CA1043806A

CA1043806A - Phenoxy-alkyl-carboxylic acid derivatives

Info

Publication number: CA1043806A
Application number: CA218,899A
Authority: CA
Inventors: Hans P. Wolff; Ernst-Christian Witte; Kurt Stach; Harald Stork; Felix H. Schmidt
Original assignee: Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1974-02-06
Filing date: 1975-01-29
Publication date: 1978-12-05
Also published as: ES434446A1; ATA85775A; AR203228A1; BE825176A; DD120015A5; FR2259597A1; ZA75703B; JPS50108249A; IE40585B1; AU7701874A; IL46543A0; GB1449586A; FI750292A; SE7501083L; DK36575A; SU674670A3; IE40585L; NL7501220A; AT335439B; DE2405622A1

Abstract

ABSTRACT OF THE DISCLOSURE
New phenoxyalkyl-carboxylic acid derivatives and their process of prepar?tion are provided of the formula

Description

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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.

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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 - ~ ~

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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, . .
. .

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.

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~ .... .. ... ; . . .. ... . . . .. . . . -. :.... ... . ~

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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.

: ~ ': ..
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. . . . .. .: - - -~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.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of phenoxyalkyl-carboxylic acid derivatives of the formula (I):-(I) and pharmaceutically acceptable, pharmacologically compatible salts thereof, in which R1 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, wherein a hydroxyamino compound of the formula (II):- (II) in which n is as defined above, or a reactive derivative thereof, is reacted with a naphthoic acid of the formula (III):- (III) or a reactive derivative thereof, and with a compound of the formula (IV):- (IV) in which R1, R2 and Z are as defined above and X is a halogen or sulphonic acid ester group or, when R1 and R2 are lower alkyl radicals, with a mixture of an appropriate aliphatic ketone, of formula R1-CO-R2 , chloroform and an alkali metal hydroxide, and, when desired, recovering a derivative of formula (I) in which Z
is a hydroxyl group in the form of a pharmaceutically acceptable, pharmacologically compatible salt of a non-toxic inorganic or organic base.

2. Process according to claim 1, wherein the amino or hydroxyl groups in the hydroxyamino compound of formula (II) is blocked by a protective group and, after a first stage of the reaction, said protective group is removed, whereafter the second stage of the reaction is carried out.

3. A process according to claim 2, wherein the phenolic hydroxylgroup of said compound of formula (II) is blocked by a protective group and the resulting protected compound is reacted with a reactive derivative of said naphthoic acid of formula (III), and subsequently said protective group is removed and the resulting compound is reacted with said compound of formula (IV).

4. A process according to claim 1, wherein a reactive derivative of said compound of formula (II), of which the hydroxyl group is blocked by a protective group, is reacted with said naphthoic acid of formula (III), after which the protective group is removed and the resulting product is reacted with said compound of formula (IV).

5. A process according to claim 1, wherein a compound of formula (II), wherein the amino group is blocked by a protective group is reacted with a compound of formula (IV), after which said protective group is removed and the resulting product is reacted with a reactive derivative of said naphthoic acid of formula (III).

6. Process according to claim 1, wherein the substituent Z in the product obtained is subsequently converted into a different substituent Z, comprising i) hydrolyzing an ester of formula (I), in which Z is lower alkoxy, to produce the corresponding acid, or ii) esterifying an acid of formula (I), in which Z is hydroxyl, to produce a corresponding ester in which Z is lower alkoxy, or iii) transesterifying an ester of formula (I), in which Z
is lower alkoxy, to produce a corresponding different ester in which Z is lower alkoxy.

7. A process according to claim 1, wherein Z in the product of formula (I) is a hydroxyl group, including the step of reacting said compound of formula (I) with a non-toxic inorganic or organic base to produce a pharmaceutically accept-able, pharmacologically compatible salt.

8. A process according to claim 1, wherein the compound of formula (II) in which the phenolic hydroxyl group is blocked by a protective group is reacted with a reactive derivative of naphthoic acid of formula (III) selected from a halide, anhydride, mixed naphthoic acid-carbonic acid anhydride and imidazolide.

9. A process according to claim 1, wherein said compound of formula (II) is reacted with a reactive derivative of said naphthoic acid of formula (III) in an inert solvent.

10. A process according to claim 1, wherein said compound of formula (II) is reacted with said compound of formula (IV) in a solvent at an elevated temperature.

11. A process according to claim 1, wherein said compound of formula (II) or a reactive derivative thereof is reacted with said naphthoic acid of formula (III) or a reactive derivative thereof and with a mixture of said aliphatic ketone, chloroform and an alkali metal hydroxide.

12. A process according to claim 1 for preparing ethyl 2-{
4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionate comprising reacting 1-naphthoyl chloride with ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methyl-propionate.

13. A process according to claim 1 for preparing ethyl 4-(naphth-1-ylcarbonylaminomethyl)-phenoxy-acetate comprising reacting 1-naphthoyl chloride with ethyl 4-aminomethylphenoxy-acetate hydrochloride.

14. A process according to claim 1 for preparing ethyl 2-[4-(naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate comprising reacting 1-naphthoyl chloride with ethyl 2-(4-aminomethylphenoxy)-2-methyl-propionate.

15. A process according to claim 1 for preparing ethyl 4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy-acetate comprising reacting 1-naphthoyl chloride with ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride.

16. A process according to claim 1 for preparing ethyl 2-{4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionate comprising reacting 2-naphthoyl chloride with ethyl 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionate.

17. A process according to claim 1 for preparing ethyl 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetate comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate with 2-naphthoyl chloride.

18. A process according to claim 1 for preparing ethyl 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetate wherein said compound of formula (II) is tyramine and is reacted with naphthoyl chloride and said compound of formula (IV) is ethyl bromo acetate.

19. A process according to claim 1 for preparing ethyl 4-(naphth-2-ylcarbonylaminomethyl)-phenoxy-acetate wherein said compound of formula (II) is p-hydroxybenzylamine hydrochloride and is reacted with naphthoyl chloride and said compound of formula (IV) is ethyl bromoacetate.

20. A process according to claim 1 for preparing ethyl 2-[4-(naphth-2-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate wherein there is first formed 4-(naphth-2-yl-carbonylaminomethyl)-phenol which is reacted with ethyl .alpha.-bromo-isobutyrate.

21. A process according to claim 6 for preparing 2- {4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionic acid comprising hydrolyzing ethyl 2-{4-[2-(naphth-1-ylcarbonyl-amino)-ethyl]-phenoxy}-2-methyl-propionate.

22, A process according to claim 6 for preparing 4-(naphth-1-ylcarbonylaminomethyl)-phenoxy-acetic acid comprising hydrolyzing ethyl 4-(naphth-1-ylcarbonylaminomethyl)-phenoxy-acetate.

23. A process according to claim 6 for preparing 2-[4-(naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionic acid comprising hydrolyzing ethyl 2-[4-(naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate.

24. A process according to claim 6 for preparing 4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy-acetic acid comprising hydrolyzing ethyl 4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy-acetate.

25. A process according to claim 6 for preparing 4-(naphth-2-ylcarbonylaminomethyl)-phenoxy-acetic acid comprising hydrolyz-ing ethyl 4-(naphth-2-ylcarbonylaminomethyl)-phenoxyacetate.

26. A process according to claim 6 for preparing 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetic acid comprising hydrolyzing ethyl 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetate.

27. A process according to claim 11 for preparing 2-{4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionic acid comprising reacting N-(2-naphthoyl)-tyramine with acetone and chloroform.

28. A process according to claim 6 for preparing 2-{4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy} -2-methyl-propionic acid comprising hydrolyzing ethyl 2-{4-[2-(naphth-2-ylcarbonyl-amino)-ethyl]-phenoxy}-2-methyl-propionate.

29. A proces according to claim 6 for preparing 2-[4-(naphth-2-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionic acid comprising hydrolyzing ethyl 2-[4-(naphth-2-ylcarbonylaminomethyl)-phenoxy]-2-methyl propionate.

30. Phenoxyalkyl-carboxylic acid derivatives of the formula (I):-(I) and pharmaceutically acceptable, pharmacologically compatible salts thereof, wherein R1 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;
whenever prepared by the process of claim 1, 3 or 5, or by an obvious chemical equivalent.

31. Ethyl 2-{4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionate, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.

32, Ethyl 4-(naphth-1-ylcarbonylaminomethyl)-phenoxy-acetate, whenever prepared by the process of claim 13, or by an obvious chemical equivalent.

33. Ethyl 2-[4-(naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.

34. Ethyl 4-[2-(naphth-1-ylcarbonylamino)-ethyl]-phenoxy-acetate, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.

35. Ethyl 2-{4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionate, whenever prepared by the process of claim 16, or by an obvious chemical equivalent.

36. Ethyl 4-[2-(naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetate, whenever prepared by the process of claim 17 or 18, or by an obvious chemical equivalent.

37. Ethyl 4-(naphth-2-ylcarbonylaminomethyl)-phenoxy-acetate, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.

38. Ethyl 2-[4-(naphth-2-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionate, whenever prepared by the process of claim 20, or by an obvious chemical equivalent.

39. 2-{4-[2-(Naphth-1-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionic acid, whenever prepared by the process of claim 21, or by an obvious chemical equivalent.

40. 4-(Naphth-1-ylcarbonylaminomethyl)-phenoxy-acetic acid, whenever prepared by the process of claim 22, or by an obvious chemical equivalent.

41. 2-[4-(Naphth-1-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionic acid, whenever prepar ed by the process of claim 23, or by an obvious chemical equivalent.

42. 4-[2-(Naphth-1-ylcarbonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 24, or by an obvious chemical equivalent.

43. 4-(Naphth-2-ylcarbonylaminomethyl)-phenoxy-acetic acid, whenever prepared by the process of claim 25, or by an obvious chemical equivalent.

44. 4-[2-(Naphth-2-ylcarbonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 26, or by an obvious chemical equivalent.

45. 2-{4-[2-(Naphth-2-ylcarbonylamino)-ethyl]-phenoxy}-2-methyl-propionic acid, whenever prepared by the process of claim 27 or 28, or by an obvious chemical equivalent.

46. 2-[4-(Naphth-2-ylcarbonylaminomethyl)-phenoxy]-2-methyl-propionic acid, whenever prepared by the process of claim 29, or by an obvious chemical equivalent.

47. A pharmaceutically acceptable, pharmacologically compatible salt of a compound of formula (I) as defined in claim 7, whenever prepared by the process of claim 7 or by an obvious chemical equivalent.

48. A process according to claim 2, wherein said hydroxyamino compound of formula (II) is reacted with a reactive derivative of said naphthoic acid of formula (III);
a protective blocking group on the phenolic hydroxyl group of said hydroxyamino compound being formed in situ by said derivative of naphthoic acid.