GB1577055A

GB1577055A - 1,2,6-thiadiazin-4-one derivatives

Info

Publication number: GB1577055A
Application number: GB18263/77A
Authority: GB
Original assignee: Celamerck GmbH and Co KG
Current assignee: Shell Agrar GmbH and Co KG
Priority date: 1976-05-03
Filing date: 1977-05-02
Publication date: 1980-10-15
Also published as: FR2375223A1; DE2619090A1; IT1079620B; NL7704711A; ZA772643B; IL51981A0; BE854184A; ES458381A1; AU2477077A; HU176649B; JPS52133995A; AU500386B2; ATA286877A; FR2375223B1; IL51981A; SE7705086L; AT355036B; ES467482A1

Description

(54) 1,2,6-THIADIAZIN-4-ONE DERIVATIVES (71) We, CELAMERCK GMBH & CO. KG., a German Kommanditgesellschaft, of Ingelheim am Rhein, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to compositions comprising certain 1,2,6thiadiazinones as active ingredient, processes for the preparation of such compounds as well as to certain novel 1 ,2,6-thiadiazinones. The compositions show interesting antifungal and antibacterial activity as well as interesting herbicidal and insecticidal activity.

According to one feature of the present invention there are provided pharmaceutical compositions (as herein defined) comprising as active ingredient at least one compound of the formula

wherein X represents a chlorine atom, an imidazolyl or triazolyl group or a group of the formula -O-R1; -S-R1; -SOn-R2; -S-CS-N(R3)2 (in which R1 represents a straight or branched, saturated or unsaturated aliphatic group with up to 12 carbon atoms, optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, nitro, hydroxy, C14 alkoxy, C14 chloroalkoxy, C14 alkylthio, C36 cycloalkyl, phenyl, phenoxy,

-CO-O(C1-4 alkyl), tetrahydrofuryl, quinolyl or 2,2-dimethyl- 1 3-dioxolanyl group or by a phenyl group substituted by I to 3 halogen atoms, or by a cyano, nitro, carboxy, C14 alkyl, carbamoyl or -C0-0(C14-alkyl) group; or a cycloalkyl group with 3 to 6 carbon atoms; or a phenyl group optionally substituted by I to 3 halogen atoms and/or by C14 alkyl, C36 cycloalkyl, C14 alkoxy, C14 alkylthio, cyano, trifluoromethyl, formyl, 1 or 2 nitro group(s), a group of the formula -COR4 or phenyl; or a -N=C(CH3)2, -CH(CN)-C8H5 or naphthyl group; R2 represents a C14 alkyl, allyl or cyclohexyl group; R3 represents a methyl or ethyl group; R4 represents a C14 alkoxy, hydroxy or -NR5R6 group; R5 and R6, which may be the same or different, each represent a hydrogen atom or a C14 alkyl group; and n is 1 or 2) in association with a pharmaceutical carrier or excipient.

The term "pharmaceutical composition" as used herein is not intended to include within its scope compositions consisting merely of a compound of formula I as hereinbefore defined in admixture with water or an organic solvent in which the said compound of formula I may be prepared or purified, such compositions being free of pharmaceutical adjuvants.

According to a further feature of the present invention there are provided pesticidal and herbicidal compositions (as herein defined) comprising as active ingredient at least one compound of formula I as hereinbefore defined in association with an inert carrier or diluent.

The term "pesticidal and herbicidal compositions" as used herein is not intended to include within its scope compositions consisting merely of a compound of formula I in admixture with water or an organic solvent in which the said compound of formula I may be prepared or purified, such compositions being free of other carriers or diluents e.g. surfactants, emulsifiers, wetting agents etc.

The compounds of formula I possess herbicidal, antibacterial, antifungal and insecticidal properties and are of interest as active ingredients in pesticidal or herbicidal compositions and agents as well as in pharmaceutical agents or compositions. These compounds are also of interest as intermediates for the production of herbicides, pesticides, insecticides as well as anti-bacterial and antifungal agents.

Preferred compounds by virtue of their especially favourable properties include compounds of formula I, wheein X represents an optionally substituted alkylthio group, particularly compounds in which X represents a methylthio, ethylthio, sec. butylthio, allylthio or cyano-C14 alkylthio group; furthermore, compounds wherein X represents an optionally substituted phenoxy group, particularly a chloro-, methyl-, cyano-, or nitro-phenoxy group are also preferred by virtue of their especially favourable activity. Moreover compounds of formula I in which X represents a benzyl-mercapto group optionally substituted in the nucleus, for example, a benzylmercapto group substituted by one or two nitro groups are preferred. Finally compounds of formula I, wherein X represents an alkoxy group, particularly an n-butoxy or alkenyloxy group or compounds wherein X represents a chlorine atom are preferred.

As far as the group R1 comprises or represents an aliphatic group, such groups preferably contain up to 6 carbon atoms, mainly up to 4 carbon atoms. Among these groups optionally substituted methyl and ethyl groups are particularly preferred, but propyl and isopropyl groups are preferred.

The compound of formula I in which X represents a chlorine atom of the formula

is known and may be employed in the preparation of other compounds of formula I as hereinbefore defined.

Thus the compounds of formula I as hereinbefore defined may, for example, be prepared by one of the following process (a) to (e), which processes constitute a further feature of the present invention: (a) for the preparation of compounds of formula I as hereinbefore defined (wherein X represents an imidazolyl or triazolyl group or the group OR1 or --SR,), the reaction of a compound of the formula:

with imidazole, a triazole or a compound of the formula R1OH or R,SH (wherein R1 is an hereinbefore defined) whereby a compound of formula I is obtained.

The reaction is preferably effected by the use of about one equivalent of imidazole, a triazole or the compound of formula R1OH or R1SH. The reaction is advantageously effected in the presence of an acid acceptor, e.g. a tertiary amine.

The reaction may conveniently be effected at a temperature of from -20 to +100 C, preferably from 0 to 50"C. It is also convenient to effect the reaction in the presence of an inert solvent, for example ether, dioxan, tetrahydrofuran, benzene, toluene, ethyl acetate or acetone. For the preparation of compounds of formula I in which X represents the group OR1 an excess of an alcohol HOR1 and an equivalent of the acid acceptor, for example,-or an alcoholate of the alcohol HOR1 to be reacted may also be employed as the solvent.

b) for the preparation of compounds of formula I as hereinbefore defined (wherein X represents the group -OR1) the reaction of a solution or suspension of a compound of formula II (as hereinbefore defined) in a compound of formula R1OH (wherein R, is as hereinbefore defined) with an alkali metal or alkaline earth metal -hydroxide, hydrogen carbonate or carbonate whereby a compound of formula I is obtained. The reaction is preferably effected by the use of about one equivalent of an alkali metal- or alkaline earth metal-hydroxide, -hydrogen carbonate or -carbonate, preferably sodium- or potassium hydroxide, advantageously at a temperature of from 0 to 500 C. The reaction is preferably effected in the presence of water.

c) for the preparation of compounds of formula I as hereinbefore defined (wherein X represents the group --SO,R,), the oxidation of a compound of formula I in which X represents the group -S-R2 whereby a compound of formula I is obtained. It is advantageous to effect the oxidation with hydrogen peroxide conveniently in the presence of glacial acetic acid. For production of the sulfinyl compounds, the oxidation is preferably effected in the presence of about an equimolar amount of hydrogen peroxide at an elevated temperature e.g. 85--95"C preferably at approximately 900 C. For the oxidation to the sulfone stronger oxidation conditions are required. The oxidising agent is preferably used in excess and the reaction is allowed to run at higher temperatures, for example at approximately 100 C.

d) for the preparation of compounds of formula I as hereinbefore defined (wherein X represents the group -S-CS-N(R3)2), the reaction of a compound of formula II as hereinbefore defined with an alkali metal salt of a dimethyl or diethyl dithiocarbamate. The reaction is conveniently effected at ambient temperature advantageously in the presence of a solvent such as methanol.

e) for the preparation of compounds of formula I, as hereinbefore defined (wherein X represents the group -O-C6114-COOH), the hydrolysis of an ester of this acid e.g. according to the conventional methods.

The compounds of formula I as hereinbefore defined possess, herbicidal activity, and are,.in general, of particular interest for post-emergence processes. A preferred dosage for herbicidal use is from 0.5 to 10 kg per ha. With lower dosages compositions of the present invention which have been tested have been found to possess a selective action on dicotyles, while with higher dosages they may also be used as total herbicides.

Compositions according to the present invention also show a fungicidal activity, for example on Phytophtora, Potrytis, Tilletia, a bactericidal activity, for example, on Xanthomonas and an insecticidal activity, for example on flies.

For use the compounds of formula I are formulated into pesticidal and herbicidal agents and compositions in the conventional manner e.g. with an emulsifying, wetting or dispersing agent. As herbicides they are processed with conventional excipients and/or carriers to form concentrates or ready-for-use preparations, for example, wettable powders, emulsifiable concentrates, granulates, dusting agents and ultra-low-volume formulations.

The active ingredient content of ready-for-use compositions and agents is preferably from 0.01 to 10% by weight, however, it may be distinctly higher (up to approximately 80% by weight).

According to a further feature of the present invention there is provided a method of preventing the growth or proliferation of fungi or bacteria which comprises applying to a site infested with or susceptible to infestation by fungi or bacteria an effective amount of a composition as hereinbefore defined.

According to another feature of the present invention there is provided a method of controlling the growth of plants which comprises applying to plants an effective amount of a composition as hereinbefore defined. The composition is preferably applied in a concentration of from 0.5 to 10 kg/hectare.

According to another feature of the present invention there is provided a method of preventing of inhibiting the growth or proliferation of insects which comprises applying to a site infested with or susceptible to infestation by insects an effective amount of a composition as hereinbefore defined.

Furthermore, the compounds of formula I as hereinbefore defined show interesting physiological activity and are of potential interest for their antimycotic and antibacterial action against for example, Microsporum audouini, Trichophyton mentagrophytes, Histoplasma capsulatum, Aspergillus fumigatus, Candida aihicans, Nocardia asteroides, Staphylococcus atreus, Spreptococcus pyogenes, Proteus vulgaris, Pseudomonas aeruginosa, Mycobacterium ranae and/or Escherichia coli.

These activities may be determined, for example, according to conventional agar-dilution methods in vitro, as well as in vivo, for instance in mice, rats and rabbits.

thus, the thiadiazinones of formula I as hereinbefore defined may also be used as active ingredient for the production of pharmaceutical compositions and agents.

The pharmaceutical compositions and agents are formulated with at least one carrier or excipient and, if required, together with one or more further active substance(s) preferably in a convenitent dosage unit form.

These pharmaceutical compositions and agents are of potential interest in human or veterinary medicine. Carriers for use in the compositions and agents of the invention include organic or inorganic substances conventionally used, especially carriers appropriate for topical administration, the compositions and agents may also,. for example, be in a form suitable for enteral (e.g. oral) or parenteral administration, such substances being those which do not react with the novel compounds, for example water, vegetable oils, hydrocarbons such as alkylated naphthalines, halogenated hydrocarbons such as difluorodichloromethane (for example aerosols), benzyl alcohols, glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talcum, vaseline. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are especially convenient. For rectal administration suppositories may, for example, be employed and, for parenteral administration solutions, preferably oily or aqueous solutions may, for example, be used. Furthermore suspensions, emulsions or implantations may, for example, be used and for topical administration solutions, lotions, emulsions, sprays (aerosols), ointments, creams, pastes or powders may, for example, be employed. The compounds of formula I as hereinbefore defined, especially the novel compounds of formula I may for example, also be lyophilized and the obtained lyophilisates be applied, for example, for production of injection preparations. The above-mentioned preparations may be sterilized and/or comprise excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colourings, flavourings, and/or aromas. If desired, they may comprise as well one or several further active ingredients, such as one or more antibiotics, vitamins and/or other antimycotics.

Where the compounds of formula I as hereinbefore defined are used as pharmaceuticals, they are, in general, administered analogously to known, commercial antimycotics (for instance Clotrimazol or Miconazol). In the case of topical administration which is preferred the pharmaceutical compositions or agents in combination with carriers suitable therefor which we have tested demonstrate a high activity over a broad dilution range. Concentrations of active ingredient of from 0.1 to 10% by weight, based on the weight of the preparation used, for example, have been found to be effective for the control of fungi and bacteria. Concentrations of approximately 1 to 3% by weight are preferred.

However, the particular dose for each patient depends upon various factors, for example, upon the activity of the particular compound used, and upon the age, body-weight, general state of health. sex and nutrition of the patient, as well as on the period and type of administration, the combination of pharmaceuticals and the intensity of the disease for which the therapy is designed. Thus, it is possible to administer higher concentrations than the ones indicated in individual cases.

According to a further feature of the present invention there is provided a method of treating bacterial or fungal infections of animals other than human beings which comprises administering an effective amount of a pharmaceutical composition as hereinbefore described to an animal other than a human being.

Certain compounds of formula I have been described [see Rec. Trav. Chim.

93, 270 (1974)] but no indication of the pesticidal, herbicidal, anti-bacterial, antifungal or insecticidal activity of the compounds was disclosed.

A further feature of the present invention is thus directed to compounds of formula I as hereinbefore defined with the proviso that X is other than chlorine, methoxy, methylthio, phenoxy or phenylthio.

The present invention also relates to pharmaceutical agents as well as pesticidal and herbicidal agents comprising such novel compounds as active ingredient.

The following non-limiting Examples illustrate the invention: Example 1.

3-Butylmercapto-5-chloro-1 ,2 ,6-thiadiazin-4-one 4.5 g (0.05 mol) of n-butylmercaptan in 75 ml of tetrahydrofuran are added dropwise to a solution of 9.1 g (0.05mol) of 3,5-dichloro-l,2,6-thiadiazin-4-one and 5.1 g (0.05 mol) of triethylamine in 100 ml of tetrahydrofuran at room temperature. After stirring for one hour, the precipitate obtained is filtered off, the filtrate evaporated in vacuo, the residue taken up in methylene chloride and extracted with water. The organic phase is dried with sodium sulfate and after distilling off the methylene chloride, distilled under high vacuum. 9.9 g (90% of theory) of the title compound are obtained.

B.p.oo,i: ll2-ll50C.

Example 2.

3-Chloro-4-ethoxy-1 ,2,6-thiadiazin-4-one A solution of 2.0 g (0.05 mol) of sodium hydroxide in 10 ml of water is added dropwise to a solution of 9.1 g (0.05 mol) of 3,5-dichloro-l ,2,6-thiadiazin-4-one in 100 ml of ethanol at room temperature. After stirring for one hour at room temperature the mixture is evaporated to 1/4 of its volume. The yellow, crystalline precipitate is then filtered off with suction, dried and recrystallized from ethanol/water.

7.7g (80% of theory) of the title compound are obtained. M.p. 66"C.

Example 3.

3-Chloro-5-methoxy-1 2 ,6-thadiazin -4 -one A solution of 4.0 g (0.1 mol) of sodium hydroxide in 20 ml of water and 50 ml of methanol is added dropwise to a solution of 18.3 g (0.1 mol) of 3,5-dichloro-.l ,2,6- thiadiazin-4-one in 100 ml of methanol at OOC. The mixture is then stirred for one hour at room temperature. The crystalline precipitate obtained is filtered off with suction, washed with water and dried.

15.3 g (86%) of the title compound of m.p. 72 to 730C are obtained.

Example 4.

3-Chloro-5-isopropylmercapto-1 ,2 ,6-thiadiazin-4-one First 10.1 g (0.1 mol) of triethylamine and then 7.6 g (0.1 mol) of isopropy!- mercaptan are added dropwise to a solution of 18.1 g (0.1 mol) of 3,5-dichloro1,2,5-thiadiazin-4-one in 150 ml of tetrahydrofuran with stirring. Afterwards, the mixture is stirred for one hour at room temperature. The precipitate of triethylamine hydrochloride obtained is filtered off with suction and the filtrate is evaporated in vacuo. The evaporation residue is dissolved in chloroform, the solution is washed with 2 N hydrochloric acid, soda solution and water, dried over sodium sulfate and evaporated in vacuo. The residue is distilled under high vacuum.

14 g (63% of theory) of the title compound in the form of an orange-coloured oil are obtained.

B.p.,,,: 123--125"C.

Example 5.

3-Chloro-5-n-butoxy-1 ,2 ,6-thiadiazin-4-one 2 g (0.05 mol) of sodium hydroxide in 20 ml of water are added dropwise, with vigorous stirring, to a solution of 9.1 g (0.05 mol) of 3,5-dichloro-l,2,6-thiadiazin-4- one in 100 ml of n-butanol at OOC. After stirring at room temperature for one hour, the butanol phase is separated out and the aqueous phase extracted with 30 ml of nbutanol. The combined butanol solutions are dried over sodium sulfate. Th - excess butanol is removed in vacuo and the residue distilled off.

7.8 g (71% of theory) of the title compound are obtained as yellow oil.

B.p.02: 110113 C.

Example 6.

3-Chloro-5-methylmercapto-1 ,2 ,6-thiadiazin4-one 14.5 g (0.3 mol) of methyl mercaptan are added over a period of 90 minutes, to a solution of 36.6 g (0.2 mol) of 3,5-dichloro-1,2,6-thiadiazin-4-one and 20 g (0.2 mol) of triethylamine in 200 ml of tetrahydrofuran at -50C with stirring. Stirring is continued for 30 minutes at room temperature, the precipitate of triethylamine hydrochloride obtained is filtered off with suction and the filtrate evaporated in vacuo. The solid residue is recrystallized from n-hexane.

Example 7.

3-Chloro-S-allyloxy-1 ,2,6-thiadiazin4-one 2.0 g (0.05 mol) of sodium hydroxide in 20 ml of water are added dropwise, with vigorous stirring to a solution of 9.1 g (0.05 mol) of 3,5-dichloro-1,2,6thiadiazine-4-one and 12 g (0.2 mol) of allyl alcohol in 75 ml of acetone at -100C.

The mixture is stirred for one more hour at OOC and evaporated in vacuo. The residue is washed with water, dried and recrystallized from n-hexane. 9.0 g (88% of theory) of the title compound are obtained in the form of pale yellowish crystals of m.p. 51--52"C.

Example 8.

3-Chloro-5-isopropoxy-l ,2 ,6-thiadiazin4-one 1.2 g (0.05 gram atom) of sodium are dissolved in 150 ml of an hydros isopropanol. At 0 C, while stirring, the solution of the alcoholate, thus formed, is added dropwise to a solution of 9.1 g (0.05 mol) of 3,5-dichloro- 1,2,6-thiadiazin-4- one in 75 ml of isopropanol. The mixture is stored for 1 hour at OOC and for 24.

hours at 200 C. After distilling off the excess isopropanol in vacuo, the residue is, stirred with water, filtered off with suction, washed with water, dried and recrystallized from n-hexane. 6.0 g (58% of theory) of the title compound of m.p.

71--72"C are obtained.

Example 9.

3-Chloro-5-methylsulfinyl-l ,2 ,6-thiadiazin4-one 5.0 mls of 30% hydrogen peroxide are added dropwise, while stirring, to a solution of 9.7 g (0.05 mol) of 3-chloro-5-methylmercapto-1,2,6-thiadiazin-4-one in 100 ml of acetic acid. The mixture is heated for 1 hour to 900C and evaporated in vacuo. The crystalline residue is recrystallized from methanol. 6.1 g (58% of theory) of lemon-yellow crystals of the title compound are obtained, m.p. 132--1330C.

Example 10.

3-Chloro-5-isopropylsulfinyl-l 2 ,6-thiadiazin4-one In a similar manner to Example 9, the title compound is obtained from 3 chloro-5-isopropylmercapto- 1 ,2,6-thiadiazin-4-one and H202.

M.p. 93-940C (from hexane).

Example 11.

3-Chloro-5-methylsulfonyl-1 ,2,6-thiadiazin4-one 25 mls of 30% hydrogen peroxide are added dropwise to a solution of 9.7 g (0.05 mol) of 3-chloro-5-methylmercapto-1,2,6-thiadiazin-4-one in 100 ml of acetic acid. For 30 minutes the mixture is heated to 1000C, cooled to 200C and poured into 800 ml of iced water. The light-yellow, crystalline precipitate is filtered off with suction, washed with water and dried. 6.4 g (57% of theory) of the title compound are obtained. M.p. 1540C.

Example 12.

3-Chloro-5-dimethyldithiocarbamoyl-1 ,2 ,6-thiadiazin4-one 5.6 g (0.03 mol) of sodium dimethyldithiocarbamate dihydrate in portions is added, while stirring, to a solution of 5.5 g (0.03 mol) of 3,5-dichloro-1,2,6thiadiazin-4-one in 100 ml of methanol. After stirring for three hours at room temperature the mixture is diluted with 250 ml of water. The crystalline precipitate is filtered off with suction and dried. The crude product is mixed with hexane in methylene chloride and recrystallised. 3.2 g (40% of theory) of the title compound crystallize out; m.p. 130-135 C.

Example 13.

O-(3-chloro-1 ,2,6-thiadiazin4-one-5-yl)-acetoxime By reacting the 3,5-dichloro-l,2,6-thiadiazin-4-one with the sodium salt of acetoxime in tetrahydrofuran the title compound is obtained, m.p. 80-91 C.

The compounds listed in the following table may be obtained in a similar manner to the processes described in the above Examples: No. -X m.p. [0c] b.p.[ C]/Torr 14 -O-n-C5H11 - 105-107/0.1 15 -#-n-C8H17 140-142/0.13 16 -O-n-C12-H25 45-48 - 17 -0-n-C3H7 - 94 /0.1 0 18 -O-n-C6H13 - 128-131/0.2 19 -0-CH(CH3)-C2H5 - 110-111/0.6 20 -0-CH2-CH(CH3)2 59-61 21 -O-CH2-C#CH 158 22 -0-CH2-CH=CH-CH3 - 120-124/0.25 23 -0-CH2-CF3 3 88- 92/0.1 24 -0-CH2-CH2-C1 - 133 /0.15 25 -O-CH2-CCl3 - 135-138/0.2 26 -0-CH2-CN 116-118 27 -0-CH(CH3)-CN 102-108 28 -0-CH(CN)-n-C3H7 29 -0-tert.C4H9 30 -O-CH2-CH2-OCH3 73-75 31 -0-CH2-CH2-SCH3 No. -X m.p.[ C] b.p.[ C]/Torr

32 -0-CH24 77-82 33 -0- ( CH2) 2- 109-1 11 34 -0-CH -CH-CH 83 0 o ! 35 -0-CH2-C-OC2H5 63-67 L L -I 36 -0-C(CH3)2-C-OCH3 ( 120-126/0.04 37 -043 - 130-i34/o;25 38 -0 - 13 4-13 5/0; 1 39 -S-C2H5 55-56 40 -S-n-C3H7 - 119-121/0.1 41 -S-CH(CH3)-C2H5 - 115 /o;1 42 -5-tert. -C4H9 - 110-111/0.17 43 -S-CH2-CH=CH2 - 119-124/0.2 44 -S-CH2-CH2-CN - 172- 174/0.1 45 -S > - 145-149/0.13 46 -04 121-123 47 -O9F 139-141 48 -09 85 C1 No. -X m.p.[ C] b.p.[ C]/Torr

49 ~ o C1 143 50 -oC1 115-117 C1 51 -0 9 1 152-154 N02 52 -0 9 C1 161-163 C 3 52 -0 9 C1 161-163 CH3 53 -0 CH3 137 54 -0 o tert. -C4H9 162-164 55 3 OCH3 143-146 56 -0 o CN 185-186 57 -0 n 155-156 57 155-156 58 -0 NO2 182-184 2 59 0 X 232 60 -0 A 126 Np. X m.p.[ C] b.p.[ C]/Torr

61 -0-CH2-C(CH3)3 100-108/0.2 62 -0-CF.2-CH2-OH 96-101 63 -0-CH2-CH-C2H5 98-100 N02 64 -O-CH. I I 149-152/0,1 65 -0-CH2- 0 92-94 N CH3 CH3 66 -o- (cH2)2-O-CH2-C1 155-156/0.1 67 -0-CH-C6H5 89-91 CN 68 -0- 123 69 -0- &commat; 157 GQ 70 -S-C6H5 100-102,5 71 -S-CH2- g -C1 107-109 2 SCCH0H viscous oil, r decomposes during distillation 73 -0 Q 3r 152 No. -X m.p.[ C] b.p.[ C]/Torr

Br 74 -0- b Br 124 Br ci 75 ~o~ t 112 CH3 76 -0- CH3 130 Br cl 77 -0- X 131-132 C1 CH3 78 - 0 X C1 159 78 - 159 3 79 -0 < -C1 164 CH3 80 -0-C1 124 Br 81 -0 t 107 sC1 No. -X m.p.[ C] b.p.[ C]/Torr

82 -0 1 103 CH, 83 ~ ~ 81 CH3 84 -0-- CH3 122 CH3 C1 I 65 Cl 86 -O- 101 F 87 - -0CF3 115 88 -OeCO-OC2H5 115 89 -o-/ -OCO-t,tH2 224 9O -OXCOOH No. -X m.p. [ C] b.p.[ C]/Torr

91 -O-CH24 145 CH3 92 -O- CH24 93 -0- CH2iC1 Cl 94 -0-CII2 C1 95 -O-CH2 96 -O-CH2- -NO2 97 -S-CH C1 98 -S-CH2 Cl 99 -S-CH24 2 100 -S-CH24 F 101 - S- CH2-4 No. -X m.p.[ C] b.p.[ C]/Torr

102 -S-CH2- -F Br 103 -S-CH2 Br 104 -S-CH24 105 -S-CH2Br Cl 106 -S-CH2-( Cl 107 -S-CH2+C1 cl 108 N02 N02 109 2 110 -0bt'02 Nb. -X m.p.[0C] b.p. [ C]/Torr

111 -S-CH2-CN 112 113 -S-(CH2)4-CN 114 115 S- CH2-C1 H - CH3 CN CII i3 116 -S-C-CH3 CM 117 - 225 N 118 Herbicidal and Pesticidal Composition Examples Example A.

Wettable Powder 25% of active ingredient according to invention 55% of kaolin 10% of colloidal silicic acid 9% of lignine sulfonate (dispersion agent) 1% of sodium tetrapropylene benzenesulfonate (wetting agent) Example B.

Wettable Powder 80% of active ingredient according to invention 8% of calcium lignine sulfonate 5% of colloidal silicic acid 5% of sodium sulfate 2% of diisobutylnaphthaline sodium sulfonate Example C.

Emulsifiable Concentrates 40% of active ingredient according to invention 25% of a liquid mixture of aromatic hydrocarbons (for example Shellsol A) 25% of N-methylpyrrolidone 10% of anionic emulsifier (for example Emulsogen I 40) The concentrations referred in Examples A to C are diluted for use with water to the desired concentration of active ingredient (0.01 to 10% by weight).

The percentages referred to in Examples A to C are percentages by weight.

Pharmaceutical Composition Examples.

Example D.

Ointment 2 kg of 3-chloro-5-p-chlorobenzylmercapto- 1 ,2,6-thiadiazin-4-one are dissolved in a warm, liquified mixture of 40 kg of polyethyleneglycol 400 and 58 kg of polyethyleneglycol 1500. The solution is stirred, while cooling, and is used as an ointment for the treatment of fungal and bacterial infections.

Example E.

Cream A mixture of 20 kg of 3-chloro-5-(2-cyanoethyl)-mercapto- 1 ,2,6-thiadiazin-4- one, 200 kg of polyethyleneglycol 1000-monocetylether, 50 kg of polyethyleneglycol 1500-monocetylether, 150 kg of vaseline (registered Trade Mark), 50 kg of paraffin oil and 2 kg of sorbic acid are heated in the conventional manner and then allowed to cool. 528 kg of water are then stirred into the mixture.

Example F.

Solution 2 kg of 3-chloro-5-p-nitrophenoxy- 1 ,2,6-thiadiazin-4-one are dissolved in 98 kg of 1,2-propanediol. The solution may be used for the treatment of fungal and bacterial infections.

Example G.

Spray The spray comprises a solution of 1% by weight of 3-chloro-5-(2-cyanoethyl) mercapto-l,2,6-thiadiazin-4-one, 10% by weight of isopropyl myristate, 15% by weight of paraffin oil, 30% by weight of ethanol and 44% by weight of isopropanol.

WHAT WE CLAIM IS: I. Pharmaceutical compositions (as herein defined) comprising as active ingredient at least one compound of the formula:

wherein X represents a chlorine atom, an imidazolyl or triazolyl group or a group of the formula -O-R1; -S-R1; -SO,,-R2; -S-CS-N(R3)2 (in which R, represents a straight or branched, saturated or unsaturated aliphatic group with up to 12 carbon atoms, optionally substituted by 1 to 3 fluorine, chlorine or

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Example B.

Wettable Powder 80% of active ingredient according to invention 8% of calcium lignine sulfonate 5% of colloidal silicic acid 5% of sodium sulfate 2% of diisobutylnaphthaline sodium sulfonate Example C.

Emulsifiable Concentrates 40% of active ingredient according to invention 25% of a liquid mixture of aromatic hydrocarbons (for example Shellsol A) 25% of N-methylpyrrolidone 10% of anionic emulsifier (for example Emulsogen I 40) The concentrations referred in Examples A to C are diluted for use with water to the desired concentration of active ingredient (0.01 to 10% by weight).

The percentages referred to in Examples A to C are percentages by weight.

Pharmaceutical Composition Examples.

Example D.

Ointment

2 kg of 3-chloro-5-p-chlorobenzylmercapto- 1 ,2,6-thiadiazin-4-one are dissolved in a warm, liquified mixture of 40 kg of polyethyleneglycol 400 and 58 kg of polyethyleneglycol 1500. The solution is stirred, while cooling, and is used as an ointment for the treatment of fungal and bacterial infections.

Example E.

Cream A mixture of 20 kg of 3-chloro-5-(2-cyanoethyl)-mercapto- 1 ,2,6-thiadiazin-4- one, 200 kg of polyethyleneglycol 1000-monocetylether, 50 kg of polyethyleneglycol 1500-monocetylether, 150 kg of vaseline (registered Trade Mark), 50 kg of paraffin oil and 2 kg of sorbic acid are heated in the conventional manner and then allowed to cool. 528 kg of water are then stirred into the mixture.

Example F.

Solution

2 kg of 3-chloro-5-p-nitrophenoxy- 1 ,2,6-thiadiazin-4-one are dissolved in 98 kg of 1,2-propanediol. The solution may be used for the treatment of fungal and bacterial infections.

Example G.

Spray The spray comprises a solution of 1% by weight of 3-chloro-5-(2-cyanoethyl) mercapto-l,2,6-thiadiazin-4-one, 10% by weight of isopropyl myristate, 15% by weight of paraffin oil, 30% by weight of ethanol and 44% by weight of isopropanol.

WHAT WE CLAIM IS: I. Pharmaceutical compositions (as herein defined) comprising as active ingredient at least one compound of the formula:

wherein X represents a chlorine atom, an imidazolyl or triazolyl group or a group of the formula -O-R1; -S-R1; -SO,,-R2; -S-CS-N(R3)2 (in which R, represents a straight or branched, saturated or unsaturated aliphatic group with up to 12 carbon atoms, optionally substituted by 1 to 3 fluorine, chlorine or

bromine atoms, or by a cyano, nitro, hydroxy, C14 alkoxy, C14 chloroalkoxy, C14 alkylthio, C36 cycloalkyl, phenyl, phenoxy,

-CO-O(C14-alkyl), tetrahydrofuryl, quinolyl or 2,2-dimethyl- 1 ,3-dioxolanyl group or by a phenyl group substituted by 1 to 3 halogen atoms, or by a cyano, nitro, carboxy, C14 alkyl, carbamoyl or -CO-O(C14-alkyl); or a cycloalkyl group with 3 to 6 carbon atoms; or a phenyl group, optionally substituted by 1 to 3 halogen atoms and/or by C14 alkyl, C36 cycloalkyl, C14 alkoxy, C14 alkylthio, cyano, trifluoromethyl, formyl, 1 or 2 nitro group(s), a group of the formula -COR4 or phenyl; or a -N--C(CH3)2, -CH(CN)-C6H5 or naphthyl group; R2 represents a C14 alkyl, allyl or cyclohexyl group; R3 represents a methyl or ethyl group; R4 represents a C14 alkoxy, hydroxy or -NR5R6 group; R5 and R6, which may be the same or different, each represent a hydrogen atom or a C14 alkyl group; and n is 1 or 2) in association with a pharmaceutical carrier or excipient.
2. Compositions as claimed in claim 1 which comprise as active ingredient at least one compound of formula I in which X represents an optionally substituted alkylthio group, an optionally substituted phenoxy group, an alkoxy group or a chlorine atom.
3. Compositions as claimed in claim 2 which comprise as active ingredient at least one compound of formula I in which X represents a methylthio, ethylthio, sec.-butylthio, allylthio or cyano-C14-alkylthio group.
4. Compositions as claimed in claim 2 which comprise as active ingredient at 'least one compound of formula I in which X represents a chloro-, methyl-, cyanoor nitro-phenoxy group.
5. Compositions as claimed in claim 2 which comprise as active ingredient at least one compound of formula I in which X represents a benzylmercapto group substituted by one or two nitro groups.
6. Compositions as claimed in claim 2 which comprise as active ingredient at least one compound of formula I in which X represents an n-butoxy or alkenyloxy group.
7. Compositions as claimed in any one of claims 1 to 3 and 6 which comprise as active ingredient at least one compound of formula I wherein X represents the group -OR1 or -SR1 in which R, represents an aliphatic group.
8. Compositions as claimed in claim 7 which comprise as active ingredient at least one compound of formula I wherein X represents the group -OR1 or -SR1 in which R, represents an aliphatic group with up to 6 carbon atoms.
9. Compositions as claimed in claim 8 which comprise as active ingredient at least one compound of formula I wherein X represents the group -OR1 or -SR1 in which R, represents an aliphatic group with up to 4 carbon atoms.
10. Compositions as claimed in claim 9 which comprise as active ingredient at least one compound of formula I wherein X represents the group -OR1 or -SR1 in which R, represents an optionally substituted methyl or ethyl group.
11. Compositions as claimed in claim 9 which comprise as active ingredient at least one compound of formula I wherein X represents the group -OR1 or -SR1 in which R, represents an optionally substituted propyl or isopropyl group.
12. Compositions as claimed in any one of the preceding claims in a form suitable for enteral or parenteral administration.
13. Compositions as claimed in any one of claims 1 to 11 in a form suitable for topical administration.
14. Compositions as claimed in claim 12 in the form of tablets, coated tablets, capsules, syrups, drops, suppositories, oily or aqueous solutions, suspensions emulsions or implantations.
15. Compositions as claimed in claim 13 in the form of solutions, lotions, emulsions, sprays, ointments, creams, pastes or powders.
16. Compositions as claimed in any of claims 1 to 12 and 14 in the form of dosage units.
17. Compositions as claimed in any one of claims I to 11, 13 and 15 which contain from 0.1 to 10% by weight of active ingredient.
18. Compositions as claimed in claim 17 which contain from I to 3% by weight of active ingredient.
19. Compositions as claimed in any one of the preceding claims substantially as herein described.
20. Pharmaceutical compositions substantially as herein described in any one of Examples D to G.
21. Pesticidal and herbicidal compositions (as herein defined) comprising as active ingredient at least one compound of formula I as defined in claim 1 in association with an inert carrier or diluent.
22. Compositions as claimed in claim 21 which comprise as active ingredient at least one compound of formula I in which X represents an optionally substituted alkylthio group, an optionally substituted phenoxy group, an alkoxy group or a chlorine atom.
23. Compositions as claimed in claim 22 which comprise as active ingredient at least one compound of formula I in which X represents a methylthio, ethylthio, sec.-butylthio, allylthio or cyano-lower alkylthio group.
24. Compositions as claimed in claim 22 which comprise as active ingredient at least one compound of formula I in which X represents a chloro-, methyl-, cyano-, or nitrophenoxy group.
25. Compositions as claimed in claim 22 which comprise as active ingredient at least one compound of formula I in which X represents a benzylmercapto group substituted by one or two nitro groups.
26. Compositions as claimed in claim 22 which comprise as active ingredient at least one compound of formula I in which X represents an n-butoxy or alkenyloxy group.
27. Compositions as claimed in any one of claims 21 to 23 and 26 which comprise as active ingredient at least one compound of formula I wherein X represents the group R, or --SR, in which R, represents an aliphatic group.
28. Compositions as claimed in claim 27 which comprise as active ingredient at least one compound of formula I wherein X represents the group R, or --SR, in which R, represents an aliphatic group with up to 6 carbon atoms.
29. Compositions as claimed in claim 28 which comprise as active ingredient at least one compound of formula I wherein X represents the group R, or --SR, in which R, represents an aliphatic group with up to 4 carbon atoms.
30. Compositions as claimed in claim 29 which comprise as active ingredient at least one compound of formula I wherein X represents the group R, or --SR, in which R, represents an optionally substituted methyl or ethyl group.
31. Compositions as claimed in claim 29 which comprise as active ingredient at least one compound of formula I wherein X represents the group ---OR, or --SR, in which R, represents an optionally substituted propyl or isopropyl group.
32. Compositions as claimed in any one of claims 21 to 31 which contain an emulsifying, wetting or dispersing agent.
33. Compositions as claimed in any one of claims 21 to 32 in the form of wettable powders, emulsifiable concentrates, solutions, aerosols, granulates or dusting powders.
34. Compositions as claimed in claim 33 suitable for use without dilution and containing from 0.01 to 10% by weight of active ingredient.
35. Compositions as claimed in any one of claims 21 to 32 in the form of ultra low volume formulations.
36. Compositions as claimed in claim 35 which contain up to 80% by weight of active ingredient.
37. Compositions as claimed in any one of claims 21 to 36 substantially as herein described.
38. Pesticidal and herbicidal compositions substantially as herein described in any one of Examples A to C.
39. A method of preventing the growth or proliferation of fungi or bacteria which comprises applying to a site infested with or susceptible to infestation by fungi or bacteria an effective amount of a composition as claimed in any one of claims 21 to 38.
40. A method of controlling the growth of plants which comprises applying to plants an effective amount of a composition as claimed in any one of claims 21 to 38.
41. A method as claimed in claim 40 wherein the said composition is applied in a concentration of from 0.5 to 10 kg per hectare.
42. A method of preventing or inhibiting the growth or proliferation of insects which comprises applying to a site infested with or susceptible to infestation by insects an effective amount of a composition as claimed in any one of claims 21 to 38.
43. A method of treating bacterial or fungal infections of animals other than human beings which comprises administering an effective amount of a pharmaceutical composition as claimed in any one of claims I to 20 to an animal other than a human being.
44. A process for the preparation of compounds of formula I as defined in claim I (wherein X represents an imidazolyl or triazolyl or the group --OR, or --SR,) which comprises reacting a compound of the formula

with imidazole, a triazole or a compound of the formula R,OH or R,SH (wherein R, is as defined in claim 1) whereby a compound of formula I is obtained.
45. A process as claimed in claim 44 wherein the reaction is effected by the use of about one equivalent of imidazole, a triazole or the compound of formula R,OH or R,SH.
46. A process as claimed in claim 44 or claim 45 wherein the reaction is effected in the presence of an acid receptor.
47. A process as claimed in claim 46 wherein the acid acceptor comprises a tertiary amine.
48. A process as claimed in any one of claims 44 to 47 wherein the reaction is effected at a temperature of from -20 to 1000C.
49. A process as claimed in claim 48 wherein the reaction is effected at a temperature of from 0 to 500 C.
50. A process as claimed in any one of claims 44 to 49 wherein the reaction is effected in the presencce of ether, dioxan, tetrahydrofuran, benzene, toluene, ethyl acetate or acetone as solvent.
51. A process for the preparation of compounds of formula I as defined in claim I (wherein X represents the group --OR,) which comprises reacting a solution or suspension of a compound of formula II (as defined in claim 44) in a compound of formula R,OH (wherein R, is as defined in claim 1) with an alkali metal- or alkaline earth metalhydroxide, hydrogen carbonate or carbonate whereby a compound of formula I is obtained.
52. A process as claimed in claim 51 wherein the reaction is effected by the use of about one equivalent of the alkali metal- or alkaline earth metal-hydroxide, hydrogen carbonate or carbonate.
53. A process as claimed in claim 51 or claim 52 wherein the alkali metal hydroxide is sodium or potassium hydroxide.
54. A process as claimed in any one of claims 51 to 53 wherein the reaction is effected in the presence of water.
55. A process as claimed in any one of claims 51 to 54 wherein the reaction is effected at a temperature of from 0 to 500C.
56. A process for the preparation of compounds of formula 1 as defined in claim I (wherein X represents the group SOnR2) which comprises oxidising a compound of formula I in which X represents the group -S-R2 whereby a compound of formula I is obtained.
57. A process as claimed in claim 56 wherein the oxidation is effected by the use of hydrogen peroxide.
58. A process as claimed in claim 57 wherein the oxidation is effected in the presence of glacial acetic acid.
59. A process as claimed in any one of claims 56 to 58 for the preparation of compounds of formula I (wherein X represents the group SORT) wherein the oxidation is effected in the presence of about an equimolar amount of hydrogen peroxide at a temperature of from 85 to 950 C.
60. A process as claimed in claim 59 wherein the oxidation is effected at a temperature of about 90"C.
61. A process as claimed in any one of claims 56 to 58 for the preparation of compounds of formula I (wherein X represents the group SO2R2) wherein the oxidation is effected in the presence of a molar excess of hydrogen peroxide at a temperature of about 100"C.
62. A process for the preparation of compounds of formula I as defined in claim 1 (wherein X represents the group -S-CS-N(R3)2) which comprises reacting a compound of formula II (as defined in claim 44) with an alkali metal salt of dimethyl or diethyl dithiocarbamate.
63. A process as claimed in claim 62 wherein the reaction is effected at ambient temperature.
64. A process as claimed in claim 62 or claim 63 wherein the reaction is effected in the presence of methanol as solvent.
65. A process for the preparation of compounds of formula I as defined in claim 1 (wherein X represents the group -O-C6H4COOH) which comprises hydrolysing an ester of the compound of formula I (wherein X represents the group -O-C6H4COOH).
66. A process as claimed in any one of claims 44 to 65 substantially as herein described.
67. A process for the preparation of compounds of formula I as defined in claim 1 substantially as herein described in any one of Examples 1 to 118.
68. Compounds of formula I as defined in claim 1 when prepared by a process as defined in any one of claims 44 to 67.
69. Compounds of formula I as defined in claim 1 with the proviso that X is other than chlorine, methoxy, methylthio, phenoxy or phenylthio.
70. Compounds as claimed in claim 69 wherein X represents an optionally substituted alkylthio group.
71. Compounds as claimed in claim 70 wherein X represents an ethylthio, sec.butylthio, allylthio or cyano-lower alkylthio group.
72. Compounds as claimed in claim 69 wherein X represents a substituted phenoxy group.
73. Compounds as claimed in claim 72 wherein X represents a phenoxy group substituted by chlorine, methyl, cyano and/or nitro.
74. Compounds as claimed in claim 69 wherein X represents a benzylmercapto group optionally substituted in the aryl moiety.
75. Compounds as claimed in claim 74 wherein X represents a benzylmercapto group substituted by one or two nitro groups.
76. Compounds as claimed in claim 69 wherein X represents an alkoxy group.
77. Compounds as claimed in claim 76 wherein X represents an n-butoxy group or an alkenyloxy group.
78. Compounds as claimed in claim 69 to 71, 76 and 77 wherein X represents the group --OR, or --SR, and R, represents an optionally substituted ethyl, propyl or isopropyl group.
79. 3-Chloro-5-pchlorobenzylmercapto- 1,2,6-thiadiazin-4-one.
80. 3-Chloro-5-(2-cyanoethyl)-mercapto- 1 ,2,6-thiadiazin-4-one.
81. 3-Chloro-5-p-nitrophenoxy- 1,2,6-thiadiazin-4-one.
82. Compounds as claimed in claim 69 as herein specifically disclosed.
83. Pharmaceutical agents comprising as active ingredient at least one compound of formula I (as defined in claim 69) in association with a pharmaceutical carrier or excipient.
84. Pesticidal or herbicidal agents comprising as active ingredient at least one compound of formula I (as defined in claim 69) in association with a carrier or diluent.