CH634058A5 - 2,4-Dichlorophenylimidazolyl ethanones or ethanols, a process for their preparation and drugs containing them - Google Patents

Description

The present invention relates to new therapeutically effective 2,4-dichlorophenyl imidazolylethanols or ethanols, processes for their preparation and medicaments, in particular antifungals, which contain the new compounds.

It has already become known that phenoxyimidazolyl derivatives have good antifungal activity (see German Offenlegungsschriften 2 105 490 and 2 333 355). However, their action, especially against dermatophytes and in vivo against Candida, is no longer entirely satisfactory.

X.

Cl \

- 0 - CH - A

n

10th

6.

- Cl

(i)

in which

A represents a keto group or a CH (OH) group 15,

X stands for halogen, alkyl or optionally substituted phenyl and n stands for zero or integers from 1 to 3, and their physiologically tolerable salts have strong antimycotic properties.

Those compounds of the formula (I) in which A represents the CH (OH) group have two asymmetric carbon atoms; they can therefore exist in the two geometric isomers (erythro and threo form), which can be obtained in different proportions. In both cases they exist as optical isomers. All isomers are claimed according to the invention.

Furthermore, it was found that the 2,4-dichlorophenylimidazolylethanolones of the formula (I) are obtained if 30 l-bromo-2- (2,4-dichlorophenyl) -l-phenoxyethane-2-one of the formula

Cl

35

- O - CH - CO I

Br

- Cl

(II)

in which

40 X and n have the meaning given above, reacted with imidazole in the presence of a diluent and an acid binder. To produce the corresponding ethanols (I), the imidazolylethanes obtained in this way are reduced with complex borohydrides, optionally in the presence of a diluent.

Furthermore, the 2,4-dichlorophenylimidazolylethanols or ethanols according to the invention can be converted into the salts by reaction with acids.

Surprisingly, the Wirlc-50 substances according to the invention show a better antifungal, therapeutically useful activity than the phenoxy-imidazolyl derivatives known from the prior art, which are the most chemically and effectively obvious compounds. The substances according to the invention thus enrich the pharmacy.

If l-bromo-l- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) ethane-2-one and imidazole are used as starting materials, the course of the reaction can be represented by the following formula:

3rd

634058

cica

-O-CH-CO-i

Br

-Cl

= /

NH

Base -HBr

->

Cl-

Cl.

-O-CH-CO-N

-Cl

If 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl) -ethane-2-one and sodium borohydride are used as starting materials, the course of the reaction can be represented by the following formula :

20th

Cl-

Cl j) -0-CH-C0- <Q> -Cl

Ö

NaBIL

-> Cl-

H?

-0-CH-CH-

Û

-Cl

Formula (II) provides a general definition of the l-bromo-2- (2,4-dichlorophenyl) l-phenoxy-ethane-2-one to be used as starting materials. In this formula, X represents the halogens fluorine, chlorine, bromine and iodine, straight-chain or branched alkyl having 1 to 4 carbon atoms and phenyl optionally substituted by halogen, in particular chlorine. The index n preferably represents integers of 0.1 or 2.

The following may be mentioned as starting materials of the formula (II):

l-bromo-l-phenoxy-2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (4-fluorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (4-bromophenoxy) -2- (2,4-dichlorophenyl) -ethane -2-one l-bromo-l- (4-iodophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (2,4-dichlorophenoxy) -2- (2, 4-dichlorophenyl) -ethane - 2-one l-bromo-l- (2,6-dichlorophenoxy) -2- (2,4-dichlorophenyl) -ethane - 2-one l-bromo-l- (2, 5-dichlorophenoxy) -2- (2,4-dichlorophenyl) -ethane - 2-one l-bromo-l- (3-fluorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one 1 - Bromine-1 - (3-chlorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-Bromo-l- (3-bromophenoxy) -2- (2,4-dichlorophenyl) -ethane-2 -on l-bromo-l- (2-chlorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (4-methylphenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (4-ethylphenoxy) -2- (2,4-dichlorophenyl) -ethane-2-one l-bromo-l- (3-methylphenoxy) -2- (2nd , 4-dichlorophenyl) -ethane - 2-one l-bromo-1- (2-methylphenoxy) -2- (2,4-dichlorophenyl) -ethane - 2-one

1 -Brom-1 - (2-isopropylphenoxy) -2- (2,4-dichlorophenyl) -ethane - 2-one

1 -Bromo- l- (4-chloro-2-methylphenoxy) -2- (2,4-dichlorophenyl) - ethane-2-one l-bromo-l- (4-bromo-2-methylphenoxy) -2- (2,4-dichlorophenyl) - ethane-2-one

30th

l-bromo-l- (4-fluoro-2-methylphenoxy) -2- (2,4-dichlorophenyl) - ethane-2-one l-bromo-l- (4-iodo-2-methylphenoxy) -2- (2,4-dichlorophenyl) - ethane-2-one

35 l-bromo-l- (2,3-dimethylphenoxy) -2- (2,4-dichlorophenyl) -ethane - 2-one l-bromo-l- (4-biphenylyloxy) -2- (2,4- dichlorophenyl) -ethane-2-one l-bromo-1- (4-4'-chlorobiphenylyloxy) -2- (2,4-dichlorophenyl) -ethane-2-one

40 l-bromo-l- (4-2 ', 4'-dichlorobiphenylyloxy) -2- (2,4-dichlorophe-nyl) -ethane-2-one l-bromo-l- (4-2,4'- dichlorophenylyloxy) -2- (2,4-dichlorophenyl) - ethane-2-one l-bromo-l- (4-4'-bromobiphenylyloxy) -2- (2,4-dichlorophenyl) -45 -ethane-2- on l-bromo-1- (4-2-chlorobiphenylyloxy) -2- (2,4-dichlorophenyl) -ethane-2-one.

The l-bromo-2- (2,4-50-dichlorophenyl) -l-phenoxy-ethane-2-ones of the formula (II) to be used as starting materials are not yet known, but can be prepared by known processes by: known phenols of the formula

55

X.

- 0H

(III)

n

X and n have the meaning given above, 60 with a bromoacetophenone of the formula

Cl \

65

Br - CH2 - CO -

-Cl

(IV)

implements. The remaining active hydrogen atom is then exchanged for bromine in the usual way.

634058

Suitable salts for the compounds of formula (I) are salts with physiologically acceptable acids. These preferably include the hydrohalic acids, e.g. hydrochloric acid and hydrobromic acid, especially hydrochloric acid; then the phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, citric acid, sorbic acid, lactic acid, 1,5-naphthalene disulfonic acid.

Inert organic solvents are preferably suitable as diluents for the reaction according to the invention. These preferably include ketones, such as diethyl ketone, especially acetone and methyl ethyl ketone; Nitriles, such as propionitrile, especially acetonitrile; Alcohols, such as ethanol or isopropanol; Ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as toluene and 1,3-dichlorobenzene, benzene; Formamides, such as in particular dimethylformamide; and halogenated hydrocarbons such as methylene chloride, carbon tetrachloride or chloroform.

The reaction is carried out in the presence of an acid binder. All commonly used inorganic or organic acid binders can be added, such as alkali carbonates, for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or such as lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N, N-dimethylcyclohexylamine, dicyclohexylmethylamine, N, N-dimethylbenzylamine, further pyridine and diazabicyclooctane. An appropriate excess of imidazole is preferably used.

The reaction temperatures can be varied over a wide range. Generally one works between about 0 to about 150 ° C, preferably at 60 to 120 ° C, in the presence of a solvent such as acetone or methyl ethyl ketone.

When carrying out the process according to the invention, 1 to 2 mol of azole and 1 to 2 mol of acid binder are preferably employed per mol of the compounds of the formula (II). To isolate the compounds of formula (I), the solvent is distilled off, the residue is taken up in an organic solvent and washed with water. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. The residue is purified by distillation or recrystallization.

For the reduction according to the invention, polar organic solvents are suitable as diluents for the reaction according to the invention. These preferably include alcohols, such as methanol, ethanol, butanol, isopropanol, and ethers, such as diethyl ether or tetrahydrofuran. The reaction is generally carried out at 0 to 30 ° C, preferably at 0 to 20 ° C. For this purpose, about 1 mol of a borohydride, such as sodium borohydride or lithium borohydride, is used per 1 mol of the compound of the formula (II). To isolate the compounds of formula (I) the residue is e.g. taken up in dilute hydrochloric acid, then made alkaline and extracted with an organic solvent, or only mixed with water and shaken out with an organic solvent. Further processing takes place in the usual way.

Examples of particularly effective representatives of the active compounds according to the invention are, besides the preparation examples and the examples in Table I, the following: 1- (2-chlorophenoxy) -2- (2,4-dichlorophenyl) -1- (imidazol-1-yl) -

-ethane-2-one or -ol l- (2-isopropylphenoxy) -2- (2,4-dichlorophenyl) -l- (imidazole-l-

-yl) -ethane-2-one or -ol l- (2-methylphenoxy) -2- (2,4-dichlorophenyl) -l- (imidazoI-l-yI) -

-ethane-2-one or -ol l- (2-chloro-4-methylphenoxy) -2- (2,4-dichlorophenyl) -l- (imid-azol-l-yl) -ethane-2-one or . -ol.

The compounds of formula (I) according to the invention and their salts have antimicrobial, in particular strong antifungal, effects. They have a very broad spectrum of antifungal effects, in particular against dermatophytes and shoot fungi as well as biphasic fungi, e.g. against Candida species, such as Candida albicans, Epidermophyton species, such as Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, such as Trichophy-ton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporonillium feline -Species, such as Pénicillium commune. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.

Indications for use in human medicine include:

Dermatomycoses and system mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, micro-sporon species, Epidermophyton floccosum, shoots and biphasic fungi as well as molds.

Indications in veterinary medicine can include the following:

All dermatomycoses and system mycoses, especially those caused by the pathogens mentioned above.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1,2, 3 or 4 single doses or Y2, M or YA of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. Glycerin, (d) disintegrant, e.g. Agar-agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they contain the active ingredient (s) only or preferably in a specific part of the intestinal tract,

4th

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

if necessary, deliver with a delay, using e.g. Polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble excipients, e.g. Polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid)

or mixtures of these substances.

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents e.g. Contain chlorofluorocarbons.

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl-formamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycated alcohol, polyalkylene glycol, formaldehyde glycol and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Sakharin included.

The therapeutically active compounds in the pharmaceutical preparations listed above are preferably in a concentration of about 0.1 to 99.5, preferably 634058

be present from about 0.5 to 95 percent by weight of the total mixture.

In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

In general, both in human and in veterinary medicine, it has proven to be advantageous to use the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.

However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug, and the period or interval within Which is administered? In some cases it may be sufficient to get by with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

The antifungal activity of the compounds according to the invention is explained below on the basis of experiments.

Experiment A In Vitro Antifungal Efficacy

Test description:

The in-vitro tests were carried out in a serial dilution test with germinocula of an average of 5 X 104 germs / ml substrate. The following were used as nutrient medium for dermatophytes and molds:

Sabouraud's milieu d'épreuve b) for yeast:

Meat extract and dextrose broth.

The incubation temperature was 28 ° C, the incubation time was 24 to 96 hours.

5

5

10th

15

20th

25th

30th

35

40

45

50

634058

6

TABLE A In vitro antifungal activity

Active ingredient MIC - VALUES in Y / ml nutrient medium

Tricho- Candida Penicil- Asper- Micro- Torulopsis phyton albicans ïium gillus .feporon glabrata mentagr. commune species felineum

02N - ^ - 0-CH-CO-C (CH3

'1 100 100 40 100 -

û

(known)

CA.

-0-CH-CO-C (CH3) 3

40 40 100> 100> 100

Co

(known)

OH

Cl- «-CH-CH-C (CH,)

'' 8 64,> 64

n

(known)

OH »

(CH3) 3C-Q) -0-CH-CH-C (CH3) 3 32> 64,> 64> 64

O

(known)

Cl

/

'"100 40 100 -

Cl- ^ h0-CH-C0- ^ x HCl

O

Cl "--N

N

(known)

C1 \. OH

-O-CH-ChT)> x HCl

I I \ ^ / 4 - 100 40 40 -

OH

(fNi

IN

■ N

(known)

(Connections from example no.)

1 <1 32 32 32 4 4

2 <1 4 32 - 32 1

3 <1 32 8 4 32 8

12 <1 8 8 32 32 8

13 <1 32 32 - 32 8

634058

Attempt B

Antifungal in vivo efficacy (oral) in mouse candidiasis

Test description:

SPP-CFi mice were intravenously infected with 1-2 X 106 logarithmic Candida cells suspended in saline. One hour before and seven hours after the infection, the animals were treated orally with 100 mg / kg body weight of the preparations.

Untreated animals died 3 to 6 days after infection from the infection. The survival rate on the 6th day after infection was approximately 5% in untreated control animals.

Explanation of symbols:

+ + + + + = very good effect

=> 90% survivors on day 6 p.i.

+ + + + = good effect

=> 80% survivors on day 6 p.i.

+ + + = Effect

=> 60% survivors on day 6 p.i.

+ + = weak effect

=> 40% survivors on day 6 p.i.

+ = Trace effect k.W. = no effect

TABLE B

Antifungal in vivo efficacy (oral) in mouse candidiasis

Active ingredient

effect

(known)

-0-CH-CO-C (CH3) 3

O

OH

-CH-CH-C (CH3) 3 / N

k.W.

il k.W.

(Connections from example no.)

1

2 12

+ + + + + + + + + + +

Production Examples Example 1

Cl s.

Cl-

- 0 -

10th

CH - CO -

'S

IN

- Cl x HCl

15 To 65 (1 mol) imidazole in 650 ml acetonitrile, 103 g (0.26 mol) l-bromo-l- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -ethane-2 -on dripped. The mixture is heated under reflux for 40 hours. The solvent is then distilled off in vacuo, the residue is taken up in 500 ml of methylene-20 chloride and extracted four times with 250 ml of water. The organic phase is dried over sodium sulfate and concentrated by distilling off the solvent in vacuo. The residue is taken up in 1000 ml of acetone and mixed with 47 g (0.26 mol) of 1,5-naphthalenedisulfonic acid in 100 ml of acetone. The resulting precipitate is filtered off and boiled with 100 ml of acetone. The residue is mixed with 200 ml of sodium bicarbonate solution and 500 ml of methylene chloride. The organic phase is separated off, washed with 200 ml of water and concentrated by distilling off the solvent in vacuo. The residue is taken up in 200 ml of ether and an excess of dry hydrogen chloride is added. After distilling off the ether in vacuo, the oily residue is recrystallized from acetone. 31.6 g (29% 35 of theory) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl-ethane-2-one hydrochloride of melting point 146 are obtained -148 ° C.

Example 2

40

45

50

Cl \

Cl-

- 0 - CH - CH I I N. 0H

n

N

- Cl

O

ü TJ

45.5 g (0.108 mol) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazole-1-yl-ethane-2-one hydrochloride (Example 1) are converted into 100 ml of methanol dissolved and mixed with 4.32 g (0.108 mol) of sodium hydroxide. At 0 ° to 5 ° C., 4.5 g (0.12 mol) of sodium borohydride are added in portions and the mixture is stirred for 15 hours at room temperature. 60 ml of concentrated hydrochloric acid are then added dropwise at 0 ° C. and the mixture is stirred again at room temperature for 15 hours. The reaction mixture is then stirred into 800 ml of saturated sodium hydrogen 60 carbonate solution and extracted with 500 ml of methylene chloride. The organic phase is dried over sodium sulfate and concentrated by distilling off the solvent in vacuo. The residue is recrystallized from ether. 30 g (72.5% of theory) of l- (4-chlorophen-65 oxy) -2- (2,4-dichlorophenyl) -l-imidazol-l-yl-ethanol-2-ol are obtained as a mixture of isomers from the melting point 108-110 ° C.

The following compounds of Table 1 are obtained analogously to the examples mentioned above.

634058

TABLE 1

Cl

\

[T-

- 0 - CH - A - <(!> - Cl

Fn s

10th

15

20th

Example Xn A Melting point (° C)

No.

3 2,4-Cl2 CO 205-215 (xHCl)

4 4-0-C1 CO 145-148 (x HCl)

5 4- <n> CO 160-162 (x HCl)

6

4-F

CO

160 (x HCl)

25th

7

-

CO

162-168 (x HCl)

8th

2,6-Cl2

CO

180 (x HCl)

9

3-C1

CO

168-171 (x HCl)

30th

10th

4-CH3

CO

110 (x HCl)

11

4-C1, 2-CH3

CO

177-178 (x HCl)

12

2,4-Cl2

CH (OH)

208-218

(Mixture of isomers) (x HCl)

35

13 CH (OH) 158-170

\ - '(isomer mixture) (x HCl)

14 - CH (OH) 156-159 40

(Mixture of isomers) (x HCl)

15 3-C1 CH (OH) 165-167

(Mixture of isomers) (x HCl)

Claims (5)

634058 PATENT CLAIMS 1. Therapeutically effective 2,4-dichlorophenylimidazolyl ethanes or ethanols of the general formula Cl \ - 0 - CH - A - - Cl in which A represents a keto group or a CH (OH) group, X represents halogen, alkyl or optionally substituted phenyl and n represents zero or an integer from 1 to 3, and their physiologically tolerable salts. 2. A process for the preparation of 2,4-dichlorophenyl-imide-azolylethanolones of the formula (I) according to Claim 1, in which A represents a keto group, characterized in that l-bromo-2- (2,4-dichlorophenyl) - l-phenoxy-ethane-2-one of the formula Cl \ - 0 - CH - CO I Br - Cl in which X and n have the meaning given in claim 1, reacted with imidazole in the presence of a diluent and an acid binder. 3. A process for the preparation of 2,4-dichlorophenyl-imide-azolylethanols of the formula I according to claim 1, in which A represents a group CHOH, characterized in that one carries out the process according to claim 2 and the compound of the formula I obtained, in which A means a keto group, reduced with a complex borohydride. 4. The method according to claim 3, characterized in that one carries out the reduction in the presence of a diluent. 5. Medicament, characterized by a content of at least one 2,4-dichlorophenylimidazolylethanol or ethanol of the formula I according to claim 1. It has been found that the new therapeutically effective 2,4-dichlorophenylimidazolylethanols or ethanols of the general formula (I) (II)