Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-11
2000-08-01
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514248, 514252, 514256, 514258, 514259, 514315, 514320, 514321, 514322, 514326, 514318, 514317, 544237, 544238, 544278, 544284, 544287, 544335, 544336, 544410, 546194, 546197, 546198, 546199, 546207, 546208, 546210, 546214, 546221, A01N 4340, A01N 4358, C07D23730, C07D40100, C07D21168
Patent
active
060967617
DESCRIPTION:
BRIEF SUMMARY
This application is the national stage of application No. PCT/EP97/00584 filed on Feb. 7, 1997, which application claims priority from EP 96200379.4, filed on Feb. 15, 1996.
The present invention is concerned with novel compounds of formula (I) having superior gastrokinetic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Journal of Medicinal Chemistry, 1993, 36, pp 4121-4123 discloses (1-butyl-4-piperidinyl)methyl-8-amino-7-chloro-1,4-benzodioxane-5-carboxyl ate hydrochloride, i.e. SB 204070, as a highly potent and selective 5-HT.sub.4 receptor antagonist.
Naunyn-Schmiedeberg's Archives of Pharmacology (1994) 349, pp 546-548 discloses (1-butyl-4-piperidinyl)methyl 8-amino-7-iodo-1,4-benzodioxan-5-carboxylate as being a selective and high affinity 5-HT.sub.4 -receptor antagonist, in particular for human atrial 5-HT.sub.4 -receptors.
WO 93/05038, published on Mar. 18, 1993 (SmithKline Beecham PLC) discloses a number of substituted 4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylates having 5 HT.sub.4 receptor antagonistic activity.
WO 94/10174, published on May 11, 1994 (SmithKline Beecham PLC) discloses 5-(1-(3-pyridylmethyl)-4-piperidinyl)methyl-8-amino-7-chloro-1,4-benzodiox an-carboxylate, [1-(2-carboethoxyethyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodio xan-5-carboxylate, [1-(3-hydroxybutyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan- 5-carboxylate having 5 HT.sub.4 receptor antagonistic activity.
The above prior art documents all disclose substituted 4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylates and the analogues thereof having 5 HT.sub.4 receptor antagonistic activity. Compounds showing 5HT.sub.4 antagonism are taught to have potential interest in the treatment of, for example, irritable bowel syndrome, in particular the diarrhoea aspects of irritable bowel syndrome, i.e. these compounds block the ability of 5HT (which stands for 5-hydroxytryptamine, i.e. serotonin) to stimulate gut motility (see WO 93/05038, page 8, lines 12 to 17). The present gastroprokinetic compounds differ in structure mainly by the presence of a hydroxy- or an alkyloxy group on the central piperidine ring.
Bioorganic & Medicinal Chemistry Letters (1994) vol 4, No 5, pp 667-668 discloses oxazolo, oxazino and oxazepino[3,2-a]indole derivatives as being 5 HT.sub.4 receptor antagonists.
The present gastroprokinetic compounds differ in structure mainly by the presence of a 2,3,4,5-tetrasubstituted phenylmoiety in stead of the oxazolo, oxazino and oxazepino[3,2-a]indole moiety.
WO 95/25100, published on Sep. 21, 1995, discloses the use of substituted piperidinyl ethyl or propyl 4-amino-5-chloro-2-methoxybenzoic esters as 5 HT.sub.4 agonists. The present compounds differ in structure by the different orientation of the central piperidine ring and the different substitution pattern on said piperidine ring.
EP 0 299 566, published on Jan. 18, 1989, discloses N-(3-hydroxy-4-piperidinyl)benzamides having gastrointestinal motility stimulating activity.
EP 0 309 043, published on Mar. 29, 1989, discloses substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides having gastrointestinal motility stimulating activity.
EP 0 389 037 discloses N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives as having gastrointestinal motility stimulating activity.
The latter three prior art documents all disclose carboxamide derivatives, while the compounds of the present invention all have an ester function and there is a methylene between the ester oxygen and the piperidine ring.
The problem that this invention sets out to solve is to provide compounds having gastrointestinal motility stimulating properties, particularly having superior gastric emptying activity. Said compounds are also shown to be orally active.
The solution to this problem is provided by the novel compounds of formula (I
REFERENCES:
patent: 5616583 (1997-04-01), Van Daele et al.
patent: 5739134 (1998-04-01), Van Daele et al.
Journal of Medicinal Chemistry, vol. 36, No. 25, 1993, pp. 4121-4121, XP000196066, L.M. Gaster et al.
Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 5, 1994, pp. 667-668, XP000196105, L.M. Gaster et al.
Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 349, No. 5, 1994, pp. 546-548, XP000196110, A.J. Kaumann et al.
Bosmans Jean-Paul Rene Marie
D'Haen Henri Elisabeth Frans
Decleyn Michel Anna Jozef
Love John Christopher
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Schroeder Ben
Shah Mukund J.
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