CH620674A5 - Acetylenic sulfamidobenzamides which can be used in therapeutics - Google Patents

Description

The present invention relates to novel acetylenic sulfamido derivatives of aminoalkylbenzamides intended for application

3

620 674

therapeutic, their salts with therapeutically acceptable inorganic and organic acids, their preparation process and their use for the preparation of pharmaceutical compositions containing them. These compounds and their salts can be used, in particular, in the treatment of digestive and / or psychosomatic disorders.

We already knew benzamides substituted on the nitrogen atom by a basic chain. The main derivatives of this chemical class present the structure of amides of ortho-methoxybenzoic acid with a diamine. These are in particular the Meto-chlopramide (A) described by Thominet in the American patent N ° 3177252 (Society of Scientific and Industrial Studies of Ile-de-France), the Sulpiride (B) described by Miller in the American patent N ° 3342826 (Scientific and Industrial Studies Company of Lonjumeau), Sultopride (C) described in French patent N ° 2187309 (Delagrange Laboratory) and Tiapride (D) described by Bulteau and Acher in German patent N ° 2327192 :

/ C2H5

; 0-nh-ch „-ch -n * ^

H

° 2H5

in which R represents one of the following groups: alkyl

- (CH ^ -N / "" ^, - (ch,) - n s \ e - n lower alkyl i ° -CH

V

o2H5 °.

ch-, 0os;> 2

The compounds according to the invention correspond to the general formula:

-co-nh-r

X-

T

15

n representing one of the numbers 2,3 and 4 and (CH2) „, which can also signify the group - CH2 - CH -, X in position 2,3 or 4 with respect to

CH3

20 to the carboxamide group, represents a hydrogen or halogen atom or a lower alkoxy, R 1 and R 2 represent, taken separately, hydrogen atoms or lower alkyls or, taken together with the adjacent carbon atom, a saturated carbon ring, and R3 represents a hydrogen atom or a group

/ R4

—CH2—, R4 and R5 representing, taken separately, Rs lower alkyls or, taken together with the adjacent nitrogen atom, one of the following groups:

25

3 *

35

/ \ / \

-N O, -N N-CH

\ _V W / ~~ \

-N N-benzyl.

40 ^ /

The invention also includes N- (N'-ethyl pyrrolidino-2 'methyl) (dimethyl-1 ", 1" propynyl-2 "amino sulfonyl) -4 benzamide."

The saturated carbon ring that Ri and R2 can form with the adjacent carbon atom can be, for example, a cyclo ring.

45 hexyl.

In the following examples, the new compounds are designated by a code number in order to facilitate the presentation of the text and the presentation of the results of the experiments to which they have been subjected.

The starting materials used for the preparation of these compounds can be prepared according to the following reaction scheme:

c - oh

Rn

SO,

, -nh-A-csc-r,

laughed

+ nh2-c-c = c-r3

I

R2

c - oh

P2

r_

so-nh - c - c - c

- r,

620 674

4

These sulfamidoacetylene acids are new and serve as intermediates for preparing the derivatives of general formula I by amidi-fication with an amine of formula R — NH2, of a sulfamido-benzoic acid of formula:

: ooh x-

V ï1

SO0-NH-C-Ca £ ~ R.

(he)

I

R2

R, X, Ri, R2 and R3 having the meanings mentioned above, or p- (N-dimethyl-r, 2-propynyl-aminosulfonyl) -benzoic acid or a reactive functional derivative of said acids .

As reactive functional derivative, there may be used, in particular, an acid halide such as chloride or bromide, a mixed anhydride such as those corresponding to the partial formula - OCO - O - lower alkyl, or an aminolysable ester.

The operating modes are illustrated in the following examples:

Example 1:

N- (N'-ethylpyrrolidino-2 'methyl) 2-methoxy hydrochloride

(dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -5 benzamide

(F 1603)

a) Preparation of N- (dimethyl-l'-propyn-2 'yï) 3-carboxy-4-methoxy benzenesulfonamide

In a solution of 106.5 g (1.28 mol) of methyl 2-butyn-3 amine-2 and 1250 cm3 of water, with stirring on an ice bath, introduce in fractions of 100 g (0.4 mol ) 3-carboxy-4-methoxy benzenesulfonyl chloride. Keep stirring overnight at room temperature then acidify to pH 1 with a 6N hydrochloric acid solution. Spin, wash with water and recrystallize from ethyl acetate. 88 g of product with a melting point of 168 ° C. are recovered. Yield 75%.

b) Preparation of F 1603

In a solution of 74.5 g of N- (dimethyl-1'-r propyn-2 'yl) -carboxy-3-4-methoxy benzenesulfonamide, 25.35 g of triethylamine and 750 cm3 of tetrahydrofuran, add dropwise drop with stirring at 0 ° C a solution of 29.90 g of ethyl chloroformate in 60 cm3 of tetrahydrofuran for 2 h at 0 ° C and introduce dropwise a solution of 32.11 g of N-ethylamino-methyl-2 Pyrrolidine in 60 cm3 of tetrahydrofuran.

Keep stirring at room temperature, then distill until dry. Take up with water and basify with C03K2. Spin, wash with water and dry. 80 g of product are recovered. Yield 80%. Melting point 136 ° C.

Hydrochlorination

Dissolve the product in 4 volumes of methanol and add, while warming, an ethanolic solution saturated with HCl until pH 1. Concentrate and add ethyl ether until the end of precipitation. The product of formula is recovered with a yield of 90%:

- CH.

O 11 C

- NH -

- NH -

Ïh3

VS -

I

CH_

C H C - H

Crude formula: C2oH30C1N304S Molecular mass: 444 Melting point: 205 ° C White crystals s IR spectrum: Vmh at 3370 cm "1 (free) and 3140 cm" 1 (bound);

vc = c at 1600 cm-1 and vs = Q at 1300-1350 cm-1 and 1150 cm "1-1200 cm" 1.

Plate chromatography:

- support: silica gel 60 F 254 Merck io - solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.45

Solubility: soluble in water.

Example 2:

15

N- (N'-N'-N'-diethylamino-2 'ethyl) methoxy-2 (iiimethyl-1 "-l" propinyl-2 "aminosulfonytf-5 benzamide hydrochloride (F 1744)

The procedure is as in Example 1, but using diethyl-20 aminoethylamine; we obtain the product of formula:

O - CH,

3 O

And

C - NH - CII2 - CH2- N

H

And

HIS -

H

CH3

I

VS -

Cl

C = CH

CH.

35

40

Crude formula: C19H30CIN3O4S Molecular mass: 431.98 White crystals Melting point: 195 ° C Plate chromatography:

- support: silica 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.45

45 Solubilities: soluble at 25% in water, soluble at 4% in ethanol at 95 ° GL and at 8% in dimethylacetamide.

Example 3:

N- (N'-N'-N'-diethylamino-2 'propyl) methoxy-2 50 (dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -5 benzamide maleate (F 1737)

The procedure is as in Example 1, but using diethyl-amino-2-propylamine, then the free base is treated with maleic acid; we obtain the product of formula:

CH,

O

li

VS

- NH - CH - CH - N

H and

\ /

"Read ® ^ And

CH,

S02 - NH - C - C 5.CH

CH.

° 2c

HO C.

5

620 674

Crude formula: C24H35N3O8S Molecular mass: 525.63 White crystals Melting point: 146 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.62

Solubilities: soluble in water at 10% and in ethanol at 95 ° GL.

Example 4:

N- [N'-N'-diethylaminp-3 'propyl) methoxy-2 (dimethyl-1 1 "propynyl-2" aminosulfonyî) -5 benzamide The procedure is as in Example 1, but using diethyl-aminopropylamine, we obtain the product of formula:

CH, O O And

3 1 11 /

C-NH-CH2-CH2-CH2-N ^

And

Example 6:

N- (N'-ethylpiperidino-3 ') methoxy-2 (dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -5 hydrochloride benzamide, monohydrate (F 1740)

The procedure is as in Example 1, but using N-ethyl amino-3 piperidine; we obtain the product of formula:

C - NH "

CH,

h n "■ / \

Cl

H20

And

-nh-c-c3ïc-h

L.

25

ch3

so2-nh-c-c = ch I

ch3

Crude formula: C20H31N3O4S Molecular mass: 409.55 White crystals Melting point: 110 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: ethanol at 95 ° GL / ammonia 95/5

- revelation: UV and iodine

- Rf: 0.45

IR spectrum: vc = 0 1635 cm-1

Example 5:

N- (N'-N'-diethylamino-4 'butyl) methoxy-2 (dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -5 benzamide The procedure is as in Example 1, but using diethylamino-butylamine ; we obtain the product of formula:

CH3- * O

O

C - NH - CH, - CH, - CH, - CH;

CH3

Crude formula: C2oH3oClN304S, H20 Molecular mass: 462 White crystals Melting point: 203 ° C 30 Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.23

35 Solubilities: soluble in water at 25%, in ethanol at 95 ° GL, at 5% and at 50% in dimethylacetamide.

Example 7:

(2-pyrrolidino-2 'ethyl) methoxy-2 (dimethyl-1 "-1" 40-propynyl-2 "aminosulfonyl) -5 benzamide hydrochloride (F 1529)

The procedure is as in Example 1, but using N- (2-amino-ethyl) pyrrolidine; we obtain the product of formula:

SO ,, —NH — C — C = CH

2 I ch3

Crude formula: C2iH33N304S Molecular mass: 423.58 White crystals Melting point: 129 ° C Plate chromatography:

support: silica gel 60 F 254 Merck solvent: ethanol at 95 ° GL / ammonia 95/5 UV revelation and iodine Rf: 0.42

Crude formula: Ci9H28ClN304S Molecular mass: 429.97 Light beige crystals 60 Melting point: 220 ° C

Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine 65 - Rf: 0.45

IR spectrum: vn-h at 3400 cm-1; v = c_H at 3280 cm-1; Vc = o at 1660 cm-1; vc = c at 1595 cm-1; vs = o at 1300-1350 cm-1 and 1150-1200 cm'1

620 674

6

Example 8:

N- (pyrrolidino-2 'ethyl) hydrochloride (dimethyl-1 "-1"

2-propynyl "aminosulfonyl) -3 benzamide (F 1528)

a) Preparation of N- {dimethyl-1'-1 'propynyl-2') 3-carboxy benzenesulfonamide

110 g of 3-carboxy benzenesulfonyl chloride are introduced into a solution of 133 g of 2-methyl-3-butyn-3-amine-2 and 1300 cm 3 of water.

Maintain stirring at room temperature for 10 h.

Acidify with a 6N hydrochloric acid solution, wash with water.

Extract with ethyl acetate, dry.

72% of product is recovered.

b) N- (2-pyrrolidinoethyl) hydrochloride (dimethyl-1'-1 'propynyl-2' aminosulfonyl) -3 benzamide

In a solution of 32 g of N- (dimethyl-l'-r propynyl-2 ') - 3-carboxy benzenesulfonamide in 250 cm3 of benzene and 12.7 g of triethylamine, added dropwise with vigorous stirring 14.3 g of ethyl chloroformate dissolved in 15 cm3 of benzene.

Maintain 4 h with stirring at room temperature. Wring out the triethylamine hydrochloride formed, wash with benzene and then introduce dropwise, with stirring, 13.7 g of N- (2-amino-ethyl) -pyrrolidine. Leave to stir vigorously overnight at room temperature, glaze, filter and hydrochloride.

71% of product of formula is recovered:

O

- nh - ch „-

ch - n '

/

H

CH.

s02 - nh - c - c

Cl c - h

CH.

and

- NH - CH

CH.

Cl

Crude formula: C18H26C1N303S Molecular mass: 399.94 White crystals Melting point: 186-187 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck.

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.55

IR spectrum: vsc_H at 3280 cm-1; vN_H at 3160 cm-11 vc = o at 1660 cm "1

Solubilities: soluble in water at 50%, soluble in ethanol at 95 ° GL at 5% and at 25% in dimethylformamide.

Example 9:

N- (N'-ethylpyrrolidino-2 'methyl) hydrochloride

(dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -3 benzamide (F 1634)

The procedure is as in Example 8, but using N- (ethyl-60-aminomethyl) -2 Pyrrolidine; we obtain the product of formula: (Formula at the top of the next column)

Crude formula: C19H28C1N303S Molecular mass: 414

White crystals

Melting point: 195 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

C - CHC - H

I

CH „

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.55

IR spectrum: Vnh at 3300 cm "1; vc = c at 2120 cm-1; vc = o at 1665 cm-1

Solubility: very soluble in water.

Example 10:

N- (N'-ethylpyrrolidino-2 'methyl) (dimethyl-1 "-1" propynyl-2 "aminosulfonyî) -4 benzamide, maleate (F 1738)

a) Preparation of p- (N-dimethyl-l'-l-propynyl-2 'aminosulfonyt) benzoic acid

In a solution of 27.2 g of methyl 2-butyn-3 amine-2 in 250 cm3 of water, introduce dropwise at 0 ° C with vigorous stirring 24 g of p-carboxybenzenesulfonyl chloride.

Leave overnight with stirring at room temperature. Acidify, filter, wash with water and dissolve the crystals in ethyl acetate after drying. The product with melting point 204-205 ° C is recovered with a yield of 70%.

b) Preparation of N- (N'-ethylpyrrolidino-2 'methyl) (dimethyl-1 "-1" propynyl-2 "sulfonyï) -4 benzamide

In a solution of 20 g of p-carboxy N-fdimethyl-l'-l-propynyl-2 aminosulfonyl) benzoic in 200 cm3 of tetrahydrofuran, introduce 10.5 cm3 of triethylamine then a solution of 8.96 g of chloroformate ethyl in 20 cm3 of tetrahydrofuran.

Maintain 1 h with stirring at 0 ° C then add a solution of 9.65 g of N-ethyl pyrrolidino-2 methylamine in 20 cm3 of tetrahydrofuran. Leave overnight at room temperature with stirring and distill until dry.

Treat with a bicarbonate solution, extract with ethyl acetate, wash with water and dry. After recovery of the free base, treatment is carried out with an ethanolic solution of maleic acid; a product of formula: 80% yield is recovered:

c - nh - ch,

0, c

\

ch3

I

-NH-C-CsC-H I

ch3

Crude formula: C23H31N307S Molecular mass: 493.58 White crystals Melting point: 145 ° C

HCO,

/

CH

II

CH

7

620 674

Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.36

Solubilities: soluble in water at 2% and in ethanol at 95 ° GL at 3%.

Example 11:

N- (2-pyrrolidino-ethyl) hydrochloride (dimethyl-1 "-1" propynyl-2 "aminosulfonyî) -3 chloro-4 benzamide (F 1530)

a) Preparation of N- {1-dimethyl-2-propynyl) 2-chloro-5-carboxy benzenesulfonamide

In a solution of 80 g of methyl 2-butyne-3 amino-2 in 800 cm3 of water, introduce at 0 ° C with stirring 76.5 g of chloro-2-carboxy-5 benzenesulfonyl chloride.

Maintain stirring for 8 h at room temperature. Acidify, wring out and dissolve the crystals obtained in ethyl acetate. Decant, dry, filter and crystallize.

A product melting at 210 ° C. is recovered with a yield of 92%.

b) Preparation of the hydrochloride of N- (pyrrolidino-2 'ethyl) (dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -3 chloro-4 benzamide

To a solution of 26.97 g of N- (dimethyl-ll propynyl-2) -choro-2-carboxy-5 benzenesulfonamide in 270 cm3 of tetrahydrofuran, add 15 cm3 of triethylamine and 12 g of ethyl chloroformate in solution in 15 cm3 of tetrahydrofuran.

Leave for 4 h with stirring and introduce dropwise at 0 ° C with vigorous stirring a solution of 11.42 g of N- (2-amino-ethyl) -pyrrolidine in 15 cm3 of tetrahydrofuran. Maintain agitation at room temperature overnight.

Distil until dry, treat with a bicarbonate solution. Wash the crystals obtained with water, dissolve in ethyl acetate, decant, dry. Then hydrochloride by adding an ethanolic solution saturated with hydrochloric acid.

The product of formula is recovered, with a yield of 70%:

n ♦ /

c - nh - ch - ch2 - n

AT - -

Crude formula: C18H25Cl2N303S Molecular mass: 434.38 Beige crystals Melting point: 211 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.51

IR spectrum: vN_H at 3310 cm-1; v = c_H at 3300 cm "1; vc = c at 2120 cm-1; vc = o at 1660 cm-1; vc = c at 1600 cm-1 and vs = o at 1150-1200 cm" 1 and 1300-1350 cm "1

Solubilities: soluble in water at 4%, soluble at 2% in ethanol at 95 ° GL and at 5% in dimethylformamide.

Example 12:

N- {N'-ethylpyrrolidino-2 'methyl) hydrochloride (1-dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -3 4-chloro benzamide (F 1635)

The procedure is as in Example 11, but using N-ethyl 2-amino-methylpyrrolidine, the product of formula is obtained:

Crude formula: C19H27C] 2N303S Molecular mass: 448.42 White crystals Melting point: 172 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: butanol / acetic acid / water 6/2/2

- revelation: UV and iodine

- Rf: 0.59

IR spectrum: vN_H at 3290 cm-1; v = c_H at 3280 cm-1; vc = 0 to 1660 cm "1 and vc = c to 1600 cm" 1

Solubilities: very soluble in water, soluble at 1% in ethanol.

Example 13:

N- (N'-ethylpyrrolidino-2 'methyl) 2-methoxy (1-ethynyl-cyclohexylaminosulfonyl) -5 hydrochloride benzamide (F 1742)

a) Preparation of 2-methoxy acid (1-ethynyl-1 cyclohexyl-aminosulfonyî) -5 benzamide

In a solution of 25.8 g of 1-ethynyl cyclohexylamine in 300 cm3 of water, introduce with ice and with vigorous stirring 17.5 g of 3-carboxy-4-methoxy benzenesulfochloride.

Keep stirring at room temperature overnight. Acidify, wring and dry. A product melting at 195 ° C. is recovered with a yield of 75%.

b) Preparation of N- (N'-ethylpyrrolidino-2 'ethyl) methoxy-2 (1-ethynyl-cyclohexylaminosulfonyl) -5 hydrochloride benzamide

In a solution of 15.6 g of 2-methoxy acid (1-ethynyl-1 'cyclohexylamino sulfonyl) -5 benzamide in 160 cm3 of tetrahydrofuran and 7 cm3 of triethylamine, add with vigorous stirring while freezing a solution of 5.55 g of ethyl chloroformate in 10 cm3 of tetrahydrofuran. Keep stirring for 1 hour at 0 ° C. and drop by drop a solution of 5.95 g of N-ethyl pyrrolidino-2 'methylamine in 10 cm3 of tetrahydrofuran.

Leave to stir at room temperature overnight. Distill until dry and treat with a 10% bicarbonate solution. The crystals obtained are treated with a methanol solution saturated with hydrochloric acid.

The product of formula:

C Formula at the top of the next column)

Crude formula: C23H34CIN2O4S Molecular mass; 484.06 White crystals Melting point: 208 ° C Plate chromatography:

- support: silica 60 F 254 Merck s

10

15

20

25

30

35

40

45

50

55

60

65

620 674

8

O CH.

NH CH.

-N ^

H

Cl

Cs = CH

Crude formula: C18H25N3O4S Molecular mass: 407.53 White crystals Melting point: 128 ° C 5 Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.37

10 IR spectrum: vc = 0 to 1640 cm-1

Example 16:

N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (pyrrolidino-4 "dimethyl-1" -1 "butynyl-2" aminosulfonyt) -5 benzamide (F 1735) of formula:

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.6

Solubilities: soluble in water and in ethanol at 95 ° GL at 2%, and at 10% in dimethylacetamide.

In a similar way to the previous products, we have prepared:

Example 14:

N- (N'-ethyl pyrrolidino-2 'ethyl) methoxy-2 (diethyl-l "-l" propynylaminosulfonyï) -5 hydrochloride benzamide of formula:

O - CH O

3 ^

- C - Nile

CÎL I <L

CH,

CH.

H

:NOT

And

S O - NH

c - c la c - H

C »2 - CH3

Crude formula: C22H34.O4.dN3S Molecular mass: 472.05 White crystals Melting point: 218 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.47

IR spectrum: vc = 0 to 1645 cm-1

Example 15:

N- (N'-ethylpyrrolidino-2 'ethyl) methoxy-2 (propylamino sulfonyl) -5 benzamide of formula:

CH_

C - NH - CH "

11 2

O

NOT

And

Crude formula: C25H38N4O4S _ Molecular mass: 490.67

Cl Beige crystals

35 Melting point: 115 ° C

Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine 40 - Rf: 0.20

Solubilities: insoluble in water, 50% soluble in ethanol and in dimethylacetamide.

Example 17:

45 N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (morpholino-4 "dimethyl-1" -1 "butynyl-2" aminosulfonyl) -5 benzamide of formula:

CH,

S02 - NH - CH - C ~ C - H

Crude formula: C25H38N405S 65 Molecular mass: 506.59 Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: ethanol / ammonia 95/5

9

620 674

- revelation: UV and iodine

- Rf: 0.52

Example 18:

N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (N "-methyl-piperazine-4" dimethyl-1 "-1" butynyl-2 "aminosulfonyl) -5 benzamide of formula:

y ch.,

- NH -

ch.

Crude formula: c32h45n5o4s Molecular mass: 595.80 White crystals Melting point: 135 ° C s Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.5

io IR spectrum: vc = o at 1645 cm "1 Example 20:

N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (N "-N" -diethyl-4 "dimethyl-1" -1 "butynyl-2" aminosulfonyl) -5 benzamide 15 of formula:

/

c - nh -

S02 - NH - C - C

ch.

E C - CH2 - N

/ \

r N \ /

ch.

Crude formula: c26h41n5o4s Molecular mass: 519.13 White crystals Melting point: 105 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: ethanol / ammonia 95/5

- revelation: UV and iodine

- Rf: 0.34

Example 19:

N- (N'-ethylpyrrolidino-2 'methyï) méthoxy-2 (N "-benzyl-pipérazine-4" diméthyl-1 "-1" butynylaminosulfonyl) -5 benzamide of formula:

C - NH - CH,

CH.

NOT

X

And

S02 - NH - C - C

CH,

! I \ /

C - CH2 - N ^ N - CH2 -

O - CH,

C - CH „- N

/

\

And

And

30

50

Crude formula: C25H40N4SO4 Molecular mass: 492.68 White crystals Melting point: 95 ° C Plate chromatography:

- support: silica gel 60 F 254 Merck

- solvent: chloroform / methanol / water 65/25/4

- revelation: UV and iodine

- Rf: 0.26

IR spectrum: vc = 0 to 1640 cm "1

Experimentation

The previously described chemical compounds have been the subject of toxicological, pharmacological and clinical experiments with a view to determining the possibilities of application in the therapeutic field.

A) Toxicology:

The compounds have been subjected to toxicity controls. The acute toxicity of certain compounds determined by the lethal dose 50 is reported in the table. It was tested on batches of 10 mice orally and intraperitoneally calculated according to the method of Miller and Tainter.

Compounds

LD 50 i.p. (mg / kg)

LD 50 oral (mg / kg)

F 1603

> 500

> 1000

F 1744

400

> 1000

F 1529

250

600

F 1530

100

300

F 1528

50

175

F 1634

250

600

F 1635

250

600

F 1735

> 500

> 1000

F 1737

> 500

> 1000

F 1738

400

> 1000

F 1742

400

1000

Sulpiride

320

800

Metoclopramide

150

600

620674

10

The derivatives whose sulfamido chain is polyazotated are very little toxic and the LD 50 by oral route are greater than 1 g / kg (examples 19,18,17,16 and 20).

B) Pharmacodynamics

An antiemetic property has been demonstrated by antagonism of apomorphine according to Burkman, “Arch. Int. Pharma-codyn. ”, 1962, 137.396. As an example, some results are reported in the table below:

Compounds

Doses in ng / kg

% inhibition compared to controls

F 1603

20

50

100

100

F 1530

500

25

F 1528

100

30

F 1529

1000

50

F 1634

50

50

F 1635

1000

30

F 1744

30

50

F 1737

20

60

F 1735

100

60

The activity varies depending on the nature of the amide.

Certain compounds have an activity on this test equal to or greater than that of Sulpiride or metoclopramide. The visceral effects have also been studied and more specifically the activity on intestinal transit, according to Janssen "J. Pharm, pharmacol. ”, 1957,9, 381.

The compounds F1603, F 1744, F 1737, F1735, as well as the products of Examples 4,5,19,20, show an acceleration of the intestinal transit compared to the controls.

These derivatives reduce the number of ulcers in rats after ligation of the pylorus, which may be linked to effects on the central nervous system.

C) Therapeutic applications

Clinical trials were carried out for certain compounds which are the subject of the invention, more particularly F1603, F1744, F1735 and the compounds of Examples 4,5,18,19. They have been applied in the treatment of psychosomatic digestive disorders in anxious or overworked subjects, vomiting and digestive discomfort in pregnant women and drug intolerances.

These compounds can also be used in everyday psychopathology.

Pharmaceutical preparations containing these active ingredients can be administered orally or parenterally. For oral administration, tablets or capsules can be used. These pharmaceutical compositions may also contain other therapeutically acceptable active ingredients.

By way of examples, some pharmaceutical preparations are described illustrating the use of the active principles which are the subject of the invention:

1) Capsules F 1603 50 mg

2) Tablets

F 1744 10 mg

Microcrystalline cellulose Mg stearate

3) Solution for injection F 1735 50 mg per 2 ml vial.

25

r

Claims (5)

620674 2 1. Sulfamidobenzamides intended for therapeutic application and corresponding to the formula: , CO-NH-R (I) l1 -NH-C-C = C-R- R, in which R represents one of the following groups: r ~ alkyl - (CH2) n-N lower alkyl -CH V n representing one of the numbers 2,3 and 4 and (CH2) n can also signify the group - CH2 - CH—, X in position 2,3 or 4 with respect to CH3 to the carboxamide group represents a hydrogen or halogen atom or a lower alkoxy, Ri and R2 represent, taken separately, hydrogen atoms or lower alkyls or, taken together with the adjacent carbon atom, a ring saturated carbon, and R3 represents a hydrogen atom or a group / R. —CH2 — N ^, R4 and R5 representing, taken separately, R-5 lower alkyls or, taken together with the adjacent nitrogen atom, one of the following groups: -NOT -NOT o o / \ -NOT V_ / N-CH 3 * N-benzyl, as well as N- (N'-ethylpyrrolidino-2 'methyl) (dimethyl-1 ", 1" propynyl-2 "aminosulfonyl) -4 benzamide, and their salts with therapeutically acceptable mineral and organic acids. 2. Sulfamidobenzamides and their salts according to claim 1, consisting of: N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 hydrochloride (dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -5 benzamide hydrochloride of N- (N'-N'-diethylamino-2 'ethyl) methoxy-2 (dimethyl-1" -l "propynyl-2" aminosulfonyl) -5 benzamide N- (N'-N'-N'-diethylamino-2 'propyl) maleate-2-methoxy (dimethyl-1 "-1" propynyl-2 "aminosulfonyl) -5 benzamide N- (N'- N'-diethylamino-3 'propyl) methoxy-2 (dimethyl-l "-l" 2-propynyl-aminosulfonyl) -5 benzamide N- (N'-N'-diethylamino-4 'butyl) 2-methoxy (dimethyl-1 "-l" 2-propynyl aminosulfonyl) -5 benzamide 5 N hydrochloride - (N'-ethylpiperidino-3 ') methoxy-2 (dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -5 benzamide, monohydrate (2-pyrrolidino-2 'ethyl) hydrochloride-2 (dimethyl-l" -l "propynyl-2" aminosulfonyl) -5 benzamide io N- (2-pyrrolidino-ethyl) hydrochloride (dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -3 benzamide N- {N-ethylpyrrolidino-2, 'methyl) hydrochloride (dimethyl-1" - l " 2-propynyl-aminosulfonyl) -3 benzamide N- (N'-ethylpyrrolidino-2 'methyl) (dimethyl-1 "-l" propynyl-2 "aminosulfonyl) -4 benzamide, maleate N- hydrochloride (pyrrolidino- 2 'ethyl) (dimethyl-l "-l" 2-propynyl-aminosulfonyl) -3 4-chloro-benzamide N- (N'-ethylpyrrolidino-2 'methyl) hydrochloride (dimethyl-l "-l" 2-propynyl-aminosulfonyl) -3 4-chloro benzamide hydrochloride N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (1-ethynyl-cyclohexylaminosulfonyl) -5 benzamide N- (N'-ethylpyrrolidino-2 'ethyl) hydrochloride 2-methoxy (diethyl 1-1 "-1" propynylaminosulfonyl) -5 benzamide N- (N'- ethylpyrrolidino-2 'ethyl) methoxy-2 (propylamino-sulfonyl) -5 benzamide N- (N'-ethylpyrrolidino-2' methyl) methoxy-2 (pyrrolidino-4 " dimethyl-1 "-l" butynyl-2 "aminosulfonyl) -5 benzamide N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (morpholino-4" 30 dimethyl-l "-l" butynyl-2 "aminosulfonyl ) -5 benzamide N- (N'-ethylpyrrolidino-2 'methyl) methoxy-2 (N "-methyl-piperazine-4" dimethyl-l "-l" butynyl-2 "aminosuIfonyl) -5 benzamide N- ( N'-ethylpyrrolidino-2 'methyl) methoxy-2 (N "-benzyl-35 piperazine-4" dimethyl-l "-l" butynyl-2 "aminosulfonyl) -5 benzamide N- (N'-ethylpyrrolidino-2' methyl) 2-methoxy (N "-N" -diethyl-4 "dimethyl-1" -l "butynyl-2" aminosulfonyl) -5 benzamide 3. Process for the preparation of the compounds according to claim 40 cation 1, characterized in what is condensed an amine of formula R — NH2 with a sulfamidobenzoic acid of formula: COOH x- (II) r Ì1 SG ^ -NH-C-CsC-R, 2 I ^ 50 R2 R, X, Rt R2 and R3 having the meanings mentioned above, or with p- (N-dimethyl-1 ', r propynyl-2' aminosulfonyl) -benzoic acid or with a reactive functional derivative of said acids. 4. Use of the compounds according to claim 1 for the preparation of a pharmaceutical composition intended for the treatment of digestive and / or psychosomatic disorders. 5. Use according to claim 4, characterized in that the composition can be administered by oral, rectal or parenteral route. 60 teral. 6. Use according to claim 4 or 5 of one of the compounds according to claim 2.