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Publication numberUS3674850 A
Publication typeGrant
Publication dateJul 4, 1972
Filing dateDec 22, 1969
Priority dateDec 7, 1969
Publication numberUS 3674850 A, US 3674850A, US-A-3674850, US3674850 A, US3674850A
InventorsDavid Richard Duke Osborne
Original AssigneeLever Brothers Ltd
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Substituted salicylanilides
US 3674850 A
Abstract
The specification discloses salicylanilides and halogenated salicylanilides wherein either or both the aniline or salicyl rings are substituted with a member of the class consisting of phenoxy and halophenoxy groups and the use of these compounds as effective germicides particularly in detergent compositions, such as soap bars.
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I United States Patent [151 3,674,850

Osborne 1 July 4, 1972 [54] SUBSTITUTED SALICYLANILIDES 58 Field of Search ..260/559 [72] Inventor: David Richard Duke Osborne, Bedford, [56] References Cited England [73] Assignee: Lever Brothers Company, New York, UNITED STATES PATENTS NY. 3,013,058 12/1961 Ritchter ..260/559 [22] Flled: 1969 Primary Examiner-Henry R. Jiles [21] Appl.No.: 887,427 Assistant Examiner-Harry l.Moat1 Attorney-Brumbaugh, Graves, Donohue & Raymond Related US. Application Data [63] Continuation of Ser. NO. 764,040, Sept. 25, 1968, [57] ABSTRACT Continuation of Ser. No. 51 1,989, Dec. 6, 1965. The specification discloses salicylanilides and halogenated salicylanilides wherein either or both the aniline or salicyl rings [30] Foreign Application Priority Data are substituted with a member of the class consisting of phenoxy and halophenoxy groups and the use of these com- Dec. 7, 1969 Great Britain ..49,805/64 pounds as effective germicides particularly in detergent positions, such as soap bars. [52] US. Cl. ..260/559 S, 424/324 [51] Int. Cl ..C07c 103/38 21 Claims, N0 Drawings SUBSTITUTED SALICYLANILIDES This application is a continuation of my United States application Ser. No. 764,040, filed Sept. 25, 1968, which in turn is a continuation of my United States application Ser. No. 511,989, filed Dec. 6, 1965.

The present invention relates to a new class of gerrnicides.

It is well known that halogenated salicylanilides have germicidal properties. The use of such compounds is described in Angew. Chem., 1955, 67, 145 (D. Jerchel and H. Oberheiden) and J. Pharm. Sci., 1961, 50, 831 (H. Lemaire, C.H. Schrarnm and A. Cahn).

It has now been discovered that the effectiveness of such compounds as gerrnicides can be increased by modifying their molecular structure by replacing at least one of the H atoms attached to C in either or both of the aromatic rings of the salicylanilide residue by a phenoxy or halogenated phenoxy group. It has also been found that the similar introduction of a phenoxy or halogenated phenoxy group into salicylanilide itself results in a useful germicide. As halogen, chlorine and bromine are particularly suitable.

Accordingly, the invention provides a salicylanilide wherein at least one of the H atoms attached to C in either or'both of the aromatic rings of the salicylanilide residue is replaced by a phenoxy or halogenated phenoxy group of from zero to the total number of the remaining H atoms attached to C in said aromatic rings in replaced by halogen.

The compounds where the phenoxy substituent is in th aniline ring of the salicylanilide are preferred.

Another aspect of the invention is a germicidal composition containing a salicylanilide of the invention.

The salicylanilides of the invention have been found to be effective in soap against both gram-positive (Staph. aureus) and gram-negative (E. coli) bacteria. Accordingly, another aspect of the invention is a saponaceous composition containing a salicylanilide of the invention.

It has also been discovered that mixtures of the salicylanilides of the invention with certain well known germicides for use in detergent compositions, namely, 3,4,4'-trichlorocarbanilide (TCC), 3,5,4'-tribromo-salicylanilide (TBS) and 2,2-dihydroxy-3, 5, 6, 3, 6'-hexachloro-diphenylmethane (G 1 1) display synergistic bacteriostatic effect. The invention further includes synergistic bacteriostatic mixtures of the sal icylanilides of the invention with 3,4,4'-trichlorocarbanilide, 3 .5 ,4-tribromosalicylanilide or 2.2 -dihydroxy-3,5,6,3',5.6'- hexachIoro-diphenylmethane. Accordingly, another aspect of the invention is a germicidal composition containing a synergistic bacteriostatic mixture of a salicylanilide of the invention and 3,4,4'-trichlorocarbanilide, 3,5,4-tribromosalicylanilide or 2, 2'-dihydroxy-3. 5, 6, 3', 5, 6-hexachloro-diphenylmethane. A further aspect of the invention is a saponaceous composition containing a synergistic bacteriostatic mixture of a salicylanilide of the invention and 3,4,4-trichlorocarbani- Iide, 3,5,4'-tribromosalicylanilide or 2,2-dihydroxy-3.5,6,3. 5Z6-hexachloro-diphenylmethane.

The salicylanilides of the invention can be prepared by a variety of methods. For example, one method is the condensation of a haloaminodiphenylether (A) with a halogen-substituted salicylic acid (B), A and B being prepared by standard methods for the preparation of such compounds; another method is the direct halogenation of a phenoxy salicylanilide.

EXAMPLE 1.

3,5,3'-trichloro-6'-(p-chlorophenoxy)-salicylanilide.

A slurry of 1.8 g. of 4,4'-dichloro-2-amino diphenyl ether and 1.4 g. 3,5-dichlorosalicylic acid in ml. of xylene was refluxed with 0.3 m1. of phosphorus trichloride for 3 hours and the reaction mixture filtered hot. The solution on cooling deposited 1.6 g. (51 Percent) of 3,5,3'-trichloro-6'-(pchlorophenoxy)-salicyanilide which was recrystallized from a benzene-petroleum ether mixture to give crystals of m.p. 195-196 C.

The finger imprint rating of the compound was determined TBS G11 M.l.C. 0.2 0.5 0.6

In each of the following Examples, the compounds were prepared by a method similar to that described in Example 1.

EXAMPLE 2.

3,5,3'-trichloro-6'-(o-chlorophenoxy)-salicylanilide. Melting point 193-195 C; M.l.C. 1.0.

EXAMPLE 3 5 ,3 -(o-chlorophenoxy )-salicylanilide. Melting point l73175C; M.l.C. 0.3.

EXAMPLE 4 3 ,5,3'-trichloro-6'-phenoxy-salicylanilide. Melting point 15 l152 C; M.l.C. 0.8.

EXAMPLE 5 5,3-dichloro-6'-phenoxy-salicylanilide. Melting point 163-164 C; M.l.C. 0.1.

EXAMPLE 6 3-chloro-6-(o-chlorophenoxy)-salicylanilide. Melting point 142-l44 C; M.l.C. 3.0.

EXAMPLE 7 3'-chloro-6-(p-chlorophenoxy)-salicylanilide. Melting point 169-171 C; M.l.C. 1.0.

EXAMPLE 8 3-chloro-6'-phenoxy-salicylanilide. Meltin gpoint 1S2l54 C; M.l.C. 0.24.

EXAMPLE 9 The M.l.C. of mixtures of the compounds of Examples l-8 with TCC, TBS and G 1 1 were obtained and compared with the MIC to be expected. The results are shown in Table I below:

indicates no synergism indicates synergism indicates marked synergism Example TCC TBS G 1 1 1 2 +1- 3 4 5 EXAMPLE l0 3,5,3-Trichloro-6'-(2,4,5-trichlorophenoxy)-salicylanilide.

A mixture of 11.7g (0.036 moles) of 2,4,5,4'-tetrachloro-2 '-aminodiphenyl ether, 8.3g (0.04 moles) of 3,5-dichloro salicylic acid and 1.8 ml. of phosphorus trichloride in 125 ml. of chlorobenzene was refluxed for 3 hours, filtered hot and allowed to crystallize. 12.9g (70.1 percent) of a solid (melting point 1947 C) was obtained which, after 4 recrystallizations from chlorobenzene had a melting point of 201-4C, and was shown to be pure by thin layer chromatography on silica,

by the method described in J. Phannacol. Sci., 1961, 50, 827. eluted with petroleum ether: acetone: acetic acid, (:5:2).

The M.I.C. of the compound was 0.5 In each of the following Examples, the compounds were prepared by a method similar to that described in Example 10.

EXAMPLE ll 5,3'-dichloro-6'-(p-chlorophenoxy)-salicylanilide. MIC 0.1

EXAMPLE l2 3,5,3-tribromo-6'-(p-bromophenoxy)-salicylanilide. MIC 0.6

3,5-dichloro-6-(p-chlorophenoxy)-salicylanilide. MIC 0.2 m.p. l58-9 C.

EXAMPLE l7 3,5-dichloro-6-(o-chlorophenoxy)-salicylanilide. MIC 0.9 m.p. l55-6C.

EXAMPLE 18 The MIC of mixtures of the compounds of Examples 1 l-l with TCC, TBS and G1 I were compared with the MIC to be expected, as in Example 9. The results are shown in Table II below.

Example TCC TBS G1 I 1 l l2 H H The halogenated amino diphenyl ethers employed in Examples l and were synthesized by zinc/dilute acid reduction of the corresponding nitro compound using a five to six-fold excess of zinc. 'I'he nitro compound was obtained via an Ullmann synthesis using conditions similar to those described by R.V. Henley, J. Chem. Soc., 1222 (1930).

What is claimed is:

1. A salicylanilide having from 0 to 8 halogen atoms selected from the class consisting of chlorine and bromine on the salicylanilide residue and wherein one of the aromatic carbon atoms in the aniline ring bears a substituent selected from the class consisting of phenoxy and halogenated phenoxy groups having from I to 3 halogen atoms selected from the class consisting of chlorine and bromine.

2. A salicylanilide having from O to 8 halogen atoms selected from the class consisting of chlorine and bromine on the salicylanilide residue and wherein the carbon atom in the 6' position in the aniline ring bears a substituent selected from the class consisting of phenoxy and halogenated phenoxy groups having from 1 to 3 halogen atoms selected from the class consisting of chlorine and bromine.

3. A salicylanilide according to claim 1 in which the halogenated phenoxy substituent is a p-chloro-phenoxy group.

4. A salicylanilide according to claim 1 in which the halogen substituent or substituents in the aromatic ring or rings is chlorine.

5. 3,5,3-trichloro-6'-(p-chlorophenoxy)-salicylanilide.

6. 3,5,3-trichloro-6'-(o-chlorophenoxy)-salicylanilide.

7. 5,3'-dichloro-6-(o-chlorophenoxy)-salicylanilide.

8. 3,5,3'-trichloro-6'-phenoxy-salicylanilide.

9. 5,3-dichIoro-6'-phenoxy-salicylanilide.

l0. 3-chloro-6-(o-chlorophenoxy)-salicylanilide.

I l. 3'-chloro-6'-(pl-chlorophenoxy):salicylanilide.

12.3'-chloro-6- enoxy-sallcylamlide.

l3. 3,5,3'-trichloro-6'-(2,4,5-trichlorophenoxy)-salicylanilide.

l4. 5,3-dichloro-6-(p-chlorophenoxy)-salicylanilide.

15. 3,5,3-tribromo-6'-(p-bromophenoxy)-salicylanilide.

16. 6-(p-chlorophenoxy)salicylanilide.

I7. 5'-chloro-6-phenoxy-salicylanilide.

I8. 3,5-dichlor0-6'-phenoxy-salicylanilide.

19. 3,5dichloro-6-(p-chlorophenoxy)-salicylanilide.

20. 3.5-dichloro-6-(ochlorophenoxy)-salicylanilide.

21. A salicylanilide having from zero to eight halogen atoms on the salicylanilide residue and wherein one of the aromatic carbon atoms in the aniline ring bears a substituent selected from the class consisting of phenoxy and halogenated phenoxy groups having from one to three halogen atoms.

l i i

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3013058 *Oct 15, 1958Dec 12, 1961Velsicol Chemical Corp2-methoxy-3, 6-dichlorophenylacetates
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US20060173024 *Feb 14, 2006Aug 3, 2006Cytokinetics, Inc.Compositions and methods for treating heart failure
US20100121107 *Jul 21, 2009May 13, 2010Chi-Huey WongCrystal structure of bifunctional transglycosylase pbp1b from e. coli and inhibitors thereof
US20150232417 *Feb 24, 2014Aug 20, 2015Academia SinicaCrystal structure of bifunctional transglycosylase pbp1b from e. coli and inhibitors thereof
EP1503986A2 *Dec 20, 2002Feb 9, 2005Cytokinetics, Inc.Compositions and methods for treating heart failure
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Classifications
U.S. Classification564/179
International ClassificationC07C233/12
Cooperative ClassificationC07C233/12
European ClassificationC07C233/12