Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-05
2002-09-17
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S232000, C546S207000, C549S429000, C549S497000, C549S491000, C514S333000, C514S335000, C514S357000
Reexamination Certificate
active
06452013
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage of PCT/EP98/04189, filed Jul. 7, 1998, which application claims priority from EP application nos. 97.202.180.2, filed Jul. 11, 1997 and EP 98.200.624.9, filed Feb. 27, 1998.
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 4-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-methoxy-benzamide as a potent and selective 5HT
4
-receptor antagonist.
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-carboxamides having 5HT
4
-receptor antagonistic activity.
WO 94/10174, published on May 11, 1994 (SmithKline Beecham PLC) discloses a number of substituted 4-pyridinylmethyl oxazino[3,2-a]indole-carboxamide derivatives having 5HT
4
-receptor antagonistic activity.
The above prior art documents all disclose substituted 4-piperidinylmethyl carboxamides and the analogues thereof having 5HT
4
-receptor antagonistic activity. Compounds showing 5HT
4
antagonism are taught to have potential interest in the treatment of, for example, irritable bowel syndrome, in particular the diarrhea aspects of irritable bowel syndrome, i.e. these compounds block the ability of 5HT (which stands for 5-hydroxy-tryptamine, 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.
WO 93/16072, published on Aug. 19, 1993 discloses 5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide having 5 HT
4
receptor antagonistic activity.
Bioorganic & Medicinal Chem. Lett., 1996, 6, pp. 263-266, and WO-96/33186 (Pharmacia S.P.A.), published on Oct. 24, 1996, disclose 4-amino-N-(1-butyl-4-piperidinyl)methyl-5-chloro-2,3-dihydro-7-benzofurancarboxamide having 5 HT
4
receptor agonistic activity.
The compounds of the present invention differ from the previous prior art documents due to the presence of a hydroxy or a C
1-6
alkyloxygroup on the 3 position of the central 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, published on Sep. 26, 1990, discloses N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives having gastrointestinal motility stimulating activity.
The latter three prior art documents all disclose carboxamide derivatives wherein the amide function is bonded directly with the piperidine ring, while the compounds of the present invention all have an amide function wherein a methylene group is present between the carbamoyl nitrogen and the piperidine ring.
EP-0,774,460, published on May 21, 1997, and WO-97/11054, published on Mar. 27, 1997 disclose a number of benzoic acid compounds as 5-HT
4
agonists useful for treating gastric motility disorders.
The compounds of the present invention differ from the latter two prior art documents due to the presence of a hydroxy or a C
1-6
alkyloxy group on the 3- or 4-position of the central piperidine ring. Furthermore, those compounds of the present invention wherein R
2
is other than hydrogen are also structurally different over said prior art documents.
The problem this invention sets out to solve is to provide compounds having gastrointestinal motility stimulating properties, particularly having superior gastric emptying activity. Preferably said compounds should be orally active.
The solution to this problem is provided by the novel compounds of formula (I) that differ structurally from the prior art, inter alia, by the presence of a hydroxy or a C I6alkyloxy group on the 3- or 4-position of the central piperidine ring, or by the presence of a methylene group between the carbamoyl group and the piperidine ring.
The present invention concerns a compound of formula (I)
a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid or base addition salt thereof, wherein
R
1
is C
1-6
alkyloxy, C
2-6
alkenyloxy or C
2-6
alkynyloxy;
R
2
is hydrogen, C
1-6
alkyl or C
1-6
alkyloxy;
R
3
is hydrogen or halo;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen or C
1-6
alkyl;
L is C
3-6
cycloalkyl, C
5-6
cycloalkanone, or C
2-6
alkenyl, or L is a radical of formula
-Alk-R
6
(b-1),
-Alk-X-R
7
(b-2),
-Alk-Y-C(═O)—R
9
(b-3), or
-Alk-Y-C(=O)—NR
11
R
12
(b-4),
wherein
each Alk is C
1-12
alkanediyl; and
R
6
is hydrogen, hydroxy, cyano, C
1-6
alkylsulfonylamino, C
3-6
cycloalkyl, C
5-6
cycloalkanone, or Het
1
;
R
7
is hydrogen, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
cycloalkyl, or Het
2
;
X is O, S, SO
2
or NR
8
; said R
8
being hydrogen or C
1-6
alkyl;
R
9
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkyloxy or hydroxy;
Y is NR
10
or a direct bond; said R
10
being hydrogen or C
1-6
alkyl;
R
11
and R
12
each independently are hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, or R
11
and R
12
combined with the nitrogen atom bearing R
11
and R
12
may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C
1-6
alkyl, amino or mono or di(C
1-6
alkyl)amino, or said R
11
and R
12
combined with the nitrogen bearing R
11
and R
12
may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C
1-6
alkyl; and
Het
1
and Het
2
each independently are selected from furan; furan substituted with C
1-6
alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C
1-6
alkyl; a dioxolane; a dioxolane substituted with C
1-6
alkyl, a dioxane; a dioxane substituted with C
1-6
alkyl; tetrahydropyran; a tetrahydropyran substituted with C
1-6
alkyl; pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C
1-6
alkyl; pyridinyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C
1-6
alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C
1-6
alkyl, C
1-6
alkyloxy, amino and mono and di(C
1-6
alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C
1-6
alkyloxy, C
1-6
alkyl or halo; pyrazinyl; pyrazinyl substituted with one ore two substituents each independently selected from halo, hydroxy, cyano, C
1-6
alkyl, C
1-6
alkyloxy, amino, mono- and di(C
1-6
alkyl)amino and C
1-6
alkyloxycarbonyl;
Het
1
can also be a radical of formula
Het
1
and Het
2
each independently can also be selected from the radicals of formula
R
13
and R
14
each independently are hydrogen or C
1-4
alkyl.
As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; C
3-6
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C
2-6
alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; C
2-6
alkynyl defines straight and branched chain h
Bosmans Jean-Paul Rene Marie Andre
De Cleyn Michel Anna Jozef
Surkyn Michel
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Patel Sudhaker B.
Raymond Richard L.
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