Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
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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.
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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.
8 EXAMPLE I
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
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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.
21 EXAMPLE II
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
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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
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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
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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
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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
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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.
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~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.
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