Note: Descriptions are shown in the official language in which they were submitted.
9~Z6
The present invention relates to 4-keto-phenoxyacetic acids, their
reduced derivatives and their oximes as well as the pharmaceutically accept-
able alkali or amine addition salts of these acids, their preparation and
their thereapeutic use as uricosuric non-diuretic agents.
The compounds according to the invention are those of the following
general formula
~v3 C ~ CH2 LOOH
in which
A represents O or S, one of Zl and Z2 represents H and the other OH or Z
and Z2 taken together represent an oxygen atom or the group NOH, and Xl and
X2 are the same or different and each represents a hydrogen or a halogen atom,
or a methyl group, with the proviso that the benzene nucleus is never sub-
stituted by two halogen atoms in ortho- position with respect to one another.
Certain dihalogenated compounds of this type have been described in
Canadian Patent No. 907,023; these are uricosuric agents but above all power-
ful diuretic agents. However, in the treatment of certain conditions, for
example gout, it is necessary to administer medicaments which are exclusively
uricosuric, any associated diuretic effect being unwanted and, indeed, damag-
ing. In addition, it is known that numerous diuretics currently used have a
hyperuricemic effect, which necessitates the simultaneous administration of
uricosurics in the treatment of certain cardiovascular illnesses and the com-
pounds of formula I have a certain importance in this therapeutic area.
The cornpounds of formula I can be prepared by reacting, in an
.
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alkaline medium, a phenol of the formula II
~ C ~ OH
in which A, Xl and X2 have the meanings given above, with a compound of the
formula XCH2COOR (III), in which X represents a halogen atom and R represents
a hydrogen atom or an alkyl group. The compound so obtained is saponified
when it is an ester ~R = alkyl), and in appropriate cases a chemical reduction
of the ketone function is carried out with the object of obtaining the corres- -
ponding alcohol, or the ketone can be reacted with hydroxylamine to obtain the
oxime.
10The ketones of the formula I ~Zl and Z2 = ) can also be prepared by
a Friedel Crafts type reaction between a heterocyclic acid chloride of the
formula
~ ~IV)
COC 1
and a phenol ether of the formula
X
OCH2R ' ~V)
X2
in which Xl, X2 and A have the meanings given above and R' represents a
hydrogen atom, a COOH or COOR" group, R" being an alkyl group.
~hen the reaction is carried out with a methylether ~V, R=H), the
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compound of formula I is obtained by using a process known per se, which is
demethylation by aluminium chloride or pyridine hydrochloride, followed by
reaction on the phenol in a basic medium of chloro ~or bromo) acetic acid or
of one of its esters followed, if necessary, by a hydrolysis reaction.
When the compounds of the formula I carry on the benzene nucleus in
the ortho-position to ~he ether function at least one halogen substituent it
is preferable to carry out the Friedel Crafts reactions on anisole, to
demethylate the ether so obtained, and then to halogenate the benæene nucleus
of the 4-keto phenol by the action of C12, Br2 or I2 before preparing the
phenoxy acetic acid ether.
The alcohols of the formula I (Zl=H and Z2=OH) are prepared accord-
ing to the invention by the chemical reduction of a corresponding ketone of
the formula I. For example, a ketone in the form of an alkali salt thereof in,
for example, alcoholic solution, may be reduced by the action of sodium
borohydride. Alternatively, the corresponding ketone in the form of an ester
thereof in solution in isopropanol may be reduced by the action of aluminium
isopropylate. Reduction provides the two optical isomers in equal quantities.
The oximes of the formula I (Zl and Z2=N01-1) are prepared according
to the invention by reacting a corresponding ketone with hydroxylamine. Con-
veniently this may be effected by the action of hydroxylamine hydrochloride onthe ketone in solution in pyridine. The oximes are generally obtained in the
form of a mixture of their two stereoisomers. The relative proportions of
these two isomers of the carbimino group can be determined, for example, by
nuclear magnetic resonance spectroscopy.
The acid salts of the compounds of formula I may be prepared by the
action on the acid in solution in, for example, an alcohol or a ketone, of an
alkaline hydroxide or a pharmaceutically acceptable amine.
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The following Examples illustrate the invention but do not limit it.
The compounds mentioned have been subjected to analytical study (elementary
analysis, potentiographic titration I.R. and N.M.R. spectra) and they are
characterised by their melting points determined upon a Kofler bench.
EXAMPLE 1
4-(2-Thenoyl)-2,6-dimethyl-phenoxyacetic
A) (2-Thienyl) (3,5-dimethyl-4-methoxyphenyl)ketone
Into a solution of 60 g of 2,6-dimethyl anisole and 62.7 g of the
chloride of 2-thiophene carboxylic acid in 250 ml of anhydrous methylene
chloride there was introduced over 30 minutes 58.5 g of aluminium chloride
while maintaining the temperature at about 10C. The reaction medium was
brought to the reflux temperature of the solvent for 2~ hours, then poured on-
to one kg of crushed ice mixed with 150 ml of concentrated hydrochloric acid.
The organic phase was decanted, the aqueous phase extracted with methylene
chloride, and the organic phase washed with an aqueous solution of sodium
hydroxide, then with water. After drying and evaporation of the solvent, 110
g of an oil was isolated which was distilled under reduced pressure to give 89
g of ketone. Boiling point (14 mm Hg) = 225 C.
B) (2-Thienyl) (3,5-dimethyl-4-hydroxyphenyl)ketone
A mixture of 20 g of the ketone obtained according to A) and 46 g of
pyridine hydrochloride were kept for 6 hours at 180C and then poured onto
iced water. The mixture was extracted with ethyl ether, then Wit}l an aqueous
solution of sodium hydroxide. After acidifying the solution, the phenol was
extracted in ethyl ether, the solvent evaporated and the residual oil distilled
to give 17 g of pure phenol. Boiling point (0.15 mm Hg) = 185 C - m.pt. =
50C. -.
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C) Ethyl-4-~2-thenoyI)-2,6-dimethyl-plien_xyacetate
There was kept for 3 hours at 60C a solution in 150 ml of dimethyl-
formamide of 10 g of the phenol obtained according to B), 3 g of potassium
hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the sol-
vent evaporated, the residue dissolved in ethyl ether, and the impurities ex-
tracted in a basic aqueous solution. After concentration of the solvent, 11.2
g of the ester were obtained which melted at 89C.
D) 4-(2-Thenoyl)-2,6-dimethyl-phenoxyacetic acid
11 g of the ester obtained according to C) were dissolved in 150 ml
of aqueous ethanol (50/50) containing 2.7 g of sodium hydroxide; the solu~ion
was kept for 3 hours at 95C, the ethanol evaporated under reduced pressure
and the aqueous phase acidified 9.4 g of the acid precipitated - m.pt. =
115C
EXAMPLE 2
_ _
4-(2-ThenoyI)-2,3-dimethyl-phenoxyacetic acid
A) (2-Thienyl) (2,3-dimethyl-4-methoxyphenyl)ketone
This compound was prepared in 86% yield by using step A) of Example
1 with the chloride of 2-thiophene carboxylic acid and 2,3-dimethyl anisole.
B) (2-Thienyl)~2,3-dimethyl-4-hydroxyphenyl?ketone
123 g of the preceding ether were dissolved in 1300 ml of benzene
and there was introduced into the solution over a period of 1 hour 30 minutes
133 g of aluminium chloride. The mixture was kept for 5 hours at its reflux
temperature and then poured onto a mixture of ice and hydrochloric acid. The
phenol was extracted in ether and purified by dissolving in an aqueous solution
of sodium hydroxide from which it precipitated by acidification. There was
obtained 67 g of the product melting at 144C.
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C) Ethyl-4-(2-thenoyI)-2,3-dimethyI phenoxyacetate
~ Into a solution of sodium ethylate prepared by the action of 2.3 g
of sodium on 200 ml of ethanol, there was introduced 23.2 g of the phenol of
step B), 14.9 g of sodium iodide and 13.5 g of ethylchloroacetate. The mix-
ture was kept under reflux for 8 hours, the hot solution filtered and the
solvent evaporated, the phenol which had not reacted being eliminated from the
residue by extraction in an aqueous sodium hydroxide solution. There was thus
isolated after drying 22.15 g of pure acetate in the form of an oil.
D) 4-(2-Thenoyl)-2,3-dimethyI-phenoxyacetic acid
This compound was obtained by hydrolysis of its ethyl ester in
aqueous ethanol in the presence of potassium hydroxide. After recrystallisa-
tion in ben~ene or 1,2-dichloroethane the pure acid melted at 134C.
EXAMPLE 3
4-[(2-Thienyl)hydroxymethyl]-?,3-dimethyl-phenoxya_etic acid
There was poured into 5 ml of a 0.2N sodium hydroxide solution con-
taining 0.8 g of sodium borohydnide a solution of 8.15 g of 4-(2-Thenoyl)-
2,3-dimethyl-phenoxyacetic acid and 2.1 g of sodium hydroxide in 75 ml of
water. After 12 hours of stirring at ambient temperature the solution was
acidified by the addition of acetic acid then hydrochloric acid. The pre-
cipitate was isolated ancl then recrystallised in an acetone/water (50/50) mix-
ture. There was thus obtained 7 g of the acid which melted at 154C. -.
EXAMPLE_4
4-(2-furoyl)-2,6-dibromo-phenoxyacetic acid
A) (2-Furyl) (3,5-dibromo-4-hydroxyphenyl)ketone
There was introduced into a solution of 28 g sodium acetate and 6 ml
methanol 19 g o (2-furyl) (4-hydroxyphenyl) ketone (m.pt. = 164C) prepared
according to the method described in Example 1 A) and B), and then there was
`:
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introduced dropwise 11 ml of bromine dissolved in 14 ml of acetic acid. After
2 hours stirring at ambient temperature, the mixture was ~oured into three
volumes of water and the precipitate isolated. After recrystallisation in
dichloroethane there was obtained 22 g of phenol dibromide melting at 164C.
B) Ethyl-4-~2-furoyl)-2,6-dibromo-phenoxyacetate
There was kept under reflux for 6 hours 300 ml of methylethylketone
containing 21 g of the phenol of step A), 15 g of potassium carbonate and 18 g
of ethylbromoacetate. After hot filtration the solvent was evaporated and the
solid recrystallised in ethanol. 21 g of the ester were obtained which melted
at 114C.
C) 4-(2-furoyl?-2,6-dibromo-phenoxyacetic acid
This compound was obtained by hydrolysis of its ester from step B)
in aqueous ethanol ~50/50) in the presence of potassium carbonate with 90%
yield. It melted at 167C.
EXAMPLE 5
4-[(2-furyI)hydroxymethyl]-2,6-dibromo-phenoxyacetic acid
A) Isopropyl 4-[(2-furyl)hydroxyrnethyl]-2,6-dibromo-phenoxyacetate
10 g of ethyl 4-(2-furoyl)-2,6-dibromo-phenoxyacetate and 9.8 g oE
aluminium isopropylate were dîssolved in 300 ml of isopropanol and the mixture
was kept for 20 hours at 82C with distillation off of the acetone as it
formed. The solvent was then evaporated and the mixture poured into iced
water. The precipitate formed was discarded and the final product extracted
in ethyl ether. After drying the solvent was removed and the solid product
was recrystallised in isopropyl ether. 5.5 g of the ester were thus obtained
which melted at 119C.
B) 4-[(2-furyl)hydroxymethyl]-2,6-dibromo phenoxyacetic acid
This acid was obtained by hydrolysis with potassium carbonate in
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aqueous ethanol of the isopropyl ester of step A). It melted at 136C~
EXAMPLE 6
4-[(2-thienyl)hydroxyiminomethyl]-2,6-dimethyl-phenoxyacetic acid
4 g of 4-(2-thenoyl)-2,6-dimethyl-phenoxyacetic acid and 4 g of
hydroxylamine hydrochloride were dissolved in 30 ml of pyridine and the mixture
was kept for 3 hours at reflux. The mixture was then poured into an N aqueous
solution of hydrochloric acid and the oxime extracted in ethyl ether. The re-
maining solid, after evaporation of the solvent, was a mixture of the two
isomers of the oxime which melted at 152 C.
EXAMPLE 7
4-(2-Thenoyl)-2,6-diiodo-phenoxyacetic acid
A) (3,5-Diiodo-4-hydroxyphenyl~ (2-~hienyl) ketone and
(3-iodo-4-hydr:oxyphenyl) (2-thienyl) ketone
Into a solution of 50 g of (4-hydroxyphenyl) (2-thienyl) ketone, in
400 ml of a 3% aqueous solution of sodium hydroxide there was introduced
slowly 76.2 g of iodine and 104 g of potassium iodide in solution in 400 ml
water. After 12 hours stirring the precipitate was removed, and then a 5% -
aqueous solution of sodium bisulphite introduced until the p~l was acid. The
precipitate which appeared was isolated. It contained the mono and di:iodo
phenols which could be separated due to their differences in solubility in
chloroform. There was thus obtained after recrystallisation in ethanol 14 g
of the (3,5-diiodo-4-hydroxyphenyl) (2-thienyl) ketone which melted at 158C
and 40.2 g of (3-iodo-4-hydroxyphenyl) (2-thienyl) ketone: m.pt. = 190C
(recrystallisation in aqueous dioxane (50/50)).
B) Ethyl-4-(2-Thenoyl)-2 6-diiodo-phenoxyacetate
The sodium salt was prepared from 13.65 g of phenol by the action of
2 g of sodium methylate in methanol. The mixture in solution was poured into
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100 ml of dimethylformamide, the methanol removed and 6.2 g of ethylbromo-
acetate were introduced. After 12 hours at ambient temperature there was
introduced into the medium 3 volumes of wa~er and the mixture extracted with
ethyl ether. The ethereal phase was washed with aqueous sodium hydroxide
solution, then with water, dried, and the solvent removed. The ester was
recrystallised in 95% aqueous ethanol.
There was obtained 9 g of ester which melted at 93C.
C) 4-(2-Thenoyl)-2,6-diiodo-phenoxyacetic acid
This was prepared starting from its ester with 90% yield by
hydrolysis in aqueous ethanol in the presence of K2CO3. It melted at 160C.
EXAMPLE 8
4-(2-Thenoyl)-2-iodo-phenoxyacetic acid
A) Ethyl-4-(2-Thenoyl)-2-iodo-phenoxyacetate
This compound was prepared by using the method described in Example
7 B). It melted at 123C after recrystallisation in ethanol.
B) 4-(2-Thenoyl)-2-iodo-phenoxyacetic acid
This was prepared by hydrolysis of its ethyl ester with 97% yield.
It melted at 164 C.
EXAMPLE 9
4-~2-Thenoyl)-2-bromo-phenxoyacetic acid
.
A) Ethyl-4-(2-Thenoyl)-2-bromo-phenoxyaceta_
This ester was prepared with 95% yield by reaction of ethylbromo-
acetate with (3-bromo-4-hydroxyphenyl) (2-thienyl) ketone. The product was an
oil.
B) 4-(2-Thenoyl)-2-brom_-phenoxyacetic acid
This acid was obtained by hydrolysis in a basic medium of its ethyl
ester~ It melted at 180 C.
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The following Table I lists the structural formula and melting
points of each of the compounds of the above Examples 1 to 9, together with
structural formula and melting points for additional Examples 10 to 23 of com-
pounds prepared in like manner.
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TABEE I
.
. .. ..
Example Structural formula M.Pt. ( C)
: ~ .. ... _
2 [~ ~ O-CH2-COOH 115
S lo -CH2-COOH 134
~S C ~ O-CH2-COOH 154
Cl ~O-CH2-COOH 167
~ O-CH COOH 136
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TABLE I ~Cont)
A . , ~
Example Structural formula M.Pt. ~C)
6 CH
C ~ 30-CH2-cooH 152
NOH ,
~ Cl ~ O-C~I2-COOH 160
8 ~ Cl ~ O-CH2-COOH 164
9 ~ ICl ~ O-CH2-COO~I 180
L ~ ~ C-- O CH~-COOH
. _ . .. . . ~
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TABLE I (Cont)
_ _ ~
Example Structural formula M.Pt. ( C)
t
-CH2-COOH 144
S ICl ~ O-CH2-CI1 180
O~BrO-CH2 -COOII 190
O-CH~-COOI 195
-13-
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TABLE I (Cont)
.
_ . _ . .
Example Structural formula M.Pt. ~C) -.,
O ~ ~ ` ~3 0 -CH 2 -COO}1
0-CH2-COOH 193
~ C ~ ~ 0-CH2-COOH 202
19 ~ ~ Sodium sal e
S C ~ 0-C112-C00~1 192
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TABLE I (Cont)
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Example Structural formula M.Pt. ( C)
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21 ~ ~ ~ 0-CH2-COOH ~ 166
22 ~ ~ ~ 0-cH2-cooH ~ 207
~L c_/~O-C112-COOH 110
. . _ _ .
The compounds of the invention have been subjected to different
pharmacological tests which have revealed in particular their value as
uricosuric agents. The following results illustrate this property.
The uricosuric activity was studied on lots of 5 rats weighing 250
to 280 g. The compounds of the inven~ion were administered to the animals
orally in doses of from 5 to 200 mg/kg. One hour after this administration
and anaesthesia with ether, the animals received an intravenous injection of
1 cm3 of an aqueous 1% solution of phenol red. Samples of blood were taken
15, 30, 45 and 60 minutes after this injection and the quantity of blood
phenol red measured. This method is described by H.C. SCAR~OROUGH and G.R.
McKINNEY in J. Med. Pharm. Chem. 5 175 (1962) and E. KREPPEL in Med. Exptl. 1
285 (1959)- -15-
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All the compounds of the invention diminish the speed of elimination
of phenol red in the rat at the dosages mentioned and can thus be considered
specifically uricosuric agents. In the following Table II there are set out
the results obtained with the administration of a certain of the compounds as
well as with the administration of ben~iodarone, a uricosuric agent currently
used in human therapy.
Since in addition the LD50 of all the compounds of the invention,
determined by the method of C.I. BLISS Quart. J. Pharm. Pharmacol. 2 192-216
(1938) is orally greater than 1000 mg/~g, it can be seen that the therapeutic
index of the compounds of formula I and of their salts permit their use in
human therapy in daily doses of from 10 mg to lg.
The compounds of the invention can be administered orally or parent-
erally, optionally in association with known vehicles such as excipients or
diluents, for example, in the form of gelatine capsules, tablets or solutions.
Thus, the invention includes a pharmaceutical composition, which
composition comprises a compound of formula I or a pharmaceutically acceptablc
alkali or amine addition saIt thereof, together with a pharmaceutically
acceptable vehicle.
The invention also includes a method of inducing a uricosuric effect
in a patient without significant diuresis, which method comprises administer-
ing a compound of formula I, a pharmaceutically acceptable alkali or amine
addition salt thereofJ or a composition as defined above.
-16-
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l'ABLE II
. .
Example N Dose mg/kg Uricosuric activity (% of retention of phenol
red with reference to the control animals)
. ,
. .
after 15after 30 after 45 after 60
minutes minutes minutes minutes
. . .
2 50 + 61 + 88 + 86 + 160
3 100 + 83 + 84+ 66'+` + 21
100 + 37 + 41 + 19~ + 21
7 50 +113 +100 + 93 + 79
+ 78 + 66 + 50 + 71
8 50 + 59 + 88 + 84 ~ 35
+ 88 +111 + 92 + 52
11 100 + 69 + 75 +lOO + 75
+ 52 + 59 + 80 + 65
13 50 + 55 + 43 + 65 + 40
21 100 + 68 +123 +105 + 58
+ 48 + 23~+ 36'+` + 38
benziodarone 100 + 37 + 50 ~ 53 + 18
_ ... x stat stically non significant results
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