Note: Descriptions are shown in the official language in which they were submitted.
~0~3~0~
The present invention is concerned with new phenoxy- -
alkyl-carboxylic acid derivatives and their preparation.
The new derivatives, as well as their pharmacologically ;
compatible salts, show, in animal experiments, a considerable
lowering of the serum lipid level and of the cholesterol level, ~; -
without undesired side effects occurring. Consequently, the
new compounds according to the present invention and the salts
thereof are effective agents against atherosclerosis. Further-
more, they are valuable intermediates for the preparation of ;
antibiotics with a ~-lactam structure.
According to the invention there is provided new
phenoxyalkyl-carboxylic acid derivatives of the formula (I):-
'~'~ .' .
C0-~H-(CH2)n ~ 0-C-CO-Z (I)
[~
: - ,
wherein Rl and R2, which may be the same or different, are ;~
hydrogen atoms or lower alkyl radicals, Z is a hydroxyl group
or a lower alkoxy radical and n is 1 or 2; and the pharmaceuti-
cally acceptable, pharmacologically compatible salts thereof.
The amide group in the compounds of general formula (I) -
is present in the 1- or 2-position of the naphthalene ring.
The lower alkyl and lower alkoxy radicals in the above-
given formula (I) can be straight-chained or branched radicals
of 1 to 5 and preferably 1 to 3 carbon atoms.
According to another aspect of the invention, there
` is provided a process for preparing the new derivatives of
- formula (I) comprising reacting a hydroxyamino compound of the
formula (II)~
'' - 1- ~ "', .
:,
' ' : ~'
4~0~ :
` ': ' :
2 ~C~2)n - ~ - ~ (II)
in,which n has the same meaning as above, or a reactive derivative
thereof, optionally after the introduction of a conventional
protective group for the amino or hydroxyl group which is to be
temporarily protected, with a naphthoic acid of the formula tIII):-
COOH
~ ' '. .
I ~ (III)
or a reactive derivative thereof, and with a compound of
the formula (IV):- .
X - C - CO - Z (IV)
R2 ~ :
wherein Rl, R2 and Z have the same meanings as above and X is a re- ~
active group, or, if Rl and R2 are lower alkyl radicals, with a r :
mixture of an appropriate aliphatic ketone of formula RlCOR2, chloro-.
form and an alkali metal hydroxide, whereafter the substituent Z is
then, if desired, converted into a different substituent Z after
the condensation reaction and when Z in the product obtained is
a hydroxyl group compound (I) obtained is converted with a non- .
toxic inorganic or organic base, if desired, into a pharma-
ceutically acceptable, pharmacologically compatible salt. ;
The process according to the present invention is
preferably carried out in two stages. A first stage comprises ;
the condensation of a compound of formula (II) with a reactive
derivative of a naphthoic acid of formula (III), or with a
compound of formula (IV), followed by a second stage comprising
a reaction of the condensation product with the third component
(III) or (IV)as the case may be.
- 2 - .
, .
~ 3~0ti
The condensation of (II) and (III) is preferably
carried out by first blocking the phenolic hydroxyl group in
the compound (II) with a protective group which is easy to
remove, the protected amine obtained is then reacted with the
reactive derivative of the naphthoic acid of formula (III);
the protective group on the phenolic hydroxyl is split off and
the thus obtained reactive intermediate is reacted with the
compound of formula (IV).
In the case where the first stage ccmprises condensa-
tion of an amine of formula (II) with a compound of formula (IV?,the condensation is preferably carried out by first blocking the
amino group in the amine of formula (II) with a protective group
which i5 easy to remove, the protected amine obtained is then
reacted with the compound of formula (IV); the protective group
on the amine group is s~lit off and the thus obtained reactive
intermediate is reacted with the reactive derivative of the ~-
naphthoic acid of formula (III).
The reactive derivatives of the naphthoic acid of
formula (III) are, in particular, the halides, for example, i`-~
the fluoride, chloride, bromide or iodide, the anhydrides, the
mixed naphthoic acid-carbonic acid anhydrides and the imidazolides. -
~~hese can be reacted, for example, under the conditions of the
, .
Schotten-Baumann reaction, i.e. with the addition of a tertiary
amine, for example, pyridine, dimethylaniline or triethylamine,
with the compound of formula (II) in an inert solvent, for
example, tetrahydrofuran or dioxan, or in an excess of the
tertiary amine. A previous blocking of the phenolic hydroxyl
group in the compound of formula (II) by esterification is also
preferred but etherification with a compound of formula (IV) is
especially preferred.
The compound of formula (II) may also be employed in the
form of its acid addition salt.
~ . .... .
.' , '.
o~
On the other hand, a reactive derivative o~ a compound
(II) can also be reacted with a naphthoic acid. Reactive
derivatives of compounds (II) include, for example, the phos-
phorazoamides, which are formed in situ when a phosphorus
trihalide, for example phosphorus trichloride, is added to a
solution of a compound (II) protected on a hydroxyl group. A
tertiary amine, for example pyridine, can be used simultaneously
as acid-binding agent and solvent. If this reaction is carried
out in the presence of a naphthoic acid, then the desired amides
with protected hydroxyl function are obtained directly.
For a primary reaction of a compound (II) with a
compound (IV), it has proved to be advantageous first to convert
the amino group of the compound (II) into a protected group, for
example a phthalimide group, which, after the reaction, can
easily be split off again, for example with hydrazine or hydroxyl-
amine. However, other groups known from peptide chemistry can
also be introduced for the protection of the amine group. For
example, a formyl or acetyl radical, which, after the reaction,
can easily be split off again with a strong base, for example,
sodium hydroxide or potassium hydroxide.
The reactive group X is a leaving group in an Sn
substitution nucleophilic reaction, displaceable by a hydroxyl
group.
Reactive compounds ~V) are, in particular, those in
which X is the anion of a strong acid, for example of a hydro-
halic acid, e.g. hydrofluoric, hydrochloric, hydrobromic and
hydroiodic or sulphonic acid. The reaction càn be promoted by
converting the phenolic hydroxyl group of the compound (II) into
a phenolate, for example, by reaction with a sodium alcoholate. -
The reaction of the two components (II) and (IV) is suitably
.,, -i,
`' carried out in a solvent, for example, in toluene, a xylene,
methyl ethyl ketone or dimethyl formamide, prefQrably at an
elevated temperature.
~o~o~ .
I~ Rl and R2 signify lower alkyl radicals, then,
instead of the compounds (IV) there can also be used a mixture
of an appropriate ketone, chloroform and an alkali metal
hydroxide, for example, sodium hydroxide or potassium hydroxide.
This reaction is preferably carried out with compound (II)
naphthoylated on the amine group, using acetone as the aliphatic
ketone (cf. Gazz. Chim. ital., 77. 431/1947).
When, subsequent to the condensation reaction, it is
desired to carry out a conversion of the substituent Z, this -
can take place, for example, by hydrolysis of a carboxylic acid
ester (Z = alkoxy) to give the corresponding carboxylic acid
(Z = hydroxyl), using a mineral acid or alkali metal hydroxide in
a polar solvent, for example, water, methanol, ethanol, dioxane
or acetone. The hydrolysis is preferably carried out with a
strong base, for example, sodium or potassium hydroxide, in a
Inixture of methanol and water at ambient temperature or at a
moderately elevated temperature. On the other hand, however, a
carboxylic acid can be esterified in krDwn manner or an ester
with a particular radical Z can be converted into an ester with a
different radical Z by transesterification. The esterification
of the carboxylic acids is preferably carried out in the presence
of an acidic catalyst, for example hydrochloric acid, sulphuric
acid, P-toluene-sulphonic acid or a strongly acidic ion exchange
re~in. Transesterifications, on the other hand, require the
addition of a small amount of a basic substance, for example
of an alkali or alkaline earth metal hydroxide or of an alkali
metal alcoholate.
For the preparation of salts with pharmacologically
compatible organic or inorganic bases, the carboxylic acids of
formula (I) are reacted with appropriate bases, for example -
sodium hydroxide, potassium hydroxide, calcium hydroxide, --
ammonium hydroxide, methyl-glucamine, morpholine or ethanol-
. .
- 5 - ~ ~
~0~3~
amine. Mixtures of carboxylic acids with an appropriate
alkali metal carbonate or bicarbonate can also be considered.
In the specification, it will be understood that the
qualification that the salts are "pharmaceutically acceptable"
means that the salts have the necessary physical characteristics,
for example, stability, to render them suitable for formulation
into pharmaceutical compositions. The qualification that
the salts be "pharmacologically compatible`' is to be understood
as extending to salts of the carboxylic acids of formula (I)
with non-toxic inorganic or organic bases which have no adverse
effects to the extent that such salts would be unsuitable for
administration to living bodies.
Salts of acids of formula (I) which are not
pharmaceutically acceptable and pharmacologically compatible
form a useful aspect of the invention of the novel derivatives,
inasmuch as they can be readily converted to different salts
having the required physical and chemical characteristics to
make them suitable for administration in pharmaceutical com-
positions to living bodies.
; 20 For the preparation of pharmaceutical compositions,
at least one of the new derivatives (I) is mixed with a solid
or liquid pharmaceutical carrier or diluent and optionally with
an odoriferous, flavouring and/or colouring material and formed,
for example, into tablets or dragees, or with the addition of
appropriate adjuvants, suspended or dissolved in water or in an c ;
oil, for example, olive oil.
The derivatives (I) can be administered orally or
parenterally in liquid or solid form. As injection medium, it
is preferred to use water which contains the stabilizing agents,
solubilizing agents and/ or buffers, conventional for injection
solutions. Additives of this type include, for example,
tartrate and borate buffers, ethanol, dimethyl sulphoxide,
-- 6 --
. .
. .
1~431~~ ~ :
complex-forming agents (for example, ethylene diamine-tetraacetic
acid), high molecular weight polymers (for example, liquid poly-
ethylene oxide) for viscosity regulation or polyoxyethylene
derivatives of sorbitan anhydrides.
Solid carrier materials include, for example, starch,
lactose, mannitol, methyl cellulose, talc, highly dispersed -
silicic acid, high molecular weight fatty acids (such as stearic ,~
acid), gelatine, agar-agar, calcium phosphate, magnesium stearate,
animal and vegetable fats and solid high molecular weight polymers
(such as polyethylene glycols). Compos~itions suitable for oral
administration can, if desired, contain flavouring and sweetening
agents. For topical application, the com~ounds (I) according to
the present invention can also be employed in the form of powders
and salves. For this purpose, they are mixed with, for example,
powdered, physiologically compatible diluents or with conventional
salve bases.
The derivativesof the invention will generally be
-~ administered in daily dosages of 1.5 to 2g. and are preferably -
administered in dosage units of 250 or 500 mg. However, the
regular dosage will depend on the particular condition being ;
treated as will be clearly understood.
Having thus generally described the invention, reference
will now be made to the following examples, which will be
understood to represent preferred embodiments thereof. Variations
of these examples, such as different starting materials, will
produce different final products.
,
Example 1 -
Ethyl 2-~4-r2-(naPhth-l-YlcarbonYlamino)-ethyll-phenoxy~ -
2-methyl-propionate.
12.0 g. (63mMol) l-naphthoyl chloride are added dropwise,
with stirring and at 5 - 10C., to a solution of 15.2 g. (60 mMol)
7 _
~43~~ ~
ethyl 2- ~4-( 2-aminoethyl)-phenoxy~-2-methyl~propionate in 120 ml.
anhydrous pyridine in a cooling bath. The cooling bath used is ;
then removed and the reaction mixture stirred for a further 30
minutes for completion of the reaction at ambient temperature.
The reaction mixture is then poured onto ice, acidified with 120
ml. concentrated hydrochloric acid and the oil which separates is
taken up in ether. The ethereal solution is washed twice with
0.5N hydrochloric acid and twice with an aqueous solution of
sodium bicarbonate, whereafter it is dried and evaporated. Since
10 the product is obtained in the form of an oil, it is purified by
chromatography on silica gel in a mixture of toluene and chloro-
form. (In the following Examples, this type of purification is
not necessary). There are obtained 23.6 g. (97% of theory) ethyl
2-~4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy~-2-methyl-
propionate in the form of a colourless oil.
The following compounds are prepared in an analogous
manner:
a) Ethyl 4-(naphth-1-ylcarbonYlaminomethYl)-phenoxY-acetate
from l-naphthoyl chloride and ethyl 4-aminomethylphenoxy-
20 acetate hydrochloride; yield 76% of theory, m.p. 125 - 125.5C.,
after recrystallization from isopropanol;
b) EthYl 2-r4-(naphth-1-ylcarbonylaminomethyl)-phenoxyl-
2-methyl-propionate
from l-naphthoyl chloride and ethyl 2-(4-aminomethylphenoxy)-
2-methyl-propionate, quantitative yield, m.p. 79 - 81C., after
recrystallization from ethyl acetate-ligroin,
; c) EthYl-4- r 2-(naphth-1-ylcarbonylamino)-ethyll-phenoxy-
acetate
` from l-naphthoyl chloride and ethyl 4-(2-aminoethyl)-
30 phenoxyacetate hydrochloride; yield 69% of theory; m.p. 93 - 95C.;
;.
;., :
_ 8 -
` ::
. ~ . ,.
i~)43~0~ ~
d) Ethyl 2- ~ 2-(naphth-2-ylcarbonylamino)-eth
phenoxy~-2-methyl-propionate
from 2-naphthoyl chloride and ethyl 2-[4-(2-aminoethyl)-
phenoxy]-2-methyl-propionate, yield 77% of theory, m.p. 69 - 70 &.,
after recrystallization from cyclohexane,
e) Ethvl 4-r2-(naphth-2-ylcarbonylamino)-ethyll-phenoxy-
acetate
from ethyl 4-(2-aminoethyl)-phenoxyacetate and 2-naphthoyl
chloride, yield 76% of theory; m.p. 130 - 131 &., after
recrystallization from ethanol.
Example 2
Ethy~ 4-¦2-(naphth-2-ylcarbonylamino)-ethyll-phenoxy-
acetate ;
a) N.C-Bis-(2-naphthoyl)-tyramine
A solution of 19.2 g. (0.14 mole) tyramine in 500 ml.
anhydrous pyridine is mixed with 53.4 g. (0.28 mole) 2-naphthoyl
chloride, heated for about 15 minutes to 80 - 90C., while "- - ~
stirring and cooled somewhat, whereafter the reaction mixture ~'
is poured into 4 litres ice water. A fine crystalline precipitate
is thereby obtained immediately. After filtering off with suction
and drying, there are obtained 62.0 g. (yield practically quanti-
tative) of N,O-bls-(2-naphthoyl)-tyramine. Recrystallization
from dimethyl formamide gives a pure product with a melting point
of 205 - 206C.
b) N-(2-Naphthoyl)-tyramine
A mixture of 50 g. (0.112 mole) N~o-bis-(2-naphthoyl)-
tyramine, 1 litre methanol and 250 ml. (0.25 g. equivalents) lN
aqueous potassium hydroxide solution is stirred for 6 hours at :
40 - 50C. Subsequently, the reaction mixture is mixed with 250 ml.
(0.25 g. equivalents) lN hydrochloric acid. The yellowish pre-
cipitate which separates out is filtered off with suction and then ;
washed free of acid with an aqueous solution of sodium bicarbonate.
,: ' :.
_ g- ' ; '':
104~
After further washin~ with water, s~ction filtration and drying,
the product is recrystallized from methanol. There are obtained
21.6 g. (66% of theory) ~-(2-naphthoyl)-tyramine; m.p.
166 - 167C.
c) Ethyl 4- r 2-(naphth-2-ylcarbonylamino)-ethyll-phenoxy-
acetate.
A muxture of 27.1 g. (93 mMol) N-(2-naphthoyl)-
tyramine, 18.6 g. (0.135 mole) pulverised anhydrous potassium
carbonate and 300 ml. butan-2-one is stirred for 2 hours at
reflux temperature. Subsequently, 22.6 g. (0.135 mole) ethyl ~;
bromoacetate are added thereto and the reaction mixture maintained
at reflux temperature for 4 hours. After removing the inorganic
material by suction filtration, the liquid phase is evaporated.
The crystalline residue is washed several times with warm ether
and then dried. There are obtained 29.1 g. (83% of theory)
ethyl 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetate;
m.p. 131 - 132C. The product is identical with that of Example
1 e).
Exam~le 3
Ethyl 4-(naphth-2-ylcarbonylaminomethYl)-phenoxy-acetate.
a) 4-(2-Naphthoylaminomethyl)-phenyl-2-naphthoate i5
prepared, analogously to Example 2 a), from 2 mole 2-naphthoyl
chloride and 1 mole ~-hydroxybenzylamine hydrochloride in
pyridine, yield 96% of theory, m.p. 205 - 206C., after
recrystallization from dimethyl formamide.
b) 4-(Naphth-2-ylcarbonylaminomethyl)-phenol is prepared, -~ -
analogously to Example 2 b), from 4-(2-naphthoyl-aminomethyl)-
- phenyl 2-naphthoate by alkaline hydrolysis in methanol; yield
97% of theory; m.p. 142 - 143C., after recrystallization from
methanol.
; ~:
' ~ ,
-' ~
~ .... .. ... ; . . .. ... . . . .. . . . -. :.... ... . ~
~04380~
c) Ethyl 4-(naphth-2-ylcarbonylaminomethyl)-phenoxy-acetate is
prepared, analogously to Example 2 c), from 4-(na~*h-2-ylcarhonyl-
aminomethyl)-phenol and ethyl bromo-acetate, yield 95% of theory
m.p. 107C., after recrystallization from isopropanol.
Example 4
Ethyl 2-r4-(naphth-2-ylcarbonvlaminomethyl)-phenoxyl-
2-methyl-propionate.
A mixture of 30.5 g. (0.11 mole) 4-(naphth-2-yl-
carbonylaminomethyl)-phenol (cf. Example 3 b)), 22.8 g. (0.165 mol)
pulverised anhydrous potassium carbonate and 250 ml. butan-2-one
is heated, while stirring, for 2 hours at reflux temperature, then ~-
32.2 g. (0.165 mol) ethyl ~-bromoisobutyrate are added, as well as
a spatula tip of potassium iodide, whereafter the reaction mixture
is maintained under reflux for 24 hours. After a further addition
of 19.5 g. (0.1 mol) ethyl ~-bromoisobutyrate and 13.8 g. (0.1 mol)
potassium carbonate, the reaction mixture was heated under reflux
for a further 48 hours, while stirring. Subsequently, the
reaction mixture is filtered with suction, the liquid phase is
evaporated and the evaporation residue is taken up in chloroform.
The chloroform phase is extracted with 2~ aqueous sodium hydroxide
solution, washed until neutral, dried over anhydrous calcium
chloride and finally the chloroform is evaporated off. The
evaporation residue is recrystallized from a little ethanol.
There are obtained 25.7 g. ( 60yo of theory) ethyl 2-[4-(naphth-2- ~
ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate, m.p. 71 - 72C. ~,
. .
Example 5.
2-~4-r2-(Naphth-l-Ylcarbonylamino)-ethyll-phenoxy~ - 2-methyl-
propionic acid.
.
A solution of 9.7 g. (24 mMol) ethyl 2-~4-[2-(naphth-1-
ylcarbonylamino)-ethyl]-phenoxy ~ 2-methyl-propionate in a mixture
of 200 ml. methanol and 40 ml. lN aqueous potassium hydroxide
- 11 - "
,. ., ~
"~
~O~ D~ -
solution is heated to 50C. for 2 hours and then evaporated to
dryness in a vacuum. The residue is taken up in water, washed
twice with ether and the aqueous phase acidified. The precipitate
obtained is taken up in chloroform, the solution is dried over
anhydrous sodium sulphate and the chloroform is distilled off.
The residue is recrystallized from a mixture of ethyl acetate
and ligroin. There are obtained 6.9 g. ( 76% of theory) 2-~4-[Z-
(naphth-l-ylcarbonylamino)-eth~l]-phenoxy3-2-methyl-propionic
acid, m.p. 158 - 160&o
The following compounds are obtained in an analogous
manner:
a) 4_(~aphth-1-Ylcarbon~laminomethY~ ~henoxY-acetic acid
from ethyl 4-tnaphth-l-ylcarbonylaminomethyl)-phen
acetate; yield 75% of theory, m.p. 185 - 188&.,
b) 2-r4-(~aphth-1-ylcarbonylaminomethyl~-phenoxy1-2-
methyl-propionic acid ~ -
from ethyl 2-[4-(naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-
methyl-propionate; yield 84% of theory; m.p. 157 - 159.5 &.,
after recrystallization from isopropanol;
c) 4-r2-(Na~hth-l-ylcarbonvlamino)-ethyll-phenoxy-
acetic acid
~ from ethyl 4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy-
; acetate; yield 66% of theory; m.p. 143 - 145C., after re-
crystallization from isopropanol-water.
Example 6
: 4-(Naphth-2-ylcarbonylaminomethYl)-phenox~-acetic acid
,.
180 ml. (0.18 g. equivalents) 1~ aqueous potassium
hydroxide solution are added dropwise to a suspension of 29.0 g.
- (80 mMol) ethyl 4-(naphth-2-ylcarbonylaminomethyl)-phenoxyacetate -
in 400 ml. ethanol. Subsequently, the reaction mixture is stirred
for 2 hours at 40 - 50C. After standing o~ernight, about 250 ml.
2N hydrochloric acid are added to the slurry-like mass, together
with sufficient dimethyl formamide to give a clear solution -
- 12 _
~04~80t~ :
upon heating. After cooling, the pure acid crystallizes out. -~
There are obtained 25 g. (93% of theory) 4-(naphth-Z-ylcarbonyl-
aminomethyl)-phenoxy-acetic acid; m.p. 166 - 167C,
The following compound is prepared in an analogous
manner:
4-r2-(naphth-2-ylcarbonylamino)-ethyll-phenoxy-acetic acid
from the corresponding ethyl ester: yield 9~/O of theory, m.p.
173 - 174 &., after recrystallization ~rom dimethyl formamide.
Example 7
2-~4-r2-(Na~hth-2-ylcar~onylamino)-ethyll-phenoxy~-2-methyl-
propionic acid.
Variant I:
100 g. (1.78 mol) pulverized potassium hydroxide are
added to a suspension of 61 g. (0.21 mol) ~-(2-naphthoyl)-
tyramine in 700 ml. anhydrous acetone. Subsequently,112 g.
(0.95 mol) chloroform are slowly added dropwise at such a rate
that the reaction mixture boils gently. The reaction mixture is
further stirred for 2 hours, then poured into water and acidified
with hydrochloric acid. Subsequently, it is extracted with chloro-
form, the chloroform phase is extracted with an aqueous solution -
of sodium bicarbonate and finally the desired acid is precipitated
out of the bicarbonate solution by acidification. After
.
recrystallization from acetone, there are obtained 48 g. (61% of
theory) 2-~4-~2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-
methyl-propionic acid, m.p. 187 - 188C;~
Variant II: -
60 ml. (60 milliequivalents) lN aqueous potassium
hydroxide solution are added to a solution of 10.15 g. (25 mMol) ;
ethyl 2-{4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy~-2-methyl-
propionate in 100 ml. ethanol, whereafter the reaction mixture is
stirred for 2 hours at 40 - 50 &. and then 60 ml. (60 milli-
equivalents) lN hydrochloric acid are added thereto dropwise.
- 13 -
: ~ ': ..
.~ ` .:.. . .
. . . . .. .: - - -
~4;~l~0~ :
A fine crystalline precipitate thereby separates out, which is
filtered off with suction and washed with water. ~fter
recrystallization from acetone, there are obtained 8.5 g. (90%
of theory) 2-~4- r 2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-
methyl-propionic acid, m.p. 188 - 189C.
The following compound is obtained in an analogous
manner:
2-r4-(naphth-2-ylcarbonylaminomethyl)-phenoxyl-2-methyl-
proplonlc acld
from the corresponding ethyl ester, yield 74% of theory, m.p.
136 - 137 &., after recrystallization from acetone.
- 14 -
