EP0833634A1 - Utilisation de n-cyclohexyl benzamides pour le traitement des afflictions intestinales - Google Patents

Utilisation de n-cyclohexyl benzamides pour le traitement des afflictions intestinales

Info

Publication number
EP0833634A1
EP0833634A1 EP96924006A EP96924006A EP0833634A1 EP 0833634 A1 EP0833634 A1 EP 0833634A1 EP 96924006 A EP96924006 A EP 96924006A EP 96924006 A EP96924006 A EP 96924006A EP 0833634 A1 EP0833634 A1 EP 0833634A1
Authority
EP
European Patent Office
Prior art keywords
radical
compounds
hydrogen atom
formula
alkyl radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96924006A
Other languages
German (de)
English (en)
French (fr)
Inventor
Thierry Bouyssou
Hélène Christinaki
Alain Renaud
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiesi SAS
Original Assignee
Laboratoires Jacques Logeais SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Jacques Logeais SA filed Critical Laboratoires Jacques Logeais SA
Publication of EP0833634A1 publication Critical patent/EP0833634A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to new therapeutic applications of N-cyclohexyl benzamides.
  • Irritable bowel syndrome is defined by the presence of abdominal pain, disturbed defecation, associated or not, and generally abdominal distension.
  • constipation observed in certain forms of SU can be treated by agents stimulating the intestinal motility and more particularly colic.
  • N-cyclohexyl benzamides described in EP 0507 672 are known to stimulate digestive motility and can therefore be proposed to restore the colonic transit of patients suffering from SU with predominant constipation.
  • This threshold can be raised by different pharmacological agents such as kappa agonists or certain 5-HT 3 antagonists such as granisetron (WO 94/01095).
  • the latter compound is also known to decrease rectal motility (Aliment. Pharmacol. Ther. (1993), 7, 175-80) and other 5-HT 3 antagonists such as ondansetron (Dig. Dis. Sci. (1990), 35, 477-80) are known to slow down colonic transit.
  • the N-cyclohexylbenzamides described in EP 0507 672 unlike compounds such as granisetron, have no action against the 5-HT 3 receptors.
  • R. is a linear, branched or cyclized alkyl radical at 0, -Cg and
  • R 2 represents a hydrogen atom, a linear or branched alkyl radical in a hydroxyl radical, an alkoxy radical in or a C 1 -C 4 hydroxyalkyl radical, and
  • R 3 represents a hydrogen atom or R 2 and R 3 both represent an alkyl radical in C ⁇ C g .
  • formula I encompasses four stereoisomers.
  • the compounds used in the invention have the absolute configuration 2R, the preferred compounds being of absolute configuration 1 R, 2R.
  • the racemic compounds of cis configuration (which are equimolar mixtures of the enantiomers 1 R, 2R and 1S, 2S) contain the active isomer and can therefore be used in the invention.
  • the racemic compounds of trans relative configuration (which are equimolar mixtures of the 1S, 2R and 1 R enantiomers, 2S) can also be used in the invention.
  • the particularly preferred compounds are those corresponding to formula I where R 1 is a methyl or cyclopropylmethyl radical, R 2 a methyl radical and R 3 is a hydrogen atom.
  • the compounds of formula I can be prepared by synthetic methods described in EP 0507 672, by condensing the benzoic acids of general formula II with the diamines of general formula III having the desired heterochemistry
  • racemic diamines III of cis relative configuration are prepared according to the synthetic route described in EP 0507672 from (cis) -2-t ⁇ fluoroacetamido-cyclohexane carboxylic acid.
  • a subject of the present invention is therefore the use of the compounds of formula I or their pharmaceutically acceptable salts for the manufacture of a medicament intended for the treatment of pain of visceral origin, in particular present in patients suffering from SU.
  • a subject of the present invention is also the use of the compounds of formula I or their pharmaceutically acceptable salts for the manufacture of a medicament intended for the treatment of inflammatory colitis, such as ulcerative colitis or Crohn's disease.
  • the oral dosages for humans are approximately
  • the affinity of the compounds for the 5-HT 3 receptors was measured according to the method described in Bioch. Pharmacol. (1990), 40, (7), 1541-1550, using membrane preparations of NG 108-15 cells and the tritiated BRL 43694 as specific ligand.
  • the compounds of formula I show weak affinities for the 5-HT 3 receptors, greater than the micromolar.
  • the Ki of the ondansetron is 16 nM.
  • the first model consists in observing in the rat the abdominal contractures produced by a rectal distension applied to a previously irritated mucous membrane.
  • the number of contractures is proportional to the intensity of the pain felt.
  • a similar model has been described in Neurogastroenterol. and Mot. (1994), 6, 140 where it is shown that the products which decrease the perception of pain in humans decrease the number of contractures observed in rats.
  • a distension is performed 2:30 after irritation of the rectum.
  • the balloon is dilated with 1.5 ml of distilled water (intracolic pressure equal to 60 mm Hg on average). The dilation is maintained for 10 minutes during which the abdominal contractures are counted. The balloon is then deflated by drawing in distilled water. Results:
  • mice Male Sprague-Dawley rats (140-150 g) fasted since the previous day undergo, under general anesthesia (isoflurane), irritation of the mucous membrane of the distal colon (7 cm from the anus) with 1 ml of an aqueous solution trinitrobenzene sulfonic acid (TNB) 50 mg / ml.
  • TNB trinitrobenzene sulfonic acid
  • Treatment is given for ten days after irritation of the colon.
  • the animals are weighed every morning from D5 to D10.
  • the animals are fasted on D9 and euthanasia on D10.
  • the colonists are removed and examined macroscopically then histologically.
  • results are grouped in the table below and represent the number of animals presenting the different stages.
  • the severity of the lesions is significantly greater with placebo than with compound 6 at p> 0.05.
  • the statistical calculation was carried out by a Chi2 test by comparing the class of stages 1 and 2
  • the sum of the ratings assigned to each substructure defines an animal index taking into account both the influx of inflammatory cells and architectural distortion.
  • the treatment with compound 6 therefore shows in this model that compared to placebo, the rats have a significantly improved weight change, that the lesional aspect of the colon is less important, this improvement being correlated by a reduction in the influx of cells. inflammatory.
  • Compound 8 is obtained according to the preceding procedure from 4-amino-5-chloro-2-cyclopentyloxy benzoic acid and (1 R, 2R) 2- (4-methylpiphdinomethyl) cyclohexylamine.
  • the base is purified by chromatography on silica (eluent CH 2 Cl 2 / CH 3 C0 2 C 2 H 5 / CH 3 OH /; 80/15/5) and then crystallized from water. Fusion: 173-175 ° C - IR (C ⁇ O): 1634 cm "1 (CHCI 3 )
  • Compound 9 is obtained identically from 4-amino-5-chloro-2-cyclopropylmethoxy benzoic acid and (1 S, 2R) 2- (4-methylpiperidinomethyl) cyclohexylamine.
  • Aminoester IV (6.4 g) is treated with trifluoroacetic anhydride (17.6 ml) for 5 days.
  • the reaction medium is evaporated under vacuum and the residue is taken up in a 5% aqueous NaHCO 3 solution.
  • the aqueous phase is extracted with ethyl acetate, acidified, then extracted with ethyl acetate.
  • the product used in the previous step (1.3 g) is dissolved in ethanol (30 ml) and then treated with an aqueous solution of hydroxide sodium (0.33 g in 10 ml of water) at reflux for 7 hours. After neutralization of the reaction medium with 1N HCl, the solvents are removed under vacuum. The residue is taken up in 2N HCl, the aqueous phase extracted with ethyl ether, basified to pH 10 with 2N NaOH and extracted with ethyl acetate. The organic phase is dried over Na ⁇ SO., And evaporated under vacuum. The product (0.63 g) is obtained in the form of an oil and used without further purification.
  • Cyclohexene VI (0.57 g) is dissolved in methanol (50 ml) in the presence of 10% Pd / C (50 mg) and 3N HCl (0.85 ml). The reaction medium is stirred under a slight hydrogen pressure for 20 h. The catalyst is removed by filtration and the solvent is removed in vacuo. The residue is taken up in a saturated solution of K 2 C0 3 and the aqueous phase extracted with ethyl acetate. The organic phase is dried over Na, SO 4 and then evaporated under vacuum to provide the reduced derivative VIII (0.46 g) in the form of an oil.
  • the amide derivative VIII (0.42 g) is dissolved in 10 ml of toluene and then treated at -60 ° C with diisobutylaluminum hydride (9.4 ml of a 1 M solution in toluene) for 8 hours.
  • the reaction medium is hydrolyzed by addition of 2N HCl.
  • the aqueous phase is separated from toluene, washed with chloroform, made alkaline by addition of NaOH

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP96924006A 1995-06-23 1996-06-21 Utilisation de n-cyclohexyl benzamides pour le traitement des afflictions intestinales Withdrawn EP0833634A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9507606A FR2735693B1 (fr) 1995-06-23 1995-06-23 Nouvelles applications therapeutiques de n-cyclohexyl benzamides
FR9507606 1995-06-23
PCT/FR1996/000976 WO1997000680A1 (fr) 1995-06-23 1996-06-21 Utilisation de n-cyclohexyl benzamides pour le traitement des afflictions intestinales

Publications (1)

Publication Number Publication Date
EP0833634A1 true EP0833634A1 (fr) 1998-04-08

Family

ID=9480358

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96924006A Withdrawn EP0833634A1 (fr) 1995-06-23 1996-06-21 Utilisation de n-cyclohexyl benzamides pour le traitement des afflictions intestinales

Country Status (13)

Country Link
US (1) US5804589A (pt)
EP (1) EP0833634A1 (pt)
JP (1) JP2999557B2 (pt)
KR (1) KR100261372B1 (pt)
AU (1) AU696447B2 (pt)
BR (1) BR9608595A (pt)
CA (1) CA2221863A1 (pt)
EA (1) EA000951B1 (pt)
FR (1) FR2735693B1 (pt)
NO (1) NO976024L (pt)
NZ (1) NZ312713A (pt)
TW (1) TW464498B (pt)
WO (1) WO1997000680A1 (pt)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2766486B1 (fr) * 1997-07-25 1999-09-17 Logeais Labor Jacques Cycloalkyles benzamides stimulants de la motricite gastrointestinale haute et basse
FR2766484B1 (fr) * 1997-07-25 1999-09-17 Logeais Labor Jacques Nouveaux derives benzamides stimulants de la motricite gastrointestinale haute et basse
AU4184499A (en) 1998-05-19 1999-12-06 Renovis, Inc. Benzamide therapeutics for the treatment of inflammatory bowel disease
WO1999059582A1 (en) * 1998-05-19 1999-11-25 Centaur Pharmaceuticals, Inc. Amide therapeutics for the treatment of inflammatory bowel disease
US6083989A (en) * 1999-05-18 2000-07-04 Centaur Pharmaceuticals, Inc. Aryl nitrone therapeutics for the treatment of inflammatory bowel disease
AU1917201A (en) * 1999-11-18 2001-05-30 Centaur Pharmaceuticals, Inc. Amide therapeutics and methods for treating inflammatory bowel disease
TW200815351A (en) * 2006-05-02 2008-04-01 Astrazeneca Ab Novel compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5273973A (en) * 1988-10-24 1993-12-28 Norwich Eaton Pharmaceuticals, Inc. Antimicrobial quinolonyl esters
FR2674849B1 (fr) * 1991-04-02 1994-12-23 Logeais Labor Jacques Nouveaux derives de n-cyclohexyl benzamides ou thiobenzamides, leurs preparations et leurs applications en therapeutique.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9700680A1 *

Also Published As

Publication number Publication date
NO976024L (no) 1998-02-23
WO1997000680A1 (fr) 1997-01-09
KR19990022839A (ko) 1999-03-25
AU696447B2 (en) 1998-09-10
TW464498B (en) 2001-11-21
US5804589A (en) 1998-09-08
KR100261372B1 (ko) 2000-07-01
FR2735693B1 (fr) 1997-09-26
NZ312713A (en) 2001-06-29
AU6460696A (en) 1997-01-22
BR9608595A (pt) 1999-01-05
FR2735693A1 (fr) 1996-12-27
NO976024D0 (no) 1997-12-22
JPH10511694A (ja) 1998-11-10
JP2999557B2 (ja) 2000-01-17
CA2221863A1 (en) 1997-01-09
EA199800085A1 (ru) 1998-08-27
EA000951B1 (ru) 2000-06-26

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