DE2348956A1 - NEW ESTERS OF ACETYLATED PHENOLIC ACIDS - Google Patents

Description

24 367 n / wa

SYNTHELABO, PARIS / PRANCIA

New esters of acetylated phenolic acids

The invention relates to new esters of acetylated phenolic acids and to processes for their preparation these compounds and drugs that contain them as active ingredients.

These compounds have the formula

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CH ₃ CO-O-

COOR

0-CO-CH-

(D

one of the -OCOCH- ^ - groups is always in the 2 <r position of the Benzene nucleus, the second any of the 3, ^ - * May occupy 5- or 6-positions of the same nucleus and R represents a substituted alkyl radical -CH-A.

η is an integer from 1 to 5, the alkylene chain C Hp _{n can be} straight-chain or branched and

A represents - an alkoxycarbonyl radical-COOR ,, where R, a straight or branched alkyl group with 1 to 6 carbon atoms,

- or a carbamoyl radical-CO-:

wherein the symbols Rp and R., are identical or are different and each is a hydrogen atom, a straight-chain or branched alkyl group has 1 to 3 carbon atoms means, or

^U 2

-n:

a nitrogen-containing heterocycle residue

with 5 to 7 chain links denotes which optionally has one or more further heteroatoms contains like 0, S or N ',

or a cyano residue,

or an acyl radical-COR ,, where R, the above has given meaning,

or a hydroxy or polyhydroxy alkyl radical with straight or branched chain having 1 to 5 carbon atoms represents wherein one or more hydroxyl radicals through a straight-chain or branched alkyl radical with 1 to 5 carbon atoms can be etherified, or in which 2 of them may be etherified with cyclization to give the group -CH- (CHp) -CH, in which

C- .0

m is 0, 1 or 2 and Z is a straight-chain or branched alkylene chain with Represents 1 to 5 carbon atoms.

The compounds according to the invention are particularly useful as medicaments in human and veterinary therapy as inhibitors of thrombocytic aggregation, useful.

According to the invention, the compounds are prepared in two stages in any order: the acetylated two phenol groups and esterifies the acid group one

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Dihydroxybenzenic acid.

For the esterification of dihydroxy or diacetoxybenzoic acid one puts either the acid or one of its salts, preferably the sodium or potassium salt, with a halogenated Derivative RX in which R has the meaning given above and X is a halogen, or one sets the acid or one of its functional derivatives, in particular the chloride with a compound ROH.

If the compound "I contains two free hydroxyl groups, it can be carried out starting from a corresponding derivative which contains a -CH- (CH ₂ ) -CH group

C) 0

Gain hydrolysis in an acidic environment at a temperature of 50 to 100 ° C.

The reaction between the compound RX and the metal salt of the acid is preferably carried out at a temperature of 60 to 130 ^° C. in an apolar solvent such as dimethylformamide. When using the acid itself, the reaction is effected in the presence of a tertiary base, such as triethylamine, which acts as a solvent and acceptor of the hydrohalic acid formed. If a fractional derivative of the acid is reacted with a derivative ROH, the reaction is preferably carried out in the cold in the presence of a tertiary base which acts as an acceptor for the hydrohalic acid. The acetylation can be carried out by treatment with acetic anhydride in the presence of a tertiary base such as pyridine.

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The invention is illustrated by the following non-limiting examples.

example 1

Diacetoxy-2,5 benzoic acid (oxo-2 propyl) ester (I CO-CH ₃ ; Code No. SL-72.422)

0.1 mol of dihydroxy-2,5 benzoic acid potassium salt (potassium gentisate) are dissolved in 100 ml of dimethylformamide. One adds 0.1 mole of monochloroacetic acetone and heated under agitation for 20 minutes on the oil bath at 100 ⁰ C. After cooling, the solvent was sells under reduced pressure at water bath temperature. The intermediate ester is obtained in the form of an oil, which is then treated with a mixture of 60 ml of pyridine and 30 ml of acetic anhydride. This solution is placed in an oil bath at 100 to 110 ° C. and stirred for 20 minutes.

The solvents and the excess reactants are driven off on a water bath under reduced pressure. This gives a solidifying oil which is recrystallized from toluene. The compound melts at 82 °. The overall yield is 50 %.

Analysis: C ₁ ^ H ₁₄ O, _r (M .G. = 294) H 4th 80 Calculates % i C. 57 .20 4th 76 Found % i 57 .12

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Example 2

Diaetoxy-2,4-benzoic acid (oxo-2 propyl) ester (R = -CEU - CO-CH ₃ ) code no. SL-72.673)

To a solution of 0.1 mol of dihydroxy-2,4-benzoic acid potassium salt 0.1 mol of chloroacetone are added to 80 ml of dimethylformamide and the mixture is stirred for 15 minutes heated to 100 ° C. It is cooled and then the solvent is driven off on a water bath under reduced pressure.

The oily dihydroxy-2,4 benzoic acid (oxo-2 propyl) ester is dissolved in 80 ml of pyridine and 30 ml of acetic anhydride. It is heated again to 100 to 110 ° in an oil bath for about 20 minutes. The solvents and the excess reactants are driven off on a water bath under reduced pressure and the oily residue is recrystallized. Yield 61 %. Melting point 91 °.

Analysis: C-57. 20th Calculates % \ 57. 31 Found <? O \ Example 3

H 4.80 4.93

Diacetoxy-2,3-benzoic acid (oxo-2 propyl) ester (R = -C CO-CH ₃ ) code no. SL-72.674

The connection is applied according to the above

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Methodology established (Examples 1 and 2). Yield Kj>

Melting point 120 °. C 57. 20th Analysis: 57, 49 Calculated %: Found $ t Example 4

H 4.80

Diacetoxy-2,5 benzoic acid (carbamoyl-methyl) ester (R = -CH g-

0 C) Code no. SL-72.424

0.1 mol of chloroacetamide and 100 ml of triethylamine are added to 0.1 mol of gentisic acid. The mixture is stirred for 1 hour 30 minutes in an oil bath at 100 ^° C. After cooling, the triethylamine is decanted from the light yellow cake formed and the last traces of the solvent are driven off under reduced pressure. The solid part is taken up with 100 ml of water under a nitrogen atmosphere and with stirring. It is left to stand for 12 hours and a precipitate is obtained, which is filtered off and recrystallized from methyl ethyl ketone. The intermediate ester melts at 184 ° C.

This ester is acetylated in a manner similar to that described in Example 1. The final product melts at 120 ⁰ C. Its purification is carried out by washing with water and then with petroleum ether. Recrystallization is unnecessary. The total yield is 45 fo.

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Example 5

Analysis;

Calculated % \ C 52.93 H 4.44 N 4.75 O 37.96

Found % \ 52.76 4.47 4.83 37.88

Diacetoxy-2,4 benzoic acid (carbamoyl-methyl) ester (R = -CKU -

) Code no. SL-72.675

0.1 mol of dihydroxy-2,4-benzoic acid is dissolved in 150 ml of triethylamine and 0.1 mol of chloroacetamide is added. The mixture is heated with stirring for 2 hours in the oil bath at 100 ⁰ C. It is cooled, the triethylamine is evaporated on a water bath under reduced pressure, the oily residue is treated with water until Kristallis ation, filtered, washed with water and recrystallized.

Dissolving the thus obtained (2,4-Dihydroxy-benzoyloxy) -lacetamid in a mixture of 50 ml of pyridine and 30 ml of acetic acid · anhydride, and this mixture is heated while J50 minutes at 10O ⁰ C. The solvent and the excess reactants are evaporated under reduced pressure on a water bath and the residue recrystallizes. Overall yield 73 #. Melting point 142 °.

Analysis: C ₁₅ H ₁₅ O ₇ N (295)

Calculated % \ C52.93 H4.44 N4.75 037.96 Found % x 52.8L 4.59 5.01 37.77

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Example 6

Placetoxy-2 ^ 5-benzoic acid (isopropylidene-dioxy-2,3 propyl) ester (R = CH ₂ -CH - 9H ₀ , code Mr. SL 72-426 )

Small amounts of 256.5 g of ( 1 mol) diacet ylgentisinic acid chloride (prepared according to Milton, J. Org. Chem. 1955 * 20, p. 38), taking care that the temperature does not exceed 35.degree. After the addition is complete, the mixture is kept at room temperature with stirring for 2 hours and a significant volume of ether is added to precipitate the pyridine hydrochloride formed in the course of the reaction. After its filtration, the filtrate is washed successively with a 0.5 η sulfuric acid solution, with a saturated aqueous sodium hydrogen carbonate solution and then with water. The solution is dried over anhydrous sodium sulfate and this is filtered off. Drive off the solvent in the filtrate in a water bath under reduced pressure and treat the oily residue several times with boiling cyclohexane, which is decanted in each case. The results CycCLohexanlösung on standing in der'Kälte 194.5-g "(yield 55 #) ■ diacetoxy-2,5 benzoic acid (isopropylidene-2,3-dioxi propyl) ester in the form of colorless crystals, melting at 68 ^0C.

Analysis: Q ₁₇ H _0n Oo (352)

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Calculated %: C. 58 .01 H 5. 73 0 36. 36 Found %: 58 .31 5. 22nd 36. 05 Example J -

Diacetoxy-2,5 benzoic acid (dihydroxy ~ 2 _J 3-propyl) ester

Code no .; SL 72-427)

OH OH

Dissolve 50 g (0.142 mol) of diaoetoxy-2,5-benzoic acid (isopropylidendioxy-2,3 propyl) ester, which in example 6 in a mixture of 500 ml of water, 250 ml of alcohol and 3 ml of concentrated hydrochloric acid on. This solution is heated in a nitrogen atmosphere with stirring to 80 ° for one hour. The acetone formed and the alcohol are driven off in a water bath under reduced pressure. Dissolve the residue in ethyl acetate, this latter solution washes successively with water, with a saturated aqueous solution Sodium hydrogen carbonate solution and then again with water. Dry over anhydrous sodium sulfate, which is then filtered off. The solvent from the filtrate is evaporated and the residue is crystallized from a mixture of methylene chloride and hexane 2: 8 around.

Finally, 20 g (yield 45 %) of diacetoxy-2,5-benzoic acid (dihydroxy-2,3 propylister are obtained in the form of a colorless crystallized compound which melts at 82 ° C,

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Analysis:

Calculated £: C 53.90 H 5.17 0-41.02 Found % \ 53.78 4.9b 41.23

Example 8

Diacetoxy-2.4 benzoic acid (isopropylidene-dioxy-2.3 propyl) ester (R = CH ₂ -CH - CH ₂ ; Code No. SL 73-124 )

CH

A solution is added dropwise to a solution of 51 g '(0.383 mol) of hydroxymethyl-4-dimethyl-2,2 dioxolane-1,3 in 90 ml of pyridine, which ^{is cooled to about 10 ° C. by a water / ice bath} of 98 g (0.383 mol) of diacetoxy-2,4 benzoic acid chloride (prepared according to M. Kidneystein, DG Wang and JC Warr, J. Amer. Chem. Soc, 46 (1924), p. 2553)

By treating the reaction mixture containing this ester in an identical manner to that described in Example 1 for its positional isomer, the diacetoxy-2,4 benzoic acid (isopropylidenedioxy-2,3 ester, softer, recrystallized from cyclohexane, ^{melts at TO 0} C) . Yield 82 %.

Analysis: C ₁₇ H ₂₀ Og (352)

Calculated £: C 58.01 H 5.73 0 36.36 Found % i 57.94 5.60 '36.58

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Example 9

Diaoetoxy-2,4 benzoic acid (dihydroxy-2,3 propyl) ester (R = -CH ₀ -QH - CH ₀ j Code No. SL 73-130)

d.

DE OH

A suspension of 48 g (0.136 mol) of diacetoxy-2,4 benzoic acid (isopropylidenedioxy-2,3-propyl) ester, which was prepared according to Example 8, is stirred in a mixture of 500 ml of water, 100 ml of acetone and 1 ml concentrated hydrochloric acid and heated slowly (about 1 hour) to 75 ° C. The 2 to 3 ml of supernatant oil are decanted, the solution is extracted three times successively with chloroform, the combined extracts are washed with water, dried over sodium sulfate, filtered and the solvent of the filtrate is evaporated on a water bath in vacuo. The residue is redissolved three times successively in alcohol, this solvent being driven off each time in a water bath under reduced pressure. The oily residue is carefully dried over phosphoric anhydride in vacuo. Finally, diacetoxy-2,4 benzoic acid (dihydroxy-2,3 propyl) ester is obtained in the form of a non-crystallizable and non-desillable oil. Yield $ 45>.

Analysis: C ₁ 4 ^Η 1δ ^{( }} 8 (31 2) H' 5. 17th 0 41. 02 Calculated %: C. 53. 90 5. 45 40. 99 Found % x 53. 58

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Table I.

Be sp.
No. Code no. R. position
the second.
CH ^ COO-
group Melting point 1 SL-72.422 -CHgCOCH ₃ . 5 82 2 SL-72.673 -CHgCOCH ₃ 4th 91 3 SL-72.674 -CHgCOCH ₃ 3 120 4th SL-72.424 -CHgCONHg 5 120 5 SL-72.675 -CHgCONHg 4th 142 6th SL-72.426 -CH ₂ -CH-CHg
π η VJl 68, \ y yy
CH-. CH-z
3 3 7th SL-72.427 -CHg-CHOH-CHgO I- 5 82 8th SL-73.124 -CH ₀ -CH-CH ₀ 4th 70 3 3 9 · SL-73.130 -CHr ₁ -CH-CH ₀
i 1
OH OH 4th not crystalline
adjustable 10 SL-72.420 -CHg-CN not crystalline
sable, boiling .-
point 200 ° / ^lmm 11 SL-72.421 -CHgCOOCgH ₅ 5 84 12th SL-72.423 -CHgCON 5 94

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The compounds according to the invention were subjected to a series of pharmacological tests in which they They have shown remarkable intense antagonistic effects on platelet aggregation exhibit.

Acetylsalicylic acid is now widely recognized as one of the most valuable drugs, if not the most valuable considered in this therapeutic area, although at the same time they have other effects (analgesic, anti-pyretic and anti-inflammatory effects) and although they have some important inconveniences or side effects, in particular an irritant effect the digestive mucous membranes.

It was, however, now with the inventive ^ erbindungen found that the property of antagonistic effect on the aggregation of blood platelets are separated from the anti-inflammatory and analgesic properties, the toxicity is greatly reduced and the ulcerogenic effects are practically suppressed.

Inhibitory effect on the aggregation of your lombocytes _;

This effect is demonstrated in the rabbit. The animals receive 70 mg / kg of one of the compounds according to the invention or of acetylsalicylic acid, the control and / or the control, daily by the oral route for three consecutive days. Reference substance, in suspension in an aqueous solution of carboxymethyl cellulose (0.25 %) and polysorbate ($ 0.20). The control animals only receive these additives

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24 hours after "the third administration, a Blood is drawn by cardiac puncture and the blood is taken up over an aqueous sodium citrate solution. A plasma rich in platelets can be obtained by centrifuging at a very low speed. Their aggregation is provoked in vitro by adding 100 / Ug of adrenaline per ml of plasma, whereby one this plasma 15 minutes later according to the method of K.Breddin (Die Thrombocytenfunktion, F.K. Schattauer-Verlag, Stuttgart - New York). By microscopic observation of the blood plates obtained, one can assign these a grade from 1 to 5, with 1 being a plasma with well-individualized platelets without aggregation and 5 denotes a plasma with maximum aggregation. Under the experimental conditions are shown by the plasmas of the animals which are not antagonistic to platelet aggregation acting products have received a strongly pathological Index (4 or 5). It is believed that the animals are protected when the index is equal or less than 2.

The compounds according to the invention all have one Inhibitory effect on thrombocytic aggregation. Especially with the administered dose of:

protects SL-72.424 the animals TO 70 It SL-72.422 It It Il 50 It SL-72.423 dd It It 50 It SL-72.427 dd dd dd 70

The acetylsalicylic acid protects this to 40 to 50 anti-inflammatory and 'analgesic effects

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- Io -

It was examined whether the compounds of the invention an anti-inflammatory effect in the Sherman rat (Edema caused by carrageenin according to the protocol from CA. Winter / "Non steroidal anti-inflammatory drugs, Milan, 1964, p. 19O_7) and an analgesic Effect on the Swiss mouse (by intraperitoneal injection Compounds provoked by acetic acid according to the method of R. Koster et al (Fed. Proc. 1959,, 18, 412) and has found that these effects are zero or very weak. There were the following Get results:

Anti-inflammatory SL-72 ^{,, 427 r> E} 4 (£ ^> ^ ² ^ Effect S acetylsalioyl

acid ^DE 40 ^{= 10} °

Analgesic We- SL-72.427 DE ₅₀ = 750 mg / kg

^kung acetylsalicylic

acid

All doses are for oral administration.

Acute toxicity

The DL (- ₀ was determined orally in the experiments with the Swiss mouse of both sexes, which weighed on average 20 g, according to the method of JT Litchfield and JR and F. Wileoxon (J. Pharmacol. Exp. Therap., 1949 , 96 * 99) calculated.

The compounds according to the invention are considerably fewer

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more toxic than acetylsalicylic acid. The DLj-q could even cannot even be determined with certainty, since the animals would have had to be given too large volumes, which the Results would have falsified. The results obtained are summarized in Table II:

Table II

product

DL ₅₀ (g / kg)

SL-72.421 8L-72.422 SL-72.4235 SL-72.424 SL-72.427 acetylsalicylic acid

not determinable (DL 0> 5 g / kg) 3.9 (2.6 - 5.8)

4.7 (5.43-6.43)

not determinable (DL O'S> 5 g / kg)

3.8 (3.05-4.85) 1.5

Ulcerogenic effect

The compounds according to the invention are distinguished
by the remarkable property that they have practically no ulcerogenic effect. It is one
Investigation in the Sherman rat according to the method of JM Lwoff (j. De Pharmacologie, Paris, 1971, j2, 81)
Have been carried out.

Although the $ 50 effective dose of acetylsalicylic acid

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Represents 170 mg / kg per os, that of the compounds SL-72.421, 72.422, 72.42 ^, 72.424 and 72.427 could not be determined because of the ulcerogenic effects of these compounds is practically zero at a dose of 2000 mg / kg per os.

The results of the pharmacological tests presented above show that the compounds according to the invention which are very active as inhibitors of thrombocytic aggregation, practical non-toxic and of harmful secondary effects (uleerogenic effect) or weaving effects (anti-inflammatory and analgesic effects) are deprived in human and veterinary medicine in the preventive treatment of thrombosis are usable. They can be administered orally, endorectally or parenterally. For this latter Mode of administration are the compounds which contain one or more free hydroxyl groups and are readily soluble in water, are particularly suitable. In the drugs or pharmaceutical preparations, can the compounds according to the invention alone, associated with one another, or with other medicinal substances with which they are chemically, pharmaceutically and therapeutically compatible.

When administered orally, the unit dose can range between 1 and 1000 mg vary, with the maximum daily dose being 5000 to 6000 mg.

The compounds can be in any pharmaceutically acceptable form for such administration, i.e. tablets, Dragees, capsules, drinkable solutions or suspensions,

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and the like are present together with customary auxiliaries.

The unit dose for endorectal administration can vary between 2 and 1500 mg, the maximum dose being 6000 to 9000 mg / day. The active compounds vjer the natural in a carrier and / or diluent or artificial origin distributed as suppositories.

For parenteral administration, especially intramuscularly, the unit dose is 0.25 to 100 mg, the maximum daily dose being 500 mg. The connections may be in the form of an injectable solution or suspension adjusted to a physiologically acceptable one pH values are adjusted and may contain emulsifiers and / or preservatives.

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Claims (1)

Claims i
1. / Compounds of the formula COOR (I) CHJDO-O 2 ^ N ₁ • ~~ 5— ■ - Γί ' ΡΛ PT-T 3 ³ wherein R is a substituted alkyl radical -CH ₂ -A, wherein η is an integer from 1 to 5, the alkylene chain C Hp can be straight-chain or branched and A represents - an alkoxycarbonyl radical-COOR., Where R, a straight or branched alkyl group with 1 to 6 carbon atoms, - or a carbanoyl radical-CO-H. , wherein the symbols Rp and R i are identical or are different and each is a hydrogen atom, a straight-chain or are branched alkyl groups having 1 to 3 carbon atoms, or ^R ? . .. _al _ 409815/1177 denotes a nitrogen-containing heterocycle radical with 5 to 7 chain links which optionally contains one or more further heteroatoms such as 0, S or N, or a cyano residue, or an acyl radical-COR ,, where R, the above has given meaning. represents a hydroxy or polyhydroxy-alkyl radical with straight or branched chain with 1 to 5 carbon atoms, in which one or more hydroxyl radicals can be etherified by a straight-chain or branched alkyl radical with 1 to 5 carbon atoms, or in which 2 of them under cyclization under Preservation of the group -CH- (CHg) _1n -CH can be etherified, wherein m is 0, 1 or 2 and Z is a straight chain or represents branched alkylene chain of 1 to 5 carbon atoms. 2. A compound according to claim 1, characterized in that g e k e η η - " indicates that R represents a radical -CHp-A, in which A - either an alkoxycarbonyl radical — COOR, where R _{1 represents} an alkyl group with 1 to 5 carbon atoms, ^^^ ^R 2
7 or a carbamoyl radical-CO-N denotes, in which the symbols R ₂ and R- are identical or different - 22 - 409815/1177 and each is a water atom or an alkyl group represents with 1 to J5 carbon atoms, - or means a cyano residue, - or an acyl radical-COR «, in which R denotes the above has given meaning, - Or a dihydroxyalkyl radical with 1 to 5 carbon atoms, the hydroxyl groups of which can be etherified with cyclization in a V / eise that the group -CH- (CHg) -CH- is formed, in which m 0, 1 or 0 ζ —-o 2 represents and Z represents a straight or branched chain alkylene group having 1 to 5 carbon atoms. ; 5. Compounds according to claim 2 of the formula CH ₇ CO-O ^ / v, COOR -COCH viorin R has the same meaning as in claim 2. 4. Diacetoxy ~ 2,5j-2,4 or -2,3 benzoic acid (oxo-2 propyl) ester. 5. Diac et oxy-2,5 οαβΓ-2,4 benzoic acid (carbamoyl-methyl) ester. 6. Diacetoxy-2,5 or -2,4 benzoic acid (isopropylidene-dioxy-2,5p-opyl) ester. 7. diacetoxy-2,5 or -2,4 benzoic acid (dihydroxy-2, 3 propyl) ester. 409815/1177 8. Diaoetoxy-2,5 or -2,4 benzoic acid (cyanomethyl) ester. 9. Diacetoxy-2,5 or -2,4 benzoic acid (ethoxycarbonyl-methyl) ester. 10. Diaeetoxy-2,5 or -2,4 benzoic acid (dimethyl-carbamoylmethyl) ester. 11. Process for the preparation of the compound according to claim 1, characterized in that one the two phenol groups of a dihydroxybenzoic acid and the acid group are acetylated in any order esterified. 12. The method according to claim 11, characterized in that the esterification of the dihydroxy or diacetoxybenzoic acid by reacting the acid or one of its salts with a halogenated derivative RX carries out, wherein R has the meaning given in claim 1, and X represents a halogen. 15. The method according to claim 11, characterized in that the esterification of the dihydroxy or diacetoxybenzoic acid by reacting the acid of one of its functional derivatives with a Compound ROH carries out, where R has the meaning given in claim 1. 14. Variant of the method according to claim 11, characterized in that if the compounds (i) carry two free hydroxyl groups, a corresponding derivative which _{carries a group -CH- (CH 2} ) _m ~ CH-, where- rin m and Z have the meaning given in claim 1, hydrolyzed. , 409815/1177 Pharmaceutical preparation containing at least one of the compounds according to one of the claims 1 to 10 as active ingredient, optionally together with customary carriers and / or diluents. 409815/1177