US3706799A

US3706799A - Naphthyloxysalicylanilides

Info

Publication number: US3706799A
Application number: US881869A
Authority: US
Inventors: David Richard Duke Osborne
Original assignee: Lever Brothers Co
Current assignee: Lever Brothers Co
Priority date: 1968-12-03
Filing date: 1969-12-03
Publication date: 1972-12-19
Anticipated expiration: 1989-12-19
Also published as: GB1226438A

Abstract

NEW NAPHTHYLOXY-SUBSTITUTED ANILIDES ARE DISCLOSED. THE COMPOUNDS ARE USEFUL GERMICIDAL AGENTS. PREFERRED COMPOUNDS CONTAIN HALOGEN SUBSTITUENTS.

Description

United States Patent Oflice Patented Dec. 19, 1972 US. Cl. 260-559 S 9 Claims ABSTRACT OF THE DISCLOSURE New naphthyloxy-substituted anilides are disclosed. The compounds are useful germicidal agents. Preferred compounds contain halogen substituents.

FIELD OF THE INVENTION The present invention relates to a new class of biologically active compounds.

BACKGROUND OF THE INVENTION The use of anilides as biocidal compounds is well known. In particular, the use of phenoxy-substituted anilides is well known. Thus the use of phenoxy-substituted halogenated salicylanilides as germicides is described in British Pat. No. 1,108,393, and their use as germicides and anthelmintics is described in Netherlands patent application No. 6707849. Also, the use of phenoxy-substituted carbanilides as germicides is described in J. Med. Chem., 1968, 11, 163, and their use as anti-coccidial agents is described in Australian patent application No. 46,399/ 64.

SUMMARY OF THE INVENTION It has now been discovered that if an anilide contains a naphthyloxy substituent said anilide is a surprisingly effective biocidal agent. Thus it has surprisingly been found that presence of the weighty naphthyloxy group instead of the comparatively light phenoxy group gives comparable biocidal activity and in some instances more favourable activity. This is particularly true if said anilide is selected from the class of salicylanilides and carbanilides. It has been found that such naphthyloxy-substituted anilides show surprising germicidal activity. Also, they can be used advantageously in conjunction with detergents.

The scope of the invention, therefore, includes a naphthyloxy-substituted anilide in which said anilide is selected from the class consisting of salicylanilides and carbanilides. Preferably the naphthyloxy-substituent is in the aromatic ring of an aniline group in said anilide, particularly in the 2, Le. ortho, position of said aromatic ring.

Particularly preferred compounds of the invention are naphthyloxy-substituted anilides in which said anilide is selected from the class consisting of halogen-substituted salicylanilides and carbanilides. Other substituents can be present. Preferably the halogen is chlorine or bromine and preferably the anilide contains from 1 to 3 halogen atoms.

Illustrative structural formulae are ll3r 6 B r 5 CO.NH 3

4,6,4'-tribromo-2-ot-naphthyloxy-salicyanilide Br ---Br 6 B r;@-NH. o 0 .NHQ3

2,5 ,4',6'-tetrabromo-2'-a-naphthyloxycarbanilide An aspect of the invention is a germicidal composition containing a naphthyloxy-substituted anilide according to the invention. A preferred aspect of the invention is a germicidal detergent composition containing a naphthyloxy-substituted anilide according to the invention. The detergent composition can be in any convenient form such as liquid, paste or hard-surface cleaner but preferably should be in the form of a toilet bar. Suitable formulations for germicidal detergent compositions are given in standard textbooks, for example in Schwartz and Perry, Surface -Active Agents.

A naphthyloxy-substituted anilide according to the invention can be used in conjunction with other germicides, such as 3,4,4'-trichlorocarbanilide, 3,4,4'-tribromosalicylanilide, 2,2-dihydroxy-3,5,6,3',5',6'-hexachlorodiphenylmethane and 4,2,4'-trichloro-Z-hydroxy-diphenylether.

A further aspect of the invention is a pharmaceutical or veterinary composition containing a naphthyloxy-substituted anilide according to the invention together with a pharmaceutically acceptable or veterinarily acceptable carrier.

The anilides according to the invention can be prepared by a variety of methods. For example, one method is the condensation of a naphthylamino-phenylether with a salicyclic acid, the ether and the salicylic acid being prepared by standard methods. A salicylanilide is thereby obtained. When a halogenated salicylanilide according to the invention is required, a halogenated naphthylamino-phenylether and/or a halogenated salicylic acid can be used. An alternative method is the direct halogenation of a naphthyloxy salicylanilide.

Another example of a method of preparing an anilide according to the invention is by reaction of a naphthylamino-phenylether with an aryl isocyanate, the ether and the isocyanate being prepared by standard methods. A carbanilide is thereby obtained. As with the salicylanilides, halogenated compounds can be made by appropriate condensation or by halogenation of a naphthyloxy carbanilide.

The following illustrates the preparation of intermediates that can be used in the preparation of anilides according to the invention:

(a) 2-nitrophenyl-fi-naphthylether 50 gms. (0.3 mole) of fl-naphthol and 13.8 gms. (0.25 mole) of potassium hydroxide were dissolved in 50 mls. of absolute alcohol. The alcohol was then removed to leave the dry potassium salt, after which 30.4 gms. (0.2 mole) of o-chloronitrobenzene were added and the mixture was heated at 140 C. for 2 hours. When cool, the mixture was extracted into chloroform and the extracts Washed with 2 N sodium hydroxide and then with water. The extracts were dried over anhydrous sodium sulphate. Distillation of the residue from the chloroform extracts gave 16.0 gm. (30% of 2-nitrophenyl- 8-naphthylether, B.P. 220-230 C. at 0.8-1.5 mms.

(b) 2-nitrophenyl-a-naphthylether 47.5 gms. (0.315 mole) of a-naphthol and 17.4 gms. (0.315 mole) of potassium hydroxide were dissolved in 50 mls. of absolute alcohol. The alcohol was removed, 49.7 gms. (0.315 mole) of o-chloronitrobenzene added in the cold and the mixture heated at 140 C. for 2 hours. Working up the reaction product as in section (a) above gave, in addition to a small amount of recovered o-chloronitrobenzene, B.P. 65-75 C. at 0.6 mms., 20.4 gms. (23.8%) of 2-nitrophenyl-u-naphthylether, B.P. 195205 C. at 0.6 mm.

(c) 4-chloro-2-nitrophenyl-B-naphthylether 25 gms. (0.15 mole) of B-naphthol and 6.9 gms. (0.125 mole) of potassium hydroxide were dissolved in 50 mls. of absolute alcohol. The alcohol was removed, 19.1 gms. (0.1 mole) of 2,5-dichloronitrobenzene were added in the cold, and the mixture then heated at 140 C. for 2 hours. Working up the reaction product as in section (a) above gave 12.0 gms. (23%) of 4-chloro-2-nitrophenyl-fl-naphthylether, B.P. 220-235 C. at 1-2 mms., M.P. 58-60" C. from alcohol.

(d) 2-aminophenyl-fl-naphthylether To a vigorously stirred refluxing solution of 13 gms. of zinc dust, 25 mls. of water, 75 mls. of ethanol and 8 gms. of calcium chloride was added over a half hour period 5.0 gms. (0.037 mole) of Z-nitrophenyl-p-naphthylether, and the mixture was then refluxed for a further 2 hours. The hot solution was then filtered to remove unreacted zinc. The filtrate on cooling gave 3.0 gms. (65%) of 2-aminophenyl-B-naphthylether, M.P. 73 C.

(e) 2-aminophenyl-a-naphthylether To a stirred refluxing solution of 52 gms. of zinc dust, 100 mls. of water, 300 mls. of ethanol and 32 gms. of calcium chloride was added over a half hour period 20 gms. (0.148 mole) of Z-nitrOphenyI-u-naphthylether, and the reaction mixture was stirred for'a further two hours. The hot mixture was filtered to remove unreacted zinc, the filtrate diluted with water and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulphate. Distillation of the residue from the chloroform extracts gave 16.8 gms. (89%) of 2- aminophenyl-a-naphthylether, B.P. 190200 C. at 2.5

mms.

(f) 4-chloro-2-aminophenyl-fl-naphthylether To a stirred refluxing solution of 20 gms. of zinc dust, 150 mls. of ethanol, 50 mls. of water and 10- gms. of calcium chloride was added over a half hour period, 5.0 gms. of 4-chloro-2-nitrophenyl-fl-naphthylether, and the mixture was refluxed for a further 2 hours. The hot solution was filtered to remove unreacted zinc. The filtrate on cooling gave 3.5 gms. (77.8%) of pure 4-chloro-2-aminophenyl-fl-naphthylether, M.P. 12l-3 C.

4 The following examples illustrate the preparation and biological activity of salicylanilides and carbanilides of the invention.

EXAMPLE 1 5-chloro-2'-fl-naphthyloxysalicylanilide A solution of 2.0 gms. (0.0084 mole) of Z-aminophenyl-fl-naphthylether, 1.45 gms. (0.0084 mole) of 5- chlorosalicyclic acid and 0.5 ml. of phosphorus trichloride M IC* 0. 1

EXAMPLE 2 2'-fi-naphthyloxysalicylanilide 1.0 gms. of 2-aminophenyl-jS-naphthylether, 0.58 gm. (0.0042 mole) of salicylic acid and 0.25 ml. of phosphorus trichloride in 20 mls. of chlorobenzene were refluxed for three hours. Working up the reaction product as described in Example 1 gave 0.5 gm. (32%) of 2'19- naphthyloxysalicylanilide, M.P. 1l8-120 C. from an alcohol-water mixture.

MIC l-2 EXAMPLE 3 2'-a-naphthyloxysalicylanilide 2.0 gms. (0.0084 mole) of 2-amiophenyl-a-naphthylether, 1.16 gms. (0.0084 mole) of salicylic acid and 0.5 mole of phosphorus trichloride were refluxed in 20 mls. of chlorobenzene for three hours. Working up the reaction product as described in Example 1 gave 1.06 gms. (35.1) of 2'-a-naphthyloxysalicylanilide, M.P. -102 C. from 60-80 petroleum ether.

MIC 1-2 EXAMPLE 4 3,5-dichloro-2'-u-naphthyloxysalicylanilide Prepared, as described above in Example 1, from 2.0 gms. (0.0084 mole) of 2-amino-u-naphthylether, 1.74 gms. (0.0084 mole) of 3,5-dichloro-salicylic acid and 0.5 mls. of phosphorus trichloride. Recrystallisation of the product obtained gave 1.54 gms. (42.8%) of 3,5-dichloro- 2-a-naphthyloxysalicylanilide, M.P. l67170 C. from an alcohol-water mixture.

MIC 0.5-1.0

EXAMPLE 5 3,S-dichloro-2'-fl-naphthyloxysalicylanilide A solution of 2.0 gms. (0.0084 mole) of Z-aminophenyl-,B-naphthylether, 1.74 gms. (0.0084 mole) of 3,5- dichlorosalicylic acid and 0.5 m1. of phosphorus trichloride in 25 mls. of chlorobenzene was stirred and refluxed for three hours. The hot reaction mixture was filtered, and the filtrate evaporated to one half of its original volume in a current of dry air. The precipitated solid was filtered, washed with 60-80 petroleum ether to give 2.9 gms. (85%) of 3,5-dichloro 2' 6 naphthyloxysalicylanilide, M.P. -191 C. from an alcohol-water mixture.

MIC 0.5-1.0

EXAMPLE 6 3 ,5 ,3 -trichloro-2'-fl-naphthyloxysalicylanilide A solution of 1.5 gms. (0.005 mole) of 4-chloro-2- amino-,S-naphthylether, 1.03 gms. (0.005 mole) 3,5-di- *Minimum Inhibitory Concentration against Staph. aureus in parts per million.

chlorosalicylic acid and 0.25 ml. of phosphorus trichloride was refluxed in 20 mls. of chlorobenzene for three hours. Working up the reaction product as described in Example 5 gave 1.8 gms. (73.6%) of 3,5,3-trichloro-2-fl-naphthyloxysalicylanilide, M.P. 209l C.

MIC 1.0

EXAMPLE 7 -chloro-2'-a-naphthyloxysalicylanilide A solution of 2.0 gms. (0.0084 mole) of Z-aminophenyl-a-naphthylether 1.45 gms. (0.0084 mole) of 5- chlorosalicylic acid and 0.5 ml. of phosphorus trichloride in mls. of chlorobenzene was refluxed for three hours. Working up the reaction product as described in Example 5 gave 0.85 gm. (25.6%) of 5-chloro-2'-a-naphthyloxysalicylanilide, M.P. 184-6 C. from an alcohol-water mixture.

MIC 0.1-0.5

EXAM PLE 8 3,4-dichloro-2'-,8-naphthyloxycarbanilide To a stirred solution of 2 gms. (0.0084 mole) of 2- aminophenyl-a-naphthylether in 20 mls. chloroform was added 1.58 gms. (0.0084 mole) of 3,4-dichlorophenylisocyanate, and the mixture stirred for 3 /2 hours. The chloroform was removed under reduced pressure, and the crude product washed twice with 60-80 petroleum ether. Recrystallisation of this solid from an alcohol-water mixture gave 1.948 gms. (54.4%) of 3,4-dichloro-2-u-naphthyloxy-carbanilide, M.P. 18l-3 C.

MIC 1-2 EXAMPLE 1O 3,3',4-trichloro-2'-fl-naphthyloxycarbanilide To 1 gm. (0.0037 mole) of 4-chloro-2-aminophenyl-B- naphthylether in 15 mls. chloroform was added 0.7 gm.

(0.0037 mole) of 3,4-dichlorophenylisocyanate, and the reaction mixture treated as in Example 8. Recrystallisation of the crude product from an alcohol-water mixture gave 0.88 gm. (51.8%) 3,3,4-trichloro-2-fi-naphthyloxycarbanilide, M.P. 189-91.

MIC l-2 By way of comparison, the MIC of salicylanilide is 50.

What is claimed is:

l. A naphthyloxy-substituted salicylanilide selected from the group consisting of 2-(alphaenaphthyloxy)-.salicylanilides and 2'-(beta naphthyloxy) salicylanilides and wherein from 0 to 3 of the 3, 4, 5, 6, 3, 4, 5' and 6 positions of the salicylanilide may have attached thereto a chlorine atom instead of a hydrogen atom.

2. A naphthyloxy-substituted salicylanilide according to claim 1 which is 2'-(alpha-naphthyloxy)-salicylanilide.

3. A naphthyloxy-substituted salicylanilide according to claim 1 which is 2'-(beta-naphthyloxy)-salicylanilide.

4. A naphthyloxy-substituted salicylanilide according to claim 1 which is substituted with 1 to 3 chlorine atoms.

5. A naphthyloxy-substituted salicylanilide according to claim 4 which is 5-chloro-2'-(beta-naphthyloxy)-salicylanilide.

6. A naphthyloxy-substituted salicylanilide according to claim 4 which is 3,5-dichloro-2'-(alpha naphthyloxy)- salicylanilide.

7. A naphthyloxy-substituted salicylanilide according to claim 4 which is 3,5-dichloro-2'-('beta-naphthyloxy)-salicylanilide.

8. A naphthyloxy-substituted salicylanilide according to claim 4 which is 3,5-3-trichl0ro-2'-(beta naphthyloxy)- salicylanilide.

9. A naphthyloxy-substituted salicylanilide according to claim 4 which is 5-chloro-2-(alpha-naphthyloxy)-salicylanilide.

References Cited UNITED STATES PATENTS 3,549,704 12/1970 Katerberg et a1 260-559 HENRY R. JILES, Primary Examiner H. I. MONATZ, Assistant Examiner U.S. Cl. X.R.