EP0998469A1

EP0998469A1 - Benzamide cycloalkyl stimulating high and low gastrointestinal motricity

Info

Publication number: EP0998469A1
Application number: EP98940330A
Authority: EP
Inventors: Christian Jeanpetit; Thierry Bouyssou; Hélène Christinaki; Serge Biosa; Olivier Boucheix
Original assignee: Laboratoires Jacques Logeais SA
Current assignee: Laboratoires Jacques Logeais SA
Priority date: 1997-07-25
Filing date: 1998-07-24
Publication date: 2000-05-10
Also published as: WO1999005133A1; FR2766486A1; CO4990983A1; FR2766486B1; AU8867998A; AR014901A1; TNSN98137A1; ZA986632B

Abstract

The invention concerns compounds of general formula (I) in which: R1 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; R2 and R3 are H, a C1-C6 alkyl group or a hydroalkyl group, m = 1 or 2, and n = 1, 2 or 3. The invention also concerns pharmaceutical compositions containing said compounds, and their uses for treating dysfunction of the high and low digestive tube.

Description

CYCLOALKYLES BENZAMIDES STIMULANTS OF HIGH AND LOW GASTROINTESTINAL MOTORITY

The present invention relates to the use of benzamide-type compounds as stimulants of gastrointestinal motility, their pharmaceutically acceptable salts and their quaternary ammonium salts, as well as their production methods. The compounds according to the present invention are also analgesics.

Benzamides and in particular 4-amino-5-chloro-2-methoxybenzamides such as metoclopramide (A)

(AT)

have been known for a long time for their activity on gastrointestinal motility but this is only present on the upper digestive sphere and absent or marginal on the lower digestive sphere (colon).

The therapeutic applications of these compounds are therefore an antiemetic effect, a. treatment of gastroesophageal reflux, a treatment of dyspepsia but they do not have the effectiveness necessary to be able to be used within the framework of the treatment of pathoiogies of the lower disgestive sphere, in particular pathoiogies of the type chronic disorders of transit, atony colic,

Thus, MN ABOUL-ENEIN et al. (Sci. Pharm. 58, 273-280, 1990) prepared spiro-type compounds, analogues of metoclopramide, in order to evaluate their anti-emetic activity and in particular compound B:

(B) Only compounds possessing a terminal diethylamine have been synthesized and at no time is any activity on the lower gastrointestinal motility (colic) of these compounds mentioned.

Patents EP 0507 672 and Fr 95 07606 describe N-cyclohexyl benzamides and in particular the derivative (C):

(VS)

as an analgesic and stimulant of gastrointestinal motility. The cyclohexyl part of the molecule is substituted in positions 1 and 2.

Finally, patent WO 96/05166 describes compounds which stimulate gastrointestinal motility, for example of structure (D):

(D)

Most of the compounds exemplified have a terminal amino dimethylamine. A single compound exemplified (n = 1) has a terminal piperidine and this is not substituted. The cyclohexyl part is always present at α of the terminal amine

The inventors of the present application have discovered that the spiro compounds, that is to say having a cylohexyl substituted in position 1, 1 but at α of the amide and having a pipéπdine substituted or not are powerful stimulants of gastrointestinal motility high and low unlike compounds (A), (B), and (D) For example, compounds (B) and (D) do not have activity on motor skills in electromyography (EMG) gastro -colic in rabbits, compound (A) having activity only on the upper part

The compound (C) which differs from the compounds according to the invention by a substitution in position 1, 2 of cyclohexyl is active on the upper and lower parts in the gastro-colonic EMG in the rabbit However, on a colonic model in the dog which from an anatomical point of view is much closer to man than the rabbit (Y RUCKEBUSCH et al, INRA Scientific and agronomic news, Digestive mechanics in mammals, Ed MASSON, 99-104), the compounds according to l have a higher activity than compound (C)

In addition, the position of the piperidinoalkyl group on the cyclohexyl is very important for the activity since a cyclohexyl substituted in position 1, 3 (E)

(E) is inactive in gastrointestinal EMG in rabbits

It was therefore unexpected that a substitution of cyclohexyl at position 1, 1 be active

The present invention therefore relates to compounds of general formula I

in which :

- Ri is a linear, branched or cyclized C- alkyl group _| to C5 or a C3 to CQ cycloalkyl group, said alkyl group possibly being able to form a ring of 4 to 5 carbon atoms in the ring, in association with the carbon in position 3 of the aromatic ring, and with that carrying the oxygen atom,

- R2 is H, a C- alkyl group | with linear or branched Cg, OH or a hydroxyalkyl group in which the linear or branched C 4 to C4 alkyl group,

- R3 is H, a C- alkyl group _| with linear or branched C5, OH or a hydroxyalkyl group in which the alkyl group is C- | with linear or branched C4, provided that R2 and R3 cannot simultaneously represent OH,

- m = 1 or 2; n = 1, 2 or 3.

The piperidine nitrogen atom can also be in N-oxide (N ⁺ -O ^" ) form or salified with a pharmaceutically acceptable acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, formic or acetic acid, propionic, glycolic, oxalic, fumaric, lactic, succinic, tartaric, malic, pamoic.

The piperidine can also be in the form of a quaternary ammonium salt according to the following formula:

where Y is a C- alkyl group | to Cg, or a benzyl group, and X ^" is Br or I ^" .

The preferred compounds according to the invention are those of formula I in which R- | = CH3 or methylcyclopropyle, n = 1, m = 1, R2 = OH or alkyl and R3 = H, and preferably still, those of formula I in which R ^ = CH3, n = 1, m = 1, R2 = CH3 and R3 = H (compound of Example 8 below), or R- | = methylcyclopropyle, n = 1, m = 1, R2 = CH2CH3 and R3 = H (compound of Example 6 below). The subject of the invention is the use of one or more compounds? of formula 1 described above, for the preparation of a medicament intended for the treatment of dysfunctions of the upper and lower digestive tract such as

- in the case of dysfunctions of the upper digestive tract emesis, esophageal achalasia gastroparesis, gastroesophageal reflux, dyspepsia, pseudo chronic intestinal obstruction,

- in the case of dysfunctions of the disgestive tube low colonic atony slowing down of colonic transit transient constipation and chronic idiopathic constipation, chronic colonic pseudo-obstruction syndrome of the colon or irritable intestine These compounds of the invention are mainly used as stimulants of upper and lower intestinal motility, in particular in the context of the treatment of the abovementioned pathologies and can also be used as visceral analgesics The invention also relates to any pharmaceutical composition comprising one or more compounds of formula I described above, in combination with a pharmaceutically acceptable vehicle Advantageously, the pharmaceutical compositions of the invention can be administered by oral, parenteral or rectal route

Preferably, the pharmaceutical compositions according to the invention are characterized in that the dosage of active principle is approximately 0.1 μg / kg / day to 20 mg / kg / day by oral and rectal route and approximately 0, 1 μg / kg / day to 2 mg / kg / day parenterally

Preferred pharmaceutical compositions according to the invention are presented in a form which can be administered orally, in a unit dose of 10 μg to 200 mg of active principle per dose, and preferably of 0.1 mg to 200 mg of active principle per dose. 1 to 4 times a day

Also preferred compositions according to the invention are presented in a form which can be administered parenterally, in a unit dose of 10 μg to 100 mg of active principle per injection, at the rate of 1 to 2 injections per day. The abbreviations used in the description of the processes for preparing the invention and in the detailed description of the experimental part are the following:

Ac 0 Acetic anhydride

AcOEt Ethyl acetate

AcOH Acetic acid

AIBN 2,2-azabisisobutyronitrile

Ar Aryle

Boc tert-butoxycarbonyle

CDI Carbonyldiimidazole

DCM Dichloromethane

DIBAL-H Diisobutylaluminium hydride

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

And ₃ N Triethylamine

NBS N-bromosuccinimide

NMM N-methyl morpholine

PhtNK Potassium phthalimide

RT Ambient temperature

TFA Trifluoroacetic acid

TFAA Trifluoroacetic Anhydride

THF Tetrahydrofuran

The compounds according to the invention can be obtained according to scheme 1 below

IVbis

Diagram 1 in which R <| , R2, R3, n and m are as defined above.

Stage 1 consists in condensing diamine II on acid III by one of the coupling methods known in the literature, preferably by an acid chloride prepared with thionyl chloride in toluene at reflux for 1 h then reaction with the corresponding diamine in dichloromethane at room temperature for 30 minutes to 12 h. The hydrolysis of acetyl is carried out in the presence of a sodium hydroxide-EtOH mixture at 60 ° C. for 30 minutes at

24h. Thus step 1 leads to the obtaining of compound IV, namely to a compound of formula I mentioned above in which R-j = CH3, and R2, R3, n and m are as defined above.

Step 2 consists in demethylating compound IV with sodium ethane thiolate

(CH3CH2SNa, prepared from ethanethiol and a base such as NaH) in a solvent such as DMF or DMSO at 80-90 ° C for 15 minutes to 2 h then alkylate the phenate formed with an R- group _j X, (X being a leaving group such as for example a halogen, a mesylate or a triflate, and R- | being as defined above with the exception of CH3), at 60 ° C. for 15 minutes at 24 h to obtain compound IVbis, namely to a compound of formula I mentioned above in which R- | is as defined above, with the exception of CH3, and R2, R3, n and m are as defined above.

Another method for obtaining the compounds of the invention is carried out according to scheme 2.

Step 4

Diagram 2

in which step 3, leading to the compound of formula VI in which R- | , R2, R3, n and m are as defined above in the context of formula I, consists in coupling diamine II to the previously o-alkylated acid V by a coupling method known in the literature preferably with chloride of oxalyl in a solvent such as THF or CH2Cl2 at room temperature for 30 minutes to 24 hours.

Step 4 consists in deacetylating the amine of the above-mentioned compound VI in the presence of a sodium hydroxide-ethanol mixture at 60 ° C. for 30 minutes to 24 h to yield the compound of the above-mentioned formula I in which R- | , R2, R3, n and m are as defined above. Compounds V can be obtained according to scheme 3 below

Step 8 Step 9

Diagram 3

wherein step 5 consists in demethylating compound VII with BBr3 in a solvent such as dichloroethane at a temperature between 60 and 83 ° C for 30 minutes to 24 h., which leads to compound VIII.

Step 6 consists in esterifying acid VIII with for example thionyl chloride and an alcohol such as methanol at reflux for 1 h to 24 h, which leads to compound IX.

Step 7 consists in alkylating phenol IX in DMF in the presence of a base such as NaH to

80 ° C for 1 hour to 24 hours with an R- group _| X (X being a leaving group such as halogen, mesylate or triflate, and R- | being as defined above), which leads to compound X.

Step 8 consists in hydrolyzing the ester X in a sodium hydroxide-ethanol mixture at room temperature for 30 minutes to 10 h, which leads to compound XI.

Step 9 consists in acetylating amine XI in the presence of acetic acid and acetic anhydride to

60 ° C for 1 h to 24 h, which leads to the aforementioned compound V in which R- | is as defined above. The diamines II (m = 1) can be obtained according to the following diagram 4

ci H Step 10

Step 11

2 ^R3

Diagram 4

in which step 10 consists in protecting the amine with a protective group such as for example trifluoroacetyl, tert-butyoxylcarbonyl or benzoyl, according to the methods known in the literature.

Step 11 consists in coupling the corresponding piperidine by coupling methods known in the literature with, for example, carbonyl diimidazole in a solvent such as

THF at room temperature for 1 to 24 hours.

Step 12 consists in reducing the amide with a comparable reduction with the protective group, for example UAIH4 in THF at reflux for 1 to 24 h. Step 13 consists in deprotecting the amine with, for example, trifluoroacetic acid in

CH2Cl2 at room temperature for 30 minutes at 12 h or HCI 12N in a closed reactor at

140 ° C for 24 h to 6 days.

Step 14 consists in reducing the acid using an alkyl chloroformate in the presence of N-methyl morpholine with NaBH 4 in methanol for 1 h to 24 h and then Swern oxidation.

Step 15 consists in carrying out a reductive amination with NaBH3CN in the presence of the corresponding piperidine.

Step 16 consists in deprotecting the amine before reduction of the amide with NaBH4 in ethanol at reflux for 48 h. Step 17 consists in reducing the amide with for example DIBAL-H in toluene at room temperature for 30 minutes to 24 hours.

The 4-alkyl-piperidines can be obtained according to the following scheme 5:

Diagram 5

Step 18 consists in reducing the corresponding pyridine with hydrogen in the presence of a catalyst such as for example platinum oxide in ethanol.

III - Experimental part

Example 1: 4-amino-5-chloro-2-methoxy N- [1 - (4-propylpiperidin-1yl methyl) cyclohexyl] benzamide

Step A: 1-Trifluoroacetylamino1-Cyclohexane carboxylic acid

In a flask containing 137.7 g (0.0767 mol) of the hydrochloride of 1 -amιno cyclohexane carboxylic acid are added at 0 ° C 325 ml (2.3 mol) of acetic anhydride. The reaction mixture is stirred for 4 h at room temperature then it is hydrolyzed at 0 ° C with 800 ml of water. The precipitate is filtered, washed with water to pH = 7 and then dried at 65 ° C under 0.01 mmHg for 5 h.

177.77 g are obtained. YId: 96%

IR (KBr) 1727 (vCOCF ₃ ); 1706 (vCOOH)

¹ H NMR (CD ₃ ) ₂ SO) δppm: 12.5 (s, 1 H, COOH); 9.16 (s, 1H, NHCOF ₃ ); 2.09 (dt, 2H);

1.73 (ddd, 2H); 1, 16-1, 58 (m, 6H,).

Step B: 1- (4-propylpiperidin-1ylcarbonyl) 1-trifluoroacetylaminocyclohexane

7 g (29 mmol) of A and 4.74 g (0.29 mmol) of carbonyldiimidazole followed by 30 ml of tetrahydrofuran are introduced into a flask provided with magnetic stirring and under nitrogen. After 1 h of stirring at room temperature 3.72 g (29 mmol) of 4-propylpiperidine diluted in 26 ml of THF are added dropwise. After 24 h, the solvent is evaporated in vacuo and the residue is taken up with 200 ml of dichloromethane. The organic phase is extracted 3 times with 100 ml of an 8% sodium hydrogen carbonate solution. The dichloromethane phase is dried over sodium sulfate and concentrated in vacuo. An oil is obtained which crystallizes in an ether / acetone mixture 90/10 v / v. 7.77 g are obtained. YId: 76%. Mp: 121 ° C

IR (CHCI ₃ ): 3430 (vNH); 1731 (vNHCOCF ₃ ); 1731 (v CO, tertiary amide) ¹ H NMR (CDCI ₃ ) δppm: 6.36 (s, 1 H, NHCOCF3); 4.36 (m, 2H); 2.7 (dt, 2H); 2.06 (m, 4H); 1.85-1.58 (solid, 6H); 156 - 1.18 (massive, 8H); 1.06 (ddd, 2H). Step C: 1- (4-propylpiperidin-1yl carbonyl) cyclohexylamine

To a flask containing 7.71 g (2.2 mmol) of B diluted in 110 ml of absolute ethanol are added 5.02 g (0.133 mol) of sodium borohydride The reaction mixture is heated for 4 days at 60 ° C. The solvent is evaporated under vacuum and the residue taken up with 250 ml of water, is acidified to pH = 1 with 2N HCl The aqueous phase is extracted with diethyl ether then it is basified at pH = 12 with a NaOH solution concentrated, and re-extracted with diethyl ether

The organic phase is dried and concentrated in vacuo A yellow oil is obtained 4.99 g

Yield 90%

IR (CHCI ₃ ) 1604 (vCOCF ₃ )

¹ H NMR (CDCI ₃ ) δppm 4.77 (dt, 2H), 2.72 (ddd, 2H), 1, 9 (ddd, 2H), 1.77-1 (massιf, 19H),

0.72 (t, 3H)

Step D: 1- (4-propylpiperidin-1ylmethyl) cyclohexylamine

118 ml of DIBAL-H 1 M in toluene are introduced into a flask containing a solution of 4.96 g (20 mmol) of C in 76 ml of toluene and dropwise, at -60 ° C. The reaction mixture is stirred 17 h at room temperature and then at 0 ° C. is hydrolyzed successively with 3.8 ml of water saturated with NaCl 37 ml of HCl 6N After decantation and elimination of the toluene phase the aqueous phase is basified to pH = 12 with a solution concentrated NaOH then the amine is extracted with diethyl ether The organic phase is dried and concentrated under vacuum A yellowish oil is obtained 4.63 g 99% yield! R (CHCI ₃ ) 1569 (δNH2) ¹ H NMR (CDCI ₃ ) δppm 2.79 (dt, 2H), 2.2 (dt, 2H), 1.7-1 (solid, 3H), 0.84 (t, 3H)

Step E: 4-acetylamino-5-chloro-2-methoxy N- [1- (4-propylpiperidin-1ylmethyl) cyclohexyl] benzamide

4.1 ml (57 mmol) of thionyl chloride are added dropwise to a flask containing 4.6 g (19 mmol) of 4-acetylamino-5-chloro-2-methoxy benzoic acid in 80 ml of toluene. 45 minutes of heating at 110 ° C, the toluene is evaporated under vacuum and the residue is suspended in 8 ml of dichloromethane and is added at 0 ° C in a solution of 4.5 g (19 mmol) of amine D in 30 ml of dichloromethane After 20 h of stirring at room temperature the solvent is evaporated and the residue taken up with water is acidified to pH = 1 with 1 N HCl, then extracted with ethyl acetate The aqueous phase is basified to pH = 12 and extracted three times with dichloromethane The organic phase is dried over sodium sulfate and concentrated in vacuo The oil obtained crystallizes by adding an AcOEt / petroleum ether mixture 10/90 3.94 g Yield 45%

PF 79-86X

IR (CHCI ₃ ) 3412 (vNHCO), 1701 (vAr-CONH)

¹ H NMR (CDCI ₃ ) δppm 8.31 (s, 1 H, Ar-H), 8, 16 (s, 1 H Ar-H), 7 76 (s, 1 H, NHCO),

7.65 (s 1 H, NHCO), 4.02 (s, 3H, OCH3), 2.77 (dt, 2H), 2.68 (s, 2H), 2.24 n 7),

1, 71 -1, 04 (m, 17H), 0.9 (t, 3H)

Step F: 4-amino-5-chloro-2-methoxy N- [1 - (4-propylpiperidin-1ylmethyl) cyclohexyl] benzamide

3 88 g (8.36 mmol) of E, 42 ml of 1 M NaOH and 50 ml of 95 ° EtOH are introduced into a flask fitted with a magnetic stirrer. The reaction mixture is heated for 17 h to 80 ° C. and then the evaporated solvent and the residue taken up in 1 M NaOH and extracted twice with AcOEt and once with

CH2Cl2 The combined organic phases are dried over Na2SO4 and concentrated in vacuo

The oil obtained crystallizes in an AcOEt / petroleum ether mixture 20/80 3, 1 1 g Yield 88%

P F Kofler 129 ° C

IR (CHCI3) 3404.5 (vNH amide), 1640.9 (vCO secondary amide)

¹ H NMR (CDCI ₃ ) δppm 8.06 (s, 1 H), 7.52 (wide s, 1 H, NH), 6.3 (s, 1 H),

4.34 (broad s, 2H, NH ₂ ), 3.93 (s, 3H), 2.8 (dt, 2H), 2.72 (s, 2H), 2.23 (m, 4H).

1.69 - 1.06 (massive, 18H), 0.9 (t, 3H)

Example 2: 4-amino-5-chloro-2-cyclopropyImethoxyN- [1 - (4-propylpiperidin-1 ylmethyl) cyclohexyl] benzamide

In a flask fitted with a nitrogen inlet, containing 0.33 g (8.25 mmol) of 60% NaH in oil and 11 ml of DMF are added at 0 ° C. 0.63 ml (8, 52 mmol) of ethanethiol After 30 minutes of stirring at room temperature, a solution of 2.32 g (5.5 mmol) of Example 1 in 9 ml of DMF is added at room temperature The reaction mixture is heated 30 min at 90 ° C, then the temperature is brought back to 60 ° C before the addition of 0.79 ml (8.25 mmol) of methylcyclopropyl bromide After 21 h at 60 °, the DMF is evaporated under vacuum (pump at The residue is taken up with dichloromethane and extracted successively with a 1 N NaOH solution and water saturated with NaCl. The organic phase is dried over Na2Sθ4 and concentrated in vacuo. The crude product is purified on a column of flash silica chromatography with the eluent system: heptane / AcOEt / MeOH / NH4θH 70/25/5 / 0.2 v / v. The product obtained is filtered and washed with a diethyl ether / acetone mixture 80/20 v / v. 1.45 g are obtained. Yid:

57%.

PF (capillary): 136.5 ° C

IR (CHCI ₃ ): 3390.7 (v.NH); 1640.2 (v CONH). 1617.4 (v, aromatic cycle).

¹ H NMR ((CD ₃ ) ₂ SO) δppm: 7.8 (broad s, 1 H, NH); 7.7 (s, 1H); 6.4 (s, 1 H):

5.85 (br s, 2H, NH ₂ ); 3.9 (d, 2H); 2.68 (dt, 2H); 2.55 (s, 2H); 2.2 (dt, 2H); 2.1 (td, 2H);

1.65-0.95 (solid, 18H); 0.85 (t, 3H); 0.65 (dd, 2H); 0.45 (dd, 2H).

Example 3: 4-amino-5-chloro-2-methoxy N- [1 - (piperidin-1ylmethyl) cyclohexyl] benzamide

CIH

Step A: N- [1- (piperidin-1ylcarbonyl) cyclohexyl] benzamide

7 g (28.5 mmol) of N (1- (1-carboxycyclohexyI) benzamide; 4.62 g (28.5 mmol) of carbonyl diimidazole and 50 ml of THF are successively introduced into a flask fitted with a magnetic stirrer After 2 h of stirring at room temperature, 2.82 ml (28.5 mmol) of piperidine diluted in 30 ml of THF are added.

The reaction mixture is stirred 2.5 days and then concentrated. The residue is diluted in dichloromethane and washed successively with an 80% NaHCO 3 solution and water saturated with NaCl. The organic phase is dried over sodium sulfate and concentrated in vacuo.

7.1 g are obtained. YId: 79%.

Mp: 242 ° C

IR (CHCI3): 3443 (v NHCO); 1670 (v CONH); 1623 (v CO-piperidine)

¹ H NMR (CDCI3 + CD3OD) δppm: 7.62 (d, 2H, Ar-H); 7.34 (m, 3H);

3.5 (dd, 4H); 2.07 (dt, 2H); 1.85 (ddd, 2H); 1, 7-1, 16 (massive, 12H). Step B: N- [1 - (piperidin-1ylmethyl) cyclohexyl] benzamide

1.67 g (44 mmol) of lithium aluminum hydride and 80 ml of distilled THF are introduced into a reactor equipped with mechanical stirring, then at 0 ° C. the amide A is added diluted in 20 ml of THF The reaction mixture is heated for 30 minutes at 60 ° C. The reaction is cold hydrolyzed successively with 1.67 ml of water, 1.67 ml of 15% NaOH and 5 ml of water The salts are filtered and washed with diethyl ether The organic filtrate is concentrated and the residue dissolved in water is extracted twice with diethyl ether The combined organic phases are washed with a solution of water saturated with NaCl, dried over Na2SO4 and concentrated in vacuo A solid is obtained, it is filtered and washed with petroleum ether 5.61 g Yield 85% PF 124X

IR (CHCI3) 3439.4 (v NHCO), 1654 (v CONH)

¹ H NMR (CDCI3) δppm 7.76 (dd, 2H Ar-H), 7.43 (m, 3H), 6 4 (broad 1 H, NH), 265 (s, 2H), 2.54 (dd, 4H), 2.4 (dt, 2H), 1.67-1.4 (massive, 14H)

Step C: 1 (piperidin-1ylmethyl) cyclohexylamine

15.45 g (18 mmol) of B dissolved in 79 ml of concentrated HCl (12 N) are introduced into a closed flask with screw cap and heated at 140 ° C under pressure for 6 days The acid phase is diluted with 200 ml of water and extracted twice with ethyl acetate The aqueous phase is made alkaline with a NaOH solution and extracted with diethyl ether 3 times The combined ether phases are dried over Na2SO4 and concentrated in vacuo A colored oil is obtained

3.29 g

Yield 92%

IR (CHC.3) 3178 (v NH ₂ )

¹ H NMR (CDCI3) δppm 2.49 (dd, 4H), 2.19 (s, 2H), 1.62-1.21 (solid, 18H)

Step D: 4-acetylamino-5-chloro-2-methoxy N- [1 - (piperidin-1ylmethyl) cyclohexyl] benzamide

According to example 1

Mp 81 ° C

IR (CHCI ₃ ) 3412.5 (v NH), 1701 (v CONHAr), 1651, 4 (v ArCONH) H NMR (CDCI3) δppm 8.3 (s, 1 H), 8.15 (s, 1 H ), 7.79 (s, 1 H), 7.66 (s, 1 H), 4.02 (s, 3H),

2.7 (s, 2H), 2.5 (dd, 4H), 2.27 (m, 5H), 1.7-1.21 (massive, 14H) Step E: 4-amino-5-chloro-2-methoxy N- [4- (piperidin-1ylmethyl) cyclohexyl) benzamide hydrochloride

According to example 1.

Mp: 190-193 ° C

IR (KBr): 3415.6 (v NHCO-Ar, NH ₂ arom); 1653.9 (v CONH)

¹ H NMR ((CD ₃ ) ₂ SO) δppm: 9.7 (broad s, NH ⁺ piperidine); 7.81 (s, 1H, NH); 7.65 (s, 1H);

6.51 (s, 1H); 6.14 (s, 2H, NH ₂ ); 3.85 (s, 3H, OCH ₃ ); 3.42 (d, 2H); 3.3 (m, 2H); 3.02 (m, 2H)

2.3 (dt, 2H); 1, 85-1, 14 (massive, 14H).

Example 4: 4-amino-5-chloro-2-cyclopropylmethoxy N- [1 - (piperidin-1ylmethyl) cyclohexyl] benzamide

According to example 2

PF (capillary): 123-127 ° C

IR (CHCI3): 3390.6 (v NHCO); 1640 (v CONH)

¹ H NMR (CDCI3) δppm: 8.11 (s, 1 H); 7.94 (br s, 1H, NH); 6.23 (s, 1H); 4.33 (s broad, 2H,

NH ₂ ); 3.86 (d, 2H); 2.69 (s, 2H); 2.46 (t, 4H); 2.3 (dt, 2H); 1, 7-1, 2 (solid, 15H);

0.74 (dd, 2H); 0.47 (dd, 2H).

Example 5: 4-amino-5-chloro-2-methoxy N- [1- (4-ethylpiperidin-1yl methyl) cyclohexyl] benzamide

Step A: N - [- 1 (4-ethylpiperidin-1ylmethyl) cyclohexyl] benzamide

According to example 3:

Mp: 104 ° C

IR (CHCI ₃ ): 1656 (v CONH)

¹ H NMR (CDCI ₃ ) δppm: 7.74 (dd, 2H, Harom); 7.42 (m, 3H); 6.4 (br s, 1H, NJH);

2.85 (dt, 2H); 2.7 (s, 2H); 2.43 (td, 2H); 2.3 (ddd, 2H); 1.7-1.02 (solid, 15H); 0.9 (t, 3H)

Step B: 1 (4-ethylpiperidin-1ylmethyl) cyclohexylamine

According to example 3:

IR (CHCI ₃ ): 1569.7 (δ, NH ₂ )

¹ H NMR (CDCI3) δppm: 2.82 (dt, 2H); 2.21 (m, 4H); 0.64-1 (massive, 19H); 0.9 (t, 3H, CH3)

Step C: 4-acetylamino-5-chloro-2-methoxy N- [1- (4-ethylpiperidin-1ylmethyl) cyclohexyl] benzamide

According to example 1

Mp: 91 ° C (Kόfler)

IR (CHCI3): 3412 (v NHCO); 1701 (v CONH-Ar)

¹ H NMR (CDCI3) δppm: 8.3 (s, 1H); 8.16 (s, 1H); 7.77 (s, 1H, NH); 7.64 (s, 1H, NH);

4 (s, 3H, OCH3); 2.8 (dt, 2H); 2.7 (s, 2H); 2.27 (m, 6H); 1.7-1 (massive, 16H); 0.9 (t, 3H)

Step D: 4-amino-5-chlσro-2-methoxy N- [1- (4-ethylpiperidin-1ylcyclohexyl] benzamide

According to example 1

PF (capillary): 65-85X slow resin

IR (CHCI3): 3404 (v NHCO); 1641 (v CONH) 1 H NMR (CDCI3) δppm: 8.07 (s, 1H); 7.53 (br s, 1H, NH); 7.27 (s, 1H); 6.4 (s, 1H);

4.35 (br s, 2H, NH ₂ ); 3.92 (s, 3H, OCH3) Example 6: 4-amino-5-chloro-2-cyclopropylmethoxy N- [1 - (4-ethylpiperidin-lylmethyl] cyclohexyl] benzamide

According to example 2.

PF (capillary): 146 ° C

IR (CHCI ₃ ): 3390 (v NH2); 1640 (v CONH)

¹ H NMR ((CD ₃ ) ₂ SO) δppm: 7.85 (s, 1 H); 7.7 (s, 1H); 6.4 (s, 1H); 5.85 (br s, 2H, NH ₂ );

3.88 (d, 2H); 2.7 (dt, 2H); 2.58 (s, 2H); 2.2 (dt, 2H); 2.12 (ddd, 2H); 1.65-0.9 (massive, 16H)

0.85 (t, 3H); 0.65 (dd, 2H); 0.45 (dd, 2H).

Example 7: 4-amino-5-chloro-2-cyclopropylmethoxy N- [1 - (4-hydroxypiperidin-lylmethyl) cyclohexyl] benzamide

Step A: 1- (4-hydroxypiperidin-1ylcarbonyl) 1-trifluoroacetylamino cyclohexane

According to example 1

Mp: 168 ° C

IR (CHCI3): 3428 (v NHCOCF3); 1731, 5 (v COCF3); 1629 (v Tertiary CO-amide)

¹ H NMR ((CD ₃ ) ₂ SO) δppm: 4.7 (d, 1 H, OH); 3.84 (dt, 2H); 3.65 (m, 1H); 3.04 (m, 2H);

2-1, 1 (massive, 16H).

Step B: 1- (4-hydroxypiperidin-1ylcarbonyl) cyclohexylamine

According to example 1

IR (CHCI3): 1609 (v tertiary CO-amide) ¹ H NMR (CDCI3) δppm 4.43 (dt, 2H), 3.93 (m, 1H), 3.3 (m, 2H) 2.13-1.22 (solid, 17H)

Step C: (4-hydroxypiperidin-1ylmethyi) cyclohexylamine

According to example 1

IR (CHCI3) 3344 (v NH2)

¹ H NMR (CDCI3) δppm 3.65 (m, 1H), 2.77 (ddd, 2H), 2.36 (ddd, 21 H), 2.23 (s, 2H),

1.9-1.19 (massive, 16H)

Step D: 4-acetylamino-5-chloro-2-cyclopropylmethoxy N-1 (4-hydroxypiperidin-1yi methyl) cyclohexyl benzamide

From 4-acetylamιno-5-chloro-2-cyclopropylmethoxy benzoic acid, according to example 1, step E

IR (CHCI3) 3382 (v NHCO), 1702, 1646 (v CONH)

¹ H NMR (CDCI3) δppm 8.23 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 4 (d, 2H)

3.69 (m, 1H), 3.61 (m, 1H); 2.73 (ddd, 2H), 2.3 (ddd, 4H), 1.84-1.15 (m, 18H); 0.7 (ddd, 2H),

0.5 (ddd, 2H)

Step E: 4-amino-5-chloro-2-cyclopropylmethoxy N- [1- (4-hydroxypiperidin-1yl methyl) cyclohexyl] benzamide

According to example 1, step F

PF.153-166X

IR (CHCI3). 3391 (v NH, v NH ₂ ); 1640 (v CONH)

¹ H NMR (CDCI3) δppm: 8.1 (s, 1H); 7.9 (s, NH); 6.22 (s, 1H); 4.3 (s, 2H, NH ₂ ); 3.9 (d, 2H);

3.62 (ddd, 1H), 2.8 (m, 2H); 2.75 (s, 2H); 2.4 (m, 4H); 1.8-1.5 (solid, 10H), 0.95 (dd, 2H),

0.75 (dd, 2H)

Example 8: 4-amino-5-chloro-2-cyclopropylmethoxy N- (1 - (4-methylpiperidin-1yi methyl) cyclohexyl] benzamide

CIH

Step A: 1 - (4-methylpiperidin-1ylcarbonyl) trifluoroacetylamino cyclohexane

According to example 1

IR (CHCI ₃ ): 3430.5 (v NHCO); 1731, 7 (v COCF3); 1628.7 (v CO-piperidine-CH ₃ )

¹ H NMR (CDCI3) δppm: 6.42 (broad s, 1 H, NH); 4.34 (dt, 2H); 2.74 (td, 2H); 2.02 (m, 4H);

1.992-1.25 (solid, 9H); 1.09 (td, 2H); 0.92 (d, 3H)

Step B: 1- (4-methylpiperidin-1ylcarbonyl) cyclohexylamine

According to example 1

IR (CHCI3): 1604 (v tertiary CO-amide)

¹ H NMR (CDCI3) δppm: 4.74 (dt, 2H); 2.74 (td, 2H); 2 (td, 2H); 1, 71-1, 22 (solid, 15H);

1, 1 (td, 2H); 0.96 (d, 3H)

Step C: 1- (4-methylpiperidin-1ylmethyl) cyclohexylamine

According to example 1

IR (CHCI ₃ ): 1570 (δ NH ₂ )

¹ H NMR (CDCI3) δppm: 2.77 (dt, 2H); 2.27 (td, 2H); 2.2 (s, 2H); 1.6-1.15 (massive, 17H);

0.94 (d, 3H)

Step D: 4-acetylamino-5-chloro-2-methoxy-N- [1- (4-methylpiperidin-1yl methyl) cyclohexyl] benzamide

According to example 1

IR (CHCI3): 3412.9 (v, NHCO); 1701 (vCONH-Ar); 1648.7 (vAr-CONH); ¹ H NMR (CDCI3) δppm 8.3 (s, 1H), 815 (s 1H), 7.77 (wide s, 1H, NH), 765 (wide s, 1H, NH), 4.02 (s, 3H, OCH3), 2.77 (dt, 2H), 2.72 (s, 2H), 2.32 (s, 3H, COCH3., 2.26 [m, 4H), 1.71 - 1.1 (massive, 11 H), 9.03 (d, 3 H)

Step E: 4-amino-5-chloro-2-methoxy-N- [1- (4-methylpiperidιn-1yl methyl) cyclohexyl] benzamide

According to example 1

IR (CHCI3) 3404.5 (v, NHCO), 1640 (vAr-CONH),

¹ H NMR (CDCI3) δppm 8.05 (s, 1H), 7.55 (wide s, 1H, NH), 7.3 (s, 1H), 6.3 (s, 1H), 4.36 ( s broad, 2H, NH ₂ ), 3.95 (s, 3H, OCH3), 2.8 (dt, 2H), 2.7 (s, 2H), 2.56 (m, 4H), 1.7 - 1.1 (solid, 12H), 091 (d, 3H)

Example 9: 4-amino-5-chloro-2-cyclopropylmethoxy-N- [1- (4-methylpiperidin-1yl methyl) cyclohexyl] benzamide

According to example 2

Capillary PF 129.5-132.5 °

IR (CHCI3) 3390, 9 (v NH amide), 1640 (v CO secondary amide)

¹ H NMR (CDCI3) δppm 8.1 (s, 1H), 7.94 (wide s, 1H, NH), 6.26 (s, 1H),

4.34 (broad s, 2H, NH ₂ ), 3.86 (d, 2H), 2.76 (dt, 2H), 2.7 (s, 2H), 23 (dt, 2H), 2.21 (td, 2H),

1.7 - 1.07 (solid, 14H), 0.9 (d, 3H), 0.74 (dd, 2H), 0.12 (dd, 2H) Example 10: 4-amino-5-chloro-2-ethoxy N- [1- (4methylpiperidin-1ylmethyl) cyclohexyl] benzamide

According to example 2

Capillary PF 153 ° C

IR (CHCI ₃ ): 3398.9 (vNH); 1640.5 (vCONH) H NMR (CDCI3) δppm: 8.1 (s, 1H); 7.77 (br s, 1H, NH); 6.28 (s, 1H);

4.36 (br s, 2H, NH ₂ ); 4.12 (q, 2H); 2.79 (dt, 2H); 2.68 (s, 2H); 2.26 (clump, 4H);

1.77 - 1.07 (massive, 16H); 0.9 (d, 3H)

Compound E: cis 4-amino-5-chloro 2-cyclopropyl methoxy N- [3- (4-methylpipyridin- 1 -ylmethyl) cyclohexyl] benzamide

Step A: 3-amino cyclohexane carboxylic acid

Prepared according to: Allan R.D .; Johnston G.A.R. and Twitchin B.; Aust. J. Chem. 1981, 34, 22316

Step B: cis 3-trifluoroacetylamino cyclohexane carboxylic acid

According to example 1 (step A)

¹ H NMR (CDCI3 + (CD) ₂ SO) δppm: 12.03 (broad s, 1 H, COOH); 9.14 (d, 1H, NH);

3.65 (m, 1H, CH-NH); 2.28 (m, 1H); 2 (d, 1H); 1.86 (d, 1H); 1.76 (m, 2H); 1.45 -1.1 (m, 4H) Step C: cis 3- (4-methyl! Piμeridin-1-yl carbonyl) 1-trifluoroacetylamino cyclohexane

According to example 1 (step B)

PFKofler 180.5

IR (KBr) cm ^" 1380.1 (vNH), 1713 (v C = O), 1614 (v C = 0 tertiary amide.

1H NMR ((CD) ₂ SO) δppm 9.3 (d, 1H, NH), 4.32 (m, 1H), 3.88 (m, 1H), 3.76 (m, 1H), 2, 92

(ddd, 1H), 2.76 (ddd, 1H), 2.45 (m, 1H) 1.8-1.1 (m, 11H), 1.08 - 0.8 (m, 2H),

0.9 (d, 3H, CH ₃ )

Step D: 3- (4-methyIpiperidin-1-ylcarbonyl) cyclohexylamine

According to example 1 (step C)

IR (CHCI ₃ ) crτr ¹ 3369.1 (vNH), 1618.1 (v C = 0 tertiary amide)

¹ H NMR (CDCI ₃ ) δppm 4.55 (m, 1H), 3.84 (m, 1H), 2.98 (ddd, 1H), 2.68 (ddd, 1H),

2.54 (m, 2H), 2.86 (m, 3H), 1.8-1.24 (m, 9H), 1.1 (m, 3H), 0.98 (d, 3H, CH3)

Step E: cis 3- (4-methylpiperidin-1-ylmethyl) cyclohexylamine

According to example 1 (step D)

IR (CHCI ₃ ) cnr ¹ 2924.5 (ahphatic vCH) H NMR (CDCI3) δppm 2.8 (m, 2H), 2.63 (m, 1H), 2.12, d, 2H), 1.96 (m, 1H), 1.9-1.7 (m 6H)

, 1.68 -1.45 (m, 4H), 1.4-1.12 (m, 4H), 1 ,? (ddd, 1H), 0.92 (d, 3H, CH3), 0.72 (m, 2H)

Step F: cis (4-amino-5-chloro-2-methoxy-N- [3- (4-methylpiperidin-1-yl methyl) cyclohexyl] benzamide, hydrochloride

According to example 1 (step B)

PF capillary slow melting 130 ° C

IR (KBr) cm ^-1 1627 (v C = O secondary amide)

1H NMR ((CD) ₂ SO) δppm 9.09 (broad s, NH + CI "), 7.63 (d, 1H, NH), 7.6 (s, 1H, Ar-H),

6.95 (s, 1H, Ar-H), 5.95 (wide s, 2H, NH), 3.8 (s, 3H, OCH3), 3.8 (m, 1H), 3.45 (m , 2H), 3.3-

2.65 (m, 4H), 2.1-1.08 (m, 13H), 1-0.7 (m, 1H), 0.9 (d, 3H, CH3)

Step G: cis 4-amino-5-chloro-cyclopropylmethoxy-N- [3- (4-methylpiperidin-1-ylmethyl) cyclohexyl] benzamide

According to example 2 P ¹¹ capillary 144 ° C

IR (CHCI ₃ ) crrr ¹ 3391, 2 (vNH), 1635.5 (v C = 0 secondary amide)

¹ H NMR (CDCI ₃ ) δppm 8.15 (s, 1 H, Ar-H), 8 (d, 1 H, NH), 6.2 (s, 1 H, Ar-H)

3 45 (broad, 2H, NH ₂ ), 3.95 (m, 1H), 3.85 (d, 2H), 2.85 (d, 2H), 2 3-2 (m, 4H) 2 -1 (m, 15H)

0 9 (d 3H, CH ₃ ), 0.75 (dd, 2H), 0.45 (dd, 2H)

Example 11: 4-amino-5-chloro-2-cyclopropylmethoxy N- [1- (4-hydroxypiperidino- 1 -ylmethyl-N-oxide) cyclohexyl] benzamide

To a solution of Example 7 (0.5 g, 1.17 mmol) in 140 ml of CH ₂ CI ₂ , add 3-chloroperbenzoic acid Stir for 4 h at room temperature

Wash with 1 N NaOH then evaporate under vacuum The product is purified on an alumina column (CH ₂ CI ₂ / AcOEt / MeOH 90/5/5)

We recover two isomers (yield 28%)

- Least polar isomer

NMR (CD ₃ OD) δ ppm 7.75 (s, 1 H), 6.4 (s, 1 H), 3.9 (d, 2H), 3.85 (s, 2H), 3.6 ( m, 2H), 3.3 (m, 2H), 2.6 (m, 2H), 2.35 (m, 2H), 1.7-1.5 (m, 10H), 1.35 (m , 2H), 0.7 (m, 2H), 0.45 (m, 2H)

- Most polar isomer

NMR (CD ₃ OD) δ ppm 7.75 (s, 1 H), 6.4 (s, 1 H), 3.9 (d, 2H), 3.8 (s, 2H), 3.7 ( m, 1 H), 3.45 (m, 2H), 3.3 (m, 4H), 2.6 (m, 2H), 2.1 (m, 2H), 1.8-1.5 ( m, 9H), 1.35 (m, 2H), 0.7 (m, 2H), 0.4 (m, 2H) Pharmacological results

I - Stimulation of gastrointestinal motility

Gastrocolic electromyography in rabbits

The principle of the test consists in recording the electrical activity of the smooth muscle directly responsible for the digestive sinstaltism. The recordings are made in the fasting rabbit

Protocol

Male New Zealand Californian rabbits weighing 2.5 to 3 kg are equipped under general anesthesia with thiobarbital, with nickel-chromium electrodes implanted on

- the lair at 1 cm from the pylorus (P-1)

- the colon at 5 and 8 cm from the ileo-caecal valve (life + 5 and life + 8 cm)

Electromyographic recordings begin five days after surgery on fasting animals that have been fasting for 12 hours and kept in containment boxes

The product to be tested is administered intravenously in a volume equal to 0.5 ml at a dose of 0.7 mg / kg. It is dissolved in 10 to 20 μl of pure acetic acid. The volume is completed with physiological saline. pH is readjusted by 0.1 N NaOH to values between 5 and

7.5

The product vehicle is used as a placebo II consists of dilute acetic acid (10 to 20 μl in 0.5 ml of physiological saline), Its pH is also readjusted by 0.1 N NaOH to values between 5 and 7 , 5

Registration begins at T0 The first intravenous injection (product or vehicle) is carried out 1 hour later (T1 h) The second intravenous injection (vehicle or product) is carried out at T2h The return to the baseline is checked before each administration

The activity of the products and the vehicle is evaluated over the 30 minutes of recording following their injection.

The statistical analysis is carried out according to the Dunnett test which compares the registration periods under vehicle to all the registration periods under the action of the products. Results

Spontaneous myoelectric activity is organized for the lair in bursts of potentials which appear in the presence of the vehicle with a frequency equal to 1.1 ± 0.3 bursts / min. in 150 rabbits.

On the colon, electrical activity is organized in slow waves (17 cycles per minute) randomly superimposed on bursts of potentials responsible for peristalsis. The results are therefore expressed as a percentage of slow waves overloaded with bursts of potentials. In the presence of the vehicle, the motor index of the life colon + 5 is equal to an average of 22 ± 6% (n = 160 rabbits), that of the life colon + 8 is equal to an average of 24 + 5% (n = 160 rabbits) The molecules tested significantly stimulate (p <0.05) digestive peristalstism when the frequency on the antrum is greater than or equal to 1.6 bursts / min and the motor index on the colon is greater than or equal to 35%, which whatever the segment recorded (colon life + 5 and colon life + 8). The results of the compounds according to the invention are given below (table I) as well as those of the comparators (compounds A-E). The compounds according to the invention significantly stimulate the proximal colon (Life + 5 and Life + 8) unlike the comparators.

Il - Colonic motility in dogs

The principle of the test consists in recording the contractile activity of the colon in the fasted and fasting animal.

Six Beagle female dogs, from 8 to 10 kg, are equipped, under general anesthesia, with strain gauges implanted on:

- the proximal colon 3 cm from the ileo-caecal valve (life + 3)

- the transverse colon 9 cm from the ileocecal valve (life + 9)

Registration begins ten days after surgery. The animal, vigilant and fasting since the previous day, is placed in a digestibility cage and connected to the recording device. The first three hours constitute the recording in the control period, then the product tested at a dose of 1 mg / kg or the vehicle (dilute acetic acid) is injected intravenously in a volume equal to 0.8 ml. The pH is between 5 and 7.5 and the osmolality is between 100 and 300 mosmol / l.

The same dog is registered every three days and receives only one injection per recording session. The activity is quantified over the two hours of recording following the injection of the molecule and compared using the Dunnett test to the recordings obtained under vehicle

The significance level is equal to 5% The parameters used to evaluate the activity of the product are the frequency of contractions and the duration of stimulation of colonic motility

In the fasted dog, during the basal period, there appear on average two contractions per hour of recording. In these experimental conditions, colonic motility is significantly stimulated (p <0.05) when the frequency of contractions is greater than or equal to 2 , 8 Comparator C is colokinetic at 0.3 and 1 mg / kg iv for an average duration of 60 minutes

The compounds according to the invention have a colokinetic activity significantly (p <0.05) greater than that of comparator C when the frequency of the contractions is greater than 4.5 and the duration of their effects is greater than 80 minutes.

By way of example, the compounds of Examples 2, 4, 6 and 9 have a colokinetic activity greater than the comparator C in duration and / or in frequency at the doses of 0.3 and 1 mg / kg

The compound of Example 6 also has a dose activity of 0.1 mg / kg, at which comparator C is inactive

The results are collated in Table II

III - Visceral analgesia

The visceral analgesic activity was studied on a model of digestive pain in the alert rat This pain is caused by the distention of the colon using a balloon

Protocol

Male Sprague-Dawley rats weighing approximately 180 g on an empty stomach since the previous day are used. Under light fluothane anesthesia, an intrarectal probe is introduced 5 cm from the anus and 1.5 ml of 1% acetic acid is injected. An hour and a half after the irritation, a latex balloon (0 to vacuum 2 mm, length 1 cm) mounted on a polyethylene catheter is introduced into the colon at the site of the irritation.

The product to be tested or the vehicle (dilute acetic acid) is administered per os in a volume of 1 ml, then the rat is placed under observation in a cπstallisoir

Colon distension is performed 2 h 30 min after irritation. It is carried out under a fixed volume equal to 1.5 ml of distilled water. Colonic distension causes digestive pain objectified by abdominal cramps, the number of which reflects the intensity of the pain. Colonic distension is maintained for 10 minutes during which the abdominal cramps are counted Statistical analysis is carried out using the Dunnett test which compares the same group of vehicle animals (6) to several groups of rats (6 animals per group) having received the molecules studied. The materiality threshold is set at 5%.

The molecules are tested orally at 1-10-100 and 1000 μg / kg. They are dissolved in

10 to 20 μl of pure acetic acid. The volume is completed with physiological saline. The pH is readjusted (0.1 N NaOH) to values between 5 and 7.5.

The vehicle used as a placebo consists of dilute acetic acid (10 to 20 μi in 1 ml of physiological saline). Its pH is readjusted (NaOH 0.1 N) to values between 5 and

7.5.

Results

Twenty to twenty two abdominal cramps, on average, are observed during the 10 minutes of colonic distension in the group of vehicle rats (n = 200 rats).

The molecules tested significantly reduce (p <0.05) digestive pain when the number of abdominal cramps is less than or equal to 15.

The results of the compounds according to the invention are given below (Table III).

The compounds according to the invention significantly reduce digestive pain.

TABLE I Gastro-colonic EMG in rabbits at 700 μg / kg i v

^* Statistically different from placebo at p <0.05 (Dunnett test) (mean ± standard deviation) The figures in parentheses correspond to the number of animals studied TABLE I (continued) Gastro-colonic EMG in rabbits at 700 μg / kg .v

^* Statistically different from placebo at p <0.05 (Dunnett test) (mean ± standard deviation) The figures in parentheses correspond to the number of animals studied

TABLE I (continued)

^* Statistically different from placebo at p <0.05 (Dunnett test) (mean ± standard deviation) The figures in parentheses correspond to the number of animals studied BOARD ! (cont.) Gastro-colonic EMG in rabbits at 700 μg / kg iv

^* Statistically different from placebo at p <0.05 (Dunnett's test) (mean ~ standard deviation) The figures in parentheses correspond to the number of animals studied

Table II Colonic motility in fasting dogs

* Statistically different from placebo at p <0.05 (Dunnett test)

# Statistically different from comparator C at p <0.05 (Dunnett test) The figures in parentheses correspond to the number of animals studied Table II (continued) Colonic motility in fasting dogs

^* Statistically different from placebo at p <0.05 (Dunnett test)

# Statistically different from comparator C at p <0.05 (Dunnett test) The figures in parentheses correspond to the number of animals studied TABLE III

Visceral analgesia in rats at 1; 10; 100 and 1000 μg / kg p.o.

(average number of abdominal cramps ± standard deviation)

^* Statistically different from placebo at p <0.05 (Dunnett test) TABLE Ml (continued)

Visceral analgesia in rats at 1: 10, 100 and 1000 μg / kg p.o.

(average number of abdominal cramps ± standard deviation)

Statistically different from placebo at p <0.05 (Dunnett test)

Claims

1. compounds of general formula I

in which :

- R- _| is a linear or branched or cyclized C- alkyl group _| to Cg or a C3 to Cg cycloalkyl group, said alkyl group possibly, if necessary, forming a ring of 4 to 5 carbon atoms in the ring, in association with the carbon in position 3 of the aromatic ring, and with that carrying the oxygen atom,

- R2 is H, alkyl C _j to Cg linear or branched, OH, or hydroxyalkyl, wherein the alkyl is C- _| with linear or branched C4,

- R3 is H, a C- alkyl group _| with linear or branched Cg, OH or a hydroxyalkyl group in which the alkyl group is C- | with linear or branched C4, provided that R2 and R3 cannot simultaneously represent OH,

- m = 1 or 2; n = 1, 2 or 3.

2. Compounds according to Claim 1, characterized in that the nitrogen atom of the piperidine is in N-oxide form or salified with a pharmaceutically acceptable acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric or formic acid. , acetic, propionic, glycolic, oxalic, fumaric, lactic, succinic, tartaric, malic, pamoic.

3. Compounds according to claim 1 or claim 2, characterized in that the piperidine is in the form of quaternary ammonium salt according to the following formula:

where Y is a C1 to C8 alkyl or benzyl, and X "is Br or I".

4. Compounds according to one of claims 1 to 3, of formula I in which R-j = CH3 or methylcyclopropyle, n = 1, m = 1, R2 = OH or alkyl and R3 = H.

5. Compounds according to one of claims 1 to 4, of formula I in which R- | = CH3, n = 1, m = 1, R2 = CH3 and R3 = H or Rj = methylcyclopropyle, n = 1, m = 1, R2 = CH2CH3 and R3 = H. 6 Pharmaceutical composition characterized in that it comprises one or more ιeu; s compo ^s er "according to one of claims 1 to 5, in combination with a pharmaceutically acceptable vehicle

7 Pharmaceutical composition according to claim 6, characterized in that it can be administered orally, parenterally or rectally

8 Pharmaceutical compositions according to claim 6 or claim 7, characterized in that the dosage of active principle is approximately 0.1 μg / kg / day to 20 mg / kg / day by oral and rectal route and approximately 0 , 1 μg / kg / day to 2 mg / kg / day parenterally

9 Pharmaceutical compositions according to one of claims 6 to 8, characterized in that they are in a form which can be administered orally, in a unit dose of 10 μg to 200 mg of active principle per dose, and preferably of 0, 1 mg to 200 mg of active ingredient per dose, at the rate of 1 to 4 doses per day

10 Pharmaceutical compositions according to one of claims 6 to 8, characterized in that they are in a form which can be administered parenterally, in a unit dose of 10 μg to 100 mg of active principle by injection, at a rate of 1 to 2 injections per day

1 1 Use of one or more compounds according to one of claims 1 to 5, for the preparation of a medicament for the treatment of dysfunctions of the upper and lower digestive tract such as

- concerning dysfunctions of the upper digestive tract Pemesis, esophageal achalasia, gastroparesis, gastroesophageal reflux, dyspepsia, pseudo chronic intestinal obstruction,

- with regard to dysfunctions of the lower digestive tract. colonic atony slowing down of colonic transit transient constipation and chronic idiopathic constipation, chronic colonic pseudo-obstruction syndrome of irritable bowel or colon.

12 Use according to claim 11, characterized in that said compounds are used as stimulants of the upper and lower intestinal motility and visceral analgesic