4-hydroxyisothiazole compounds

Details 4-hydroxyisothiazole compounds 4-hydroxyisothiazole compounds

2000-05-18

2002-04-23

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S209000

Reexamination Certificate

active

06376522

ABSTRACT:

The present invention relates to the use of 4-hydroxyisothiazole compounds as antimicrobially active substances, certain new 4-hydroxyisothiazole compounds and a process for their preparation.
It is known that certain halogenated 3-hydroxyisothiazole compounds have an excellent antimicrobial activity, as disclosed in U.S. Pat. No. 3,887,352. However it is desirable to be able to provide non-halogenated agents which are highly effective antimicrobial agents. Polymeric materials can be antimicrobially finished by incorporating halogenated compounds, the active substances being, as a result of their excellent migration properties, constantly conveyed to the surface of the corresponding material (“slow release”). For certain industrial applications, this effect is undesired since the long-term effect of antimicrobially finished materials such as textiles, paper, plastics, cellulose sponges etc. is reduced at the same time.
The object of the present invention is thus to provide non-halogenated 4-hydroxyisothiazole compounds for use as antimicrobially active substances and which, at the same time, are stable to migration.
The present invention provides the use of 4-hydroxyisothiazole compounds of the following formulae
R
1
and R
2
are independently of each other hydrogen; C
1
-C
10
alkyl; substituted C
1
-C
10
alkyl; C
1
-C
10
acyl; substituted C
1
-C
10
acyl; C
6
-C
10
aryl; substituted C
6
-C
10
aryl; C
6
-C
10
aryl carbonyl; or substituted C
6
-C
10
arylcarbonyl; as antimicrobial agents.
Of particular interest are compounds of formula (1) as an antimicrobial wherein R
1
and R
2
are both C
6
-C
10
aryl.
A preferred compound is of formula (1) wherein R
1
and R
2
are both phenyl.
A preferred compound is of formula (2) wherein R
2
is C
6
-C
10
aryl or substituted C
6
-C
10
aryl.
Another aspect of the invention are certain compounds described by formula (1) and (2) which are novel. These novel compounds include compounds of formula
R
1
and R
2
are independently of each other hydrogen; C
1
-C
10
alkyl; substituted C
1
-C
10
alkyl; C
1
-C
1
acyl; substituted C
1
-C
10
acyl; C
6
-C
10
aryl; substituted C
6
-C
10
aryl; C
6
-C
10
aryl carbonyl; or substituted C
6
-C
10
aryl carbonyl.
C
1
-C
10
alkyl may be branched or unbranched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, 1,1,3-trimethylhexyl, 1,1,3,3-tetramethylpentyl, n-nonyl, n-decyl.
C
6
-C
10
aryl may be phenyl or naphtyl.
The substituted C
1
-C
10
alkyl, substituted C
6
-C
10
aryl and substituted C
6
-C
10
arylcarbonyl may be substituted by halogen, preferably fluoro, C
1
-C
10
alkoxy or C
1
-C
6
alkyl carbonyl.
C
1
-C
10
alkoxy is straight-chain or branched alkoxy radicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, iso-pentyloxy, tertpentyloxy, heptyloxy, octyloxy, isooctyloxy, nonyloxy or decyloxy.
C
1
-C
6
alkyl carbonyl is straight-chain or branched carbonyl radicals such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl.
Another aspect of the present invention is a process for the preparation of compounds of formula (1). The process comprises reacting acetic anhydride with an acetic acid substituted on the alpha carbon by R
1
or R
2
, at a temperature of 120° C. to 180° C., preferably at a temperature of 140° C. to 160° C. The reaction scheme below shows the reaction, wherein R
4
represents R
1
or R
2
as previously defined.
The resulting ketone is then stirred with hydroxylamine hydrochloride to produce an oxime:
The oxime is then stirred with tosyl chloride in an aromatic solvent, such as pyridine, at a temperature of −5° C. to 5° C., preferably at a temperature of −2° C. to 2° C.
The tosylate is then dissolved in an ether solvent, such as tetrahydrofuran, and added to a cooled solution of potassium metal in dry alcohol, such as ethanol:
The aminoketone is then heated with thionyl chloride at a temperature of 40° C. to 60° C., preferably at a temperature of 45° C. to 55° C.:
Preferably R
4
is phenyl.
Alternatively, by the reaction steps I-IV as shown in the reaction scheme below natural amino acids are obtainable which can be reacted to amino ketones in a Dakin-West reaction (step V). Compounds of formula (2) are formed as by-products:
The experimental procedure for step I to step IV is elaborated for substrates with R=p-Fluoro substituted compounds and a general procedure is given for the remaining steps (Step V to Step VII).
Step-I:
aluminium chloride 80 g (0.6 mol) is added To a solution of ethyl oxalyl chloride 82 g (0.6 mol) in 200 ml of dichloromethane with stirring at temperature 25-30° C. over a period of 30 minutes in portions. Fluorobenzene 48 g (0.5 mol) in 200 ml of dichloromethane is added through a dropping funnel over a period of 2.5 h, maintaining the temperature at 25-30° C. Stirring is continued at the same temperature for additional 3 h. Reaction mass is then quenched over 1 l ice-cold water containing 200 ml of HCl
conc
. The organic layer is separated, passed over celite bed and dried over anhydrous Na
2
SO
4
. Dichloromethane is distilled off under reduced pressure to get 83 g (84%) of the ketone.
Step-II:
Hydroxylamine hydrochloride (12.25 g, 0.1 76 mol) is added under stirring at room temperature to a solution of the ketone (30 g, 0.153 mol) in 150 ml ethanol. Pyridine (14 ml, 0.18 mol) is added to the stirred reaction mixture and is refluxed for 2.5 h. Pyridine and ethanol are distilled off under reduced pressure. The residue is dissolved in 250 ml of ether and washed with water (200 ml). Ether extract is dried over anhydrous Na
2
SO
4
and concentrated under reduced pressure to obtain the 32 g (99%) of oxime as a mixture of syn and anti isomers.
Step-III:
2 g of 10 % Pd-C is added to a solution of oxime (20 g, 0.095 mol) in ethanol (300 ml) and acetic acid (25 ml), taken in a 1 l autoclave. Hydrogen is charged into the autoclave till a pressure of 100 psi. The mixture is stirred at 50° C. for 5 h. The catalyst is filtered off and the filtrate is concentrated to get brown coloured sticky solid. This residue is taken in dry ether and dry HCl gas passed through it to get white crystalline amine hydrochloride (15.86 g, 72%). 3.2 g (16%) of the staring material is also recovered from ether layer.
Step-IV:
13 g (0.055mol) of the &agr;-amino ester hydrochloride is hydrolysed by refluxing it in 1:1 conc. HCl (60 ml) for 4 h. Reaction mass is cooled to room temperature and pH is adjusted to ~7 to precipitate the free &agr;-amino acid (9 g, 95%).
Step V:
In a typical procedure, a mixture of &agr;-amino acid (47.3 mmol), pyridine (25 ml) and acid anhydride (0.284 mol) is refluxed for 5 h. Pyridine and excess acid anhydride are distilled off under reduced pressure. The residue is purified by column chromatography over silica to get pure a-amidoketone (81%).
Step VI:
In a typical procedure, the a-amidoketone (38.4 mmol) is refluxed with 15% conc HCl (100 ml) for 4 h. The reaction mixture is concentrated to dryness and titurated with 25 ml ethyl acetate to get &agr;-ketoamine hydrochloride as a white crystalline solid (82%).
Step VII:
There are two different procedures which are followed for the conversion of the &agr;-ketoamine hydrochloride to 4-hydroxy isothiazole. Procedure 1 is followed for &agr;-acetoamine hydrochloride (Bull. Chem. Soc. jpn. 41, 1968, 959-964) and procedure 2 is employed for higher homologous a-ketoamine hydrochlorides.
Procedure 1:
To anhydrous DMF (10 ml/1 g of &agr;-ketoamine hydrochloride), maintained at 0° C., is added dropwise thionyl chloride (12.5 mmol, 2.5 equivalents). After a lapse of 15 min, to this stirred solution is added &agr;-ketoamine hydrochloride (5 mmol, 1 equivalent) at once. The reaction mixture is stirred at the same temperature for 2 h and then at room temperature for 2 h. The mixture is then poured on ice cold

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