzo[d]thiazol-2-yl)acetamidine (MTF339)

[0115]

[0116] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-6-methoxybenzothiazole (30 mg, 1.66 mmol) in ethanol. Purified by recrystallization in methanol to give a brown solid (442 mg, 82%). 1 HNMR (200 MHz, DMSO-d 6 ): δ9.66 (br.s, 2H, 2NH), 7.79 (d, J=8.9Hz, 1H, CH-Ar), 7.58 (d, J=2.6Hz, 1H, CH-Ar), 7.07 (dd, J=8.9, 2.6Hz, 1H, CH-Ar), 3.82 (s, 3H, CH 3 ). 13 C NMR (50 MHz, DMSO-d 6): δ168.71, 157.17,

[0117] 156.78, 144.53, 133.46, 122.11, 115.22, 104.79, 93.98, 55.63. HRMS-ESI(m / z):C 10 H 8 Cl 3 N 3 OS + [M+H] + Calculated value: 323.9526; Found value: 323.9533. HPLC purity (λ 280 :95.0%;t R : 10.97 minutes (method 1).

[0118] 2,2,2-Trichloro-N-(6-ethoxybenzo[d]thiazol-2-yl)acetamidine (MTF340)

[0119]

[0120] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-6-ethoxybenzothiazole (323 mg, 1.54 mmol) in ethanol. Purified by recrystallization in methanol to give a white solid (473 mg, 91%). 1 HNMR (200 MHz, DMSO-d 6 )δ9.68 (br.s, 2H, 2NH), 7.77 (d, J=8.9Hz, 1H, CH-Ar), 7.55 (d, J=2.5Hz,

[0121] 1H, CH-Ar), 7.05 (dd, J=8.9, 2.6Hz, 1H, CH-Ar), 4.07 (q, J=6.9Hz, 2H, CH 2 ), 1.35 (t, J=7.0Hz, 3H, CH 3 ). 13 C NMR (50 MHz, DMSO-d 6 )δ168.65, 157.15, 156.03, 144.44, 133.45, 122.12, 115.58,

[0122] 105.38, 93.96, 63.62, 14.65. HRMS-ESI(m / z):C 11 H 10 Cl 3 N 3 OS + [M+H] +Calculated value: 337.9682; Found: 337.9685. HPLC purity (λ 280 ):>99.9%; t R : 12.01 min (Method 1).

[0123] N-(Benzo[d]thiazol-2-yl)-2,2,2-trichloroacetamidine (MTF341)

[0124]

[0125] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-aminobenzothiazole (300 mg, 2 mmol) in ethanol overnight. Purified by recrystallization in methanol to give a white solid (435 mg, 74%). 1 H NMR (200 MHz, DMSO-d 6 ): δ9.97 (br.s, 1H, NH), 9.57 (br.s, 1H, NH), 7.98 (dd, J=7.8, 0.9Hz, 1H, CH-Ar), 7.89 (dd, J=8 .0, 0.7Hz, 1H, CH-Ar), 7.48 (td, J=7.7, 1.4Hz, 1H, CH-Ar), 7.36 (td, J=7.6, 1.3Hz, 1H, CH-Ar). 13 C NMR (50 MHz, DMSO-d 6 ): δ170.94, 157.93, 150.41, 132.10, 126.29, 124.49, 121.72, 121.41, 93.94. HRMS-ESI(m / z):C 9 H 7 Cl 3 N 3 S + [M+H] + Calculated value: 293.9426; Found: 293.9422. HPLC purity (λ 280 ): 97.9%; t R : 11.35 minutes (Method 1).

[0126] 2,2,2-Trichloro-N-(4-methoxybenzo[d]thiazol-2-yl)acetamidine (MTF571)

[0127]

[0128] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4-methoxybenzothiazole (303 mg, 1.66 mmol) in ethanol. Purification was performed by recrystallization from a pentane / ether mixture to give a brown solid (443 mg, 82%). 1 H NMR (400MHz, chloroform-d): δ10.58 (s, 1H, NH), 7.35 (d, J=7.4Hz, 1H, CH-Ar), 7.30-7.18 (m , 1H, CH-Ar), 6.87 (d, J=7.6Hz, 1H, CH-Ar), 6.85 (d, J=7.6Hz, 1H, NH), 3.97 (s, 3H, CH 3 ). 13 C NMR (101 MHz, chloroform-d): δ 170.41, 157.34, 152.46, 140.56, 134.81, 125.46, 113.70, 107.03, 94.27, 56.02. HRMS-ESI (m / z): C 10 H 9 Cl 3 N 3 OS + [M+H] + Calculated value: 323.9526; Found value: 323.9514. HPLC purity (λ 254 ): 97.7%; t R : 7.55 minutes (Method 2).

[0129] 2,2,2-Trichloro-N-(4-methylbenzo[d]thiazol-2-yl)acetamidine (MTF572)

[0130]

[0131] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4-methylbenzothiazole (272 mg, 1.66 mmol) in ethanol. Purification was performed by recrystallization in an ethanol / water mixture to give a white solid (417 mg, 82%). 1 H NMR (400 MHz, chloroform-d): δ 10.75 (s, 1H, NH), 7.69 (dd, J = 6.7, 2.5 Hz, 1H, CH-Ar), 7.33-7.27 (m, 2H, CH-Ar), 6.88 (s, 1H, NH), 2.70 (s, 3H, CH 3 ). 13CNMR (101 MHz, chloroform-d): δ 170.68, 157.45, 149.86, 133.06, 131.38, 126.81, 124.62, 119.01, 94.30, 18.61. HRMS-ESI (m / z): C 10 H 9 Cl 3 N 3 S + [M+H] + Calculated value: 307.9577; Found: 307.9565. HPLC purity (λ 254 ):>99.9%; t R : 8.38 minutes, (Method 2).

[0132] 2,2,2-Trichloro-N-(4,6-difluorobenzo[d]thiazol-2-yl)acetamidine (MTF573)

[0133]

[0134] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4,6-difluorobenzothiazole (186 mg, 1 mmol) in THF. Purification was performed by washing with pentane to give a yellow solid (275 mg, 83%). 1 H NMR (400 MHz, chloroform-d): δ 10.45 (s, 1H, NH), 7.29 (ddd, J = 7.9, 2.4, 1.2 Hz, 1H, CH-Ar), 6.95 (td, J = 9.8, 2.4 Hz, 1H, CH-Ar), 6.95 (br. s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 171.36, 160.89, 157.96, 155.66, 153.10, 135.97, 103.75, 102.18, 94.01. 19 F NMR (376MHz, chloroform-d): δ -113.21 (td, J=8.8, 4.9Hz), -119.18 (dd, J=10.2, 5.0Hz). HRMS-ESI(m / z):C 9 H 5 Cl 3 N 3 F 2 S + [M+H] + Calculated value: 329.9232; Found: 329.9219. HPLC purity (λ 254 ):>99.9%; t R: 7.93 minutes (Method 2).

[0135] 2,2,2-Trichloro-N-(5,6-dimethylbenzo[d]thiazol-2-yl)acetamidine (MTF574)

[0136]

[0137] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-5,6-dimethylbenzothiazole (295 mg, 1.66 mmol) in ethanol. Purified by recrystallization in an ethanol / water mixture to give a yellow solid (477 mg, 89%). 1 H NMR (400 MHz, chloroform-d): δ 10.56 (s, 1H, NH), 7.61 (s, 1H, CH-Ar), 7.55 (s, 1H, CH-Ar), 6.78 (s, 1H, NH), 2.37 (s, 6H, 2CH 3 ). 13 C NMR (101 MHz, chloroform-d): δ 170.74, 157.10, 149.34, 135.41, 134.10, 130.72, 122.14, 121.60, 94.33, 20.33, 20.23. HRMS-ESI (m / z): C 11 H 11 Cl 3 N 3 S + [M+H] + Calculated value: 321.9722; Found: 321.9733. HPLC purity (λ 254 ): 97.4%; t R : 8.97 minutes, (Method 2).

[0138] 2,2,2-Trichloro-N-(6-chlorobenzo[d]thiazol-2-yl)acetamidine (MTF575)

[0139]

[0140] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-6-chlorobenzothiazole (306 mg, 1.66 mmol) in ethanol. Purification was performed by recrystallization from an ethanol / water mixture to give an off-white solid (322 mg, 59%). 1H NMR (400 MHz, chloroform-d): δ 10.46 (s, 1H, NH), 7.86-7.62 (m, 2H, CH-Ar), 7.39 (dd, J=8.7, 2.1 Hz, 1H, CH-Ar), 6.87 (s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 171.99, 157.84, 149.26, 134.51, 130.36, 127.00, 122.51, 121.21, 94.10. HRMS-ESI (m / z): C 9 H 6 Cl 4 N 3 S + [M+H] + Calculated value: 327.9031; Found value: 327.9016. HPLC purity (λ 254 ):>99.9%; t R : 8.56 minutes (Method 2).

[0141] 2,2,2-Trichloro-N-(6-methylbenzo[d]thiazol-2-yl)acetamidine (MTF576)

[0142]

[0143] Synthesized according to the general procedure using trichloroacetonitrile (0.5 mL, 5 mmol) and 2-amino-6-methylbenzothiazole (272 mg, 1.66 mmol) in ethanol. Purification was performed by recrystallization in an ethanol / water mixture to give a grey solid (488 mg, 95%). 1 H NMR (400 MHz, chloroform-d): δ 10.59 (s, 1H, NH), 7.70 (d, J = 8.3 Hz, 1H, CH-Ar), 7.58 (s, 1H, CH-Ar), 7.22 (s, 1H, CH-Ar), 6.82 (s, 1H, NH), 2.47 (s, 3H, CH 3 ). 13 C NMR (101 MHz, chloroform-d): δ 170.76, 157.27, 148.71, 134.76, 133.47, 127.75, 121.40, 121.35, 96.89, 21.68. HRMS-ESI (m / z): C 10 H 9 Cl 3 N 3 S + [M+H] + Calculated value: 307.9577; Found: 307.9566. HPLC purity (λ254 ): 99.1%; t R : 8.46 minutes (Method 2).

[0144] 2,2,2-Trichloro-N-(6-hydroxybenzo[d]thiazol-2-yl)acetamidine (MTF577)

[0145]

[0146] Synthesized according to the general procedure using trichloroacetonitrile (1.1 mL, 11 mmol) and 2-amino-6-hydroxybenzothiazole (464 mg, 3 mmol) in ethanol. Purification was performed by recrystallization in an ethanol / water mixture to give a grey solid (744 mg, 86%). 1 H NMR (400 MHz, acetone-d 6 ): δ10.26 (s, 1H, NH), 8.69 (s, 1H, OH), 8.43 (s, 1H, NH), 7.69 (d, J=8.7Hz, 1H, CH-Ar), 7.35 (s, 1H, CH-Ar), 7.01 (d, J=8.8Hz, 1H, CH-Ar). 13 C NMR (101 MHz, acetone-d 6 ): δ169.48, 158.08, 156.06, 145.32, 135.10, 123.26, 116.46, 107.44, 96.21. HRMS-ESI(m / z):C 9 H 7 Cl 3 N 3 OS + [M+H] + Calculated value: 309.9369; Found: 309.9356. HPLC purity (λ 254 ):>99.9%; t R : 6.57 minutes (Method 2).

[0147] 2,2,2-Trichloro-N-(6-ethylcarboxylate benzo[d]thiazol-2-yl)acetamidine (MTF578)

[0148]

[0149] Synthesized according to the general procedure using trichloroacetonitrile (6 mL, 59 mmol) and 2-amino-6-ethylcarboxylate benzothiazole (4.43 mg, 19 mmol) in ethanol. Purification was performed by recrystallization in ethanol to give an orange solid (3.046 g, 56%). 1 H NMR (400 MHz, benzene-d 6): δ10.51 (s, 1H, NH), 8.42 (d, J=1.7Hz, 1H, CH-Ar), 8.01 (dd, J=8.5, 1.7Hz, 1H, CH-Ar), 7.73 (d, J=8.5Hz, 1H, CH-Ar), 6.88 (s, 1H, NH), 4.31 (q, J=7.1Hz, 2H, CH 2 ), 1.32 (t, J=7.1Hz, 3H, CH 3 ). 13 C NMR (101 MHz, benzene-d 6 ): δ225.40, 217.21, 209.15, 204.73, 184.00, 178.49, 177.59, 174.56, 172.17, 144.94, 112.25, 65.41. HRMS-ESI(m / z):C 12 H 11 Cl 3 N 3 O 2 S + [M+H] + Calculated value: 365.9632; Found value: 365.9615. HPLC purity (λ 254 ): 99.7%; t R : 8.46 minutes (Method 2).

[0150] 2,2,2-Trichloro-N-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)acetamidine (MTF580)

[0151]

[0152] Synthesized according to the general procedure using trichloroacetonitrile (0.5 mL, 5 mmol) and 2-amino-6-trifluoromethoxybenzothiazole (468 mg, 2 mmol) in THF. Purified by recrystallization in ethanol to give an orange solid (298 mg, 79%). 1 HNMR (400 MHz, acetone-d 6 ): δ10.34 (s, 1H, NH), 8.73 (s, 1H, NH), 8.02 (s, 1H, CH-Ar), 7.95 (d, J=8.8Hz, 1H, CH-Ar), 7.44 (d, J=8.8Hz, 1H, CH-Ar). 13 C NMR (101 MHz, acetone-d 6 ): δ173.64, 159.24, 150.72, 146.49, 134.79, 123.48, 122.82, 120.91, 115.54, 94.86.19 F NMR (376 MHz, acetone-d 6 ): δ-58.50. HRMS-ESI(m / z):C 10 H 6 F 3 Cl 3 N 3 OS + [M+H] + Calculated value: 377.9244; Found: 377.9228. HPLC purity (λ 254 ): 95.4%; t R : 8.77 minutes (Method 2).

[0153] 2,2,2-Trichloro-N-(6-bromobenzo[d]thiazol-2-yl)acetamidine (MTF588)

[0154]

[0155] Synthesized according to the general procedure using trichloroacetonitrile (0.5 mL, 5 mmol) and 2-amino-6-bromobenzothiazole (460 mg, 2 mmol) in ethanol. Purification was performed by recrystallization in an ethanol / water mixture to give a beige solid (471 mg, 63%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 10.50 (s, 1H, NH), 7.93 (d, J = 6.2 Hz, 1H, CH-Ar), 7.67 (d, J = 6.6 Hz, 1H, CH-Ar), 7.61-7.44 (m, 1H, CH-Ar), 6.88 (s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 171.98, 157.92, 149.56, 134.94, 129.71, 124.11, 122.86, 117.91, 94.08. HRMS-ESI (m / z): C 9 H 6 Cl 3 Bn 3 S + [M+H] + Calculated value: 371.8526; Found value: 371.8511. HPLC purity (λ 254 ):>99.9%; t R : 8.75 minutes (Method 2).

[0156] 2,2,2-Trichloro-N-(4-bromobenzo[d]thiazol-2-yl)acetamidine (MTF589)

[0157]

[0158] Synthesized according to the general procedure using trichloroacetonitrile (0.5 mL, 5 mmol) and 2-amino-4-bromobenzothiazole (458 mg, 2 mmol) in ethanol. Purification was performed by recrystallization in an ethanol / water mixture to give a white solid (508 mg, 68%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 10.77 (s, 1H, NH), 7.71 (d, J = 7.1 Hz, 1H, CH-Ar), 7.62 (d, J = 7.0 Hz, 1H, CH-Ar), 7.25-7.12 (m, 1H, CH-Ar), 7.01 (s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 171.86, 158.28, 148.84, 133.85, 129.43, 125.45, 120.70, 115.16, 94.13. HRMS-ESI (m / z): C 9 H 6 Cl 3 Bn 3 S + [M+H] + Calculated value: 371.8526; Found value: 371.8511. HPLC purity (λ 254 ): 98.7%; t R : 8.57 minutes (Method 2).

[0159] 2,2-Dichloro-N-(4-methylbenzo[d]thiazol-2-yl)acetamidine (MTF619)

[0160] 2-Amino-4-methylbenzothiazole (164 mg, 1 mmol) was slowly added to dichloroacetonitrile (0.5 mL, 5 mmol), and the reaction mixture was heated overnight at 50° C. After 18 hours (TLC monitoring), the crude reaction mixture was concentrated under reduced pressure to remove excess dichloroacetonitrile and the pure product (265 mg, 97%) was obtained as a light yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d): δ 10.40 (s, 1H, NH), 7.63 (d, J = 6.7 Hz, 1H, CH-Ar), 7.24 (d, J = 7.2 Hz, 2H, CH, CH-Ar), 6.69 (s, 1H, NH), 6.27 (s, 1H, CHCl 2 ), 2.66(s, 3H, CH 3 ). 13C NMR (101 MHz, chloroform-d): δ 170.70, 158.28, 150.08, 132.80, 131.26, 126.77, 124.49, 118.92, 69.49, 18.58. HRMS-ESI (m / z): C 10 H 10 Cl 2 N 3 S + [M+H] + Calculated value: 273.9967; Found: 273.9788. HPLC purity (λ 254 ): 97.3%; t R : 11.96 minutes (Method 1).

[0161] 2,2-Dibromo-N-(4-methylbenzo[d]thiazol-2-yl)acetamidine (MTF620)

[0162]

[0163] 2-Amino-4-methylbenzothiazole (164 mg, 1 mmol) was slowly added to dibromoacetonitrile (0.4 mL, 5 mmol), and the reaction mixture was heated at 50° C. overnight. After 18 hours (TLC monitoring), the crude reaction mixture was concentrated under reduced pressure to remove excess dibromoacetonitrile, and the resulting mixture was purified by flash chromatography (cyclohexane / ethyl acetate, 95 / 5, v / v) to give the pure product (304 mg, 84%) as an orange solid. 1 H NMR (400MHz, chloroform-d): δ10.41 (s, 1H, NH), 7.60 (dd, J=7.1, 1.6Hz, 1H, CH, CH-Ar), 7.21 (d, J=7.0Hz, 2H, CH, CH-Ar), 6.69 (s, 1H, NH), 6.15 (s, 1H, CHBr 2 ), 2.64(s, 3H, CH 3 ). 13 C NMR (101 MHz, chloroform-d): δ 170.43, 159.00, 150.08, 132.81, 131.23, 126.75, 124.45, 118.91, 38.69, 18.59. HRMS-ESI (m / z): C 10 H 10 Br 2 N 3 S + [M+H] + Calculated value: 361.8957; Found: 361.8940. HPLC purity (λ 254): 95.1%; t R : 12.25 minutes (Method 2).

[0164] N-(4-Methylbenzo[d]thiazol-2-yl)benzimidamide (MTF621)

[0165]

[0166] In a sealed tube, 2-amino-4-methylbenzothiazole (164 mg, 1 mmol) and aluminum chloride (133 mg, 1 mmol) were mixed, and benzonitrile (2 mL, 20 mmol) was slowly added. The reaction mixture was heated at 100 ° C overnight. After 18 hours (TLC monitoring), the product was precipitated by adding ether, recovered by filtration, and purified by recrystallization in ethanol to obtain the pure product (188 mg, 70%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ):δ11.25(s,

[0167] 1H, NH), 11.10 (s, 1H, NH), 8.12-8.05 (m, 2H, CH-Ar), 7.90 (dd, J=7.2, 2.0Hz, 1H, CH-Ar), 7.77 ( d, J=7.3Hz, 1H, CH-Ar), 7.66 (t, J=7.7Hz, 2H, CH-Ar), 7.38-7.29 (m, 2H, CH-Ar), 2.67 (s, 3H, CH 3 ). 13 C NMR (101 MHz, DMSO-d 6 ): δ162.10, 147.96, 133.81, 131.01, 130.84, 129.09(2C), 128.80(2C), 127.25(2C), 125.21,

[0168] 119.50(2C),18.00. HRMS-ESI(m / z):C 15 H 14 N 3 S + [M+H] + Calculated value: 268.0903; Found: 268.0892. HPLC purity (λ 254 ):>99.9%; t R : 7.62 minutes (Method 1).

[0169] N-(4-Methylbenzo[d]thiazol-2-yl)thiophene-2-carboximidamide (MTF623)

[0170]

[0171] In a sealed tube, 2-amino-4-methylbenzothiazole (164 mg, 1 mmol) and aluminum chloride (133 mg, 1 mmol) were mixed, and 2-thiophene nitrile (1.9 mL, 20 mmol) was slowly added. The reaction mixture was then heated at 100 ° C overnight. After 18 hours (TLC monitoring), the product was precipitated by adding ether, recovered by filtration, and purified by recrystallization in ethanol to obtain the pure product (186 mg, 68%) as a green solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.40 (s, 1H, NH), 10.02 (s, 1H, NH), 8.22 (m, 1H, CH-thio), 7.99 (m, 1H, CH-thio), 7.77 (dd, J = 7.8, 1.5 Hz, 1H, CH-thio), 7.31-7.21 (m, 3H, CH-Ar), 2.60 (s, 3H, CH 3 ). 13 C NMR (101 MHz, DMSO-d 6 ): δ155.05, 148.22, 133.14, 131.24, 130.26, 129.23, 128.04(2C), 126.35, 123.66, 118.63(2C), 17.55. HRMS-ESI(m / z):C 13 H 12 N 3 S 2 + [M+H] + Calculated value: 274.0394; Found: 274.0461. HPLC purity (λ 254 ): 96.7%; t R : 11.22 minutes (Method 1).

[0172] N-(4-Methylbenzo[d]thiazol-2-yl)isobutylimidamide (MTF625)

[0173]

[0174] In a sealed tube, 2-amino-4-methylbenzothiazole (164 mg, 1 mmol) and aluminum chloride (133 mg, 1 mmol) were mixed, and isobutyronitrile (1.8 mL, 20 mmol) was slowly added. The reaction mixture was then stirred at 100 ° C. After 48 hours (TLC monitoring), the product was precipitated by adding ether, recovered by filtration, and purified by recrystallization in ethanol to obtain the pure product (148 mg, 63%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d 6 ): δ10.31 (s, 1H, NH), 9.82 (s, 1H, NH), 7.86-7.69 (m, 1H, CH-Ar), 7.34-7.15 (m, 2H, CH-Ar), 2.88 (s, 1H, CH), 2.58 (s, 3H, CH 3 ), 1.29 (d, J=6.9Hz, 6H, 2CH 3 ). 13 C NMR (101 MHz, DMSO-d 6 ): δ171.49, 149.05, 130.81, 130.15, 126.78, 124.26, 119.13(2C), 34.05, 19.79(2C), 18.04. HRMS-ESI(m / z):C 12 H 15 N 3 S + [M+H] + Calculated value: 234.1059; Found: 234.1052. HPLC purity (λ 254 ): 95.9%; t R : 6.17 minutes (Method 1).

[0175] N-(4-Methylbenzo[d]thiazol-2-yl)trichloroacetamide (MTF637)

[0176]

[0177] N-Methylmorpholine (0.67 mL, 6.08 mmol) and trichloroacetyl chloride (0.68 mL, 6.08 mmol) were added to a solution of 2-amino-4-methylbenzothiazole (500 mg, 3.04 mmol) in THF (7 mL), and the reaction mixture was stirred at room temperature. After 2 hours (TLC monitoring), the reaction mixture was concentrated under reduced pressure, and the crude mixture was purified by flash column chromatography with dichloromethane as eluent to obtain the title product (578.2 mg; 61%) as a brown powder. 1 HNMR (400 MHz, acetone-d 6 ): δ11.16 (s, 1H, NH), 7.77 (d, J=6.4Hz, 1H, CH-Ar), 7.43-7.20 (m, 2H, CH-Ar), 2.63 (s, 3H, CH 3 ). 13 CNMR (101 MHz, acetone-d 6): δ168.75. 168.50, 163.07, 139.19, 129.19, 127.02, 125.53, 120.90, 95.62, 17.85. HRMS-ESI(m / z):C 10 H 8 N 2 Cl 3 OS + [M+H] + Calculated value: 308.94174; Found: 308.94056. HPLC purity (λ 254 ): 96.4%; t R : 11.13 minutes (Method 2).

[0178] N-(4,6-Difluorobenzo[d]thiazol-2-yl)trichloroacetamide (MTF639)

[0179]

[0180] 2-amino-4,6-difluorobenzothiazole (186 mg, 1 mmol) was dissolved in THF (2 mL), and trichloroacetyl chloride (0.56 mL, 5 mmol) was slowly added at ambient temperature. The reaction mixture was stirred at 40 ° C for 4 hours. The crude reaction mixture was evaporated under reduced pressure to remove the solvent and excess trichloroacetyl chloride. The obtained solid was recrystallized in ethanol to obtain the pure product (303 mg, 92%) as a white solid. 1 H NMR (400 MHz, chloroform-d): δ 8.42 (s, 1H, NH), 7.39 (d, J=6.7 Hz, 1H, CH-Ar), 7.02 (t, J=9.2 Hz, 1H, CH-Ar). 13 C NMR (101 MHz, chloroform-d): δ 160.23, 160.11, 156.66, 154.60, 135.28, 133.9, 103.97, 102.96, 90.96. 19 F NMR (376 MHz, chloroform-d): δ -111.94, -120.08. HRMS-ESI (m / z): C 9 H 4 Cl 3 N 2 OSF 2 + [M+H] + Calculated value: 330.9000; Found value: 330.9066. HPLC purity (λ 254 ): 95.4%; t R : 11.53 minutes (Method 2).

[0181] N-(4,6-Dichlorobenzo[d]thiazol-2-yl)trichloroacetamide (MTF640)

[0182]

[0183] 2-amino-4,6-dichlorobenzothiazole (218 mg, 1 mmol) was dissolved in THF (2 mL), and trichloroacetyl chloride (0.56 mL, 5 mmol) was slowly added at room temperature. The reaction mixture was stirred at 40 ° C for 5 hours. The crude reaction mixture was evaporated under reduced pressure to remove excess trichloroacetyl chloride, and then the product was precipitated by adding pentane. The obtained solid was recrystallized in ethanol to obtain the pure product (316 mg, 88%) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (s, 1H, NH), 8.14 (d, J=2.5Hz, 1H, CH-Ar), 7.66 (d, J=2.0Hz, 1H, CH-Ar). 13 C NMR (101 MHz, DMSO-d 6 )δ163.31, 159.05, 141.98, 134.30, 133.43, 128.48, 126.70, 121.10, 92.17. LCMS-ESI(m / z):

[0184] C 9 H 3 Cl 5 N 2 OS + [M+H] + Calculated value: 362.8; Found: 363.3. HPLC purity (λ 254 ): 98.2%; t R : 12.99 minutes (method 1).

[0185] N-(4-Fluorobenzo[d]thiazol-2-yl)trichloroacetamide (MTF641)

[0186]

[0187] 2-Amino-4-fluorobenzothiazole (168 mg, 1 mmol) was dissolved in THF (2 mL), and trichloroacetyl chloride (0.56 mL, 5 mmol) was slowly added at room temperature. The reaction mixture was stirred at 40 ° C for 2 hours. The crude reaction mixture was evaporated under reduced pressure to remove the solvent and excess trichloroacetyl chloride. The solid was recrystallized in ethanol to obtain the pure product (304 mg, 97%) as a brown solid. 1H NMR (400 MHz, chloroform-d): δ 8.68 (s, 1H, NH), 8.40 (t, J=8.2 Hz, 1H, CH-Ar), 7.49-7.34 (m, 2H, CH-Ar). 13 C NMR (101 MHz, chloroform-d): δ 159.40, 152.98, 127.12, 126.42, 122.66, 121.59, 117.34, 109.61, 92.17. 19 F NMR (376 MHz, chloroform-d): -126.10. HRMS-ESI (m / z): C 9 H 5 Cl 3 N 2 OSF + [M+H] + Calculated value: 310.9094; Found value: 310.9020. HPLC purity (λ 254 ):>99.9%; t R : 10.61 minutes (Method 2).

[0188] 2,2,2-Trichloro-N-(4,6-dichlorobenzo[d]thiazol-2-yl)acetamidine (MTF642)

[0189]

[0190] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4,6-dichlorobenzothiazole (219 mg, 1 mmol) in THF. Purification by trituration in pentane afforded a yellow solid (344 mg, 95%). 1 H NMR (400 MHz, chloroform-d): δ 10.63 (s, 1H, NH), 7.67 (d, J=1.9 Hz, 1H, CH-Ar), 7.46 (d, J=2.0 Hz, 1H, CH-Ar), 7.02 (s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 172.42, 158.50, 146.42, 135.11, 130.23, 126.82, 126.74, 119.82, 93.99. HRMS-ESI (m / z): C 9 H 4 Cl 5 N 3 S - [M+H] - Calculated value: 361.8641; Found value: 361.8464. HPLC purity (λ 254 ):>99.9%; tR : 14.60 minutes (method 1).

[0191] 2,2-Dibromo-N-(4-bromobenzo[d]thiazol-2-yl)acetamidine (MTF643)

[0192]

[0193] 4-Bromo-1,3-benzothiazol-2-amine (1.0 mmol, 229 mg, 1 eq) was dissolved in THF (2 mL), dibromoacetonitrile (5.0 mmol, 0.45 mL, 5 eq) was slowly added at ambient temperature, and the reaction mixture was heated at 60° C. After 18 hours (TLC monitoring), the crude reaction mixture was concentrated under reduced pressure to remove excess dibromoacetonitrile, and the resulting mixture was purified by flash chromatography (cyclohexane / ethyl acetate, 95 / 5, v / v) to give the pure product (269 mg, 63%) as a yellow solid. 1 HNMR (400MHz, chloroform-d): δ10.49 (s, 1H, NH), 7.69 (dd, J=8.0, 1.1Hz, 1H, CH-Ar), 7.61 (dd, J=7.9, 1 .0Hz, 1H, CH-Ar), 7.16 (t, J=7.9Hz, 1H, CH-Ar), 6.76 (s, 1H, NH), 6.10 (d, J=1.0Hz, 1H, CH-Br2). 13 C NMR (101 MHz, chloroform-d) δ 171.81, 159.87, 149.18, 133.74, 129.43, 125.32, 120.66, 115.06, 38.49. HRMS-ESI (m / z): C 9 H 7 Br 3 N 3 S + [M+H]+ calculated: 427.7885; found: 427.7867.

[0194] 2,2,2-Trichloro-N-(4-fluorobenzo[d]thiazol-2-yl)acetamidine (MTF645)

[0195]

[0196] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2-amino-4-fluorobenzothiazole (168 mg, 1 mmol) in THF. Purified by flash chromatography on silica gel (cyclohexane / EtOAc, 10 / 9 to 9 / 1, v / v) to give a yellow solid (237 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-d): δ 10.56 (s, 1H, NH), 7.52 (dd, J = 8.0, 1.0 Hz, 1H, CH-Ar), 7.23 (td, J = 8.1, 4.7 Hz, 1H, CH-Ar), 7.15-7.07 (m, 1H, CH-Ar), 6.90 (s, 1H, NH). 13 C NMR (101 MHz, chloroform-d): δ 171.91, 158.05, 154.84, 139.31, 135.74, 118.14, 117.21, 94.09, 27.03. 19 F NMR (chloroform-d): -123.35. HRMS-ESI (m / z): C 9 H 5 Cl 3 FN 3 S - [M+H] - Calculated value: 309.9170; Found value: 309.9180. HPLC purity (λ 254 ):>99.9%; t R : 12.38 minutes (Method 1).

[0197] 2,2,2-Trichloro-N-(4,6-dimethylbenzo[d]thiazol-2-yl)acetamidine (MTF646)

[0198]

[0199] 2,3-dihydro-4,6-dimethyl-2-iminobenzothiazole (178 mg, 1 mmol) was dissolved in THF (2 mL), and trichloroacetyl chloride (0.56 mL, 5 mmol) was slowly added at room temperature. The reaction mixture was then stirred at 40 ° C for 2 hours. The crude reaction mixture was evaporated under reduced pressure to remove excess trichloroacetyl chloride. The solid was recrystallized in ethanol to obtain the pure product (276 mg, 85%) as a beige solid. 1 H NMR (400 MHz, acetone-d 6 ): δ7.64(s,1H,CH-Ar), 7.24(s,1H,CH-Ar), 2.61(s,3H,CH 3 ), 2.44(s, 3H, CH 3 ). 13 C NMR (101 MHz, acetone-d 6): δ167.83, 167.20, 136.41, 136.14, 130.85, 129.00, 126.64, 120.71, 94.82, 21.28, 17.66. HRMS-ESI(m / z):C 11 H 10 Cl 3 N 2 OS + [M+H] + Calculated value: 322.9501; Found value: 322.9568. HPLC purity (λ 254 ): 95.1%; t R : 11.95 minutes (method 1).

[0200] 2,2,2-Trichloro-N-(4-chlorobenzo[d]thiazol-2-yl)acetamide (MTF647)

[0201]

[0202] 2-amino-4-chlorobenzothiazole (184 mg, 1 mmol) was dissolved in THF (2 mL), and trichloroacetyl chloride (0.56 mL, 5 mmol) was slowly added at room temperature. The reaction mixture was stirred at 40 ° C for 2 hours. The crude reaction mixture was evaporated under reduced pressure to remove the solvent and excess trichloroacetyl chloride. The obtained solid was recrystallized in ethanol to obtain the pure product (315 mg, 96%) as a white solid. 1 HNMR (400 MHz, acetone-d 6 ): δ8.01 (d, J=7.9Hz, 1H, CH-Ar), 7.59 (d, J=7.9Hz, 1H, CH-Ar), 7.42 (t, J=7.9Hz, 1H, CH-Ar). 13 C NMR (101 MHz, acetone-d 6 ): δ164.16, 162.98, 143.15, 133.30, 127.91, 126.34, 124.74, 121.88, 93.18. HRMS-ESI(m / z):C 9 H 5 Cl 4 N 2 OS + [M+H] + Calculated value: 328.8871; Found: 328.8865. HPLC purity (λ 254 ): 95.58%; t R : 11.40 minutes (method 1).

[0203] 2,2,2-Trichloro-N-(4,6-dimethylbenzo[d]thiazol-2-yl)acetamidine (MTF648)

[0204]

[0205] Synthesized according to the general procedure using trichloroacetonitrile (0.3 mL, 3 mmol) and 2,3-dihydro-4,6-dimethyl-2-iminobenzothiazole (178 mg, 1 mmol) in THF. Purified by silica gel flash chromatography (cyclohexane / ethyl acetate, 100 / 0 to 95 / 5, v / v) to give an orange solid (144 mg, 44%). 1 H NMR (400 MHz, chloroform-d): δ 10.65 (s, 1H, NH), 7.43 (s, 1H, CH-Ar), 7.07 (s, 1H, CH-Ar), 6.78 (s, 1H, NH), 2.61 (s, 3H, CH 3 ), 2.43(s, 3H, CH 3 ). 13 C NMR (101 MHz, chloroform-d): δ 169.77, 157.11, 147.89, 134.66, 133.21, 130.89, 128.43, 118.81, 94.35, 21.65, 18.51. HRMS-ESI (m / z): C 11 H 11 Cl 3 N 3 S - [M+H] - Calculated value: 320.9656; Found value: 320.9427. HPLC purity (λ 254 ):>99.9%; t R : 13.65 minutes (method 1).

[0206] Example 2: Antimicrobial Activity

[0207] The growth inhibition effect of two S. aureus strains (RN4240, a modified laboratory strain, non-pathogenic; and S25, a pathogenic strain obtained from a patient) by the presence of our compounds was used to evaluate the efficacy of the compounds as bacteriostatic and / or bactericidal compounds.

[0208] All presented compounds were dissolved in DMSO (10 mM stock solution) and initially tested at a concentration of 50 μM. Bacterial growth was measured after 5 and 20 hours of incubation with compounds at 37°C. As positive controls, the antibiotic ampicillin and the antibiotic kanamycin were used.

[0209] The results of 53 compounds are shown in [ Figure 1 ]middle.

[0210] Compounds substituted with 4-methyl, 4-chloro, and 4,6-difluoro showed complete growth inhibition after 20 h for both strains, and the 4,6-dichloro compound showed <3% bacterial growth. Compounds containing 4-fluoro and 4,6-dimethyl substituted benzothiazole moieties also showed good inhibition against the nonpathogenic strain RN4220.

[0211] The minimum inhibitory concentration (MIC) of the compound (MTF235, MTF572 and MTF573) for which both strains showed no growth at 20 hours was determined. MIC is defined as the minimum concentration of a compound that inhibits bacterial growth. For this reason, six doses (1 μM, 5 μM, 12.5 μM, 25 μM, 50 μM, 100 μM) were tested for both strains incubated at 37°C for 20 hours. In addition, a small aliquot of those cultures that did not grow after 20 hours under the determined conditions was taken and inoculated in fresh bacterial culture medium to evaluate the minimum bactericidal concentration (MBC) after 24 hours.

[0212] The absence of bacterial growth indicates that the compound has not only a bacteriostatic effect (inhibits growth over a period of time) but also a bactericidal effect (promotes bacterial death). The results of the comparison of the bacteriostatic and bactericidal activities are summarized in Table 1 below.

[0213]

[0214]

[0215] Minimum inhibitory concentration (MIC, 20 h incubation) and maximum bactericidal concentration (MBC, 24 h incubation) of S. aureus strains RN4220 and S25.

[0216] 2 strains of Staphylococcus aureus :

[0217] RN4220 (non-pathogenic)

[0218] S25(Pathogenicity)

[0219] MIC: Minimum inhibitory concentration

[0220] MBC: Minimum bactericidal concentration

[0221] Example 3: Cytotoxicity

[0222] HEK293: 24 h in the presence of fungicide compounds or DMSO

[0223] Evaluation method: CyQUANT TM LDH Cytotoxicity Assay Kit.

[0224] The results are in [ Figure 2 ] is shown in ].

[0225] Cytotoxicity was assessed by quantification of extracellular lactate dehydrogenase (LDH) when compounds were incubated with HEK 293T cells in the same concentration range as MIC and MBC. LDH: positive control, DMEM: negative control. N=3.

[0226] The preliminary safety of these compounds on host cells was evaluated by using the extracellular lactate dehydrogenase (LDH) release model of human embryonic kidney 293 cells (HEK293). When incubated at their active doses, the compounds MTF235, MTF573, MTF640, MTF642 and MTF643 showed similar extracellular lactate dehydrogenase (LDH) quantitative levels to the DMSO control, but did not show cytotoxic activity.

[0227] :……

Claims

1. A compound having the following formula I: in -R1 represents O or NH, -R2 represents a linear, branched or cyclic alkyl group containing 1 to 8 carbon atoms, which may be interrupted by a group selected from -O-, -S-, -(C=O)-, NH and may be substituted by one or more halogens; an alkylene group containing 1 to 8 carbon atoms and which may be substituted by one or more halogens, Phenyl or arylene, -R3, R4 and R5 independently represent -H; halogen; a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens; CN; -NO2; OX1, wherein X1 is selected from -H, a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens; COOR6; OCOR6; SO2NR6R7; NR6R7; NR6COR7 or OR6, wherein R6 and R7 are the same or different, and R6 and R7 represent H or an alkyl group containing 1 to 8 carbon atoms, Used as medicine.

2. A compound having the following formula I: in -R1 represents O or NH, -R2 represents a linear, branched or cyclic alkyl group containing 1 to 8 carbon atoms, which may be interrupted by a group selected from -O-, -S-, -(C=O)-, NH and may be substituted by one or more halogens; an alkylene group containing 1 to 8 carbon atoms and which may be substituted by one or more halogens, Phenyl or arylene, -R3, R4 and R5 independently represent -H, halogen, a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens, -NO2 or OX1, wherein X1 is selected from -H, a linear or branched alkyl group containing 1 to 8 carbon atoms which may be substituted by one or more halogens, For its use as a medicine.

3. A compound of formula (I) for use according to any one of claims 1 or 2, wherein R2 represents a straight or branched alkyl group containing 1 to 5 carbon atoms substituted by at least one halogen.

4. The compound of formula (I) for use according to any one of claims 1 to 3, wherein R2 represents a linear or branched alkyl group containing 1 to 5 carbon atoms substituted by 3 halogens.

5. A compound of formula (I) for use according to any one of claims 1 to 4, wherein at least one of R3 or R5 represents a straight or branched alkyl group containing 1 to 6 carbon atoms which may be substituted with one or more halogens, or a halogen, and R4 represents H.

6. A compound of formula (I) for use according to any one of claims 1 to 5, wherein R3 represents halogen or a linear or branched alkyl group containing 1 to 3 carbon atoms.

7. A compound of formula (I) for use according to any one of claims 1 to 6, wherein R1 represents NH.

8. A compound of formula (I) for use according to any one of claims 1 to 7, wherein R2 represents C(R'1)3, wherein said R'1 represents halogen.

9. The compound of formula (I) for use according to any one of claims 1 to 8, wherein at least one of R3, R4 or R5 represents -H.

10. The compound of formula (I) for use according to any one of claims 1 to 9, which has one of the following formulae: as well as 11. The compound of formula (I) for use according to any one of claims 1 to 10, wherein the compound is used as an antibiotic.

12. A compound of formula (I) for use according to any one of claims 1 to 10, wherein the compound is used to treat an infectious disease associated with at least Gram-positive bacteria or Gram-negative bacteria.

13. according to the compound of any one of the formula (I) in claim 1 to 10, wherein in the formula (I), R1 represents O, R2 represents CCl3, R3 and R4 represent H and R5 represent Cl except the compound; and wherein in the formula (I), R1 represents O, R2 represents CCl3 or CH2Cl and R3, R4 and R5 represent H except the compound; and the compound of the following formula except 14. Compounds of formula (I) wherein R1, R2, R3, R4, R5 are as defined in any one of claims 1 to 10, and the compound is complexed with at least one metal ion.

15. A pharmaceutical composition comprising at least a compound of formula (I) Wherein R1, R2, R3, R4, R5 are as defined in any one of claims 1 to 10, a salt or metal complex thereof, and a pharmaceutically acceptable carrier.

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