Anti-fungal composition and method
United States Patent 1191 Fujinami et al.  
 [ 1 Apr. 8, 1975 Tadashi Ooishi, Osaka, all of Japan I [73] Assignee: Sumitomo Chemical Co., Ltd.,  
 Osaka, Japan [22] Filed: Nov. 13, 1972 [211 Appl. No.: 305,998  
 Related US. Application Data [63] Continuation of Ser. No. 86l ,l78. Sept. 25. 1969.  
 abandoned.  
 [30] Foreign Application Priority Data Nov. 27, 1968 Japan 43-87108 [52] US. Cl 424/300; 260/471 C; 424/23;  
 &#39; 424/46; 424/357 [Sl] Int. Cl A0ln 9/20 [58] Field of Search 424/300 [56] References Cited UNITED STATES PATENTS 3.142.694 7/l964 Metivier 260/455 A FOREIGN PATENTS OR APPLlCATlONS 43-l6074 7/1968 Japan 424/300 Primary E.\&#39;amin2 rAlbert T. Meyers Assistant E.\&#39;am1:1rrDale R. Ore  
 Attorney, Agent. or Firm-Bierman &amp; Bierman 1 r ABSTRACT a-(N-Phenylcarbamoyloxy)alkanoate derivatives of the formula:  
 wherein X is halogen, Y and Z are each oxygen or sulfur and R and R are each hydrogen or lower alkyl are useful as antimicrobial agents. The derivatives are prepared by reacting a 3,5-dihalogenated phenyl isocyanate derivative of the formula:  
 wherein X and Y are each as defined above with a glycolic acid derivative of the formula:  
 wherein Z, R and R are each as defined above.  
 4 Claims, No Drawings .yl-lower It @Nri-t l-z-dn-ooon&#39; Y wherein X is halogen (e.g. chlorine, bromine, iodine), Y and Z are each oxygen or sulfur and R and R are each hydrogen or lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl), the term lower meaning the one having 1 to carbon atoms.  
 Thus, the term a-(N-phenylcarbamoyloxy)alkanoate derivatives herein used has a broad meaning and is intended to include the following four kinds of compounds: a-[ N-( 3 ,S-dihalogenated phenyl )carbamoyloxy1alkanoic acid and its derivatives [l1 Y oxygen, Z oxygen]; a-[N-(3,5-dihalogenated phenyl)thiocarbamoyloxylalkanoic acid and its derivatives H: Y sulfur, Z oxygen]; a-[N-3,5-dihalogenated phenyl)carbamoylthiolalkanoic acid and its derivatives ll: Y oxygen. Z sulfur]; and a-[N-(3,5-dihalogenated phenyl- )thiocarbamoylthio]alkanoic acid and its derivatives [1: Y sulfur, Z sulfur].  
  Specific examples of compounds in. the category of a-(N-phenylcarbamoyloxy)alkanoate derivatives [1] are as follows: a-[N-(3,5-dihalophenyl)carbamoyloxyl-lower alkanoic acid (e.g. N-(3,5- dichlorophenyl)carbamoyloxyacetic acid, N-(3,5- dibromophenyl)carbamoyloxyacetic acid, a-[N-(3,5-  
  dichlorophenyl )carbamoyloxyl-propionic acid, 04-] N- (3,5-dichlorophenyl)carbamoyloxy1-butyric acid), lower alkyl a-[N-(3,5-dihalophenyl)-carbamoyloxy]- lower alkanoate (e.g. methyl N-(3,5-dichlorophenyl)- carbamoyloxyacetate, ethyl N-(3,5-dichlorphenyl)car bamoyloxyacetate, ethyl a-[N-( 3,5- dichlorophenyl)carbamoyloxylpropionate), a-[N- (3,5-dihalophenyl)thiocarbamoyloxy1-lower alkanoic acid (e.g. N-(3,5-dichlorophenyl)thiocarbamoyloxyacetic acid, N-(3,5-dibromophenyl)thiocarbamoyloxyacetic acid, a-[ N-( 3 ,5- dichlorophenyl)thiocarbamoyloxylpropionic acid), lower alkyl a-[N-(3,5-dihalophenyl)thiocarbamoyloxalkanoate (e.g. methyl N-(3,5- dichlorophenyl)thiocarbamoyloxyacetate, ethyl N- (3,5-dichl0rophenyl)thiocarbamoyloxyacetate, ethyl a-[ N-( 3 ,S-dichlorophenyl )thiocarbamoyloxy]propionate), a-[N-(3,5-dihalophenyl)carbamoylthiol-lower alkanoic acid (e.g. N-(3,5-dichlorophenyl)carbamoylthioacetic acid, N-(3,5-dibromophenyl)carbamoylthioacetic acid, a-[N-(3,5&#39;dichlorophenyl)carbamoylthiol-propionic acid), lower alkyl a-[N-(3,5- dihalophenyl)carbamoylthio1-lower alkanoate (e.g. methyl N-(3,5-dichlorophenyl)carbamoylthioacetate, ethyl N-(3,5-dichlorophenyl)carbamoylthioacetate, ethyl a-[N-(3,S-dichlorophenyl)carbamoylthio1pro- 2 pionate), oz-[N-(3,5-dihalophenyl)thiocarbamoylthio]- lower alkanoic acid (e.g. N-( 3,5-  
 dichlorophenyl)thiocarbamoylthioacetic acid, N-(3,5- dibromophenyl)thiocarbamoylthioacetic acid, a-[N- (3,5-dichlorophenyl)thiocarbamoylthio]propionic acid), lower alkyl ,a-[N-(3,5- dihalophenyl )thiocarbamoylthiol-lower alkanoate (e.g. methyl N-(3,5-dichlorophenyl)thiocarbamoylthioacetate, ethyl N-(3,5-dichlorophenyl)thiocarbamoylthioacetate, ethyl a-[N-(3,5- dichlorophenyl)thiocarbamoylthio]-propionate), etc.  
  It has now been found that said a-(N-phenylcarbamoyloxy)alkanoate derivatives [1] exhibit a strong anti-microbial activity against a wide variety of microorganisms including phytopathogenic fungi and parasites of industrial products. This finding is an unexpected and surprising property in light of the fact that analogous compounds such as the corresponding 3,5- unhalogenated derivatives show no appreciable activity.  
  A basic object of the present invention is to embody the novel a-(N-phenylcarbamoyloxy)alkanoate derivatives [l]. Another object of this invention is to embody the a-(N-phenylcarbamoyloxy)alkanoate derivatives [I] having a marked anti-microbial activity. A further object of the invention is to embody a process for preparing the a-(N-phenylcarbamoyloxy)alkanoate derivatives [I]. These and other objects will be apparent from the subsequent descriptions to those conversant with the art to which the present invention pertains.  
  According to the present invention, the a-(N- phenylcarbamoyloxy)alkanoate derivatives [l] are prepared by reacting a 3,5-dihalogenated phenyl isocyanate derivative of the formula:  
 X II  
 wherein X and Y are each as defined above with a glycolic acid derivative of the formula:  
  lt likH-COOR III wherein Z, R and R are each as defined above.  
  Examples of the 3,5-dihalogenated phenyl isocyanate derivative [ll] are 3,5-dichlorophenyl isocyanate, 3,5- dibromophenyl isocyanate, 3,5-dichlorophenyl isothiocyanate, 3,5-dibromophenyl isothiocyanate, etc. Examples of the glycolic acid derivative [Ill] are glycolic acid, thioglycolic acid, methyl glycolate, ethyl glycolate, methyl thioglycolate, ethyl thioglycolate, methyl lactate, ethyl lactate, methyl thiolactate, ethyl thiolactate, etc.  
 The reaction between the 3,5-dihalogenated phenyl isocyanate derivative [I1] and the glycolic acid derivative [lll] may be carried out in an inert solvent (e.g. benzene, toluene, xylene, ether, chloroform) in the presence of a catalytic amount of an organic base (e.g. pyridine, triethylamine, N-methylmorpholine) at a temperature ranging from room temperature to reflux temperature. The reaction is usually completed within several hours. By evaporation of the solvent from the Table Test organism Minimal inhibitory concentration (ppm) Pyricularia oryzae 8 Xanthomonas oryzae 40 Pellicularia 40 Fusarium oxysporum f. niveum 40 Corticium rolfsii 8 Botrytis cinerea 200 Sclcrotinia sclerotiorum 40 Alternaria kikuchiana 40 Alternaria mali 40 (ilomerclla cingulata 8 Aspcrgillus niger 40 Some of the test results which also support the antifungal activity of the a-(N-phenylcarbamoyloxy)alkanoate derivatives [1] are shown below.  
 TEST 1 the known compound, i.e. ethyl a-(N- phenylcarbamoylthio) acetate.  
 Table Number of diseased Test compound spots per 10 leaves y 4 .5-dichlorophcnyl carhamoylthioacetate l9 Ethyl N-(3.5-dichlorophenyl)- thiocarhanioylthioacetate 9 Ethyl a-[N-(3.5-dichlorophcnyl)- thiocarbamoyloxypropionate 28 N-( 3.5-Dichlorophenyl )carbamoylthioacetic acid Ethyl N-phenylcarbamoylthioacetate 176 Control (Untreated) (93 TEST 2 The test compound in dust form (4.0% by weight concentration) was applied to rice plants cultured in pots of 9 cm in diameter and grown up to the four leaved stage. mg of the dust was applied per pot with the use of a duster. After one day, the plants were sprayed to inoculate them with a spore suspension of Coc/zliobolus miyabeanus. Three days thereafter, the number of diseased spots was counted. The results are shown in the following table. It is seen from said table that the oz-(N-phenylcarbamoyloxy)alkanoate derivatives [I] have stronger anti-fungal activity than the known compounds, ethyl N-phenylcarbamoylthioacetate and O-ethyl S,S-diphenyldithiophosphate.  
 Table Test compound Number of diseased spots per leaf Ethyl a-[ N-( 3.5-dichlorophenyl carhamoyloxylpropionate 7.8 Ethyl N-( 3,5-dichlorophenyl carbamoylthioacetate 3.6 Ethyl a-[ N-( 3.5-dichlorophenyl thiocarhamoyloxylpropionatc 6.5 N-( 3.5-Dichlorophcnyl )carbamoyl oxyacctic acid 8.9 N-( 3.5-Dichlorophcnyl )carhamoylthioacctic acid 6.1 Ethyl N-phenylcarbamoylthioacetate 58.0 O-Ethyl S.S-diphenyldithiophosphorodithiolate 23.9 Control (Untreated) 61.7  
 TEST 3 The test compound in wettable powder form was diluted with water to make a 500 ppm concentration. The dilution was then applied to pumpkin seedlings cultured in pots of 12 cm in diameter and grown up to the three to four leaved stage. 7 ml of the dilution was applied per pot. After one day, the plants were sprayed to inoculate them with a spore suspension of Sphaerot/zeca jizliginea. Ten days thereafter, an infectious state was observed on the upper four leaves, and the degree of damage was calculated from the invectious area according to the following equation:  
 Degree of damage 2 (Infection index X Number of leaves)/(T0tal number of leaves X 5) X 100 wherein the infection index was determined based on the following criteria:  
 Infectious area lndex number None 0 Small 1 Medium 3 Large 5 The results are shown in the following table, from which it is seen that the a-(N-phenylcarbam0yloxy)alkanoate derivatives [1] have strong anti-fungal activity in a level nearly equal to that of a commercially available anti-fungal agent, dinocap (4,6-dinitro-2-( lmethylheptyl)phenyl crotonate Table Test compound Degree of damage Ethyl a-[ N-( 3,5-dichlorophenyl Table-Continued Test compound Degree of damage TEST 4 Into each pot (9 cm in diameter) there was charged field soil, and a soil (10 ml) infected with Pelliculariu filamenlosu was dispersed over the surface. The test compound in emulsifiable concentrate form was diluted with water to make a 500 ppm concentration, and the dilution was poured into said pot at a concentration of ml per 3.3 m&#39;-. After 2 hours, 10 seeds of cucumber were sowed therein. 5 days thereafter, the infectious state of the grown seedlings was observed, and the percentage of stand was calculated according to the following equation:  
 Percentage of stand (Number of healthy seedlings in treated plot/Number of germination in untreated plot) x 100 The results are shown in the following table, from which it is seen that the a-(N-phenylcarbamoyloxy)alkanoate derivatives [1] have strong anti-fungal activity in a level nearly equal to that of a commercially available anti-fungal agent. pentachloronitrobenzene.  
 Table Test compound Percentage of stand Ethyl N-( 3,5-dichlorophcnyl carbamoylthioacctate 93.8 Ethyl N( 3.5-dichlorophenyl thiocarhamoylthioacetate 100.0 Ethyl a-IN-(3,5-dichlorophenyhthiocarbamoyloxylpropionate 90.2 N-( 3.5-Dichlorophenyl )carbamoylthioacctic acid 89.1 Ethyl N-phenylcarbamoylthioacetate 0 Pentachloronitrobenzene 88.5 Control (Untreated) 0 such as dust, Wettable powder, oil spray, aerosol, tablet, emulsifiable concentrate, pellet or granule. Besides the oz-(N-phenylcarbamoyloxy)alkanoate derivatives [l], the anti-microbial compositions may contain one or more known fungicides (e.g. Blasticidin S, Kasugamycin, Polyoxyin, Cellocidin, Chloramphenicol, 0,0- diethyl-S-benzylphosphorothiolate, O-ethyl-S,S- diphenylphosphorodithiolate, O-n-butyl-S-ethyl-S- benzylphosphorodithiolate, 0,0-diisopropyl-S- benzylphosphorothiolate, O-ethyl-S-benzylphenylthiophosphonate, pentachlorobenzaldoxime, pentachlorobenzyl alcohol, pentachloromandelonitrile, pentachlorophenyl acetate, iron methylarsonate, ferric ammonium methyl arsonate, 7-1,2,3,4,5,6-hexachlorocyclohexane, 1,1,l-trichloro-2,2-bis(pchlorophenyl)ethane, 0,0-dimethyl-O-(pnitrophenyl)-phosphorothioate, S-[ l ,2-bis(ethoxy carbonyl)ethyl] 0,0-dimethyl phosphorodithioate, 0,0- dimethyl S-(N-methylcarbamoylmethyl) phosphorodithioate, O-ethyl O-p-nitrophenyl phenylphosphonothiorate, a-naphthyl N-methyl carbamate, 0,0-dirnethyl- O-(p-nitro-m-methylphenyl) phosphorothioate, 3,4,5,-  
 6-tetrahydrophthalimidemethyl chrysanthemate, 3,4- 7  
 dimethylphenyl N-methylcarbamate, 0,0-diethyl O- (2-isopropyl-6-methyl-4-pyrimidinyl)thiophosphate. 0,0-dimethyl-2,2-dichlorovinyl phosphate, l,l-bis(pchlorophenyl )-2,2,2-trichloroethanol, 1,2- dibromoethane, l,2-dibromo-3-chloropropane. zinc ethylene bis(dithiocarbamate), manganese ethylene bis(dithiocarbamate 2,3-dichloro-l ,4- naphthoquinone, N-(trichloromethylthio)-4- cyclohexene-l,Z-dicarboximide, N-( l,l ,2,2- tetrachloroethylthio )-4-cyclohexene-l ,2- dicarboximide, 6-methyl-2,3-quinoxaline dithiol cyclic carbonate, tetrachloroisophthalonitrile. sodium pdimethylaminobenzenediazosulfonate, 2,4-dichloro-6- (2-chloroanilino)s-triazine, 2,4-dichlorophenoxyacetic acid, 4-chloro-2-methylphenoxyacetic acid, 3,4- dichloropropionanilide, 2,4-dichlorophenyl-4&#39;- nitrophenyl ether, 2-chloro-4,6-bis(ethylamino)-striazine, sodium N-( l-naphthyl)phthalamate, etc.). The microbial compositions may also contain one or more materials known to be active as insecticides, nematocides, acaricides, herbicides, fertilizers, soil conditioners, soil disinfectants or plant growth regulators. Examples of typical microbial compositions according to this invention are:  
 a. Dusts obtained by dispersing at least one of the a-(N-phenylcarbamoyloxy)alkanoate derivatives [I] as the active ingredient in a concentration of 0.1 to 50 by weight in an inert carrier (e.g. talc, diatomaceous earth, wood flour, clay).  
 b. Wettable powders obtained by dispersing at least one of the a-(N-phenylcarbamoyloxy)alkanoate derivatives [I] as the active ingredient in a concentration of 0.1 to by weight in an inert absorbent carrier (e.g. diatomaceous earth) together with a wetting and/or dispersing agent such as an alkali metal salt of a long aliphatic sulfate chain, a partly neutralized sulfuric acid derivative of either a petroleum oil or a natural occurring glyceride, or a condensation product of an alkylene oxide with an organic acid.  
 c. Emulsifiable concentrates obtained by dispersing at least one of the a-(N-phenylcarbamoyloxy)alkanoate derivatives [1] as the active ingredient in a concentration of 0.1 to 50% by weight in an organic solvent (e.g. dimethylsulfoxide) plus an emulsifier such as an alkali metal salt of a long aliphatic sulfate chain, a partly neutralized sulfuric acid derivative of either a petroleum oil or a natural occurring glyceride, or a condensation product of an alkylene oxide with an organic acid.  
 (1. Compositions of the a-(N-phenylcarbamoyloxy) alkanoate derivatives [I] formulated in the manner commonly employed in the art for the preparation of microbicidal granules. dusts and aerosols.  
 Practical and presently preferred embodiments of the present invention are illustratively shown in the following Examples. In these Examples, parts and percent are by weight.  
 EXAMPLE 1 Preparation of the a-(N-phenylcarbamoyloxy)alkanoate derivatives [1]: A 200 milliliter volume flask is charged with 3.5-dihalogenated phenyl isocyanate derivative [ll] (O.l mol) and a catalytic amount of pyri dine and isopropyl ether (50 ml). A solution of glycolic acid derivative [III] (0.1 mol) in isopropyl ether (50 ml) is added dropwise thereto while stirring. The resultant mixture is heated with reflux for 1 hour. After cooling, the precipitated cyrstals are collected by filtration and dried to yield a-(N-phenylcarbamoyloxy)alkanoate derivative [l] at a very high yield.  
  Examples of the a-(N-phenylcarbamoyloxy)alkanoate derivative [l] prepared by the above procedure are shown in the following table:  
 and mixed well to make a dust containing 3 /r of the ac tive ingredient. The dust is applicable as such.  
 EXAMPLE 3 Preparation of dust:  
  Ethyl a-IN-(3,5-dichlorophenyl)]carbamoylthioacetate (4 parts) and talc (96 parts) are crushed and mixed well to make a dust containing 4 of the active ingreclient. The dust is applicable as such.  
 EXAMPLE 4 Preparation of wettable powder:  
  Ethyl N-(3,5-dichlorophenyl)thiocarbamoylthioacetate (50 parts), a wetting agent (alkylbenzenesulfonate) (5 parts) and diatomaceous earth parts) are crushed and mixed well to make a wettable powder containing of the active ingredient. The wettable powder is diluted with water and then applied.  
 EXAMPLE 5 Table gt rting materials I Product 3,5-Diha10genabed Glycolic acid (1(N-Pheny1 l&#39;leltield Elementary analysis phenyl isoc anate derivative carbamoyloxy)- |ing Calcd. derivative II] III] alkanoace 1 oint (Found) derivative l-Ll c) c H N 01 s 3,5-Dic2lorol&#39;tzj&#39;lt Ethyl aL -(3,?- 75.0-7 .0 95 47.08 4.28 4.58 23.16 phenyl cyanate a (47.24) (4.01) (4.48) (22.97)  
 A propionate 3,5-Dz1ciilorot fytlhyll l t g hfi 4 3.5 15 0 93 42.87 3.60 4.55 23.01 10.45 pheny socyana e iog yco a. e ic orop eny 3 carbamoylmw (42.46) (3.30) (4.53) (22.80) (10.18) acetate 3.5 r l fihy l thi ri 3 .5- 155.5 90 40.75 3.42 4.32 21.85 19.78 gjjfifi ate igg gggg gg (40.63) (3.26) (4.49) 21.77) (19.41)  
  thioacetate 3,5-Dichlozg; ath c l th (Hg-(3 50.0-54.0 84 44.73 4.07 4.35 22.01 9.95 phenyl iso 0- ac a e ic crop eny cyanate thiocarbamwL (45.12) (4.22) (4.15) (21.63) (9. 2o)  
  oxvlpronionate 3,5-Dichl0ro- Glycolic N: mi i hl r 15 .5 91 40.93 2.67 5.30 26.85  
  h n l 1 00 an be cid eny carbamo 1- 158.5 P e y s y a a gmcetic (40.84) (2.77) (5.31) (26.53) 3,5-Dichl0r0- .t Thioglycolic N;(3,5;Dic1loroi 152.0 90 38.59 2.52 5.00 25.31 11.45 phenyl isocyana 8 ac d thf ga gg i g ac iii (3 .92) (2.69) (4.98) (25.56) (11.33)  
 EXAMPLE 2 EXAMPLE 6 Preparation of dust:  
  Ethyl a-lN-(3.5-dichlorophenyl)carbamoyloxy1- propionate (3 parts) and clay (97 parts) are crushed Preparation of granule:  
  N-(3,5-Dichlorophenyl)carbamoyloxyacetic acid (5 parts), clay (93.5 parts) and a binding agent (polyvinyl alcohol) (1.5 parts) are crushed and mixed well. The mixture is kneaded with water and granulated to make granules containing of the active ingredient. The granules are applicable as such.  
 EXAMPLE 7 Preparation of dust:  
  N-(3,5-Dichlorophenyl)carbamoylthioacetic acid (2 parts). O-n-butyl-S-ethyl-S-benzylphosphorodithiolate (1.5 parts), Kasugamycin (0.1 part) and clay (96.4 parts) are crushed and mixed well to make a dust containing 3.6 7: of the active ingredients. The dust is applicable as such.  
 EXAMPLE 8 Preparation of dust:  
  Ethyl a-[ N-( 3,5-dichlorophenyl )carbamoyloxy]- propionate (2 parts), O-n-butyl-S-ethyl-S-benzylphosphorodithiolate (1.5 parts), 0,0-dimethyl-O-(3- methyl-4-nitrophenyl)phosphorothioate (2 parts), 3,4-  
 dimethylphenyl-N-methylcarbamate (1.5 parts) and wherein X is halogen, Y and Z are each oxygen or sulfur, R is hydrogen or lower alkyl and R is hydrogen or lower alkyl, said active derivative being present in at least an amount effective to suppress fungal growth, and an inert carrier.  
  2. A method for suppressing the growth of fungi comprising the step of contacting said fungi with an a-(N- phenylcarbamoyloxy) alkanoate derivative of the formula:  
 wherein X is halogen, Y and Z are each oxygen or sulfur, R is hydrogen or lower alkyl and R is hydrogen or lower alkyl, said derivative being present in at least an amount effective to suppress fungal growth.  
  3. The composition as claimed in claim 1 wherein X is chlorine, bromine or iodine and R and R are each individually selected from the group consisting ofhydrogen and alkyl having 1 to 5 carbon atoms.  
  4. The method as claimed in claim 2 wherein X is chlorine. bromine or iodine and R and R are each individually selected from the group consisting of hydrogen and alkyl having 1 to 5 carbon atoms.