FR2520739A1 - NOVEL INDOLEACETIC ESTER DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

NEW DERIVATIVES OF INDOLEACETIC ESTER, OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R -H, -COR OR R ALKYL, ALCENYL, PHENYL SUBSTITUT OR NOT, -COAR OR A ALKYLENE, ALKYLENEOXYBS, PROPYLENE AND R PHTIENYL NON-SUBSTITUTE , OR CO-C (R) C (R) - R OR RH, HALOGEN, CN, ALKYL, PHENYL, RH, ALKYL OR PHENYL AND R PHENYL SUBSTITUTES OR NOT. THESE DERIVATIVES ARE USEFUL IN PARTICULAR FOR THE TREATMENT OF HEADACHE, TOOTH PAIN, LUMBAGOS, MYODYNIA AND RHEUMATISMAL DISEASES.

Description

This invention relates to ester derivatives of indole-

  acetic acid, process for their preparation and their use as non-steroidal anti-inflammatory analgesics for the treatment of headaches, ailments

  of teeth, lumbago, myodynia and rheumatic diseases.

  Indomethacin is a drug that has been widely used as a non-steroidal anti-inflammatory analgesic for the treatment of ailments.

  headache, toothache, lumbago, myodynia and rheumatic diseases.

  However, it is known that when indomethacin is administered by

  orally, adverse effects such as gastrointestinal disturbances

  accompanied by ulcers in this case.

  such as congestion and hemorrhage of the stomach, may be more or less induced not only in the case of long-term administration as is necessary in the treatment of rheumatic diseases, but also in the case of administration. in the short term As a result, there is a

  how much and how much of what can be administered.

  We have conducted extensive studies to reduce the effects

  of indomethacin and as a result we found that a

  linked to an indoleacetic ester, obtained by reacting a butadiene compound

  nediol with indomethacin, has analgesic and antiinflammatory action

  similar to that of indomethacin and the pernicious effects clearly

  smaller than those of indomethacin.

  Accordingly, it is an object of the present invention to provide a novel indoleacetic ester derivative which is useful as

  non-steroidal anti-inflammatory analgesic.

  Another object of the invention is to develop a

  assigned for the preparation of a new indoleacetic ester derivative of

type mentioned above.

  These and other objects according to the invention have been realized, as will become clearer later, by means of an indoleacetic ester derivative represented by the following formula (I) CH 3

CH 30 CH 2 COOCH

H 3 CH-OR (I)

C = O CH 3

  C-1 in which R represents a hydrogen atom, -COR 1 o R 1 represents a

  alkyl group, an alkenyl group or an unsubstituted phenyl group or

  characterized by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a formyl group, a hydroxy group, an acyloxy group, an alkoxycarbonyl group or an alkylenedioxy group, COAR 2 o A represents an alkylene group; C 1 -C 4, a C 1 -C 4 alkyleneoxy group or a propenyl group A 1, and R 2 represents a phenylenon group substituted or substituted by a halogen atom, a lower alkyl group, a lower alkoxy group, a group nitro, a formyl group, a hydroxy group, an acyloxy group, an alkoxycarbonyl group or an alkylenedioxy group, or RR o P 14

CO C -C R 5

  R 3 represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or a phenyl group, R 4 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 5 represents unsubstituted or substituted lower alkyl, lower alkyloxy, acyloxy or halogen; the process for the preparation of this derivative or the reaction of a compound of general formula (II) or its reactive derivative

CH 30 CH 2 COOCH

\

S 'CH 3 (II)

C = O

C

  c: I with 2,3-butanediol of formula (III)

CH 3 CH CH CH

  O Oi (III) and this is a Zle as anti-inflammatory analgesic for the control of headaches, toothache, lumbago, myodynia and rheumatic diseases without

  cause harmful gastroenteric side effects that accompany

  the indomethacin of the prior art.

  The compound (I) of the present invention can be prepared by

  any of the following methods using

riflcatioa ceâ S -.

  (1) Indomethacin (II) or its reactive derivatives are reacted with 2,3-butanediol (III) to give indoleacetic esters (Ia) according to the following reaction dithema:

CH 53 CH 2 COOH

3 H -

NC = O 3 CH CHCHCH

t 3 3

C = O + 1

OHOH 0 H 3

> C = O CH 3

  Cl (Ia) (2) The indoleacetic esters (Ia) are then reacted with a carboxylic acid of general formula (IV) or its reactive derivative

R 6 COOR (IV)

  wherein R 6 represents an alkyl group, an alkenyl group, a phenyl group unsubstituted or substituted by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a formyl group, a hydroxy group, an acyloxy group, an alkoxycarbonyl group or an alkylenedioxy group; a group -A-R 2 in which A represents an alkylene group in

  C 1 -C 4, a C 1-4 alkyleneoxy group, a propenyl group A 1, and R 2 represent

  a phenyl group which is unsubstituted or substituted by a halogen atom, a

  lower alkyl group, a lower alkoxy group, a nitro group, a group

  formyl, a hydroxy group, an acyloxy group, an alkoxycarbonyl group, or an alkylenedioxy group, or a group R 3 R 4 in which R 3 represents

C = C R 5

  a hydrogen atom, a halogen atom, a cyano group, an alkyl group

  lower, or a phenyl group, R 4 represents a hydrogen atom, a group

  lower alkyl, or a phenyl group and R 5 represents a phenyl group unsubstituted or substituted by a lower alkyl group, a lower alkyloxy group, an acyloxy group or a halogen atom, to obtain indoleacetic ester derivatives ( lb): CH 3

CH 30 CH 2 COOCH

Y CH 3 CH-OH

C = O CH 3 + R 6 COOH

(IV) Cl (Ia) to CH 31

CH 3 O CH 2 COOCH

* CH 3 CHOCOR 6

-C = O CH 3

  Cl (Ib) (where R 6 represents the group R 1, the group -AR 2 or the group R 3 R 4

-C-C -R 5

defined above).

  (3) The 2,3-butanediol monoester derivatives of the general formula (V) CH-CHMC "-CH 3 (v) are reacted (v)

3 1 1 3 (V

OH OCOR 6

  in which R has the same meaning as above, with indomethacin

  (II) o its reactive derivatives to obtain indoleactive ester derivatives

tick (lb):

CH 30 CH 2 COOH

CH 3-CH-CH-CH 3 H 3

I I + C = O

OH OCOR 6

C (V) ()

M ci (II)

C 3

CH 30 CH 2 COOCH

c CH 3 CHOCOR 6

C = O CH 3

Cl (Ib)

  (o R 6 has the same meaning as before).

  In these processes, the reactive derivatives of indomethacin (II) and carboxylic acid (IV) are acid halides, anhydrides

  acid and mixed acid anhydrides The reaction is preferably carried out

  in the presence of deacidifying agents such as tertiary amines including pyridine, trimethylamine, triethylamine, and the like; alkali carbonates, alkali hydroxides, alkali hydrides and

analogs.

  Similarly, the reaction is preferably carried out in suitable solvents, and the reaction solvents are preferably those which do not participate in the reaction and they include, for example, ether, tetrahydrofuran, benzene, toluene, chloroform, dichloromethane

and analogues.

  After this general description of the invention, examples

  are given in order to allow a better understanding of the invention; they will illustrate but not limit it or any of

  these embodiments, unless otherwise indicated.

  EXAMPLE 1 (Synthesis of Compound 1) 17.9 g of indomethacin are suspended in 200 ml of benzene, 20 ml of thionyl chloride are then added and the mixture is stirred at 60 ° C. for 5 hours. After completion of the reaction, benzene and excess thionyl chloride are distilled off under reduced pressure to give clear yellow crystals of the acid chloride of indomethacin. The acid chloride is dissolved in 80 ml of tetrahydrofuran

  and poured into a stirred solution of 4.5 g of 2,3-butane

  diol, 10 ml of pyridine and 150 ml of tetrahydrofuran

  When the reaction is complete, the mixture is stirred at ambient temperature for 4 hours and the solvent is distilled off under reduced pressure.

  the residue in chloroform, washed with water, with chloroform

  10% water and with water in this order, then dried over anhydrous magnesium sulfate. The chloroform was distilled off and the residue was purified by column chromatography (silica gel) to obtain 15%. 5 g (72.1% yield) of the compound 1, appearing in the table

  I, in the form of light yellow crystals.

  Melting Point 106 ° -108 ° C. EXAMPLE 2 (Synthesis of Compound 3) 2.15 g of Compound 1 are dissolved in 15 ml of tetrahydrofuran, then 1 ml of pyridine is added and the solution is added dropwise in ml. ether solution of 0.78 g of oenheic acid chloride while stirring and cooling with ice The mixture is stirred at the same temperature for 30 minutes and then at room temperature for 4 hours, after which the solvent is removed by distillation under reduced pressure and the residue is dissolved in chloroform, washed with water, with

  10% hydrochloric acid, with water, with saturated sodium bicarbonate

  and with water in this order and it is known about magnesium sulfate an-

  Hydra The chloroform is distilled off under reduced pressure and the residue is purified by column chromatography (silica gel) to obtain 2.25 g (83% yield) of the yellow liquid compound 3 appearing in Table I. Example 3 (Synthesis of compound 20)

  4.5 g of 2,3-butanediol are dissolved in 60 ml of tetrahydrofuran.

  rane and mixed with 5 ml of pyridine; in this mixture, 30 ml of a tetrahydrofuran solution are added dropwise with 9.5 g of sodium chloride.

  1-cyanocinnamic acid while stirring and cooling with ice.

  The mixture is stirred at the same temperature for 30 minutes and then at room temperature.

  room temperature for 4 hours, and then the solvent is distilled off.

  under reduced pressure and the residue is dissolved in chloroform.

  The chloroform phase is washed with water, with 10% hydrochloric acid, with water, with saturated sodium bicarbonate solution and

  with water in this order and then dried over anhydrous magnesium sulfate.

  The chloroform is distilled off under reduced pressure and it is possible to

  digest the residue by column chromatography (silica gel) to obtain 5.86 g (48% yield) of a yellow liquid monoester product

blade.

  2.45 g of this monoester product are dissolved in 30 ml of tetrahydrofuran.

  hydrofuran and mixed with 2 ml of pyridine; in this mixture we pour

  dropwise 20 ml of a solution of tetrahydrofuran with 3.76 g of chlorine

  Acetate of the indomethacin acid while stirring and cooling with ice The mixture is stirred at the same temperature for 30 minutes and then

  room temperature for 4 hours; then the solvent is removed by distillation.

  under reduced pressure and the residue is dissolved in chloroform, washed with water, with 10% hydrochloric acid, with water, with saturated sodium bicarbonate and with water. this order and

  anhydrous magnesium sulphate is known. Chloroform is removed by distillation.

  under reduced pressure and the residue is purified by means of a chromatographic

  columnography (silica gel) to obtain 4.15 g (71% yield) of the compound 20 as a yellow liquid and listed in Table I.

Example 4

  Various compounds mentioned in Table I are obtained in the same manner as in Examples 1, 2 or 3 It will be noted that the compounds obtained in Examples 1-3 are also mentioned in Table I. R in RM (appm y CDCL point fusion

compose the formula 3.

  Propriffla 1 1 1 Cd311), 1.2 id 211) 1.9 (ú 111) 2.35 (a 39) 3.3% 4.0 (m 111), 3.63 (a 211) p f 106

1 1081 C

  3) 8 (311) 4.4% 5.0 (m H) 6.6 (dd 1 H) 6, 8 id 1 H) 6, 9 (d 111) 7.5, dd 411) 0.9 ( t 311) 1.0% 1.8 (m 1211) 2.0 CI: 211) 2.3 (a 311) 3, 5 tu 211) 3, 75 tu 311) Yellow Liquid 2 Co (Cil 2 4 CH 3 clear 4.6% 5 ,, 1 (m 2 H) 6, 5 (dl 111) 6.75 (d SH) 6.8 (d ili) 7, 5 (dd '41 f) 0.9 (t 311) 1.0% 1.9 im 1411) 2, 1 CI: 211) 2.35 μs 3 H) 3.65 (at 2H) 3.8 te 311) 3 Co (CH cil 2 5 3 4 p 7,%, 5 p 2 (m 2 ii) 6.6 id 1 (1) 6, 85 (d 11) 6.95 (d 111) 7.5 (dd 4H) 0.9 (t 311) 1.0 1 9 (m 1611) 2, 1 (t 211) 2, 35 (a 311) 3 M (s 211) 3, 8 (a 3 H) 4 coicil 2 6 cil 3 4, 7% S, 2 im 211) 6, 6 (d, di 11) 6 ', 8 (d111) 6, 9 (d111) 7, 5 (dd 411) 0, 9 CI: 311) 1.0% 1 9 im 1811) 2, 1 (t 211) 2, 35 (s 311) 3.6 211) 3, 75 (a 311) Co (Cil Cil 2 7 3 4 p 6% 512 (mI 2) 6.55 (dd 111) 6, B (dH) 6.9 (d bed) 7.5 (dd 411) 0.9 CI: M) 1.0-1 S (m 2011) 2.1 CI: 211) 2.3 (s 3H) 3.5 ( 9 211) 3.7 (a 311) 4.6% 5.1 (m 211) 6 Co (Cil C11 2 B 3 6, 5 (dd 1f) 6, 7 (dJ H) 6, 85 (d 111 ) 7.5 id il 4 H) 0.9 (t 311) 1 0% 1.8 (m 2211) 2, ICI: 291) 21.35 (a 311) 3.5 (2 211) 3.75 (e 311) 4.6% 5.1 you 211) 7 CO (Cil ) g Cli 2 3 6, 5 (dd bed) 6.7 (d 111) 6.8 (d 111) 7.5 (dd 411) cil 0.85 (d 611) 1.12 (d 311) 1, 22 (d 311) 1.2% 1.7 (m 3 H) 2.15 (t 211) 2, 37 (a 311) 3.63 (s 211) 1 3 COCU 2 112 U 113 3.80 (s) 311) 4.611-5.3 (m 211) 6) 62 (dd Ili) 6.88 (d 111) 6.95 (dH) 7.51 (dd 411) OP 6% 1, 9 (m 1611) 2 , 1% 2.7 (ri 1 H) 2, 37 (a 3 u) 3.63 (at 211) 3, 79 i 311) 4.61%, S, 3 (m 211) cilicii 2 cil 2 cil 3 6.62 dd 111) 6, 88 (d 111) 6.95 (d 111) 7) 15 (dd 411) 0.71% l, 1 (m -311) 1 O% I, 7 (m 16 H) 1.9% 2; 4 (m 211) 2, 36, 311) 3.64 (a 2H) 3.02 (a 311) 4.6% CH 1 O CMIUCII (Cly 2) 6 3 5, 3 (qq 211) 5, 66 (d 111) 6,62 Cd it 1 fi) 6, 8 (d1 H) 6, 9 (d 111) 6, 95 (d 1 li) 7,53 id d 419) M vi - r%) CD -4 LN -% O

TABLE I

TABLUU i (Continued) -

  -R in Melting point R m N (dppm g CDCL Compound formula (1) 3 or Properties 1 (d 311) 1, 2 (d 3 H) 2, 2% 2, 4 (m 4 11) '2 , 34,311) 3,60 211) 3, 78 (a 311) 41 7% 5, 2 (m 4 11) Yellow liquid 1 1 Co (Cl 2) 2 CHO 2 1 (m III) 6.56 (d ci Ii Y 6.8 (d 111) 6.9 (d 111) 7 45 (dd 4 il) clear

, 4% 6 /

  IJPOIP 7 (m 1811) lile% 2 t 4 (m 411) 2.38 (a M) 362 (s 211) 3.90 (a 31 t) 4.61-5 3 (m 411) 5.4, 6.2 (m.

  CH 2 CH 2 CH 2) 8 2 (a) 6 p 6 (cis 111) 6 ee (dtll6.95 (d Ili) 7.5 (dd 411) 1, 1% 1,4 (m 611 ) 2.35 (a 311) 3.65 (a 211) 3.75 (at 3H) 4.8% 5.3 (m 211) 6.2 (dH) 6.5 (dd Ili) 13 C (C11-CH-4 n1 / 617 id 1H) 6,9 (d 111) 7,11-7,8 (m1011) 611) 2.32 (a GR) 3.61 (s 211) 3, 73 Ce 311) 4, 7, S, 3 (m 211) 6.10 (d 1 H) 6.48 (dd 14 COCIF-CH-e) -Cn, 6.75 (d Ili) 6) 88 (d 111) 7.0'-7.9 (m 9 ti) o-1.5 (m 611) 2.33 (s 311) 3.6 (at 2H) 3, 78 (s 311) 3, , 8 (a 311) 4.8% 5.3 (m 211) 6, 1 (dH) COCII-c I 14 -> - Oc H, 614% 7.0 (m 411) 7 2% 7, 7 (m 811) t, 0% 1, 5 (m 611) 2.35 (a 319) 3 65 (s 211) 3.75 (9 311) 4.7% 5.2 (m 211) 6.1 Id 111) 6.5 (aa 111) 16 COCII-CH - / '- Ct 6, 7 3 (d 1 H) 6, 9 3 (d 1 el) 7, 1 M-7 4 (m 5 1 1 i 7, 5 (dd 410 1, O% I, 5 (m 611) 2, 29 (a 311) 2, 35 (a JII) 3.6 (a 211) 3.75 (at 311) 4.6% 5.3 (m 2 Ii) 6.1 (d 111) 17 COCII-Cl-M-1-Mocil 3 6 i S (dd 1 H) 6.75 (d 111) 6.95 (d 111) 7.0 % 7.9 (m911) cil 3 1.1% 1 6 (m611) 2.01 S 311) 2.37 ts 311) 3.64 (at 2 H) 3.77 in 311) 4.8% 5.4 (m211) 6.55 (dd Ili) 1 CICII 6 79 (ci 111) 6, 9 (d111) 7 2% 7, 7 S 1 011) 6 il) 2,3 (s3H) 2.45 (q 2 H) 3.64 21 i) 3 1) I 15 1, 1 (t 3 H) i% 1.5, 7 2 (s311) 4, 81.5, 4 (m21 19 c -Ct - / "% 6.52 (dd 111) 6.13 (d 111) 6.9 (d, 111) 7.2 (salt) 7.5 (dd 4H) CH 1 0, 1.6 (m 691) 2.24 (s 3 H) 3.63 (a 29) 3.73 (a 311) 4.6 '-SS (m 211) 6 45 (cl d 111) 6, 75 (d 111)

1 1 1

  COC C 11 6 9 (d 10) 7, 3 (m, 1 011) N)

Ln -

r%) C> 1 d

w -

% O 1-.1 6 lm6 ii) 2 liq) 6.35

  735 (c 311) 3.65 (t 211) 318 (o 311) 4.8% 3.4 (m 211) 6.3 (9.

  Liquid (dl 111) 6; 79 (dIR) 6.9 (d-111) 0.07, 7 lm911) light yellow 1.0% lp 4 lm 611) 2.34 lm & 311) 3.60 in 211) 3 p 76 311) 4, 8% 50 4 μm 211) 61 5 5 ID 1 0) 2 2 CP-ICH-0 6, 8 (ci1 H) 6, 8% 7, 8 lm168) cil 3 1, 11, 5 lm 611) 2, 3 2 3 M) 2, 50 3 H) 3.6 2 (a 211) 31 72 311) 4.7%? 3 lm 2 H) 5 9 2 2 3 CO Cll-c 4 / S 1 H) 6/5 2 (dl 1 Il) 6 / at id 1 H) 6/8 9 (d 1 H) 7 ip 1% 7, 9 cm 98 )

  0.9% J, 4 μm 6H) 2.36 (9,311) 3.6 (s' 211) 3 p 76 (a 38) 4/6% 5 2 (m 211) 6 IF 2 (s 111) 6/6.

  cilate c (dd 111) 6/8 5 (d1 H) 6.95 (c'l 11) 7 d &% 7, 9 lm1 4 11) TABLE I (Continued) R in the fo MU 14 (1) Item amalgamation; Example 5 (Synthesis of Compound 27) 17.9 g (0.05 moles) of benzene were suspended in 200 ml of benzene (m.p. ) of indomethacin then mixed with 20 ml of thionyl chloride and continued by stirring at 60-70 ° C for 5 hours After the completion of the reaction, benzene and excess thionyl chloride are removed by distillation. under reduced pressure to obtain the acid chloride of the

  dometacin as light yellow crystals.

  This acid chloride is dissolved in 80 ml of tetrahydrofuran and a stirred solution of 4.5 g of 2,3-butanediol, 10 ml of pyridine and 150 ml of tetrahydrofuran is added dropwise in portions. After completion of the drop, the mixture is stirred at room temperature for 4 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in chloroform, washed with water, with 10% hydrochloric acid and then with water. water in this order then dried over anhydrous magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (silica gel) to give 15.5 g (72.1% yield). of the monoester product in the form of light yellow crystals 8.6 g (0.02 mol) of this monoester product are dissolved in 1 ml of tetrahydrofuran, mixed with 4 ml of pyridine and 40 ml of a solution are then added dropwise. 3.25 g (0.21 moles) of chloride

  of p-toluic acid while stirring and cooling with ice.

  After stirring at this same temperature for 30 minutes and then for 4 hours at room temperature, the solvent is distilled off under reduced pressure and the residue is dissolved in chloroform, washed with water, with 10% hydrochloric acid. , with water, saturated sodium bicarbonate and

  water in this order and then dry on anhydrous magnesium sulfate.

  chloroform was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain 7.2 g (73% yield) of compound 27, shown in Table 11, as

a yellow liquid.

  Example 6 (Synthesis of Compound 41) 4.5 g (0.05 mol) of 2,3-butanediol are dissolved in 60 ml of tetrahydrofuran and mixed with 5 ml of pyridine and then 9.3 g are added dropwise ( 0.05 moles) of x-methylphenoxyacetic acid chloride while stirring and cooling with ice After stirring at the same temperature for 30 minutes and then at room temperature for 4 hours, the solvent is distilled off under reduced pressure and Dissolve the residue in chloroform. The chloroform phase is washed with water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution and water in this order, then known on anhydrous magnesium sulfate. The chloroform is distilled off under reduced pressure and the residue is purified by column chromatography to obtain 6.3 g (53% yield) of the monoester product in the form of a liquid.

-pale yellow.

  2.38 g (0.01 mol) of this monoester product are dissolved in 30 ml of tetrahydrofuran and mixed with 2 ml of pyridine, and then 20 ml of a 3.76 g tetrahydrofuran solution are added dropwise thereto. (0.01

  moles) of indomethaean acid chloride After stirring at the same time

  during 30 minutes and then at ambient temperature for 4 hours, the solvent is distilled off under reduced pressure and the residue is dissolved in chloroform, followed by washing with water, with 10% hydrochloric acid, with water, with a solution of sodium bicarbonate

  saturated with water in this order and drying over magnesium sulfate

  Hydrate The chloroform is distilled off under reduced pressure and the residue is purified by column chromatography (silica gel) to obtain 4.16 g (72% yield) of the compound 41, mentioned in Table II,

in the form of a yellow liquid.

Example 7

  Various compounds mentioned in Table II are prepared in the same manner as in Examples 5 or 6 In this table,

  also the compounds obtained in Examples 5 and 6.

TABLE II

  IL in the formula (1) Property $ RM N OMM (CDCL 3) viscous liquid 611) 2.27 Co 311) 3.6 (o 2 H) 3.74 Ce 311) 4.91 5.4 (m ') 211) 6, 55 (dd Ili) 6.8 (d Ili) 619 yellow (d iii) 7 J 1% 8 O (m 91 i) 26 Co-n -ct 110% IPS (m 611) 2.3 ( s 311), 3.64 2H) 3.76 (at 3H) 2H) 6.55 (dd 111) 6 # 75 (d 111) 6.9 (il IIi) 7.2 (d 211) - 7.5 (il d 4 H) 7.7 (il 2 H) 27 c Ofc II, 611) 2.26 (a; 311) 2 P 32 fisIii) 3/64 2 u) 3.76 (s 311) 4.9% 5.4 (m211) 6.55 (d 111) 6 p 75 (d111) 6 9 (d 111) 7.1 (d 211) 7.45 (d il 411) 7 7 (d 2 u) cil 1 (m611) 1.2 (d 6 H) 2.3 (a 3 H) 2.5% 3.2 (m111) 316 W 211) 3.8 (s 31 f) 4, 9- 5.4 (in211) 28 Co-cIl, 3 cil 6.5% 7.0 (m 311) 7.1% 8, O (m8 H) C11 OM, 5 (in 614) 1, 32 (9911 2.3 (s 3 H) 3.6 (at 2 h) 3.8 (9 310-4.9% 5.4 (m211) 6.4% 7.1 (m 311) 29 CO c with, lt) 1.0% 1 5 im 611) 2.25 (s 311) 1.55 (s 211) 3.70 (s 310 3.76 (o 311) 4.91.5.4 (m) 211) 614% 7.0 (m 511) Co- (, -Oc II, 7.1% 7.9 (m 611) Ocil Pp 155% 157 'C 1, 1% I, 5 (m 611) 2 , 22 (to 311) S (s 21 i) 3, 70 (s 311) 3 76 (s 311) 3 AMS 3 (f) 3.88 (a 311)

C 3

  31 0 - (/ Ocil Crystals yellow 4? 9% 5 y 4 (OC 113 m 20) 6, "7, O (m 3 H) 7, 1% 7.7 Cm 611) 3 clear Pf 1 IR -I 20 ' C 1 0% 1.5 (m 61 f) 2.3 (s 311) 3.6 (a 211) 3.75 (a 31 i) 418,%, S 4 (m 2 il) 6.3% 7 O (m 311) 7, 11% 8.2 32 C 04-40, light yellow crystals (m Sif), viscous K 1.1% 1, 6, (m 691) 2, 3 (a 311) 3, 6 (s 211) 3 JF) (s 311) 4.9, 5.4 (m 21 t) 6/45% 7.0 r, 311; 7, 2% 8 '1 (in 811) 33 c O- / '- c 11 Yew toOfs, id) 11. 1% 1.5 (m 611) 2.25 (s 311) 3 6 (s 211), û (s M) 4.8' 5, S (m 211) 5.8 A, 2 (k 9 111) 6.4% 7.1

34 C -% 5 _ 011

  S w r 1 ii) ui r'i J C> 1-4 LN% O 1? O% 115 (m eo) 2.3 (at 6 n); 3 62 (211) 3.84 311) 4? Ffl> 5 (m 211) 6.6 (dd 111) 6.05 (to bed) 33 = g of the same drug and a 6 p 95 (d 11) 7, 05 (d211) 7.6 (at d 4 11) 9 (d 211) 1, O% if 5 Cm 611) 2, 3 Ce 311) 3.65 (ae 21 i) 3, 8 4 31 t) 3 , 96,311) 5, ffl, 5 (m 2 u) 6 5% 7, 1 (m 311) 36 C 04 -, - coo =, 712% 812 (m 811) 0 1.0% 1.5 (m 611) 21 3 (a 311) 3 96 5 (a 211) 388 (a3 ti) 4, ffl, 5 (m2 0) 610 (9211) 6, 5% 7.1 (m4 11) 3 7 Co o >, 71 M p 9 (m6 11) 1, O% 1 3 (m 6f) 2135 (s 311) 3 -4 2 (s 2 il) 3, 5 3 (s 2 H) 3 d O (s 311 ) 4, 7% 51-2 (m 211) 6 / 4-7 j 1 (m 311) 7/2

38 COCIII-0

  (L.511) 7.2% 717 (d d 411) 01 9% 1? 4 (m 611) 2, 35 (a 3 H) 2, 2% 2 6 (m 211) 2 6% 3 O (m 211) 3.6 (9 211) 3.75 (e 311) 4.61 3 (m 2 ii) / p Y 39 Co (Cly 2) 2-0 6.5 B (dd 111) 6, 85 (d 1 11) 6.9 (d Ili) 7, 1 3 (1-3511 ) 7.4 S (cid 410 (m 611) 2.3 S (9.3 H) 3 6 (a 211) 3.8 (9 311) Ely 38 211) 47% 5 3 (m 2 H) 6, 5% 7.4 (m 811) cocoyl CJ 4, / -% 2 7.55 (dd 411) cil 3 0.9% 1.4 (m 6101 1.4% 1/8 (in311) 2, 37 (a 311) 3, 60 (m 2 H) 3.81 (9,311) 4, 73 (lit) 4 j 7% 5 j 3 (m2111 6, 5% 7 t 4 (m 811) 7, 55 (dd, 4 fl) 1, Im11, 5 (m 611) 2.36 (a 311) 3.03 (d 2 H) 3, 60 (a 211) 3) 80 (9,311) ill 7% (FIG. m 211) 5 ', & 1.6, 5 (m 1 11)

4 2 COCH cil cti F% -

  2 6/26 (d 111) 6,6 (dd 111) 6 86 (d M 6,, 96 (d 111) 7 23 (t 511) 7 lp 46 (dd iiii) y R dme the form (1) TABLE 1 1 NMR (CDU) è- 4- 9%) ui rj c Ili IL.4% o compla propria

  The compounds of formula (I) according to the present invention possess

  anti-inflammatory and ulcerative

  previously mentioned, and the test results for these effects are

indicated below.

  Pharmacological Action Several groups of Donryu male rats, each weighing about 200 g and each group comprising 7 rats, are prepared and put on a diet for 48 hours; then the compounds to be tested are each suspended in an aqueous solution of 1% sodium carboxymethylcellulose and orally administered to rats 60 minutes after administration of the compound, the volume of the sole of each foot is measured. The rats were then injected subcutaneously with 0.1 ml of a physiological saline solution of carrafenine at 1% in the plant of the right hind paw. Three hours after the injection, the degree of edema was compared. groups to which the 1% sodium carboxymethylcellulose aqueous solution was administered to the controls to obtain a

rate of inhibition of edema.

  Seven hours after the injection, the tested rats are sacrificed and autopsied to extract the entire stomach and the inhibitory effect on gastric damage is shown in terms of ulceration coefficient.

  are shown in Table III.

Table III

  Compound No Dose (mg / kg) Inhibition Rate Coefficient of Edema (%) Ulceration

40 1.5

75 5.4

37 2.2

77 3.8

26 0.1

65 0.8

31 2.5

67

  4.8 1 Table TTT (Site) Compound No Dose (mg / kg) Inhibition rate Coefficient of edema (%) ulceration

27 50 68 1.6

50 70 0.8

36 50 52 3.2

41 50 60 2.1

Indoeetin 10 51 16.8

50 77 34.6

  As is evident from Table 1, the compounds of the present invention have high inhibition levels against carrageenin edema and only a very slight degree of ulcer presence which is a pernicious effect.

  nonsteroidal anti-inflammatory analgesic substances.

  The compounds according to the invention may in particular be administered

  orally or rectally, in particular in the form of compositions containing as active principle at least one of said compounds, in association with

  a pharmaceutically acceptable vehicle.

  Finally, these compounds and compositions may be administered in humans at a rate of 0.01 to 20 mg / kg / dose (1 multiple dose per day) in the case of oral administration and 0.005 to 10 mg / kg. mg / kg / dose (1 to multiple seizures per day) in the case of non-oral administration, such

  than rectal administration.

  The invention being now fully described, it is obvious to those skilled in the art that it is possible to make many changes and modifications without departing from the spirit and scope of the invention. invention.

Claims (10)

  Indoleacetic ester derivative characterized in that it is represented by the general formula (I): CH 3 CH 30 CH 2 COOCH ' CH 3 CH-OR (1) C = O CH 3 '' '' '' '   In which R represents a hydrogen atom, -COR 1 o R 1 represents a   alkyl group, an alkenyl group or an unsubstituted phenyl group or   halogen atom, a lower alkyl group, a lower alkoxy group, a qitro group, a formyl group, a hydroxy group, an acyloxy group, an alkoxycarbonyl group or an alkylenedioxy group, -COAR 2 o A represents a C 1 -C 4 alkylene group, a C 1 -C 4 alkyleneoxy group or a   propenylene group, and R 2 represents an unsubstituted or substituted phenyl group.   halogen atom, lower alkyl group, lower alkoxy group, nitro group, formyl group, hydroxy group, acyloxy group, alkoxycarbonyl group or alkylenedioxy group, R R CO-to-R 5   R 3 represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or a phenyl group, R 4 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 5 represents a phenyl group which is unsubstituted or substituted by a lower alkyl group,   a lower alkyloxy group, an acyloxy group or a halogen atom.   Indoleacetic ester derivative according to claim 1,   characterized in that R represents hydrogen.   Indoleacetic ester according to claim 1, characterized in that   that R represents -COR 1, R 1 being as defined in claim 1.   4 Indoleacetic ester derivatives according to claim 1, characterized in that R represents -COAR 2, A and R 2 being as defined in claim 1.   Process for the preparation of indoleacetic ester of formula (Ia) CH 3 CH 3 CH 2 COOCH CH 3 L C = 2 O CH 3   C) (Ia), characterized in that it comprises the reaction of a compound of general formula (II) or of a derivative reactive derivative CH 3 O CH 2 COOH   C = O Cl (II) with 2,3-butanediol of formula (III) GB 3-GB-GB-CH 3   (III) -6 Process for the Preparation of an Indoleactive Ester Derivative of a General Factor (Ib) CH 3 C 3 O CH 2 COOCH CH 3 CHUCOR 6   In which R 6 has the same meaning as below, characterized in that it comprises the reaction of an indoleacetic ester of formula (Ia) CH 3 CH 30 CH 2 COOCH Y CH 3 CH-OH (Ia) C = O CH 3 Q   C1 with a carboxylic acid of general formula (IV) or its reactive derivative 1 SR 6 COOR (IV)   wherein R 6 represents an alkyl group, an alkenyl group, a phenyl group unsubstituted or substituted by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a formyl group, a hydroxy group, a acyloxy group, an alkoxycarbonyl group or a group   alkylenedioxy; a group -A-R 2 in which A represents an alkylene group   C 1 -C 4 oxyen, or a propenylene group, and R 2 represents a phenyl group unsubstituted or substituted by a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a formyl group, a group   hydroxy, an acyloxy group, an alkoxycarbonyl group or an alkylene group   dioxy, or a group R 3 R 4 in which R 3 represents a hydrogen atom, I 1 C C -R 5   a halogen atom, a cyano group, a lower alkyl group or a group   phenyl, R 4 represents a hydrogen atom, a lower alkyl group or a phenyl group and R represents an unsubstituted phenyl group or 5   substituted by a lower alkyl group, a lower alkyloxy group, a   acyloxy group or a halogen atom.   Process for the preparation of an indoleacetic ester derivative of the general formula (Ib) CH. CH 30 CH 2 COOCH N CH 3 CH-OCOR 6 (Ib) 3 2 C = O CH 3   Wherein R has the same meaning as in claim 6,   characterized in that it comprises the reaction of a monoester derivative of 2,3-   butanediol of the general formula (V) CH-CH-CH-CH 3 i 3 (V) OH OCOR 6   in which R 6 has the same meaning as in claim 6, with a compound of formula (II) or its reactive derivative CH 30 CH 2 COOCH H t I (II) C = O $   Cl 8 Drug in particular with anti-inflammatory and analgesic properties, characterized in that it is constituted by the derivative according to any one Claims 1 to 4.   9 Pharmaceutical composition, characterized in that it is constituted   by at least one derivative according to any one of claims 1 to 4,   combination with a pharmaceutically acceptable carrier.