CH627728A5 - Preparation of carboxylic acids derived from indane - Google Patents

Description

627728

CLAIMS 1. Process for the preparation of a compound of formula:

in which R4 is a phenyl radical substituted by one or two halogen atoms, or a thienyl radical, A is a lower alkylene group and Q is a lower alkyl group, characterized in that a compound of formula is prepared:

(I)

cooh in which R is a phenyl radical substituted by at least one substituent chosen from halogens and acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl and sulfamido groups; a thienyl radical substituted by at least one substituent chosen from halogens and lower alkyl radicals; or a furyl radical substituted by a lower alkyl group, and of its therapeutically acceptable salts, characterized in that a compound of formula is reacted, according to the Friedel and Crafts reaction:

cooh by the process according to claim 1, it is transformed into its acid chloride, and is reacted with a dialkylaminoalkylamine of formula H2N — A — N (Q) 2, at a temperature between 15 10 and 20 ° C.

20

di)

COOfi »

The subject of the invention is a process for the preparation of a compound of formula:

R -

in which R 'is a lower alkyl radical, with an acyl halide of formula:

r-c-x

(III)

X being a halogen atom, and submitting the intermediate compound of formula:

(IV)

coor "

to alkaline hydrolysis.

2. Process for the preparation of a compound of formula:

coor2

in which R2 is a di (lower alkyl) lower aminoalkyl radical and R3 is a thienyl or furyl radical, characterized in that a compound of formula is prepared:

cooh by the process of claim 1 and that it is condensed with a corresponding haloalkyldialkylamine, in an alcoholic solvent medium.

3. Process for the preparation of a compound of formula:

(I)

cooh

In which R is a phenyl radical substituted by at least one substituent chosen from halogens and acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl and sulfamido radicals; a thienyl radical substituted by at least one substituent chosen from halogens and a lower alkyl radical, or a furyl radical substituted by a lower alkyl radical.

In particular when R is a phenyl radical, it is substituted by at least one substituent chosen from chlorine and the acetamido, dimethylamino, methylsulfonyl, dimethylsulfonyl and sulfamido radicals; when R is a substituted thienyl radical, it is substituted with at least one substituent chosen from chlorine and the methyl radical; when R is a furyl radical, it is substituted by a methyl radical.

The new acids are in particular p- (dimethyl-amino) benzoyl-5 indane-2 carboxylic acids, p- (methylsulfonyl) benzoyl-45 5 indane-2 carboxylic acid, (parasulfamidobenzoyl) -3 indane-2 carboxylic acid, (paradimethylaminosulfonyl) benzoyl -5 indane-2 carboxylic, (acetamido-4 'chloro-3') benzoyl-5 indane-2 carboxylic, [(methyl-3 'thénoyl) -2'] -5 indan-2 carboxylic, [(dichloro-4, 5 'thenoyl) -2 /] -5 indane-2 carboxylic, [(methyl-5' furoyl) -2 '] -5 so indane-2 carboxylic.

The present invention also relates to the preparation of aminoesters, such as the lower dialkyl lower aminoalkyl esters. These amino esters are derived from the carboxylic acids represented by the general formula I in which R is a thienyl or furyl radical. 55 The aminoesters are in particular the (2-thoyl-2 ') - 5 indane-2 carboxy-late from N, N-diethylamino-2' ethyl, (2-furoyl) - 5-indane-2 carboxy-late from N, N diethylamino -2 ethyl.

The present invention also relates to the preparation of lower alkyl amides lower aminoalkyl derivatives of carboxylic acids, represented by the formula:

conh-a-n (q)

conhan (q)

in which A is a lower alkylene group, Q is a lower alkyl group and R4 is a phenyl radical substituted by a

3

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or two halogens, or a thienyl radical. The carboxamides are in particular diethylaminoethylcarboxamides, such as benzoyl-5 N (N ', N'-diethylamino-2' ethyl) indane-2 carboxamide, (thénoyl-2 ') - 5N (N', N 'diethylamino-2 ethyl) indan-2 carboxamide and (dichloro-2 ', 5' benzoyl-) 5 N (N'N 'diethylamino-2' ethyl) indan-2 carboxamide. s

The new derivatives are prepared from an ester of formula (II) in which R ′ is a lower alkyl group:

(ii)

An aroyl halogen of formula (II) is reacted on the latter, according to the conditions of the Friedel and Crafts reaction.

R4-COX (III)

in which R4 has the abovementioned meaning and X represents a halogen. Then, the compound obtained is subjected to alkaline hydrolysis.

The acylation reaction can be carried out with or without solvent,

but preferably with a suitable solvent such as methylene chloride, carbon sulfide, etc., at temperatures ranging from 0 ° C to the boiling point of the solvent, preferably at the reflux temperature solvent. Among the Lewis acids which can be used, aluminum chloride is preferred, the various reagents may be present in stoichiometric amounts or in excess, preferably in excess as regards the aroyl halide and aluminum chloride, this excess of up to 400%. 30

As regards in particular the compounds in which R is a phenyl group substituted by a sulfamido or dimethyl-sulfamido radical, one starts from an ester of formula (IV), obtained by the first step above:

r - co ^ (iv) 35

40

coor1

wherein R 'is a lower alkyl group and R a phenyl group substituted by an amino radical.

The compound (IV) in which R and R ′ have the abovementioned meanings is subjected to a diazotization according to the techniques known per se, then the aryldiazonium salt obtained is treated with a solution of sulfur dioxide in acetic acid in the presence of a copper salt, preferably cupric chloride, so as to obtain a compound of formula (IV):

water, in the presence of hydrogen and a hydrogenation catalyst, preferably palladium on carbon and at an appropriate temperature.

The compounds of formula (IV) are thus obtained for which R is a phenyl group substituted by a dimethylamino radical, R ′ having the meaning cited above.

Finally, when R is a radical substituted by at least one halogen, these compounds are obtained by treating a compound of formula (IV) in which R is a monosubstituted phenyl, thienyl or furyl radical and R 'has the meaning mentioned above, by a solution of halogen in acetic acid, this solution may or may not be saturated, and the reaction taking place at temperatures ranging from room temperature to that of reflux.

The anti-inflammatory, analgesic and anti-platelet aggregation pharmacological activity of the compounds according to the invention has been demonstrated on animals.

A. The products are generally not very toxic. The LD 50 is determined in mice.

B. The analgesic activity was determined in mice by the method of Koster et al. ("Fed. Proc.", 1959,18,412). We are looking for the active dose 50 of the product which, administered orally, reduces painful contractions caused by intraperitoneal injection of an acetic acid solution by 50%.

C. Anti-inflammatory activity was shown by the carrageenan edema test according to Winter et al. ("Proc. Exp. Biol. Med.", 111, 544-47). We seek the protection conferred by treatment with the product administered per os to the rat against edema triggered by injection under the arch of a suspension of carrageenan. The active dose DA 30 is that which inhibits 30% of the edema.

D. The protective activity against early inflammation was determined on the albino guinea pig according to the method of Winder et al. ("Arch. Inv. Pharmacodyn.", 1958,116,261). We are looking for the DA 50 of the product which, administered orally to the animal, decreases the erythema produced by 50% by exposure to ultraviolet radiation from the shaved dorsal surface of the guinea pig.

E. The antiplatelet efficacy of platelets is determined in vitro by induced aggregation with collagen according to the method of Börn.

The results are recorded in the following table. The active doses are expressed in mg / kg, with the exception of platelet aggregation where it is the minimum active concentration in y / ml.

(Table at the top of the next page)

The therapeutic compositions containing as active principle at least one compound according to the improvement and a solid or liquid pharmaceutical carrier or diluent can be in the form of tablets, injectable solutions, suppositories and the like.

r -

(IV) 50

Example of formulation Active ingredient ....

200 mg coor "

wherein R 'has the same meaning as above and R is a phenyl radical suitably substituted by a chlorosulfonyl radical.

By treating the latter with gaseous ammonia or in solution in water or in a lower alkanol, the compound of formula (IV) is obtained, in which R is a phenyl radical substituted by a sulfamido radical. If the ammonia is replaced by dimethylamine, a compound of formula (IV) is obtained in which R is a phenyl radical substituted by a dimethylsulfamido radical.

As regards the compounds in which R is a phenyl radical substituted by a dimethylamino radical, a compound of formula (IV) is treated in which R ′ is a lower alkyl group and R a phenyl radical substituted by an amino radical, by the formaldehyde in its monomeric form, pure or in solution in

Excipients

Lactose 30 mg

55 Wheat starch. : 29 mg

Talc 10 mg

Gelatin 5 mg

Alginic acid 20 mg

Starch 5 mg

Magnesium stearate 1 mg

For one 300 mg tablet

Therapeutic compositions containing as active ingredient an indane derivative according to the improvement are effective as anti-inflammatory, analgesic and anti-platelet aggregating agents at doses of between 50 and 500 mg per unit dose, the dosage can be adjusted for obtain the optimal therapeutic response.

627728

4

DL 50

Acetic acid DA 50

DA 30 carrageenan

UV DA 50

Collagen aggregation

[(3-methyl 'thenoyl) -2'] - 5 indan-2-carboxylic acid

1200

37

26

25

10

[(Methyl-5 'furoyl) -2'] - 5 indan-2 carboxylic acid

2400

8

10

16

1

[Paradimethylaminobenzoyl] -5 indan-2 carboxylic acid

960

3

14

20

0.5

(Paramethylsulfonylbenzoyl) -5 indane-2 carboxylic acid

2800

35

40

10

1

(Parasulfamidobenzoyl) -5 indane-2 carboxylic acid

> 3200

25

43

90

5

Carboxylic acid (paradimethylaminosulfonylbenzoyl) -5 indane-2

2600

80

160

> 300

10

f (Acetamido-4'chloro-3 ') benzoyl] -5 indane-2 ethyl carboxylate

3200

35

60

80

5

[(4'-dichloro, 5 'thenoyl) -2] -5 indane-2 carboxylic acid

180

30

42

90

7.5

(2'-Thénoyl ') - 5 indane-2 carboxylate of N, N 2-ethyl-diethylamino, hydrochloride

2160

4

8

10

0.25

(Furoyl-2 ') - 5 indane-2 carboxylate of N, N 2-ethylethylamino, hydrochloride

1200

8

18

20

1

Benzoyl-5 N- (N'N 'diethylamino-2' ethyl) indane-2 carboxamide, Oxalate

1100

30

9

25

2.5

(2-Thénoyl-2) - 5 N- (N'N '2-ethyl diethylamino) 2-indane carboxamide, Oxalate

660

2.5

8

10

0.25

(Dichloro-2 ', 5' benzoyl) -5N (N'N 'diethyl-amino-2' ethyl) indan-2 carboxamide, Oxalate

720

15

25

50

2.5

(4 'Dimethylamino benzoyl) -5 methyl indane-2 carboxylate

1450

2.5

12

24

0.25

Examples of the preparation of the compounds are given below which illustrate the improvement, without limitation.

Example 1:

[(3-methyl 'thenoyl) -2'] -5 indan-2 carboxylic acid CHo

Ci6H1403S P.M. = 286.33

a) [! Methyl-3 'thenoyl) -2'J -5 indane-2 methyl carboxylate: C17Hl603S.

In a 250 ml reactor equipped with a stirrer, a condenser fitted with a calcium chloride guard, a vial

bromine and a thermometer, 18.5 g (0.139 mol) of aluminum chloride and 14.1 g (0.08 mol) of 50 methyl indan-2-carboxylate are introduced dropwise through the ampoule. bromine. The temperature reaches 35 ° C at the end of the addition. Heat slightly to homogenize. Then, at a temperature in the region of 20 ° C., 12.8 g (0.08 mol) of 3-methyl-2-thiophene-2-carboxylic acid chloride are added dropwise. It is then gradually heated up to around 55 70-80 ° C. This temperature is maintained for 30 min, then allowed to return to around 40 ° C. At this point, methylene chloride is added and then the solution obtained is poured into ice water containing hydrochloric acid. The organic phase is decanted, washed with soda water and then with water. It is dried over sodium sulfate, filtered, the filtrate is concentrated and the residue is distilled. A thick oily fraction Ebo is collected, 7 torr: 180-200 ° C.

Infrared spectrum:

vCO: 1740 cm_1vCO: 1640 cm-1.

NMR spectrum:

65 - mass of 5 aromatic protons centered around 7.4 ppm;

- peak of 3 OCH3 protons at 3.4 ppm;

- peak of 5 indane protons at 3.33 ppm;

- peak of 3 protons CH3 at 2.4 ppm.

5

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b) Transition to [- (methyl-3 'thénoyl) -2'] -5 indane-2 carboxylic acid:

6.7 g (0.0223 mol) of ester obtained under a dissolved in 30 ml of methanol, 2.8 g (0 g) are successively introduced into a 250 ml reactor equipped with stirring and a condenser. 0.05 mol) of potassium hydroxide dissolved in 30 cm3 of methanol. The mixture is heated at reflux for 1 hour. Concentrate to dryness, take up in water, wash with ether in an alkaline medium. The aqueous phase is acidified cold with hydrochloric acid; a solid precipitates. It is wrung, washed with water, dried. By recrystallization from ethyl acetate, a solid io is obtained, melting at 136-138 ° C (capillary tube).

Infrared spectrum:

vCO: 1700 cm_1vCO: 1635 cm "1.

NMR spectrum: 15

- massif of 5 aromatic protons centered around 7.32 ppm;

- peak of 5 indane protons around 3.4 ppm;

- peak of 3 methyl protons at 2.47 ppm;

- peak of 1 OH proton around 10.7 ppm.

Acidity index: 20

Found: 195. Calculated: 190.

Centesimal analysis:

Calculated: C 67.13 H 4.93 S 11.20%

Found: C 67.06 H 4.99 S 11.24% 25

Example 2:

[(5-methyl 'furoyl) -2'] -5 indan-2 carboxylic acid.

a) [(Methyl-5 'furoyl) -2'] -5 methyl indane-2 carboxylate:

CnHl60A. ^

In a 250 ml reactor, equipped with an agitator, a condenser provided with a calcium chloride guard, a dropping funnel and a thermometer, 11.4 g (0.086 mol) of aluminum chloride suspended in 30 ml of methylene chloride and 5.5 g (0.0382 mol) of chloride of 5-methyl furan carboxylic acid-2 in solution in 30 ml of methylene chloride. The mixture is brought to a temperature of 20 ° C. and then dropwise added a solution of 5.6 g (0.0318 mol) of methyl indan-2 carboxylate in 50 cm3 of methylene chloride. The mixture is left stirring for 2 h at ambient temperature, then heating for 3 h at reflux. It is left to stand overnight, then poured into a bath of acidulated ice water. Extraction is carried out with methylene chloride, the extract is washed with soda water, with water, dried over sodium sulphate, filtered, the filtrate is concentrated and the residue is distilled. An Ebi ton- fraction is collected: 195-205 ° C.

Infrared spectrum: 55

vCO: 1740 cm_1vCO: 1645 cm-1.

NMR spectrum:

- massif of 4 aromatic protons around 7.33 ppm;

- 1 aromatic proton around 6.2 ppm;

- peak of 5 indane protons at 3.3 ppm;

- peak of 3 OCH3 protons at 3.7 ppm;

- peak of 3 CH3 protons at 2.47 ppm.

b) Transition to [(methyl-5 'furoyl) -2'] -5 indane-2 carboxylic acid:

2.7 g 65 (0.0095 mol) of ester obtained under a dissolved in 16.5 cm3 of methanol and 1.16 g (0.0208 mol) of potassium hydroxide are successively introduced into a 50 ml reactor. solution in 16.5 cm3 of water. The mixture is left at room temperature for 48 h. Concentrate to dryness, take up in water, wash with ether in an alkaline medium, then acidify the aqueous phase. Extracted with ether, dried over sodium sulfate, filtered and concentrated the filtrate. The residue obtained after recrystallization from an ethyl acetate / hexane mixture melts at 128-130 ° C (capillary tube).

Infrared spectrum:

vCOnOOcm-SCOilôSS cm "1.

NMR spectrum:

- 1 OH proton around 10.6 ppm;

- massif of 4 aromatic protons centered around 7.5 ppm;

- 1 aromatic proton around 6.8 ppm;

- 5 indane protons at 3.36 ppm;

- 3 protons CH3 at 2.47 ppm.

Centesimal analysis:

Calculated: C 71.10 H 5.22%

Found: C 70.99 H 5.16%

Example 3:

(4-Dimethylamino-benzoyl) -5 indane-2 carboxylic acid.

a) (4-dimethylamino benzoyl) -5 methyl indane-2 carboxylate:

C20H21NO3.

We can proceed as follows:

a) In a 250 cm3 autoclave, 5 g (0.017 mol) of (amino-4 'benzoyl) -5 methyl indane-2 carboxylate, 100 cm3 of ethanol, 26 cm3 of 36% formaldehyde are introduced. in water, in the presence of 2 g of Pd / C at 5%. The mixture is heated to approximately 40 ° C. with stirring after having loaded the autoclave with hydrogen. After absorption of the theoretical amount, it is filtered to remove the catalyst. The ethanol is concentrated in vacuo, taken up in water and extracted with ether. It is dried over sodium sulfate, filtered and the filtrate is concentrated. The residue after recrystallization from an ethyl acetate / diisopropyl ether mixture melts at 87-89 ° C (capillary tube).

Infrared spectrum:

vCO: 1740 cm "1 vCO: 1640 cm-1.

Disappearance of NH2 bands.

NMR spectrum:

- doublet of 2 aromatic protons: 7.85 ppm;

- multiplet of 2 aromatic protons: 7.55 ppm;

- multiplet of 1 aromatic proton: 7.25 ppm;

- doublet of 2 aromatic protons: 6.7 ppm;

- peak of 3 CH3 protons: 3.8 ppm;

- solid mass of 5 indane protons: 3.35 ppm;

- peak of 6 CH3 protons: 3.1 ppm.

Centesimal analysis:

Calculated: C 74.29 H 6.55 N4.33%

Found: C 74.41 H 6.60 N 4.42%

b) 9.6 g (0.068 mol) of methyl iodide, 4.9 g (0.034 mol + 5%) of K2CO3, 30 cm3 of dimethylformamide and 5 g (0.017 mol) are introduced into a 125 cm3 autoclave of methyl (4-amino benzoyl) -5 indan-2 carboxylate. The mixture is left stirring for 24 h. The dimethylformamide is evaporated in vacuo, taken up in water, extracted with ether. It is dried over sulfate, filtered and the filtrate is concentrated. The residue obtained is recrystallized from an ethylediisopropyl ether acetate mixture. A product is obtained whose physical and spectral characteristics are identical to those of the product obtained according to a.

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c) Transition to (dimethylamino-4 'benzoyl) -5 indane-2 carboxylic acid:

According to Example 1b, from 5.6 g (0.017 mol) of (dimethyl-amino-4 'benzoyl) -5 indane methyl carboxylate and 1.95 g (0.0348 mol) of potassium hydroxide in 60 ml of methanol. By recrystallization from ethyl acetate, a solid melting at 164-165 ° C. is obtained (capillary tube).

Infrared spectrum:

vCO: 173ö cm-1 vCO: 1620 cm-1.

NMR spectrum:

- massif of 7 aromatic protons centered around 7.23 ppm;

- peak of 5 indane protons at 3.3 ppm;

- peak of 6 protons CH3 at 3.1 ppm.

a) According to Example 1 a, methyl (paraniethylsulfonyl) benzoyl-5 indanecarboxylate is prepared from 14.5 g

(0.107 mol) of aluminum chloride and 11 g (0.0475 mol) of paramethylsulfonylbenzoic acid chloride, all in 60 ml of methylene chloride, and 7 g (0.0397 mol) of indan-2 methyl carboxylate in 30 ml of methylene chloride. After concentration and recovery of the residue with hexane, a solid is obtained which is used crude.

b) According to Example 1b, the acid is prepared from 3 g (0.0084 mol) of ester obtained under a, 1.1 g (0.02 mol) of potassium hydroxide in 50 ml of methanol. By recrystallization from ethanol, a solid melting at 187-190 ° C is obtained (capillary tube).

Centesimal analysis:

Calculated: C 73.77 H 6.19 N 4.53%

Found: C 73.90 H 6.05 N 4.53%

Example 4:

(Paramethylsulfonyl) benzoyl-5 indane-2 carboxylic acid.

ch3-s02

c18h16o5s

M.P. = 344.37

Infrared spectrum:

vCO: 1710 cm-1vCO: 1670 cm "1.

15 NMR spectrum:

- massif of 7 aromatic protons centered around 7.8 ppm;

- peak of 5 indane protons at 3.33 ppm;

- peak of 3 CH3 protons at 3.17 ppm.

20 Acidity index:

Calculated: 163. Found: 155.

Centesimal analysis:

Calculated: C 62.78 H 4.68 S 9.31% 25 Found: C 62.90 H 5.01 S 9.17%

Example 5:

. 30 (Parasulfamidobenzoyl) -S indan-2 carboxylic acid.

h2n - s02.

C17H15N05S P.M. = 345.36

a) (ParachlorosulfonylbenzoylJ-5 indane-2 methyl carboxylate: 40 C1BHlsClOsS

14.7 g (0.05 mol) of (4-amino) are introduced into a 250 ml reactor with stirring, thermometer and dropping funnel

benzoyl) -5 methyl indane-2 carboxylate. At a temperature between 0 and 10 ° C., 40 ml of 24% hydrochloric acid 45 are added, then, between 0 and 5 "JC, a solution of 3.8 g of sodium nitrite in 10 ml of water. diazonium salt thus formed is then added to

cooh

15 ° C to a stirred mixture of 80 ml of acetic acid saturated with sulfur dioxide and 2.8 g of cupric chloride dissolved in 5 ml of water. The mixture is left to return to ambient temperature, warmed to around 40 ° C. to finish the reaction, left to stand overnight. The next day, we take up in ice water, wring out the solid which precipitates. We make sure of the product obtained by NMR and infrared spectrography.

b) Transition to methyl (parasulfamidobenzoyl) -5 indane-2 carboxylate:

h2n - s02

c18h17no5s

M.P. = 359.40

15.6 g (0.041 mol) of the derivative obtained under a, 150 ml of chloroform are introduced into a 500 ml reactor with stirring, condenser, dropping funnel. Then, with good stirring, 100 ml of 15% ammonia are added. The A h is allowed to stir at room temperature. It is taken up in water and chloroform. The chloroform phase is decanted, dried over sodium sulfate, filtered and concentrated. By recrystallization of the residue in an ethyl acetate / diisopropyl ether mixture, a solid melting is obtained at 147-149 ° C (capillary tube).

Infrared spectrum:

vNH: 3400-3320 cm "NCO: 1745 cm" 1 vCO: 1660 cm-1.

CO

cooch

3

NMR spectrum:

- range of 7 aromatic protons around 7.66 ppm;

- peak of 2 NH2 protons at 6.1 ppm;

- peak of 3 OCH3 protons at 3.7 ppm;

- peak of 5 indane protons at 3.3 ppm.

c) Transition to acid:

By operating according to Example 1 b from 11 g (0.0306 mol) 65 of ester obtained under b in solution in 100 ml of ethanol and 3.4 g (0.06 mol) of potassium hydroxide in solution in 100 ml of water, after recrystallization of the product obtained from an acetic acid / water mixture, a solid melting at 157-158 ° C. is obtained (capillary tube).

7

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Infrared spectrum:

vNH: 3320 cm "1 vCO: 1720 cm" 1 vCO: 1650 cm-1.

NMR spectrum:

- range of 7 aromatic protons around 7.6 ppm;

- peak of 2 NH2 protons around 6.6 ppm;

- 1 OH proton at around 10.5 ppm;

- 5 indane protons at 3.4 ppm.

Centesimal analysis:

Calculated: C 59.12 H 4.38 N 4.06 S 9.28% Found: C 59.38 H 4.14 N 4.09 S 9.24%

Example 6:

(Paradimethylaminosulfonyl) benzoyl-5 indane-2 carboxylic acid:

ch

3 \

n-so,

ch

3

c19h19no5s

M.P. = 373.41

a) (Paradimethylaminosulfonyl) benzoyl-5 indane-2 methyl carboxylate: CZ0H21NOsS:

It is prepared according to Example 5b from 28 g (0.074 mol) of methyl (parachlorosulfonylbenzoyl) -5 indane-2 carboxylate in 90 cm3 of chloroform, 34 ml (0.148 mol) of a 40-dimethylamine solution % in water.

b) Transition to acid:

According to Example 5c, from 21 g (0.0545 mol) of crude ester obtained at a in 200 ml of water, 6.15 g (0.11 mol) of potassium hydroxide in 200 ml of ethanol . After recrystallization from an ethyl acetate / hexane mixture, a solid melting at 144-145 ° C. is obtained (capillary tube).

Infrared spectrum:

vCO: 1700 cm ~ 1 mCO: 1660 cm ~ 1.

cooh

NMR spectrum:

■ - peak of 4 aromatic protons at 7.97 ppm;

- massif of 3 aromatic protons at 7.53 ppm;

- peak of 5 indane protons at 3.3 ppm;

- peak of 6 CH3 protons at 2.8 ppm.

Centesimal analysis:

Calculated: Found:

C 61.11 C 61.09

H 5.13 H 5.19

N 3.75 N 3.71

S 8.57% S 8.64%

Example 7:

35 [(Acetamido-4 'chloro-3') benzoyl] -5 indane-2 ethyl carboxylate:

ch3-co-nh c21h20cino4

M.P. = 385.8

co.

cooc2h5

8.8 g (0.025 mol) of ethyl (para-acetamidobenzoyl) -5 indane-2 carboxylate, 30 ml of acetic acid are introduced into a 250 ml reactor with stirring, condenser, • dropping funnel and thermometer. . At a temperature in the region of 10 ° C., 40 ml of acetic acid saturated with chlorine are added dropwise. The initial suspension gradually disappears. The mixture is left to return to ambient temperature for 1 hour, then the acetic acid is concentrated under vacuum. An oil is obtained which, by recrystallization from an ethyl acetate / hexane mixture, gives a solid, melting at 126-127 ° C (capillary tube).

Infrared spectrum:

vNH: 3350 cm "1 vCO: 1740 cm" 1 vCO: 1690 cm "SCO: 1650 cm" 1.

NMR spectrum:

- 1 aromatic proton around 8.6 ppm;

- range of 6 aromatic protons centered around 7.5 ppm;

- quadruplet of 2 CH2 protons around 4.2 ppm;

- 5 indane protons at 3.33 ppm;

- peak of 3 CH3 protons at 2.23 ppm;

- peak of 3 CH3 protons at 1.3 ppm.

Centesimal analysis:

Calculated: C 65.37 H 5.23 Cl 9.19 N3.63% Found: C 65.50 H 5.22 Cl 9.15 N3.63%

Example 8:

Acid [(dichloro-4 ', 5' thenoyl) -2'J -5 indane-2 carboxylic:

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5.2 g (0.017 mol) of is introduced into a 250 ml reactor equipped with stirring, a condenser, a dropping funnel and a tube allowing a gas bubbling within the reaction mixture. [(chloro-5 'thénoyl) -2'] - 5 indane-2 carboxylic acid. 27 ml of acetic acid saturated with chlorine are added thereto at around 15 ° C. Then heated in a water bath to 75 ° C while bubbling chlorine into the reaction mixture. After cooling, a solid is isolated by wringing. The latter, recrystallized from ethyl acetate, sees its melting point stabilize at 190-192 ° C (capillary tube).

Infrared spectrum:

vCO: 1720 cm "SCO: 1650 cm" 1.

NMR spectrum:

- mass of 3 indane protons plus 1 thiophene proton centered around 7.5 ppm;

- peak of 5 indane protons at 3.33 ppm.

Centesimal analysis:

Calculated: C 52.80 H 2.95 Cl 20.78 S 9.40%

Found: C 52.86 H 2.98 Cl 20.82 S 9.48%

Example 9:

(2'-Thénoyl ') - 2 indane-2, N, N-2' diethylamino carboxylate ethyl:

C21H25N03S P.M. = 371.48

a) In a 500 ml reactor equipped with stirring, a condenser, a dropping funnel, 27.1 g (0.1 mol) of (2-thénl-2 ') acid are successively introduced. indan-2 carboxylic, 200 ml of isopropanol, 16.6 g (0.1 mol + 20%) of potassium carbonate, 17.2 g (0.1 mol) of chloroethyldiethylamine hydrochloride, 150 ml of isopropanol. It is heated for 15 h at reflux. Concentrate to dryness, take up in water and dilute hydrochloric acid, wash with ether in an acid medium. One passes in an alkaline medium on the aqueous phase and extracted with ether. It is dried over sodium sulfate, filtered and the filtrate is concentrated. The residue is distilled and a fraction Eb0 7_0 8 roof 230-240 ° C is collected.

Infrared spectrum:

vCO: 1740 cm-1 vCO: 1650 cm-1.

NMR spectrum:

- range of 6 aromatic protons around 7.47 ppm;

- triplet of 2 CH2 protons around 4.2 ppm;

- peak of 5 indane protons at 3.33 ppm;

35

- mass of 6 CH2 protons around 2.7 ppm;

- triplet of 6 CH3 protons around 1.07 ppm.

b) Switching to the hydrochloride:

C21H26C1N03S. M.P. = 407.94.

According to known techniques, after recrystallization from ethanol, a solid melting at 157-158 ° C. is obtained (capillary tube).

Acidity index:

Found: 132. Calculated: 137.

Infrared spectrum:

vCO: 1745 cm_1vCO: 1630 cm-1.

Centesimal analysis (hydrochloride):

Calculated: C 61.83 H 6.43 Cl 8.69 N3.43 S 7.86%

Found: C 61.86 H 6.57 Cl 8.56 N3.40 S 7.89%

Example 10:

(Furoyl-2 ') -5 indane-2 carboxylate of N, N 2-ethylethylamino:

C2iH25N04 P.M. = 355.42

cooch2-ch2-n

c2h5

C2H5

Prepared according to Example 9 from 21.4 g (0.0835 mol) of (2-furoyl-2 ') - 2 indan-2-carboxylic acid, 14.2 g (0.0835 mol 4- 20%) potassium carbonate and 14.4 g (0.0835 mol) of chloroethyldiethylamine hydrochloride. By distillation, an Ebo fraction, 5-0.4 torr * 200-220 ° C., is collected.

Infrared spectrum:

vCO: 1740 cm-1vCO: 1650 cm "1.

NMR spectrum:

- range of 3 aromatic protons around 7.83 ppm;

- massif of 2 aromatic protons around 7.3 ppm;

- 1 aromatic proton around 6.53 ppm;

- mass of 2 CH2 protons around 4.1 ppm;

- peak of 5 indane protons at 3.33 ppm;

55 - • massif of 6 CH2 protons around 2.7 ppm;

- solid mass of 6 CH3 protons around 1.07 ppm.

Switching to hydrochloride:

60 C21H26ClNO +.

After recrystallization from an ethyl acetate / ethanol mixture, a solid melting at 165-166.5 ° C. is obtained (capillary tube).

Acidity index:

Calculated: 142. Found: 143.

65

Centesimal analysis (hydrochloride):

Calculated: C 64.36 H 6.69 Cl 9.05 N3.57%

Found: C 64.44 H 6.49 Cl 8.98 N3.53%

627728

Example 11:

Benzoyl-5 N (N ', N' diethylamino-2 'ethyl) indan-2 carboxamide:

M.P. = 364.47

c2h5

o-nh-ch2-ch2-n

c? .h5

25.5 g (0.2 mol + 10%) of (N'N 'diethylamino) are introduced into a 250 ml reactor equipped with stirring, a condenser with a dropping funnel and a thermometer ) -2 ethylamine in 50 ml of dioxane. At a temperature between 10 and 20 ° C., a solution of 30.2 g (0.1 mol) of 5-benzoyl-indan-2-carboxylic acid chloride in 50 ml of dioxane is added. It is then left to return to ambient temperature and then run for 1 hour at this temperature. The dioxane is concentrated in vacuo, taken up in ice water and extracted with ether in an alkaline medium. The ether extract is dried over sulfate, filtered and the filtrate concentrated. An oil is obtained on which an Oxalate is made. After recrystallization from an acetone / alcohol mixture, a melting point of 153-154 ° C. is obtained (capillary tube).

Acidity index:

Calculated: 246. Found: 226.

Infrared spectrum:

vCO: 1660 cm-1.

Centesimal analysis for C25H30N2O6:

Calculated: Found:

C 66.07 C 66.10

H 6.65 H 6.50

N 6.17% N 6.18%

Example 12:

(2'-Thénoyl ') - 5 N (N', N '2-diethylamino-ethyl) indane-2 carboxamide:

\ s co

C21H26N202

M.P. = 370.51

Prepared according to Example 11 from 9.4 g (0.03 mol) of 2-thénoyl-2-indan-2-carboxylic acid chloride, 7.7 g (0.066 mol) of (N ', N 'diethylamino) -2 ethylamine, 120 ml of dioxane. By passing to the oxalate, a solid melting at 110.5-112 ° C. is obtained after recrystallization from acetone (capillary tube). 40

Acidity index:

Calculated: 243. Found: 247.

co-nh-ch2-n ^

-c2h5

c2h5

NMR spectrum:

- range of 6 aromatic protons around 7.4 ppm;

- mass of 5 indane protons + 8 CH2 protons around 3.33 ppm;

- triplet of 6 CH3 protons around 1.27 ppm.

Centesimal analysis for C23H28N206S:

Calculated: C 59.98 H 6.13 N 6.09 S 6.96%

Found: C 59.95 H 6.26 N 5.96 S 7.06%

Infrared spectrum: vCO: 1630 cm-1.

45

Example 13:

(Dichloro-2 ', 5') - 5 N (N ', N' diethylamino-2 'ethyl) indan-2 carboxamide:

Cl co

C23H26C12N202 P.M. = 433.38

Prepared according to Example 11 from 17.6 g (0.048 mol) of 2-dichloro-acid chloride, - 5 ') 5-benzoyl-indane-2-carboxylic acid, 13.9 g (0.12 mol) of (N'N 'diethylamino) -2 ethylamine, 80 ml of dioxane. By passage through the oxalate and after recrystallization from acetone, a solid melting at 103-104 ° C. is obtained (capillary tube).

Acidity index:

Calculated: 216. Found: 206.

Infrared spectrum:

vCO: 1670 cm-1.

c0-nk-ch2-ch2-n c2h5

c2h5

NMR spectrum:

- range of 6 aromatic protons centered around 7.46 ppm; 60 - mass of 5 indane protons 4-8 CH2 protons around 3.43 ppm;

- triplet of 6 CH3 protons around 1.33 ppm;

- 1 NH proton around 8.3 ppm.

6J Centesimal analysis for C25H28C12N206:

Calculated: C 57.37 H 5.39 N5.35 Cl 13.55% Found: C 57.38 H 5.48 N5.39 Cl 13.56%

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