Preparation and the use of halopropargylated cyclic quaternary ammonium compounds as antimicrobial agents

Abstract

Antimicrobial compounds of the formula ##STR1## wherein R is selected from (A)(C.sub.1 to C.sub.20) straight or branched alkyl, optionally substituted with hydroxy, halogen, alkoxy, phenoxy, or --C(.dbd.O)R' wherein R' is selected from C.sub.1 -C.sub.20)alkyl, (C.sub.1 -C.sub.20)alkoxy, phenoxy, or NHR" wherein R" is (C.sub.1 -C.sub.6)alkyl or phenyl; (B) benzyl; (C) phenethyl; (D) cyanoethyl; (E) 2-cyanoethyl; (F) propargyl; and (G) allyl;X=halogen (chlorine, bromine, or iodine), phosphate, acetate, benzoate, citrate, tartrate, alkyl- or aryl-sulfonate, alkylsulfate; and ##STR2## represents a 3-to 7-membered ring that contains at least one nitrogen atom optionally substituted with one or more substituents selected from (C.sub.1 -C.sub.3)alkyl, halo, and carboxyl, said ring optionally containing one or two hetreoatoms in addition to said one nitrogen atom, selected from sulfur, oxygen, and a second nitrogen;Processes for inhibiting microbial growth, and compositions suitable therefore are also disclosed.

Description

I. BACKGROUND OF THE INVENTION

A. Field of the Invention

This invention relates to novel quaternary ammonium antimicrobial compounds and their use.

B. Description of the Prior Art Quaternary ammonium compounds having the general formula (A): ##STR3## wherein R.sub.1, R.sub.2, and R.sub.3 are all substituted or unsubstituted carbon chains were disclosed in U.S. Pat. No. 4,521,412 as having antifungal and antibacterial activity.

Tropium quaternary ammonium compounds having the general structure (B): ##STR4##

wherein X=chlorine were evaluated for hypotensive activity in J. Org. Chem., 24, 1607 (1959). No antimicrobial activity was mentioned in this paper.

The chloride salt and saccharinate salt of tropium (C) (i.e. X=saccharine) were mentioned in U.S. Pat. No. 4,521,412. ##STR5##

Cyclic quaternary ammonium compounds which do not contain an iodopropargyl group have been disclosed in J. Pharmacol. Exptl. Therap., 121, p.347 (1957), where piperazine mono-quaternary salts were shown to have activity against mouse pinworm.

U.S. Pat. No. 4,233,055 discloses substances of the following general structure (D) for inhibiting the growth of plants and for promoting the ripening and abscission of fruit. ##STR6##

R=alkyl, alkenyl, alkynyl

Cyclic quaternary ammonium compounds have been claimed to be used as surface active agents, bactericides, biocides, algicides or fungicides, as exemplified by the following: ##STR7##

DD-278-268-A, Fungicides ##STR8##

U.S. Pat. No. 4,472,412 (1984), Fungicides ##STR9##

U.S. Pat. No. 3,506,666 (1970), For the control of algae, bacteria and fungi. ##STR10##

U.S. Pat. No. 2,971,006 (1961), claimed to be used as surface active agents, bactericides, biocides, and particularly as fungicities.

Japanese Patent 67-026603B discloses a method of producing 3-halo-2-propynylamines of the formula

(R.sub.1)(R.sub.2)N--CH.sub.2 CC--X in which R.sub.1 and R.sub.2 may be joined to form a saturated cyclic 6-membered piperidine or morpholine ring.

II. SUMMARY OF THE INVENTION

Many of the antimicrobials of the prior art are ineffective against gram negative bacteria, have toxicity, and/or environmental problems. It is an object of this invention to provide antimicrobial compounds which have excellent activity against a broad spectrum of fungi and bacteria, and have favorable toxicological and environmental profiles.

Their objects and others are achieved by the present invention which comprises compounds having antimicrobial activity having the formula: ##STR11## wherein

R is selected from (A) (C.sub.1 to C.sub.20) straight or branched alkyl, optionally substituted with hydroxy, halogen, alkoxy, phenoxy, or --C(.dbd.O)R' wherein R' is selected from (C.sub.1 -C.sub.20)alkyl, (C.sub.1 -C.sub.20)akloxy, phenoxy, or NHR" wherein R" is (C.sub.1 -C.sub.6)alkyl or phenyl; (B) benzyl; (C) phenethyl; (D) cyanoethyl; (E) 2-cyanoethyl; (F) propargyl; and (G) allyl;

X=halogen (chlorine, bromine, or iodine), phosphate, acetate, benzoate, citrate, tartate, alkyl- or aryl-sulfonate, alkylsulfate; and ##STR12##

represents a 3-to 7-membered ring that contains at least one nitrogen atom optionally substituted with one or more substitutents selected from (C.sub.1 -C.sub.3)alkyl, halo, and carboxyl, said ring optionally containing one or two hetreroatoms in addition to said one nitrogen atom, selected from sulfur, oxygen, and a second nitrogen.

III. DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

Preferred compounds of the invention are those wherein R.dbd.C.sub.10 to C.sub.16 alkyl, ##STR13## is pyrrolidinium, piperidinium, morpholinium, dimethylmorpholinium, or tetramethylmorpholinium, and X is bezenesulfonate or methane sulfonate. Preferred compounds include the following:

1.1-(2-hydroxyethyl)-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 2. 1-(12-hydroxydodecyl)-l-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 3. 1-(8-hydroxyoctyl)-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 4. 1-(7-hydroxyheptyl)-1-(3-iodopropargyl)-pyrrolidinium 4-methybenzenesulfonate 5. 1-(9-hydroxynonyl)-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 6. 1-tetradecyl-1-(3-iodopropargyt)-pyrrolidinium 4-methylbenzenesulfonate 7. 1-hexadecyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 8. 1-tridecyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 9. 1-butyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 10. 1-pentadecyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 11. 1-decyl-1-(3-iodopropargyl-pyrrolidinium 4-methylbenzenesulfonate 12. 1-octyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 13. 1-dodecyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 14. 1-hexyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 15. 1 -undecyl -1 -(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 16. t-octadecyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 17. -methyl-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 18. 1-(2-hydroxyethyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 19. 1 -(11-hydroxyundecyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 20. 1-(12-hydroxydodecyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 21. 1-(9-hydroxynonyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 22. 1-(2-ethoxycarbonylethyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 23. 1-(8-hydroxyoctyl)-1-(3-iodopropargyl )-1-piperidinium 4-methylbenzenesulfonate 24. 1-(7-hydroxyheptyl)-1-(3-iodopropargyl)-piperidinium- 4methylbenzenesulfonate 25.1-(tetradecyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 26. 1-(hexadecyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate 27. 1 -(12-hydroxydodecyl)-1 -(3-iodopropargyl)-hexamethyleneiminium 4-methylbenzenesulfonate 28. 4-tetradecyl-4-(3-iodopropargyl)-morpholinium 4-methylbenzenesulfonate 29. 4-methyl-4-(3-iodopropargl)-morpholinium 4-methylbenzenesulfonate 30. 1-dodecyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate 31. 1-tridecyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate 32. 1-hexadecyl-1-(3-iodopropargy)-pyrrolidinium benzenesulfonate 33. 1-pentadecyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate 34. 1 -tetradecyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate 35. 1-hexadecyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 36. 1-tridecyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 37. 1-dodecyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 38. 1-pentadecyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 39. 1-tetradecyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 40. 1-hexadecyl-1-(3-iodopropargyt)-morpholinium methanesulfonate 41. 4-tetradecyl-4-(3-iodoprolyargyl)-morpholinium benzenesulfonate 42. 4-tetradecyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 43. 4-tetradecyl-4-(3-iodopropargyl)-2,6-dimethylmorpholinium 4-methylbenzenesulfonate 44. 1-hexadecyl-1-(3-iodopropargyl)-hexamethyleneiminium 4-methylbenzenesulfonate 45. 1-tetradecyl-1-(3-iodopropargyl)-hexamethyleneiminium 4-methylbenzenesulfonate 46. 4-hexadecyl-4-(3-iodopropargyl)-2,6-dimethylmorpholinium 4-methylbenzenesulfonate 47. 4-hexadecyl-4-(3-iodopropargyl)-2,6-dimethylmorpholinium benzenesulfonate 48. 4-hexadecyl-4-(3-iodopropargyl)-2,6-dimethylmorpholinium methanesulfonate 49. 4-hexadecyl-4-(3-iodopropargyl)-morpholinium 4-methylbenzenesulfonate 50. 4-hexadecyl-4-(3-iodopropargyl)-morpholinium benzenesulfonate 51. 1-(tetradecyl)-1-(3-iodopropargyl)-2-methylpiperidinium benzenesulfonate 52. 1-(tetradecyl)-1-(3-iodopropargyl)-4-methylpiperidinium benzenesulfonate 53. 1-(tetradecyl)-1-(3-iodopropargyl)-1,2,3,6-tetrahydropyridinium benzenesulfonate 54. 1-(tetradecyl)-1-(3-iodopropargyl)-2-methylpiperidinium 4methylbenzenesulfonate 55. 1-(tetradecyl)-1-(3-iodopropargyl)-2-methylpiperidinium methanesulfonate 56. 1-(tetradecyl)-1-(3-iodopropargyl)-imidazolinium benzenesulfonate 57. 4-(tetradecyl)-4-(3-iodopropargyl)-thiomorpholinium benzenesulfonate 58.3-(tetradecyt)-3-(3-iodopropargyl)-imidazolidinium benzenesulfonate 59. 1-tetradecyl-1-(3-iodopropargyl)-piperidinium benzenesulfonate 60. 1-hexadecyl-1-(3-iodopropargyl)-piperidinium benzenesulfonate 61. 1-hexadecyl-1-(3-iodopropargyl)-piperidinium methanesulfonate 62. 1-tetradecyl-1-(3-iodopropargyl)-piperidinium methanesulfonate 63. 1-(dodecyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 64. 1-(dodecyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate 65. 1-(decyioxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium 4methylbenzenesulfonate 66.4-(decyioxycarbonyl)methyl-4-(3-iodopropargyl)-morpholiniurn 4methylbenzenesulfonate 67. 4-(decyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium benzenesulfonate 68. 4-(dodecyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium 4-methylbenzenesulfonate 69. 1-tetradecyl-1-(3-iodopropargyl)-pyrrolidinium bromide 70. 1-(decyloxycarbonyl)methyl-1-(3-iodopropargyt)-pyrrolidinium benzenesulfonate 71. 4-tetradecyl-4-(3-iodopropargyl)-morpholinium bromide 72. 4-tetradecyl-4-(3-iodopropargyl)-rnorpholinium iodide 73. 4-benzyl-4-(3-iodopropargyi )-morpholinium 4-methylbenzenesulfonate 74. 4-benzyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 75. 1-(dodecyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 76. 4-(dodecyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 77. 1-n-butyl-1-(3-iodopropargyl)-pyrrolidinium bromide 78. 1-decyl-1-(3-iodopropargyl )-pyrrolidinium bromide 79. 1-dodecyl-1-(3-iodopropargyl)-pyrrolidinium bromide 80. 1-hexadecyl-1-(3-iodopropargyl)-pyrrolidinium bromide 81. 4-[5-(hexyloxycarbonyl)lpentyl-4-(3-iodopropargy1)-morpholinium 4-methylbenzenesulfonate 82. 1-[5-(hexyloxycarbonyl)]pentyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 83. 4-[5-(hexyloxycarbonyl)]pentyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 84. 1-[5-(hexyloxycarbonyl)]pentyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate 85. 1-tetradecyl-1-(3-iodoproparygyl)-piperidinium n-butylsulfonate 86. 4-tetradecyl-4-(3-iodopropargyl)-morpholinium n-butylsulfonate 87. 1.-tetradecyl-1-(3-iodopropargyl)-pyrrolidinium n-butylsulfonate 88. 4-pentadecyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 89. 4-tridecyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 90. 4-dodecyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 91. 4-decyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 92. 4-n-octyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 93. 4-n-butyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 94. 4-ethyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 95. 4-[2-(decyloxycarbonyl)]ethyl-4-(3-iodopropargyl)-morpholinium methanesulfonate 96. 4-[2-(decyloxycarbonyl)]ethyl-4-)3-iodopropargyl)-morpholinium 4-methanesulfonate 97. 1-[2-(decyloxycarbonyl)]ethyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate 98. l-[2-(decyloxycarbonyl)]ethyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonte 99. 4-n-butyl-4-(3-iodopropargyl)-morpholinium bromide 100. 4-hexadecyl-4-(3-iodopropargyl)-morpholinium bromide 101. 4-dodecyl-4-(3-iodopropargyl)-morpholinium bromide Table 1 shows the structures and the physical data of these representative compounds. __________________________________________________________________________Structures and Physical Data ##STR14## (I) No. ##STR15## R X Melting Point__________________________________________________________________________ ##STR16## C.sub.2 H.sub.4OH ##STR17## 136-138.degree. C.2 ##STR18## C.sub.12 H.sub.24OH ##STR19## 65-70.degree. C.3 ##STR20## C.sub.8 H.sub.16OH ##STR21## 61-67.degree. C.4 ##STR22## C.sub.7 H.sub.14 OH ##STR23## oil5 ##STR24## C.sub.9 H.sub.18OH ##STR25## 89-92.degree. C.6 ##STR26## C.sub.14 H.sub.29 -n ##STR27## 141-143.degree. C.7 ##STR28## C.sub.16 H.sub.33 -n ##STR29## 139-144.degree. C.8 ##STR30## C.sub.13 H.sub.27 -n ##STR31## 140-142.degree. C.9 ##STR32## C.sub.4 H.sub.9 -n ##STR33## 140-143.degree. C.10 ##STR34## C.sub.15 H.sub.31 -n ##STR35## 143-144.degree. C.11 ##STR36## C.sub.10 H.sub.21 -n ##STR37## 137-138.degree. C.12 ##STR38## C.sub.8 H.sub.17 -n ##STR39## 136-138.degree. C.13 ##STR40## C.sub.12 H.sub.25 -n ##STR41## 140-141.degree. C.14 ##STR42## C.sub.6 H.sub.13 -n ##STR43## 122-124.degree. C.15 ##STR44## C.sub.1 H.sub.23 -n ##STR45## 140-141.degree. C.16 ##STR46## C.sub.81 H.sub.37 -n ##STR47## 138-141.degree. C.17 ##STR48## CH.sub.3 ##STR49## 174-178.degree. C.18 ##STR50## C.sub.2 H.sub.4OH ##STR51## 109-112.degree. C.19 ##STR52## C.sub.11 H.sub.22OH ##STR53## 89-93.degree. C.20 ##STR54## C.sub.12 H.sub.24OH ##STR55## 91-95.degree. C.21 ##STR56## C.sub.9 H.sub.18OH ##STR57## 93-98.degree. C.22 ##STR58## C.sub.2 H.sub.4CO.sub.2 Et ##STR59## 95-99.degree. C.23 ##STR60## C.sub.8 H.sub.16OH ##STR61## 129-135.degree. C.24 ##STR62## C.sub.7 H.sub.14OH ##STR63## 100-108.degree. C.25 ##STR64## C.sub.14 H.sub.29 -n ##STR65## 140-144.degree. C.26 ##STR66## C.sub.16 H.sub.33 -n ##STR67## 148-150.degree. C.27 ##STR68## C.sub.12 H.sub.24OH ##STR69## 75-79.degree. C.28 ##STR70## C.sub.14 H.sub.29 -n ##STR71## 153-154.degree. C.29 ##STR72## CH.sub.3 ##STR73## 130-137.degree. C.30 ##STR74## C.sub.12 H.sub.25 -n ##STR75## 95-97.degree. C.31 ##STR76## C.sub.13 H.sub.27 -n ##STR77## 95-100.degree. C.32 ##STR78## C.sub.16 H.sub.33 -n ##STR79## 110-111.degree. C.33 ##STR80## C.sub.15 H.sub.31 -n ##STR81## 107-109.degree. C.34 ##STR82## C.sub.14 H.sub.29 -n ##STR83## 104-106.degree. C.35 ##STR84## C.sub.16 H.sub.33 -n OSO.sub.2.CH.sub.3 113-117.degree. C.36 ##STR85## C.sub.13 H.sub.27 -n OSO.sub.2.CH.sub.3 100-105.degree. C.37 ##STR86## C.sub.12 H.sub.25 -n OSO.sub.2.CH.sub.3 108-112.degree. C.38 ##STR87## C.sub.15 H.sub.31 -n OSO.sub.2.CH.sub.3 113-118.degree. C.39 ##STR88## C.sub.14 H.sub. 29 -n OSO.sub.2.CH.sub.3 85-90.degree. C.40 ##STR89## C.sub.16 H.sub.33 -n OSO.sub.2.CH.sub.3 111-114.degree. C.41 ##STR90## C.sub.14 H.sub.29 -n ##STR91## 134-136.degree. C.42 ##STR92## C.sub.14 H.sub.29 -n OSO.sub.2.CH.sub.3 108-112.degree. C.43 ##STR93## C.sub.14 H.sub.29 -n ##STR94## 105-109.degree. C.44 ##STR95## C.sub.16 H.sub.33 -n ##STR96## 80-85.degree. C.45 ##STR97## C.sub.14 H.sub.29 -n ##STR98## 60-65.degree. C.46 ##STR99## C.sub.16 H.sub.33 -n ##STR100## glassy47 ##STR101## C.sub.16 H.sub.33 -n ##STR102## glassy48 ##STR103## C.sub.16 H.sub.33 -n OSO.sub.2.CH.sub.3 glassy49 ##STR104## C.sub.16 H.sub.33 -n ##STR105## 152-154.degree. C.50 ##STR106## C.sub.16 H.sub.33 -n ##STR107## 134-136.degree. C.51 ##STR108## C.sub.14 H.sub.29 -n ##STR109## viscous oil52 ##STR110## C.sub.14 H.sub.29 -n ##STR111## viscous oil53 ##STR112## C.sub.14 H.sub.29 -n ##STR113## 90-94.degree. C.54 ##STR114## C.sub.14 H.sub.29 -n ##STR115## viscous oil55 ##STR116## C.sub.14 H.sub.29 -n OSO.sub.2.CH.sub.3 viscous oil56 ##STR117## C.sub.14 H.sub.29 -n ##STR118## 116-120.degree. C.57 ##STR119## C.sub.14 H.sub.29 -n ##STR120## 173-177.degree. C.58 ##STR121## C.sub.14 H.sub.29 -n ##STR122## viscous oil59 ##STR123## C.sub.14 H.sub.29 -n ##STR124## 128-130.degree. C.60 ##STR125## C.sub.16 H.sub.33 -n ##STR126## 136-139.degree. C.61 ##STR127## C.sub.16 H.sub.33 -n OSO.sub.2.CH.sub.3 semi-solid62 ##STR128## C.sub.14 H.sub.29 -n OSO.sub.2.CH.sub.3 semi-solid63 ##STR129## CH.sub.2 COOC.sub.12 H.sub.25 ##STR130## 104-106.degree. C.64 ##STR131## CH.sub.2 COOC.sub.12 H.sub.25 ##STR132## 81-83.degree. C.65 ##STR133## CH.sub.2 COOC.sub.10 H.sub.21 ##STR134## 108-109.degree. C.66 ##STR135## CH.sub.2 COOC.sub.10 H.sub.21 ##STR136## semi-solid67 ##STR137## CH.sub.2 COOC.sub.10 H.sub.21 ##STR138## semi-solid68 ##STR139## CH.sub.2 COOC.sub.12 H.sub.25 ##STR140## semi-solid69 ##STR141## C.sub.14 H.sub.29 -n Br semi-solid70 ##STR142## CH.sub.2 COOC.sub.10 H.sub.21 ##STR143## 80-82.degree. C.71 ##STR144## C.sub.14 H.sub.29 -n Br 141-144.degree. C.72 ##STR145## C.sub.14 H.sub.29 -n I 85-88.degree. C.73 ##STR146## Benzyl ##STR147## 161-165.degree. C.74 ##STR148## Benzyl OSO.sub.2.CH.sub.3 168-170.degree. C.75 ##STR149## CH.sub.2 COOC.sub.12 H.sub.25 OSO.sub.2.CH.sub.3 50-53.degree. C.76 ##STR150## CH.sub.2 COOC.sub.12 H.sub.25 OSO.sub.2.CH.sub.3 semi-solid77 ##STR151## C.sub.4 H.sub.9 -n Br 169-172.degree. C.78 ##STR152## C.sub.10 H.sub.21 -n Br 118-121.degree. C.79 ##STR153## C.sub.12 H.sub.25 -n Br semi-solid80 ##STR154## C.sub.16 H.sub.33 -n Br 70-73.degree. C.81 ##STR155## (CH.sub.2).sub.5 COOC.sub.6 H.sub.13 ##STR156## 124-126.degree. C.82 ##STR157## (CH.sub.2).sub.5 COOC.sub.6 H.sub.13 ##STR158## 75-77.degree. C.83 ##STR159## (CH.sub.2).sub.5 COOC.sub.6 H.sub.13 OSO.sub.2.CH.sub.3 semi-solid84 ##STR160## (CH.sub.2).sub.5 COOC.sub.6 H.sub.13 OSO.sub.2.CH.sub.3 semi-solid85 ##STR161## C.sub.14 H.sub.29 -n OSO.sub.2 C.sub.4 H.sub.9 -n 145-150.degree. C.86 ##STR162## C.sub.14 H.sub.29 -n OSO.sub.2 C.sub.4 H.sub.9 -n 140-143.degree. C.87 ##STR163## C.sub.14 H.sub.29 -n OSO.sub.2 C.sub.4 H.sub.9 -n semi-solid88 ##STR164## C.sub.15 H.sub.31 -n OSO.sub.2.CH.sub.3 111-113.degree. C.89 ##STR165## C.sub.13 H.sub.27 -n OSO.sub. 2.CH.sub.3 110-113.degree. C.90 ##STR166## C.sub.12 H.sub.25 -n OSO.sub.2.CH.sub.3 glassy91 ##STR167## C.sub.10 H.sub.21 -n OSO.sub.2.CH.sub.3 semi-solid92 ##STR168## C.sub.8 H.sub.17 -n OSO.sub.2.CH.sub.3 semi-solid93 ##STR169## C.sub.4 H.sub.9 -n OSO.sub.2.CH.sub.3 64-65.degree. C.94 ##STR170## C.sub.2 H.sub.5 OSO.sub.2.CH.sub.3 155-159.degree. C.95 ##STR171## (CH.sub.2).sub.2 CO.sub.2 C.sub.10 H.sub.21 ##STR172## semi-solid96 ##STR173## (CH.sub.2).sub. 2 CO.sub.2 C.sub.10 H.sub.21 OSO.sub.2.CH.sub.3 semi-solid97 ##STR174## (CH.sub.2).sub.2 CO.sub.2 C.sub.10 H.sub.21 ##STR175## 75-78.degree. C.98 ##STR176## (CH.sub.2).sub.2 CO.sub.2 C.sub.10 H.sub.21 OSO.sub.2.CH.sub.3 semi-solid99 ##STR177## C.sub.4 H.sub.9 -n Br 190-191.degree. C.100 ##STR178## C.sub.16 H.sub.33 -n Br semi-solid101 ##STR179## C.sub.12 H.sub.25 -n Br semi-solid__________________________________________________________________________

Compounds of the invention can be prepared by the following reaction: ##STR180##

Generally, a tertiary cyclic amine of the formula (II) can be reacted with an iodopropargyl compound of the formula (III), in which X represents halogen or a sulfonate group, in the presence of a suitable solvent at temperature between 0.degree. and 100.degree. C.

The compounds of formula (II) and formula (III) are generally commercially available or can be prepared by known methods in the literature. Examples of compounds of formula (II) are 1-methylpiperidine, 1-butylpyrrolidine, 1-(2-hydroxyethyl)-piperidine. Examples of compounds of formula (III) are 3-iodopropargyl-1-chloride, 3-iodopropargyl-1-bromide, and 3-iodopropargyl-1-(4-methylbenzene)sulfonate.

Alternatively, the compounds of the invention can be prepared by the following reaction: ##STR181##

wherein X' is either halogen, alkyl sulfate, alkyl sufonate, or aryl sulfonate.

The following examples illustrate a few embodiments of the invention.

EXAMPLES

EXAMPLE 1

Preparation of Iodopropargyl Methanesulfonate ##STR182##

To the solution of 3-iodopropargyl alcohol (5 g, 27.5 mmol) in methylene chloride (150 mL) at 0.degree. C. under nitrogen was added triethylamine (2.8 g, 27.5 mmol). To the above solution, methanesulfonyl chloride (3.2 g, 27.5 mmol) was added dropwise with stirring (magnetic stirrer). The reaction mixture was stirred at 0.degree. to 5.degree. C. for 2 hrs. The reaction mixture was washed with 0.5N HCl (50 mL), diluted sodium bicarbonate (50 mL), water (3.times.50 mL), and brine. The organic phase was dried over MgSO.sub.4 and filtered. The filtrate was concentrated on a rotary evaporator to afford 5.5 g (yield: 76.9%) of iodopropargyl methanesulfonate as a tan oil. An .sup.1 H NMR spectrum (CDCl.sub.3) showed the desired compound.

EXAMPLE 2

Preparation of Iodopropargyl 4-Methylbenzenesulfonate ##STR183##

Into a 500 mL 4-neck round bottom flask, equipped with a magnetic stirrer and an addition funnel, in an ice bath were placed iodopropargyl alcohol (10 g, 54.9 mmol) in THF (20 mL) and sodium hydroxide (3.4 g, 84.6 mmol) in water (20 mL) To the above cold mixture was added a solution of p-toluenesulfonyl chloride (10.4 g, 54.95 mmol) in THF (20 mL) from an addition funnel. The reaction mixture was stirred for 2 hrs. below 5.degree. C. The reaction mixture was then poured into ice water and the precipitate was collected by suction-filtration and washed with water. After drying under vacuum, the precipitate afforded 17.2 g (yield: 93.4%) of iodopropargyl 4methylbenzenesulfonate as an off-white solid, mp=75.degree.-78 .degree. C. An NMR spectrum showed the desired compound.

EXAMPLE 3

Preparation of 1-Tetradecyl-1-(3-Iodopropargyl)-Pyrrolidinium 4-Methylbenzenesulfonate (Compound 6) ##STR184##

In a 250-mL round bottom flask, equipped with a magnetic stirrer, a heating mantle and reflux condenser, were placed 1-bromotetradecane (10 g, 36 mmol), acetonitrile (100 mL) and pyrrolidine (5.1 g, 72 mmol). The reaction mixture was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and was concentrated on a rotary evaporator to a residue. Water and ethyl acetate were added. The organic phase was separated and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness affording 7.2 g (75% yield) of 1-tetradecylpyrrolidine, as a light yellow semi-solid. This intermediate was subjected to the next step without further purification.

In a 250-mL round bottom flask, equipped with magnetic stirrer, heating mantle, and reflux condenser, were placed 1-tetradecylpyrrolidine (2 g, 7.49 mmol), acetone (20 mL), and iodopropargyl 4-methylbenzenesulfonate (2.6 g, 7.76 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The precipitated product was collected by suction-filtration and washed with ether. After drying under vacuum, a white solid of 1-tetradecyl-1-(3-iodopropargyl)pyrrolidinium 4-methylbenzenesulfonate was obtained, 2.1 g (47% yield). mp=141.degree.-143.degree. C. An NN4R spectrum showed the desired compound. An elemental analysis was also performed:

Elemental Analysis of:

______________________________________ % C % H % N % S % I______________________________________Calculated 55.71 7.68 2.29 5.31 21.02Found 55.89 7.93 2.32 5.25 20.73______________________________________

EXAMPLE 4

Preparation of 1-Methyl-1-(3-Iodopropargyl)-Piperidinium 4-Methylbenzenesulfonate (Compound No-17) ##STR185##

In a 250-mL round bottom flask equipped with a magnetic stirrer were placed 1-methylpiperidine (0.3 g, 3.02 mmol) and ether (10 mL). To the above solution was added iodopropargyl 4-methylbenzenesulfonate (1 g, 2.97 mmol). The mixture was stirred at room temperature for 24 hrs. The white solid was collected by suction-filtration, washed with ether and dried in air affording 0.9 g (68.4% yield), m.p.=174.degree.-178 .degree. C. An NMR spectrum showed the desired structure and the elemental analysis showed the following:

______________________________________ % C % H % I______________________________________Calculated 44.1% 5.20% 29.1%Found 44.2% 5.13% 29.0%______________________________________

EXAMPLE 5

Preparation of 4-Tetradecyl-4-(3-Iodopropargyl)Morpholidinium 4-Methylbenzenesulfonate (Compound No-28) ##STR186##

In a 250-mL round bottom flask, equipped with a magnetic stirrer, a heating mantle and reflux condenser, were placed 1-bromotetradecane (15.9 g, 57.3 mmol), acetonitrile (75 mL), and morpholine (10 g, 114.7 mmol). The reaction mixture was refluxed for 4 hrs. The reaction mixture was cooled to room temperature and was concentrated to a residue on a rotary evaporator. Water and ethyl acetate were added. The organic phase was separated and washed with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness affording 15.2 g (94% yield) of 4-tetradecylmorpholine as a tan oil. This intermediate was subjected to the next step without further purification.

In a 250-mL round bottom flask, equipped with magnetic stirrer, heating mantle, and reflux condenser, were placed 4-tetradecylmorpholine (1.7 g, 6 mmol), dry acetone (2.5 mL), and iodopropargyl 4methylbenzenesulfonate (2 g, 6 mmol). The reaction mixture was stirred at room temperature for 40 hrs. The solvent was then evaporated to a residue. The residue was made a slurry with ether and the resultant white suspension was suction-filtered, washed with ether and dried under vacuum, affording 2 g (55.5% yield) of 4-tetradecyl-4-(3-iodopropargyl)-morpholidiniurn 4-methylbenzenesulfonate as a white solid. mp=153.degree.-154 .degree. C. An NMR spectrum showed the desired compound.

EXAMPLE 6

Biological Activity

Biocidal (bactericidal and fungicidal) evaluations were carried out.

A minimum inhibitory concentration (MIC) value is obtained using a broth, two-fold serial dilution test performed as follows: A stock solution or dispersion of the test compound, typically at a concentration of 1%, is made in a 5:3:2 solvent solution of acetone. methanol, and water. A volume of the stock solution is dispensed into culture media to give an initial starting test concentration of 500 ppm compound.

When the test is ready to be done, each vessel in the dilution series, except the first vessel, contains an equal volume of compound free broth. The first vessel contains twice the volume of broth with the starting concentration of test compound. One half of the broth from the first vessel is transferred to the second vessel- After being mixed, one half the resulting volume is removed from the second vessel and transferred to the third vessel. The entire cycle is repeated sufficiently to give a series of concentrations amounting to 500, 250, 125, 63, 31, 16, 8, and 4, 2, 1, 0.5, 0.25 ppm respectively.

Each vessel is then inoculated with a cell suspension of the appropriate test organism. Bacteria are grown in broth, fungi on agar slants for a time and at a temperature appropriate to the species being tested, and algae are a mixture of green algae and blue-green bacteria grown in a nutrient media. At the end of the growth period, in the case of bacteria, the broth is vortexed to disperse the cells.

In the case of fungi, the spores are harvested by pipetting water onto the slant and dislodging the spores with a sterile loop. The cell/spore suspension is standardized by controlling incubation time, temperature, and the volume of the diluent. The suspension is then used to inoculate the vessels containing the broth compound.

The vessels are then incubated at the appropriate temperature. After the incubation, the vessels are examined for growth/no growth. The minimum inhibitory concentration (MIC) is defined as the lowest concentration of compound that results in complete inhibition of growth of the test organism.

The organisms tested to demonstrate biocidal activity are shorten in the following table:

TABLE 2A______________________________________MICROORGANISMS USED IN THE BIOCIDES TESTSName GRAM ATCC Abbreviation used______________________________________BACTERIA1. Pseudomonas aeruginosa (-) 15442 Psae2. Staphylococcus aureus (+) 6538 Saur3. Escherichia coli (-) 11229 EcolFUNGUS4. Aspergillus niger 6275 Anig______________________________________ The result of minimum inhibitory concentration (MIC) tests of compounds of this invention is shown in Table 2. TABLE 2__________________________________________________________________________Biocidal MIC ResultsMIC (ppm) (G-) (G-) (G+) (fungus)Bacteria: Psae Ecol Saur AnigMedia: M9G TSB M9G TSB M9G TSB TSB__________________________________________________________________________Cpd No 1 >250 125 -- >250 16 32 >250 2 >250 >250 -- 250 32 32 32 3 >500 >500 -- >500 500 >500 >500 4 >500 >500 >500 500 500 500 250 5 >500 >500 >500 >500 63 63 250 6 4 4 4 4 0.5 0.5 <0.25 7 4 8 4 2 <0.25 <0.25 1 8 16 16 2 4 0.5 1 1 9 500 >500 500 250 250 250 50010 8 250 4 32 <0.25 1 <0.2511 250 500 16 32 2 16 412 500 >500 32 63 2 16 1613 32 250 32 32 1 16 1614 500 500 250 125 16 16 25015 32 32 1 2 0.25 0.25 1616 500 500 16 63 1 1 3217 250 125 -- 250 32 32 12518 250 125 -- 250 16 32 25019 250 250 -- 32 2 16 3220 >250 >250 -- 250 8 63 12521 >250 >250 -- >250 >250 >250 6322 >250 >250 -- >250 >250 >250 1623 >500 >500 -- >500 63 250 >50024 >500 >500 -- >500 63 500 >50025 8 2 2 16 0.25 0.25 826 4 16 4 4 0.25 0.25 1627 >250 >250 -- 250 16 32 3228 4 4 1 2 0.25 0.25 829 500 500 250 125 500 500 50030 63 63 2 16 1 1 131 32 32 1 16 0.5 <0.25 132 32 125 4 16 <0.25 <0.25 <0.2533 8 32 1 2 <0.25 <0.25 <0.2534 2 2 0.25 0.25 <0.25 <0.25 0.2535 >500 >500 4 63 0.5 0.25 436 32 63 2 8 <0.25 <0.25 137 63 125 2 16 0.5 0.5 0.2538 32 63 1 8 <0.25 <0.25 0.539 63 63 1 2 <0.25 <0.25 0.540 4 4 0.5 <0.25 <0.25 0.5 <0.2541 2 4 <0.25 <0.25 <0.25 0.5 242 1 4 <0.25 <0.25 <0.25 0.5 143 2 4 <0.25 0.5 <0.25 0.5 144 8 8 8 16 8 4 845 4 4 <0.25 <0.25 <0.25 <0.25 146 16 16 8 8 <0.25 <0.25 247 8 8 2 2 <0.25 <0.25 0.548 8 8 2 <0.25 0.5 149 8 8 1 2 <0.25 0.5 150 8 8 1 1 <0.25 0.5 0.551 16 16 4 2 <0.25 <0.25 0.552 16 16 8 2 <0.25 <0.25 <0.2553 8 16 2 1 <0.25 <0.25 <0.2554 250 125 8 16 1 8 155 125 125 4 16 1 8 156 8 63 <0.25 <0.25 <0.25 <0.25 <0.2557 0.5 4 <0.25 0.5 <0.25 <0.25 0.558 125 >500 4 8 0.5 4 859 32 125 8 16 4 4 860 63 250 2 16 1 2 1661 16 125 8 8 2 2 862 16 63 2 4 0.25 0.25 0.2563 64 125 2 4 2 4 264 32 32 1 4 0.25 0.25 865 64 125 2 4 2 1 1666 64 250 2 8 0.5 8 12567 125 250 2 8 0.5 8 12568 32 64 2 8 0.5 2 1669 8 32 1 4 0.25 0.25 470 125 250 2 8 1 2 3271 8 32 1 4 0.25 0.25 472 16 64 0.5 4 0.25 0.25 473 >500 >500 125 125 125 250 12574 >500 >500 64 125 125 250 6475 32 125 2 8 0.25 2 876 64 125 2 8 0.25 2 3277 >500 >500 64 64 250 250 >50078 250 500 2 4 0.25 2 879 32 64 1 4 0.25 1 280 16 125 2 8 0.5 0.5 181 >500 >500 64 64 4 16 12582 >500 >500 32 64 2 8 12583 >500 >500 16 32 4 8 12584 >500 >500 16 32 2 8 3285 8 32 1 4 0.25 0.25 486 8 32 2 8 0.5 1 887 16 64 2 4 0.25 0.25 488 8 32 2 4 0.25 0.25 489 16 64 2 8 1 2 890 16 125 2 4 2 4 1691 250 >500 4 8 1 8 3292 >500 >500 32 64 8 16 12593 >500 >500 125 125 >500 >500 50094 >500 >500 125 125 500 >500 >50095 500 500 16 64 32 64 3296 500 >500 8 64 32 64 1697 250 500 16 32 8 16 1698 500 500 16 32 8 32 16__________________________________________________________________________

From Table 2, the most active compounds are those with R=C.sub.10 to C.sub.16. Furthermore, the cyclic quaternary ammonium compounds which contain an iodopropargyl group, such as those in this invention, are surprising in that they have excellent activity against Gram negative bacteria, such as Pseudomonas aeruginosa or Escherichia coli, when compared with the corresponding cyclic quaternary, ammonium compounds which do not contain an iodopropargyl group.

EXAMPLE 7

Comparative

Table 3 shows the comparison from MIC test results of several representative iodopropargylated cyclic quaternary ammonium compounds of the invention and their corresponding non-iodopropargylated analogues (compound number followed by "A").

The last compound is also a comparative compound and is the tropiumbenzyl sulfonate quat from U.S. Pat. No. 4,521,412, identified as "Bayer analogue."

TABLE 3__________________________________________________________________________Comparison of Iodopropargylated- andNon-iodopropargylate-QuatsMIC (ppm) (G-) (G-) (G+) (fungus)Bacteria: Psae Ecol Saur AnigMedia: M9G TSB M9G TSB M9G TSB TSB__________________________________________________________________________Cpd No6 4 4 4 4 0.5 0.5 <0.256A 125 250 125 250 <0.25 <0.25 <0.2534 2 2 0.25 0.25 <0.25 <0.25 0.2534A 125 250 16 32 1 0.25 1617 250 125 -- 250 32 32 12517A >500 >500 >500 >500 >500 >500 >500Bayer 63 125 15 63 32 125 --Analogue__________________________________________________________________________

EXAMPLE 8

Comparative

Table 4 shows the comparison of MIC test results of three compounds of the present invention, 1-(tetradecyl)-1-(3-iodopropargyl)-piperidinium 4-methylbenzenesulfonate, 4-tetradecyl-4-(3-iodopropargyl )-morpholinium benzenesulfonate, and 4-tetradecyl-4-(3-iodopropargyl)-morpholinium methanesulfonate (Compounds 25, 41 and 42, respectively) with the two most c;osely related compounds from Japanese Patent 67-026603B, N-(3-iodo-2-propynyl)-piperidine and N-(3-iodo-2-propynyl)-morpholine (Compounds J1 and J2 respectively). These Japanese compounds are the iodopropargyl amines corresponding to the quaternary ammonium compounds of the present invention.

These five compounds were tested side-by-side against six organisms, Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneurnoniae (K. pneumoniae), Enterobacter aerogenes (E. aerogenes), Proteus mirabilis (P. mirabilis), Staphylococcus aureus (S. aureus), and Aspergillus niger (A. niger). The MIC tests were performed as in example 6.

TABLE 4______________________________________MIC Values (ppm) Invention Compounds Japanese CompoundsOrganism #25 #41 #42 J1 J2______________________________________P. aeruginosa 8 8 16 >500 >500K. Pneumoniae 4 4 4 125 500E. Aerogenes 1 2 1 32 250P. mirabilis 4 4 4 125 500S. aureau 0.5 0.5 1 125 250A. niger 8 8 8 16 8______________________________________

As can be seen from the data, the quaternary ammonium compounds of the present invention are surprisingly and significantly more active against the organisms tested than those of the Japanese reference.

The compounds of the invention can be used to inhibit the growth of microbes by introducing a microbicidally effective amount of one or more of said compounds onto, into, or at a locus subject to microbial attack. Loci such as wood, paint, adhesive, glue, paper, pulp/paper slurries, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed, and industrial cooling water can be protected.

The amount of compound suitable is about 5 to about 300 ppm based on weight of said locus. Generally, the microbicide is applied in a carrier such as water, solvent, or the like.

While the invention has been described in detail, various modifications and alterations should become readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. Compounds having antimicrobial activity having the formula: ##STR187## wherein R is C.sub.1 to C.sub.5) alkyl substituted with --C(.dbd.O)R' wherein R' is (C.sub.6 -C.sub.12) alkoxy;

X=chlorine bromine, iodine, phosphate, acetate, benzoate, citrate, tartrate, alkyl- or aryl-sulfonate, or alkylsulfate; and ##STR188## represents a 5- to 7-membered ring selected from the group consisting of pyrrolidinium, piperidinium, morpholinium, hexamethyleneiminium, tetrahydropyridinium, immidazolinium, thiormorpholinium, and thiazonlidinium, optionally substituted with one or more (C.sub.1 -C.sub.3)alkyl groups.

2. Compound according to claim 1 selected from the group consisting of

1-(dodecyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate

1-(dodecyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate

1-(decyioxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium 4methylbenzenesulfonate

4-(decyioxycarbonyl)methyl-4-(3-iodopropargyl)-morpholiniurn 4methylbenzenesulfonate

4-(decyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium benzenesulfonate

4-(dodecyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium 4-methylbenzenesulfonate

1(decyloxycarbonyl)methyl-1-(3-iodopropargyl)-pyrrolidinium benzenesulfonate

1-(dodecyloxycarbonyl)methyl-1-(3iodopropargyl)-pyrrolidinium methanesulfonate

4-(dodecyloxycarbonyl)methyl-4-(3-iodopropargyl)-morpholinium methanesulfonate

4-[5-(hexyloxycarbonyl)]pentyl-4-(3-iodopropargyl)-morpholinium 4-methylbenzenesulfonate

1-[5-(hexyloxycarbonyl)]pentyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate

4-[5-(hexyloxycarbonyl)]pentyl-4-(3-iodopropargyl)-morpholinium methanesulfonate

4-[2-decyloxycarbonyl)]ethyl-4-(3-iodopropargyl-morpholinium 4-methylbenzenesulfonate

4-[2-(decyloxycarbonyl)]ethyl-1-(3-iodopropargyl)-morpholinium-4-methanesulfonate

1-[2-(decyloxycarbonyl]ethyl-1-(3-iodopropargyl)-pyrrolidinium 4-methylbenzenesulfonate

1-[2-(decyloxycarbonyl)]ethyl-1-(3-iodopropargyl)-pyrrolidinium methanesulfonate.