CA1093084A - 2-r-substituted-1,2,5-thiadiazole-3-ones antimicrobials - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of the formula:

Description

10930~4 13 DISCLOSURE OF THE INVENTION:
14 This invention relates to a new class of anti-bacterial and antifungal compounds, particularly 2-R-16 substituted-1,2,5-thiadia201e-3-ones. Although derivatives 17 of 1,2,5-thiadiazoles are known, for instance, U.S.P.
18 3,854,000 and U.S.P. 3,763,176, such compounds must 19 necessarily have a halogen in the 4-position. The compounds of this invention are halogen free.
21 The 2-R-substituted-1,2,5-thiadiazole-3-ones of 22 this invention have the structural ~ormula:

~C~
CH ~-R
Il I
N S

(I) 23 where R is a hydrocarbon group of from 1-16 carbon atoms 24 including Cl to C16 alkyl, phenyl-Cl to C10 alkyl, and phenyl. In general, it is preferred that the hydrocar~on ~0~3084 l group R contain from 6-14 carbon atoms, C12 alkyl and benzyl

2 be:ing the most preferred groups. The term "alkyl" includes

3 straight or branched hydrocarbon radicals. R includes, for

4 example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, 1-(2-ethyl)propyl, hexyl, 1-(2,3-dimethyl)-6 butyl, heptyl, 1-(2-ethyl-4-methyl)butyl, octyl, nonyl, 7 decyl, dodecyl, hexadecyl, 4-t-butylphenyl, 2,4-diethyl-8 phenyl, 4-ocylphenyl, 3-heptylphenyl, 4-hexylphenyl a~d 9 2,4,6-triethylphenyl.
The compounds of this invention are prepared by 11 reacting an amide of formula II with at least one mole of 12 sulfur monohalide, S2X2, where X is bromine or chlorine.

2 C 2 C ~H S2X2 II

O X ~O
1~ + 11 - I
N ~-R ~S/

(III) (IV) (a minor amount) 13 The reaction is conducted in any inert solvent such 14 as dimethylformamide or hexamethylphosotriamide at a temper-ature of from about -10C. to 60C. for from about 10 to 18 16 hours.
17 The molar ratios of glycine R-substituted amide 18 free base or salt to SX2 can range from 1:2 to 1:5 althou~h 19 a molar ratio of 1:3 is most satisfactory.
. After reaction is complete, the solvent is stripped 21 under vacuum.
22 The 2-R-substituted-1,2,5-thiadiazole-3-ones are 23 neutral compounds readily extractable from acidic or basic 24 mixtures.

~0~30~4 1 The rather minor quantities of compound IV produced 2 in the preparation of product III can be removed by usual 3 techniques such as distillation, crystallization as well as 4 column chromatography.
The following examples are presented to illustrate 6 the invention but should not be construed as lLmitations 7 thareof.

9 2-n-Dodecyl-1,2,5-thiadiazole-3-one N-n-Dodecyl-2-aminoacetamide.HCl (23.55 g., 84.6 11 mmoles) is added in portions over 45 minutes to a stirred 12 solution of sulfur monochloride (34.8 g., 258 mmoles~
13 dimethylformamide in 75 ml. (DMF), maintaining the reaction 14 temperature between 5C.-8C. During the addition, the mixture became quite thick and 25 ml. DMF is added. After 16 the addition is complete, another 25 ml. DMF is added and 17 the reaction mixture allowed to warm to room temperature and 18 stirred for 18 hours. The reaction mixture is poured into 19 1 liter water and extracted three times with 300 ml. ether.
The ether i~ dried (Na2SO4) and evaporated to dryness. The 21 solid residue was chromatographed on silica gel to afford 22 18.44 g. of 2-n-dodecyl-1,2,5-thiadiazole-3-one (813 yield), 23 m.p. 68C.-70C. (hexane).
24 Analysis calculated for Cl~H26N2OS C, 62-18; H, 9.69; N, 10.36; S, 11.85. Found C, 62.37; H, 9.53; N, 10.50;
26 S, 12.00.
27 The above procedure is general for the preparation 28 of the 2-Cl to C16-R-substituted-1,2,5-thiadiazole-3-ones 29 of this invention and the entire range of products are 158~5 ~0~3~0~4 1 obl:ained by employing 2-Cl to C16-R-substituted-~-amino-2 acetamide in analogous molar quantities to the N-n-dodecyl-3 2-aminoacetamide.
4 T~3LE I
Product ~0 ~ ~-R
6 REACT~NTS S~
7 R-2-aminoacetamide S~X2 R
,, ~
8 H2NCH2CONHCH2~ . HCl S2C12 -CH
9 H2NCH2CONHCH3 . HCl S2C12 -CH3 10 H2NCH2CONH2~ . HCl S2C12 -~
H2NCH2CONH2CH2CH2CH3 . HCl S2C12 -CH2CH2CH3 12 H2NCH2CONH2CH-(CH3)2 S2C12 -CH(CH3)2 13 The N-substituted-2-aminoacetamides intermediates, 14 required for the synthesis of the 2-substituted-1,2,5-thiadiazole-3-ones, can be prepared by standard methods 16 (James R. Vaughan, Jr., and Ruth L. Osato, J. Amer. Chem.
17 Soc., 74, 676 (1952), and Miklos Bodansky and Vincent Du 18 Vigneaud, J. Amer. Chem. Soc., 81, 5688 (1959)). The 19 following example for N-_-dodecyl-2-aminoacetamide hydro-chloride is typical.

22 N-n-Dodecyl-2-aminoacetamide Hydrochloride 23 Step A: N-Benzyloxycarbonyl glycine (209.2 g., 24 1 mole) is suspended in 600 ml. CHC12 and 140 ml. triethyl-amine is added. A solution gradually results. This 26 mechanically stirred solution is cooled in an ice-salt bath 27 and ethyl chloroformate (110 g., 1 mole~ is added dropwise 28 over 45 minutes, keeping the temperature at 0C.-3C. The 1584 6I~

30~4 1 resulting mixture is stirred in the cold an additional one-2 ha:Lf hour. A solution of n-dodecylamine (185.4 g., 1 mole) 3 in 250 ml. CH2C12 is added dropwise, keeping the temperature 4 beLow 10C. After the addition, the mixture is allowed to come to room temperature and stirred for 20 hours; diluted 6 with 500 ml. CH2C12 and washed with water, then diluted 7 NaOH, then water, dried and evaporated to dryness. The 8 residual solid is suspended in 1 liter petroleum ether (30C.
9 -60C.) and boiled for 15 minutes, cooled and filtered, yielding 228.3 g. of N-n-dodecyl-(2-benzyloxycarbonylamino)-11 acetamide, m.p. 112C.-115C. (dec.) (benzene-petroleum 12 ether).
13 Analy~iS calculated for C12H36~23 C~ 70-18;
14 H, 9.64; N, 7.44. Found: C, 69.76; H, 9.26; N, 7.56.
Step B: 10 G. of N-n-dodecyl-(2-benzyloxycarbonyl-16 amino)acetamide is suspended in 200 ml. MeOH and 1 g. 10% Pd/
17 charcoal hydrogenated until no more H2 is absorbed. The 18 resulting suspension is acidified with 3 ml. concentrated 19 HCl and filtered. The solution is concentrated under vacuum until the product begins to crystallize. It is warmed to 21 dissolve the solid and ether added to induce crystallization.
22 This is iltered to yield N-n-dodecyl-2-aminoacetamide 23 hydrochloride (5 g.) as white crystals, m.p. 200C.
24 Analysis calculated for C14H30N2O.HC1 C, 60-30;
H, 11.21; N, 10.04; Cl, 12.71. Found C, 60.49; H, 11.27;
26 N, 10.Z3; Cl, 12.94.
27 In an analogous manner Cl-C16-alkylamines can be 28 substituted for a similar molar quantity of the n-dodecyl-29 amine to prepare the entire range of the compounds of this invention. Thus, substituting respectively benzylamine, 31 methylamine, aniline, 2-aminopropane and l-aminopropane 15846I~

1 for the n-dodecylamine there is obtained N-benzyl-2-amino-2 acetamide . HCl; N-methyl-2-aminoacetamide . HC1; N-phenyl-3 2-aminoacetamide . HCl; isopropyl-2-aminoacetamide . HCl;
4 and N-propyl-2-aminoacetamide . HClo The compounds of our invention are broad spectrum 6 antibacterial and antifungal agents. For use, the compounds 7 described herein can be applied neat or employed in a diluted 8 form. Satisfactory diluents include any inert material not 9 destructive of the antimicrobial activity and especially liquid formulations comprising aqueous dispersions, solutions, 11 and emulsions. Solid diluents include talc, corn starch, 12 alumina and diatomaceous earth. The anti~icrobial agents of 13 this invention can also be deposed on materials such as 14 natural fibers including paper, cotton, wool and synthetic fibers such as nylon, polypropylene, as well as upon inan~mate 16 surfaces including hard surfaces such as wood, glass, metal, 17 tile, rubber, plastic, and porous surfaces such as concrete, 18 leather and the like.
19 Another application is alone or in solution or suspension or in conjunction with soaps or detergents for 21 use in cleansing the skin, particularly in presurgical 22 scrubbing formulations, or in formulations for controlling 23 the growth of Corynebacterium acnes. C. acnes is a strain 24 of bacteria implica~ed in acne conditions, especially Acne vul~aris, wherein applications of as little as 1 to 5 ppm.
26 is effective in controlling such skin dwelling bacteria.
27 Larger concentrations can be used, if desired, without 28 irritation or discomfort such as 2500 ppm and higher. Where 29 the cleansing formulation is diluted with water upon use, the ~0~330~34 1 formulation can comprise from 0.01% by weight and more of 2 the compounds of this invention.
3 In addition, the compounds described herein can 4 be employed in impounded water, such as swimming pools, ponds or industrially-used water such as papermill water 6 to inhibit growth of undesirable bacteria, fungi, and/or 7 algae at levels as low as 0.5-5 ppm.
8 In the control of slime-producing microorganisms g and algae in recirculating industrial waters, particularly cooling operations and especially installations such as 11 cooling towers, the compounds of this invention are usually 12 employed alone, but can also be used in combination with 13 other antimicrobial agents. Concentrations in the recir-14 culating water of as little as 1 x 10 4% by weight are effective in inhibiting microbial growth. To insure effec-16 tiveness, especially against more resistant strains of micro-17 organisms, and also when make-up water is added to replace 18 water lost by evaporation and the like, concentrations of 19 from 1 x 10 4% to 5 x 10 2% by wei~ht are most satisfactory.
Dosage may be continuous or as intermittent "shock treat-21 ment", i.e., addition in a 10-20 minute period every 4-8 22 hours. They are especially useful against bacteria and 23 fungi responsible for stunting the growth and even destruc-24 tion o~ many types of crop-producing plants. In agriculture, severe problems are faced in the raising of cotton, beans, 26 corn and other crops because of the loss of yield per acre 27 due to the action of soilborne fungi on seed and on the 28 roots of the young plants. Control or elimination of these 29 losses can be accomplished by the use of the compounds herein described as soil disinfectants in accordance with 31 the invention. They can also be used for the control of 158~6IA

10930~

1 bacterial and fungal diseases on trees and stored crops.
2 In formulating the compounds of this invention for 3 thle above uses, these compounds can be employed in combina-4 tion with other antimicrobial agents, surfactants, insecti-cides, defoamers, odorants, or as chelates of metals such as 6 copper, ca~cium, magnesium and iron.
7 Wettable powder formulations for use as a disper-8 sant in water represent a practical means for good distri-9 bution in soil. Other methods of achieving the same results include the preparation of dusts. All of the 11 thiadiazole-3-ones can be blended as fine po~ders with the 12 commonly used powder diluents such as talc, clay, refined 13 silicates, wood flour, sand, magnesium oxide, calcium 14 carbonate, fuller's earth, kaolin, diatomaceous earth, mica, pumice and the like. The powder can have the 16 following formulation:
17 Percent 18 R-Substituted-1,2,5-thiadia~ole-3-one 1-75 19 Inert Diluent (clay, talc, etc.) 25-99 The mixtures may be ~inely powdered, e.g., to 21 the 1-10 micron average particle size, or be made by 22 blending the already finely powdered ingredients.
23 For application as agricultural disinfectants 24 the dusts may be applied to the seed and surrounding soil at the time of planting. The concentration of the sterilant 26 is adjusted to give an effective, nonphytotoxic dosage in 27 the soil. In general, the soil concentration should be from 28 10 to 25 parts per million (of active ingredient). For most 29 economical and effective use the dusts can be applied in bands of 6 to 8 inches centered on the rows just prior to ~093~84 1 seeding. The material can then be rototilled to a depth of 2 several inches. This mode of treatment saves material and 3 protects the root system of young plants against microbial 4 attack. For the protection of a given crop, such as cabbage, the band spread of antimicrobial can vary from 6 8 inches for black root disease to 12-15 inches for club 7 root disease prevention. Similarly, the depth to which 8 the fungicide should be distributed can vary from 2 to 6 9 inches.
The wettable powders can be prepared by the 11 addition of 0.1-5% of a wetting agent to the powder blends.
12 Many dispersing agents are commercially available which are 13 nonphytotoxic at the required concentrations. These may, 14 for example, be alkali metal and amine salts of sulfated and sulfonated acids, alcohols, and oils, or polyethoxylated 16 alkyl phenols, long chain fatty amine quaternary salts, 17 partial phenols, long chain fatty amine quaternary salts, 18 partial fatty acid esters of polyhydric alcohols, etc.
1~ Some dispersants can be used in preparing emulsifiable concentrate~ of the polyamines in organic solvents. Many 21 of these agents are available in solvent-soluble form.
22 The manner of application to the soil is similar to the 23 dusts. Spray equipment is used to spread the suspensions 24 or emulsions over the soil and by discing, the fungicidal agents can be uniformly distributed to varying depths.
26 Spray application is also effective for band-limiting the 27 dosages.

~093084 1 Other agricultural uses for these formulations 2 involve the eradication of bacterial blights of plants by 3 application to the involved surface areas. The compounds 4 of this invention show high orders of bacterial inhibition and are especially useful for this purpose. Some of the 6 diseases which are of commercial importance in decreasing 7 yield and quality and are controlled by the compositions 8 of the invention are fire blight of apple and pear, 9 bacterial spot on stone fruit, cherry leaf spot, walnut blight, com~on blight of bean, bacterial spot of tomato 11 and pepper, and potato seed piece decay. The effective 12 concentration of R-substituted-1,2,5-thiadiazole-3-one 13 required varies from 5-200 parts per million parts of 14 the material to be protected. They may be applied as dusts, powder dispersions in water ac emulsions in water, 16 or as aqueous dipping baths. Other plant diseases which 17 can ~e controlled by treatment with these formulations 18 are fungal in origin, such as the many kinds of powdery 19 mildew and leaf scabs.
For seed treatment, proportions as low as 1 to 21 4 ounces per hundred weight (550 to 600 ppm on seed) are 22 effective against various fungi.
23 The compounds of the invention can be used in form 24 of aqueous suspensions or emulsions, the base products being generally insoluble in water. For this type of formulation 26 various powdered carriers can be employed to aid in achiev-27 ing uniform distribution. Talc, fuller's earth, calcium 28 silicate, calcium carbonate, clays and the like are admixed 29 with the agent along with wetting and dispersing agents and sticking agents. For maximum chemical compatability those 31 which are non-ionic in character are preferred. Other non-32 ionic or cationic surfactants are also satisfactory.

Claims (11)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for preparing compounds of the formula:

wherein R is an alkyl group of from 1 to 16 carbon atoms, benzyl or phenyl comprising reacting an amide of the formula:

with at least one mole of a sulfur monohalide, SX2, wherein X is bromine or chlorine, at a temperature of from -10°C. to 60°C. for 10 to 18 hours.

2. A method of preparing compounds of the formula:

wherein R is a hydrocarbon of from 1 to 16 carbon atoms comprising reacting a mole of a compound of the formula:

with from 2 to 5 moles of sulfur monohalide.

3. A process according to Claim 1, wherein R is alkyl.

4. A process according to Claim 1, wherein R is isopropyl.

5. A process according to Claim 1, wherein R is propyl.

6. A process according to Claim 1, wherein R is dodecyl.

7. A compound prepared according to the process of Claim 1 having the formula:

wherein R is an alkyl group of 1-16 carbon atoms, benzyl or phenyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

8. A compound according to Claim 7, wherein R is alkyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

9. A compound according to Claim 7, wherein R is isopropyl, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

10. A compound according to Claim 7, wherein R is propyl, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

11. A compound according to Claim 7, wherein R is dodecyl, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.