Salicylic acid derivatives, processes for their preparation,...

Details Salicylic acid derivatives, processes for their preparation,... Salicylic acid derivatives, processes for their preparation,...

2001-07-02

2003-07-15

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ortho-hydroxybenzoic acid or derivative doai

C560S034000, C562S439000, C564S186000, C564S147000, C564S202000

Reexamination Certificate

active

06593315

ABSTRACT:

The present invention relates to salicylic acid derivatives of the formula I
where the index and the substituents are as follows:
X is halogen, NO
2
, cyano, C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy;
m is 0, 1, 2 or 3, it being possible for the substituents X to differ from each other if n is greater than 1;
A is OH, C
1
-C
4
-alkoxy, NH
2
, NHCH
3
or N(CH
3
)
2
;
R
1
is phenyl, naphthyl, C
3
-C
10
-cycloalkyl, 5-membered or 6-membered hetaryl or 5-membered or 6-membered heterocyclyl containing one to three N atoms and/or one O or S atom or one or two O and/or S atoms, the ring systems being unsubstituted or substituted by one to three radicals R
a
:
R
a
is cyano, nitro, amino, aminocarbonyl, aminothiocarbonyl, halogen, hydroxyl, C
1
-C
6
-alkyl, C
1
-C
6
-haloalkyl, C
1
-C
6
-alkylcarbonyl, C
1
-C
6
-alkylsulfonyl, C
1
-C
6
-alkylsulfoxyl, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-haloalkoxy, C
1
-C
6
-alkyloxycarbonyl, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, C
1
-C
6
-alkylaminocarbonyl, di-C
1
-C
6
-alkylaminocarbonyl, C
1
-C
6
-alkylaminothiocarbonyl, di-C
1
-C
6
-alkylaminothiocarbonyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkenyloxy, phenyl, phenoxy, benzyl, benzyloxy, 5- or 6-membered heterocyclyl, 5- or 6-membered hetaryl, 5- or 6-membered hetaryloxy, C(═NOR
&agr;
)—OR
&bgr;
or OC(R
&agr;
)
2
—C(R
&bgr;
)═NOR
&bgr;
,
 the cyclic radicals, in turn, being unsubstituted or substituted by one to three radicals R
b
:
R
b
is cyano, nitro, halogen, hydroxyl, amino, aminocarbonyl, aminothiocarbonyl, C
1
-C
6
-alkyl, C
1
-C
6
-haloalkyl, C
1
-C
6
-alkylsulfonyl, C
1
-C
6
-alkylsulfoxyl, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-haloalkoxy, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, C
1
-C
6
-alkylaminocarbonyl, di-C
1
-C
6
-alkylaminocarbonyl, C
1
-C
6
-alkylaminothiocarbonyl, di-C
1
-C
6
-alkylaminothiocarbonyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkenyloxy, C
3
-C
6
-cycloalkyl, C
3
-C
6
-cycloalkenyl, phenyl, phenoxy, phenylthio, benzyl, benzyloxy, 5- or 6-membered heterocyclyl, 5- or 6-membered hetaryl, 5- or 6-membered hetaryloxy or C(═NOR
&agr;
)—OR
&bgr;
;
 R
&agr;
, R
&bgr;
is hydrogen or C
1
-C
6
-alkyl;
R
2
is hydrogen, cyano, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
1
-C
6
-haloalkyl, C
1
-C
6
-alkoxy or C
1
-C
6
-alkylthio,
 the hydrocarbon radicals being unsubstituted or partially or fully halogenated or it being possible for them to have attached to them one to three groups R
c
:
R
c
is halogen, cyano, nitro, hydroxyl, C
1
-C
6
-alkyl, C
1
-C
6
-haloalkyl, C
1
-C
6
-alkylcarbonyl, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-haloalkoxy, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylamino,
 di-C
1
-C
6
-alkylamino, C
2
-C
6
-alkenyl, C
3
-C
6
-alkenyloxy, C
3
-C
6
-alkynyloxy or C
1
-C
4
-alkylenedioxy which can be halogenated.
Furthermore, the invention relates to processes for the preparation of these compounds, to compositions comprising them, and to their use for controlling harmful fungi.
WO-A 97/08135, DE-A 197 10 609 and WO-A 99/27783 disclose acylaminosalicylamides for controlling harmful fungi.
However, their action is unsatisfactory in many cases.
It is an object of the invention to provide compounds with an improved action.
We have found that this object is achieved by the compounds defined at the outset. Moreover, there have been found processes for their preparation, compositions comprising them and methods of controlling phytopathogenic harmful fungi using the compounds I.
The compounds of the formula I differ from those of the prior art by the hydrazide group.
The compounds of the formula I show an increased efficacy against harmful fungi compared with the known compounds.
Compounds of the formula I can be prepared for example starting from alkyl salicylates of the formula II where A is C
1
-C
4
-alkoxy and Z is a protecting group which can be eliminated under acidic conditions, such as, for example, an acetyl group.
Compounds of the formula II can be obtained by free-radical halogenation under generally customary conditions, especially advantageously by bromination with N-bromosuccinimide (NBS) using azobisisobutyronitrile (AIBN) as free-radical initiator with exposure to light [cf. J. Amer. Chem. Soc., Vol. 71 (1949), p. 2137 et seq; ibid., Vol. 90 (1968), p. 1797 et seq]. Compounds of the formula II where A is methoxy, Z is acetyl and Hal is bromine are preferred.
This reaction is usually carried out at temperatures of from 20° C. to 150° C., preferably from 50° C. to 100° C., in an inert organic solvent [cf. Can. J. Chem., Vol. 33 (1955), p. 1819; J. Org. Chem., Vol. 49 (1984), p. 2158].
Suitable solvents are halogenated hydrocarbons such as carbon tetrachloride, chloroform and chlorobenzene. Mixtures of the solvents mentioned may also be used.
In general, the starting materials are reacted with each other in equimolar amounts. It may be advantageous for the yield to employ NBS in an excess based on II.
The starting materials II required for the preparation of the compounds I are commercially available, known from the literature [Bull. Soc. Chim. Fr., Vol. 9 (1966), p. 2821; Biotechnol. Lett., Vol. 15 (1993), p. 469; J. Fluorine Chem., Vol. 74 (1995), p. 69] or can be prepared in accordance with the literature cited.
The dihalo compounds of the formula III are oxidized with elimination of the protecting group Z under acidic conditions to give the keto compounds IV.
This reaction is usually carried out at temperatures of from 20° C. to 150° C., preferably from 20° C. to 100° C., in an inert organic solvent in the presence of an acid (cf. Org. Synth., Vol. 20 (1940), p. 92].
Suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, especially preferably methanol, ethanol and n-propanol. Mixtures of the solvents mentioned may also be used.
Acids and acidic catalysts which are used are inorganic acids such as hydrofluoric acid, aqueous hydrochloric acid, hydrobromic acid, sulfuric acid and perchloric acid, Lewis acids such as boron trifluoride, aluminum trichloride, iron(III) chloride, tin(IV) chloride, titanium(IV) chloride and zinc(II) chloride, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid.
In general, the acids are employed in catalytic amounts, but they may also be used in equimolar amounts, in an excess or, if appropriate, as solvents.
To prepare compounds I where A is NH
2
, NHCH
3
or N(CH
3
)
2
, salicylic esters IV are reacted with ammonia or methylamine to give salicylamides of the formula IV.1 where R
3
is hydrogen or methyl; the reaction with dimethylamine gives compounds of the formula IV.3:
This reaction is usually carried out at temperatures of from 20° C. to 150° C., preferably from 20° C. to 100° C., in an inert organic solvent [cf. Arch. Pharm. (1982), p. 941].
Suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles such as acetonitrile, alcohols, and dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, especially preferably N,N-dimethylformamide and N,N-dimethylacetamide. Mixtures of the solvents mentioned may also be used.
In general, the starting materials are reacted with each other in equimolar amounts. It may be advantageous for the yield to employ the amine in an excess based on IV.
The imino group is usually eliminated from IV.1 at temperatures of from 20° C. to 150° C., preferably from 20° C. to 100° C., in an inert organic solvent in the presence of an acid [cf. J. Chem. Soc. (1957), p. 3807; J. Or

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