N-substituted...

Details N-substituted... N-substituted...

2001-08-20

2003-01-21

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S255050, C514S256000, C514S266220, C514S269000, C514S252030, C514S318000, C514S320000, C514S321000, C514S322000, C514S326000, C514S331000, C544S238000, C544S237000, C544S287000, C544S298000, C544S321000, C544S333000, C544S336000, C544S405000, C546S194000, C546S196000, C546S197000, C546S210000

Reexamination Certificate

active

06509339

ABSTRACT:

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.
Compounds structurally related to the present novel compounds are disclosed in the prior art. WO 93/05038, published on Mar. 18, 1993, discloses (1-butyl-4-piperidinyl)methyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 HT
4
receptor antagonistic activity. WO 93/16072, published on Aug. 19, 1993 discloses (1-butyl-4-piperidinyl)methyl-5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylate hydrochloride having 5 HT
4
receptor antagonistic activity. Recently, Fancelli D. et al.,
Bioorganic & Medicinal Chem. Lett.,
6:263-266, 1996, and WO-96/33186, published on Oct. 24, 1996, disclose (1-butyl-4-piperidinyl)methyl-4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylate hydrochloride having 5 HT
4
receptor agonistic activity.
WO 94/29298, published on Dec. 22, 1994 discloses 8-amino-7-chloro-1,4-benzodioxan-5-(1-butyl-4-piperidinyl)carboxylate having 5 HT
4
receptor antagonistic activity. WO 94/10174, published on May 11, 1994 discloses 5-(1-(3-pyridylmethyl)-4-piperidinyl)methyl-8-amino-7-chloro-1,4-benzo-dioxancarboxylate, [1-(2-carbo-ethoxyethyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate, [1-(3-hydroxybutyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 HT
4
receptor antagonistic activity. Also, WO-96/28424, published on Sep. 19, 1996, discloses disubstituted 1,4-piperidine esters and amides having 5 HT
4
receptor antagonistic activity.
The cited prior art documents disclose compounds having 5 HT
4
receptor antagonistic activity and may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders. In particular, these compounds are thought to be useful in the treatment of irritable bowel syndrome (IBS), especially the diarrhoea aspects of IBS by blocking the ability of 5-HT to stimulate gut motility.
The problem which this invention sets out to solve is to provide gastric prokinetic compounds, i.e. the actual stimulation of gastric motility.
It is generally believed that gastric prokinetic activity is correlated with 5 HT
4
receptor agonist activity, i.e. the opposite of 5 HT
4
antagonist activity, (King F. D. et al.,
J. Med. Chem.,
36:683-689, 1993 and Langlois M. et al.,
Bioorganic & Medicinal Chem. Lett.,
4:1433-1436, 1994).
Hence it was surprising to find that the present compounds of formula (I) show gastric prokinetic activity.
In one embodiment, this invention concerns the use of compounds of formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R
1
is C
1-6
alkyloxy, C
2-6
alkenyloxy or C
2-6
alkynyloxy;
R
2
is hydrogen or C
1-6
alkyloxy,
or when taken together R
1
and R
2
may form a bivalent radical of formula
—O—CH
2
—O—  (a-1),
—O—CH
2
—CH
2
—  (a-2),
—O—CH
2
—CH
2
—O—  (a-3),
—O—CH
2
—CH
2
—CH
2
—  (a-4),
—O—CH
2
—CH
2
—CH
2
—O—  (a-5),
—O—CH
2
—CH
2
—CH
2
—CH
2
—  (a-6),
 wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C
1-6
alkyl;
R
3
is hydrogen or halo;
L is C
3-6
cycloalkyl, C
5-6
cycloalkanone, C
2-6
alkenyl optionally substituted with Ar, or L is a radical of formula
 wherein
Alk is C
1-12
alkanediyl;
R
4
is hydrogen, C
1-6
alkylsulfonylamino, C
3-6
cycloalkyl, C
5-6
cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het
1
;
R
5
is hydrogen or C
1-6
alkyl;
R
6
is Het
2
;
R
7
is hydrogen, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
cycloalkyl, Ar or Het
2
;
X is O, S, SO
2
or NR
8
; said R
8
being hydrogen, C
1-6
alkyl or Ar,
R
9
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, Ar, ArC
1-6
alkyl, di(Ar)methyl, C
1-6
alkyloxy or hydroxy;
Y is NR
10
or a direct bond; said R
10
being hydrogen, C
1-6
alkyl or Ar;
R
11
and R
12
each independently are hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, Ar or ArC
1-6
alkyl, 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;
each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, aminosulfonyl, C
1-6
alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl; 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 or 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;
with the proviso that L is other than n-butyl when R
1
and R
2
are taken together to form a bivalent radical of formula (a-2);
for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach.
In another embodiment, this invention concerns novel compounds of formula (I′)
the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R
1
is C
1-6
alkyloxy, C
2-6
alkenyloxy or C
2-6
alkynyloxy;
R
2
is hydrogen or C
1-6
alkyloxy,
or when taken together R
1
and R
2
may form a bivalent radical of formula
—O—CH
2
—O—  (a-1),
—O—CH
2
—CH
2
—  (a-2),
—O—CH
2
—CH
2
—O—  (a-3),
 —O—CH
2
—CH
2
—CH
2
—  (a-4),
—O—CH
2
—CH
2
—CH
2
—O—  (a-5),
—O—CH
2
—CH
2
—CH
2
—CH
2
—  (a-6),
 wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C
1-6
alkyl;
R
3
is hydrogen or halo;
L is C
3-6
cycloalkyl, C
5-6
cycloalkanone, C
2-6
alkenyl optionally substituted with Ar, or L is a radical of formula
 wherein
Alk is C
1-12
alkanediyl;
R
4
is hydrogen, C
1-6
alkylsulfonylamino, C
3-6
cycloalkyl, C
5-6
cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het
1
;
R
5
is hydrogen or C
1-6
alkyl;
R
6
is Het
2
;
R
7
is hydrogen, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
cycloalkyl, Ar or Het
2
;
X is O, S, SO
2
or NR
8
; said R
8
being hydrogen, C
1-6
alkyl or Ar;
R
9
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, Ar, ArC
1-6
alkyl, di(Ar)methyl, C
1-6
alkyloxy or hydroxy;
Y is NR
10
or a direct bond; said R
10
being hydrogen, C
1-6
alkyl or Ar;
R
11
and R
12
each independently are hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, Ar or ArC
1-6
alkyl, 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 be

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