Thiocarbamic acid derivatives
United States Patent [191 Biishagen et al.  
 [ TI-IIOCARBAMIC ACID DERIVATIVES [75] Inventors: Horst Biishagen, Haan/Rhld;  
  Manfred Plempel, Wuppertal-Elberfeld, both of Germany [73] Assignee: Bayer Aktiengesellschait,  
 Leverkusen, Germany [22] Filed: Sept. 27, 1972 [211 App]. No.: 292,484  
 Related US. Application Data [62 Division of Sci. No. 25,557, April 3, 1970. Pat. No.  
 [30] Foreign Application Priority Data Apr. 15, 1969 Germany 1917739 [52] US. Cl 260/243 R; 424/246;260/304; 260/327 B; 260/244 R; 260/307 D;-260/333; 260/239 BB, 260/287 R; 260/326.ll  
 [5 l] Int. Cl. C07d 93/12 [58] Field of Search 260/243 R I [56] References Cited UNITED STATES PATENTS Zivkovic et al. 260/243 Primary Examiner-John M. Ford Apr. 29, 1975 [57] ABSTRACT Compounds of the formula:  
  Y Ar-OCS-N wherein X, Y, R and n are as above defined with a thiocarbonic acid ester&#39;halide of the formula:  
 Hal CS 0 Ar wherein Hal is halogen and Ar is as above defined. These compounds are useful as antimycotics for the treatment of fungal infections which are pathogenic to humans and animals.  
 12 Claims, No Drawings THIOCARBAMIC ACID DERIVATIVES This is a division of application Ser. No. 25,557 filed Apr. 3, 1970 now U.S. Pat. No. 3,729,473.  
  The present invention is concerned with thiocarbamic acid derivatives, toa process for their produc- 5 tion, to pharmaceutical compositions useful for the treatment of mycotic infections and to methods of treating mycotic infections in humans and animals.  
 More particularly, the present invention is concerned with compounds of the formula:  
 Ar-OCS- (I) H wherein X, Y, R and n are as above defined, with a thiocarbonic acid ester halide of the formula:  
 (Ill) wherein Hal is halogen and Ar is as above defined.  
  lt is preferred that the lower alkyl, lower alkoxy and lower alkylmercapto moieties set forth above contain from I to 4 carbon atoms in the alkyl portion. These moieties may be straight&#39;or branched chain.  
  The preferred halogens are fluorine, chlorine or bromine.  
  The preferred aromatic moieties are those which contain up to 12 carbon atoms in the aromatic portion and the preferred moieties are phenyl and naphthyl. 0 The preferred substituents on the aromatic moieties are halogen, especially fluorine, chlorine or bromine, lower alkyl or lower alkoxy, and particularly lower alkyl of one to four carbon atoms or lower alkoxy of one to four carbon atoms.  
  Heterocyclic compound (ll) may be used in the form of a salt.  
  According to one embodiment of the process of the present invention the sodium salt of the heterocyclic base (ll) is first formed (e.g. in a suitable solvent such as hexamethylphosphoric acid triamide-(HMPA), dimethyl formamide (DMF) toluene or benzene) with the use of, for example, sodium hydride, and is subsequently reacted with the thiocarbonic acid ester chloride at a slightly elevated temperature (about 30 to about 50 C).  
  Obviously, it is also possible to react the heterocyclic base as such with the carbonic acid ester chloride in a suitable solvent. for example CHCL CH Cl benzene, toluene, ethanol, methanol or acetone, and with the addition of a tertiary base, for example triethylamine or N,N-dimethyl-benzylamine.  
  The heterocyclic bases and ester halides used as starting material are known and can be obtained by known methods.  
  Working up of the reaction mixtures may be carried out in the usual way.  
  The excellent antimycotic effect of the newly prepared compounds is surprising and could not be foreseen, since after the elaborate investigations of T. Noguchi, Y. Hashimoto, K. Myazaki and A. Kayi, J. Pharm. Soc. Japan, 88 (2), 227-234 (1968), 88 (3), 335-343 (1968), 88 (3)344-352 (1968) and 88 (3), 353-358 1968) it has hitherto been assumed that only compounds of the type Ar -o-sCl l-Ar have an antimycotic effect and even these only if R de- Table 1 Minimum inhibition concentration &#39;y/pcr ml test medium without serum with serum Trichophyton mentagroph. l y l -y Trichophyton equinum l -y 4 y Trichophyton verucosum l y l &#39;y Trichophyton rubrum var. Algochonosa l y l Trichophyton rubrum var. Ycsosa l y l y Trichophyton conccntricum l -y Trichophyton schoenlcin 4 y Microsporum fclincum l y Microsporum audouinii l y Microsporum gallinac 40 -y l y 50% inhibition Chromomyccs carrioni 40 y l y 40 y l 7 507: inhibi- 50% inhibition tion Epidcrmophyton floccos. l -y 4 y Nocardia brasilicnsis 4 &#39;y 50% inhibition Candida albicans y Sporotrichum 40 &#39;y 40 &#39;y C ryptococcus neoformans 40 -y 40 y Madurcllc grisca 40 &#39;y 40 &#39;y Histoplasma capsulatum 4 7 l -y Allcschcria boydii 40 7 40 &#39;y Phialophora pedrosoi 40 &#39;y 40 y Pcnicillium commune [00 y Aspergillus nigcr 100 7 HM) y ANTIMYCOTIC EFFECT lN ANIMAL TEST The representative compound tested in Table 1 exhibits a very good effect in a model experiment with trichophytia caused in guinea pigs by Trichophyton mentagrophytes, when 0.5 and 1% solutions were locally applied once daily, starting with the third day after infection, until the eighth day after infection. A rapid retrogression of the primary symptoms of infection (reddening of the skin and loss of hair) takes place, and the animals can be considered completely cured on the 10th day after infection. A typical course of infection is illustrated in Table 2.  
 as well as Microsporon species, particularly Microsporlm canis and felineum.  
 In general, it has proved advantageous to administer locally formulations containing about 1% to about 2% Table 2 Test groups Evaluation of course of infection after days post infection Untreated 1 2 3 4 5 6 7 8 9 10 control:  
  1st animal 0 0-1 0-1 1 2 2-3 3 4 4-5 5 2nd animal 0 0-1 0-1 1 l-2 2 3 3-4 4 4-5 3rd animal 0 0-1 0-1 1 1-2 2-3 3 4 5 5 Substance (a) (of Example 1 171 1st animal 0 0-1 1 l l l l l l 2nd animal 0 0-1 1 l 0-1 0-1 0-1 0-1 0-1 0-1 3rd animal 0 0-1 1 1 1 l 1 1 1 Substance (b) 17: as control 1st animal 0-1 l 1 0-1 1 1-2 2-. 2 2nd animal 0-1 1 1 1 l 1-2 2 2-1 Substance (c) 171 1st animal O-l l 1 O-1 1 1-2 l-2 l-2 2nd animal 0-1 1 1 0-1 0-1 1 l-2 l-2 3rd animal 0-1 0-1 1 0-1 0-1 1 1 2 Substance (d) 171 animal O-l O-l 0-1 O-l l l l 1 2nd animal 0-1 0-1 0-1 0-1 O-l 0 0 (1 3rd animal 0-1 0-1 0-1 0-1 1 1 1-2 1- Substance (e) 1% 1st animal 1 1-2 0-1 0-1 O-l l l 1 2nd animal 1 1-2 1 0-1 0-1 1 l 1 3rd animal ()-1 1-2 0-1 0-1 0-1 0-1 0-1 0-1 4th animal 1 1 0-1 0-1 0&#39; 0-1 0-1 0-1 In table 2, substance (a) compound of Example 1 ocarbonyl]-aniline (for comparison).  
 (c) compound of Example 24.  
 (d) compound of Example 25.  
 (e) compound of Example 42.  
 3-methyl-N-methyl-N-[ naphthyl-( 2 )-oxy-thiat which application takes place. In some cases it may be sufficient to use less than the aforesaid minimum amount whereas in other cases it will be necessary to go beyond the aforesaid upper limit. If larger amounts are administered, it may be advisable to distribute these over the day in several individual doses. The same range of dosage is envisaged for application in human Explanation of numbers: 1 reddening; 2 reddenmedicine, and the other explanations given above apply ing and beginning of loss of hair; 3 strong loss of hair; 4 beginning of bleeding ulceration; 5 expansive bleeding ulcerations.  
 A primary fungicidal effect on Dermatophytes could be found in the Warburg test for the new compound (a) 5 at concentrations of 0.2 to 1 A/ml substrate.  
  The compounds of the present invention are useful for the treatment of fungal infections in both humans and animals. With regard to the veterinary medicine aspects, they have been found especially suitable for analogously.  
  The compounds of the present invention can be applied alone or in combination with pharmaeeutieally acceptable diluents or carriers. Suitable forms for application in combination with various inert carriers are powders, sprays, aqueous suspensions, elixirs, syrups and the like. Such carriers comprise solid extenders or fillers, a sterile aqueous medium as well as nontoxic organic solvents and the like. 1n the aforesaid case. the therapeutically active compound should be present at a concentration of about 0.5 to per cent by weight of the total mixtures, that is to say in quantities which suffice to achieve the above range of dosage.  
  1n the case of aqueous suspensions and/or elixirs, the active ingredient can be used together with diluents such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type.  
  The invention further provides a medicament in dosage unit form comprising at least one of the new active compounds either alone or in admixture with a solid or liquid diluent or carrier. The medicament may include a protective envelope containing the active compound and, if used. the diluent or carrier.  
  The term medicament in dosage unit form as used in the present specification means a medicament as defined above in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a 1 unit dose of the active compound or compounds. Such portions may, for example, be in monolithic coherent form. such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets. sachets, or capsules; in ampoules. either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.  
  The invention also provides a method of combating fungus infections in humans and animals (especially domestic animals) which comprises applying to the ani- 2 mals at least one of the new active compounds either alone or in admixture with a solid or liquid diluent or carrier.  
  The following non-limitative example more particularly illustrates the present invention.  
 EXAMPLE 37.8 g (0.25 mol) 2,3-dihydro-l,4-benzothiazine were dissolved in 250 ml hexamethyl-phosphoric acid triamide and 11.3 g (0.25 mol) sodium hydride (53.3% in paraffin) were added. The mixture was stirred at room temperature until the evolution of hydrogen had stopped (about minutes). Subsequently, 55.7 g (0.25 mol) O-B-napthyl-thiocarbonic acid ester chloride were slowly added, the mixture was stirred at room temperature for 15 minutes and then at C for 15 minutes. The reaction solution was poured into 2.5 litres of water, the precipitated crude product was filtered off with suction, the adhering smears were removed by stirring with some acetone, and the product was recystallised form dioxan/ethanol.  
  64.5 g (76.5%) 2,3-dihydro-N-[naphthyl-(2)-oxythiocarbonyH-l,4-benzothiazine were obtained in the form of slightly yellowish prisms of m.p. 133 C.  
  The following compounds were obtained in an analogous way:  
  2.3-Dihydro-6-methyl-N-[ naphthyl-( 2 )-oxythiocarbonyll-l ,4-benzothiazine. After recystallisation from dioxan/ethanol, the compound forms colourless small cuboids of m.p. 128 C.  
 3. 2,3-Dihydro-6-trifluoromethyl-N-1naphthyl-(2)- oxy-thiocarbonyl l- 1 .4-benzothiazine. Colourless coarse prisms from dioxan/ethanol; m.p. 126 C.  
 2,3-Dihydro-2.6-dimethy1-N-[naphthyl-(2)-oxy- 6 2,3-Dihydro-2-methyl-N-[naphthyl-(2)-oxy- Colourless prisms of m.p. 164 C from dioxan/e- 8. 2,3-Dihydro-N-[4-chlorophenoxy-thiocarbonyl]- 1,4-benzothiazine. Shiny colourless scaly flakes (dioxan/ethanol) of m.p. C.  
 &#39; 9. 2,3,4,5-Tetrahydro-N-[naphthyl-(2)-oxythiocarbonyl]-1,5-benzothiazepine. After recrystallisation from dioxan ethanol. colourless small prisms of m.p. 167 C.  
 10. 2.3-Dihydro-N-[naphthyl-(Z)-oxy-thiocarbonyl]- l ,4-benzoxazine. Colourless broad prisms (dioxan) of m.p. 181 C. 1 1. 2,3-Dihydro-6-methyl-N-[naphthyl-(2)-oxythiocarbonyl1- l ,4-benzoxazine. Colourless prisms of m.p. 143 C from dioxan. 12. 2,3-Dihydro-6-methoxy-N-[naphthyl-( 2 )-oxythiocarbonyl]-1,4-benzoxazine. Colourless prisms (dioxan/ethanol) of m.p. 158 C. 13. 2,3-Dihydro-2,7-dimethyl-N-[naphthyl-(2)-oxythiocarbonyl]- 1 ,4-benzoxazine. Colourless small prisms (dioxan/ethanol) of m.p. 144 C.  
 14. 2,3-Dihydro-2-methyl-N-[naphthyl-(2)-oxythiocarbonyl]-l ,4-benzoxazine. Colourless prisms of m.p. 158 C from dioxan/ethanol.  
 15. 2,3-Dihydro-2,6-dimethyl-N-[naphthy1-( 2 )-oxythiocarbonyl 1 ,4-benzoxazine. After recrystallisation from dioxan/ethanol. colourless prisms of m.p. 132 C.  
 16. 2,3-Dihydro-2-methyl-6-methoxy-N-[naphthyl- (2)-oxy-thiocarbonyl]-1,4-benzoxazine. Colourless rectangular flakes (dioxan/ethanol) of m.p. 151 C.  
 17. 2.3-Dihydro-N-lnaphthyl-(2)-oxy-thiocarbonyl]- indole. Colourless prisms of m.p. 162 C from dioxan/ethanol.  
 18. 2,3-Dihydro-2-methyl-N-[ naphthy1-( 2 )-oxythiocarbonyll-indole. Colourless prisms of m.p. 138 C from dioxan. 19. l,2,3,4-Tetrahydro-N-[naphthyl-(2)-oxy-thiocarbonyl]-quinoline. Almost colourless prisms of m.p. 122 C from dioxan- /ethanol.  
 20. l,2,3,4-Tetrahydro-6-methyl-N-[naphthyl-(2) oxy-thiocarbonyll-quinoline. After recrystallisation from ethanol, colourless, thin, matted small needles of m.p. 128 C.  
 21. 1,2,3,4-Tetrahydro-2-methyl-N-[ naphthyl-( 2 oxy-thiocarbonyll-quinoline. Colourless thin small needles of m.p. 147 C from dioxan/ethanol.  
 22. 1,2.3,4-Tetrahydro-5-methyl-N-[naphthyl-(2)- oxy-thiocarbonyl]-quinoline. Colourless prisms (from ethanol) of m.p. 121 C 23. l,2,3,4-Tetrahydro-7-methyl-N-[naphthyl-(2)- oxy-thiocarbonyl]-quinoline.  
 Colourless small needles (from ethanol) of m.p. 1 14 1 24. 1.2,3,4-Tetrahydro-8-methyl-[naphthy1-(2)-oxythiocarbonyll-quinoline. After recrystallisation from ethanol, colourless flakes of m.p. 102 C.  
 25. 1,Z-Dihydro-4,6-dimethyl-[naphthy1-( 2 )-oxy-thiocarbonyl1-quinoline. After recrystallisation from dioxan/ethanol, the compound forms yellowish crystals of m.p. 124 C.  
 Table 3 Continued Com- Acid Reactant Base Reactant pound No.  
 l l B-Naphthyl-thiocarbonic 2,3-Dihydro-6-methylacid ester chloride l,4-benzoxazine Boiling p. 0.0 l/72 l2 B-Naphthyl-thiocarbonic 2,3-Dihydro-6-methoxyacid ester chloride l,4-benzoxazine M.p. 59 (platcs/ cyclohexane) l 3 B-Naphthyl-thiocarbonie 2,3-Dihydro-2,7-diacid ester chloride methyl-lA-benzoxazine B.p. 0.l/7779 l4 B-N aphthyl-thiocarbonic 2,3-Dihydro-2-methylacid ester chloride L4-benzoxazine B.p. 0.2/74 l5 B-Naphthyl-thiocarhonic 2.3-Dihydro-2 6-diacid ester chloride methyI-IA-benzoxazine B.p. 0.0l/74-76 l6 fl-Naphthyl-thiocarbonic 2,3-Dihydro-2-methyl-6- acid ester chloride mcthoxyl 4-benzoxazine B.p. 0.5/134-l38&#34; l 7 ,B-NaphthyI-thiocarbonic 2,3-Dihydro-indole acid ester chloride l 8 B-Naphthyl-thiocarbonic 2 3-Dihydro-2methylacid ester chloride indole l9 fi-Naphthyl-thiocarbonic l .2,3,4-Tetrahydroacid ester chloride quinoline B-Naphthyl-thiocarhonic l ,2 3,4-Tetrahydro-6- acid ester chloride methyluinoline B.p. 0.7 97-98 2l B-Naphthyl-thiocarbonic l ,2,3,4-Tetrahydro-2- acid ester chloride methyl-quinoline 22 B-Naphthyl-thiocarhonic L23 ,4-Tetrahydro-5- acid ester chloride methyl-quinoline B.p. 0.l/69-70 23 B-Naphthyl-thiocarhonic l 2.3.4-Tetrahydro-7- acid ester chloride methyl-quinoline B.p. 3/ll4-ll6 24 B-Naphthyl-thiocarhonic l ,2,3,4-Tetrahydro-8- acid ester chloride methyl-quinoline B. l2/l26-l27&#34; 25 [3-Naphthyl-thiocarhonic l ,S-Dihydro-k-dimethylacid ester chloride quinoline B.p. 0.5/98-l03 26 B-Naphthyl-thiocarbonic l,2-Dihydro-4-methylacid ester chloride quinoline B.p O.4/80 27 4-Fluorophenyl-thiol ,2.3,4-Tetrahydro-5- carbonic acid ester methyl-quinoline chloride 28 4-Chlorophenyl-thiol ,2,3,4-Tetrahydro-8- carbonic acid ester methyl-quinoline chloride 29 B-Naphthyl-thiocarbonic l,2,3,4-Tetrahydro-4- acid ester chloride oxo-quinoline 30 B-Naphthyl-thiocarbonic l ,2.3,4-Tetrahydro- 1- acid ester chloride methyl-6-methylmercaptoquinoxaline B.p. 0.5/164-166-l68&#34; 3 i B-Naphthyl-thiocarbonic l ,2,4,5-Tetrahydro-2- acid ester chloride mcthyl-l-ethyll ,S-benzodiazepine M.p. 5 l 32 4-Chlorophenyl-thio- 2,3-Dihydrol ,4-benzoxacarbonic acid ester zinc chloride 33 B-NaphthyLthiocarhonic 2,3,4.5-Tetrahydro-2- acid ester chloride methyll .S-benzothiazepinc B.p. 0.0l/80-83 34 B-Naphthyl-thiocarbonic l ,2.3.4-Tetrahydro-3- acid ester chloride methyl-quinoline B.p. 0.l5/74 35 B-Naphthyl-thiocarbonic l.2.3.4-Tetrahydro-6.8-  
 acid ester chloride dimethyl-quinolinc B.p. 0.0l/70-72 36 B-Naphthyl-thiocarbonic l 2.3 .4-Tetrahydro-4,6.7-  
 acid ester chloride trimethyl-quinoline B.p. ().4/l02-l05 M.p. 55 (Prismen/Ligroin) 37 B-Naphthyl-thiocarbonic l .2,3,4-Tetrahydro-3 .8-  
 acid ester chloride dimethyl-quinoline B.p. 0.5/89-9() 38 4-Chlorophenyl-thio 1.2.3 .4-Tetrahydrocarbonic acid ester quinoline chloride 39 4-Chlorophenyl-thiol 2,3.4-Tetrahydro-6- carbonic acid ester methyl-quinolinc chloride 40 4-Chlorophenyl-thiol .2,3,4-Tetrahydro-2- carbonic acid ester chloride methyl-quinoline Table 3 Continued Com- Acid Reactant Base Reactant pound No.  
 41 4-Chlorophenyl-thiol,2,3,4-Tetrahydro-3- carbonic acid ester methyl-quinolinc chloride 42 4-Chlorophcnyl-thiol ,2,3,4-Tetrahydro-4- carbonic acid ester methyl-quinoline chloride 43 4-Chlorophenyl-thiol,2 3,4-Tctrahydro-4,6-  
 carbonic acid ester dimethyl-quinoline chloride 44 B-Naphthyl-thiocarbonic I ,Z-Dihydro-quinoline acid ester chloride 45 fi-Naphthyl-thiocarbonic acid ester chloride qulnohne B.p. 0.1/69-74 46 B-Naphthyl-thiocarbonic l ,Z-Dihydro-B-mcthylacid ester chloride quinoline M.p. 73 47 4-Chlorophcnyl-thiol ,2-Dihydro-4.6-dimethylcarbonic acid ester quinoline chloride 48 4-Chlorophcnyl-thiocarhonic L2-Dihydro-3-mcthylacid ester chloride quinolinc 49 4-C hlorophcn yl-thiol.2-Dihydro-8-methylcarbonic acid ester quinoline chloride 50 B-Naphthyl-thiocarbonic l,2,3,4-Tetrahydro-4- acid ester chloride methyl-quinoline What is claimed is:  
 l. A compound of the formula:  
 Ar-O-C- 3. A compound according to claim 2 wherein Ar is napthylt 4. A compound according to claim 3 wherein Ar is naphthyl-( 2).  
 5. The compound according to claim 1 which is 2.3-  
 dihydro-N-[ naphthyl-( 2 )-oxy-thiocarbonyl]-l ,4- benzothiazine.  
 6. The compound according to claim I which is 2,3-  
 dihydro-6-methyl-N-I napthyl-( 2 )-oxy-thiocarbonyl]- 1,4-benzothiazine.  
 7. The compound according to claim 1 which is 2,3-  
 dihydro-6-trifluoromethyl-N-[naphthyl-( 2 )-0xythiocarbonyl l ,4-benzothiazine.  
 8. The compound according to claim 1 which is 2,3-  
 dihydro-Z-methyl-N-lnaphthyl-( 2 )-oxy-thiocarbonyl]- 1,4-benzothiazine.  
 9. The compound according to claim 1 which is 2,3-  
 dihydro-2.6-dimethyl-N-[naphthyl-( 2 )-oxythiocarbonyl1- l ,4-benzothiazinc.  
 10. The compound according to claim 1 which is 2,3-  
 dihydro-S ,6-benzo-N-l naphthyl-( 2 )-oxythiocarbonyl1- l ,4-benzothiazine.  
 11. The compound according to claim 1 which is 2.3-  
 dihydro-N-[ 4-fluorophenoxy-thiocarbonyl]- l ,4- benzothiazine.  
 12. The compound according to claim 1 which is 2,3-  
 dihydro-N-[4-chlorophenoxy-thiocarbonyll-l ,4- benzothiazine.