Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-03
2004-06-08
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S196000, C548S311400, C548S134000, C514S362000, C514S392000, C514S397000
Reexamination Certificate
active
06747045
ABSTRACT:
The present invention is concerned with novel aminomethylchromane compounds having fundic relaxation properties. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.
Structurally related aminomethylchromane derivatives are disclosed in U.S. Pat. No. 5,541,199 as selective autoreceptor agonists useful as antipsychotic agents. Other structurally related aminomethylchroman derivatives having affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT
1
type and therefore suitable for the treatment of disorders of the central nervous system are disclosed in U.S. Pat. No. 5,137,901.
EP-0,546,388, published on 16 Jun. 1993, discloses structurally related amino-methylchroman derivatives having affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT
1
type and for dopamine receptors of the D
2
-type. EP-0,628,310, published on 14 Dec. 1994, encompasses the use of the same aminomethylchroman derivatives for the inhibition of HIV-protease.
DE-2,400,094, published on 18 Jul. 1974, discloses 1-[1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl-2-benzimidazolinones possessing blood pressure lowering activity.
WO-93/17017, published on 2 Sep. 1993, discloses [(benzodioxane, benzofuran or benzopyran)alkylamino]alkyl-substituted guanidine as selective vasoconstrictors useful to treat conditions related to vasodilatation such as, e.g., migraine, cluster headache and headache associated with vascular disorders.
WO-95/05383, published on 23 Feb. 1995, encompasses dihydrobenzopyran-pyrimidine derivatives also having vasoconstrictive activity.
Other structurally related aminomethylchroman derivatives are disclosed in WO-97/28157, published on 7 Aug. 1997, as &agr;
2
-adrenergic receptor antagonists useful in the treatment of degenerative neurological conditions.
The compounds of the present invention differ from the cited art-known compounds structurally, by the nature of the R
5
substituent, and pharmacologically by the fact that, unexpectedly, these compounds have fundic relaxation properties. Furthermore, the compounds of the present invention have additional beneficial pharmacological properties in that they have little or no vasoconstrictor activity.
During the consumption of a meal the fundus. i.e. the proximal part of the stomach, relaxes and provides a “reservoir” function. Patients having an impaired adaptive relaxation of the fundus upon food ingestion have been shown to be hypersensitive to gastric distension and display dyspeptic symptoms. Therefore, it is believed that compounds which are able to normalize an impaired fundic relaxation are useful to relieve patients suffering from said dyspeptic symptoms.
The present invention concerns compounds of formula (I)
a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, wherein
Alk
1
is C
1-4
alkylcarbonyl, C
1-4
alkylcarbonylC
1-4
alkyl, carbonyl, carbonylC
1-4
alkyl, or C
1-6
alkanediyl optionally substituted with hydroxy, C
1-4
alkyloxy, C
1-4
alkylcarbonyloxy, C
1-4
alkylcarbonyloxyC
1-4
alkyloxycarbonyloxy, or C
3-6
cycloalkylcarbonyloxyC
1-4
alkyloxycarbonyloxy;
—Z
1
—Z
2
— is a bivalent radical of formula
—CH
2
—
(e-1),
—O—CH
2
—
(e-2),
—S—CH
2
—
(e-3),
—CH
2
—CH
2
—
(e-4),
—CH
2
—CH
2
—CH
2
—
(e-5),
—CH═
(e-6),
—CH
2
—CH═
(e-7),
—CH
2
—CH
2
—CH═
(e-8),
—CH═CH—
(e-9);
R
1
, R
2
and R
3
are each independently selected from hydrogen, C
1-6
alkyl, C
3-6
alkenyl, C
1-6
alkyloxy, trihalomethyl, trihalomethoxy, halo, hydroxy, cyano, nitro, amino, C
1-6
alkylcarbonylamino, C
1-6
alkyloxycarbonyl, C
1-4
alkylcarbonyloxy, aminocarbonyl, mono- or di(C
1-6
alkyl)aminocarbonyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, C
1-4
alkylcarbonyloxyC
1-4
alkyloxycarbonyloxy, or C
3-6
cycloalkylcarbonyloxyC
1-4
alkyloxycarbonyloxy; or
when R
1
and R
2
are on adjacent carbon atoms, R
1
and R
2
taken together may form a bivalent radical of formula
—CH
2
—CH
2
—CH
2
—
(a-1),
—CH
2
—CH
2
—CH
2
—CH
2
—
(a-2),
—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—
(a-3),
—CH═CH—CH═CH—
(a-4),
—O—CH
2
—O—
(a-5),
—O—CH
2
—CH
2
—
(a-6),
—O—CH
2
—CH
2
—O—
(a-7),
—O—CH
2
—CH
2
—CH
2
—
(a-8),
—O—CH
2
—CH
2
—CH
2
—CH
2
—
(a-9),
wherein optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by hydroxy, C
1-4
alkyl or CH
2
OH:
R
4
is hydrogen, C
1-6
alkyl, or a direct bond when the bivalent radical —Z
1
—Z
2
— is of formula (e-6), (e-7) or (e-8);
A is a bivalent radical of formula
wherein the nitrogen atom is connected to Alk
1
and,
m is 0 or 1;
Alk
2
is C
1-6
alkanediyl;
R
6
is hydrogen, C
1-6
alkyl, C
1-4
alkylcarbonyl, C
1-4
alkyloxycarbonyl, phenylmethyl, C
1-4
alkylaminocarbonyl, C
1-4
alkylcarbonyloxyC
1-4
alkyloxycarbonyl, or C
3-6
cycloalkylcarbonyloxyC
1-4
alkyloxycarbonyloxy;
R
5
is a radical of formula
wherein n is 1 or 2;
p
1
is 0, and p
2
is 1 or 2; or
p
1
is 1 or 2, and p
2
is 0;
X is oxygen, sulfur, NR
9
or CHNO
2
;
Y is oxygen or sulfur;
R
7
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, phenyl or phenylmethyl;
R
8
is C
1-6
alkyl, C
3-6
cycloalkyl, phenyl or phenylmethyl;
R
9
is cyano, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkyloxycarbonyl or aminocarbonyl;
R
10
is hydrogen or C
1-6
alkyl; and
Q is a bivalent radical of formula
—CH
2
—CH
2
—
(d-1),
—CH
2
—CH
2
—CH
2
—
(d-2),
—CH
2
—CH
2
—CH
2
—CH
2
—
(d-3),
—CH═CH—
(d-4),
—CH
2
—CO—
(d-5),
—CO—CH
2
—
(d-6),
wherein optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C
1-4
alkyl, hydroxy or phenyl, or Q is a bivalent radical of formula
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
3-6
alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 3 to 6 carbon atoms, such as propenyl, butenyl, pentenyl or hexenyl; C
1-2
alkanediyl defines methylene or 1,2-ethanediyl; C
2-4
alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 2 to 4 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, and the branched isomers thereof; C
1-5
alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 5 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, and the branched isomers thereof; C
1-6
alkanediyl includes C
1-5
alkanediyl and the higher homologues thereof having 6 carbon atoms such as, for example, 1,6-hexanediyl and the like. The term “CO” refers to a carbonyl group.
Some examples of the R
5
moiety are:
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The pharmaceutically acceptable ac
De Bruyn Marcel Frans Leopold
Schroven Marc Francis Josephine
Verschueren Wim Gaston
Wigerinck Piet Tom Bert Paul
Habte Kahsay
Janssen Pharmaceutica N.V.
Shah Mukund J.
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