Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-08
2003-04-08
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, C546S197000, C546S199000, C514S320000, C514S322000, C514S275000, C544S407000, C544S320000
Reexamination Certificate
active
06544997
ABSTRACT:
The present invention is concerned with novel compounds of formula (I) having favourable gastrointestinal 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.
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.
WO 93/16072, published on Aug. 19, 1993 discloses N-[(1-butyl-4-piperidinyl)-methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide having 5 HT
4
receptor antagonistic activity.
The compounds of the present invention differ from the cited art-known compounds structurally, by the presence of a hydroxy or a C
1-6
alkyloxygroup on the 3- or 4-position of the piperidine moiety, by the presence of a methylene group between the carbamoyl group and the piperidine ring, and by the absence of an amino group on the 4-position of the benzamide moiety.
Unexpectedly, the present compounds of formula (I) have favourable gastrointestinal properties.
The present invention concerns a compound of formula (I)
a stereochemically isomeric form thereof, an N-oxide form thereof, a prodrug thereof, or a pharmaceutically acceptable acid or base addition salt thereof,
wherein
—R
1
—R
2
— is a bivalent radical of formula
wherein in said bivalent radicals optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C
1-6
alkyl or hydroxy,
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, oxoC
5-6
cycloalkyl, or C
2-6
alkenyl,
or L is a radical of formula
wherein each Alk is C
1-12
alkanediyl; and
R
6
is hydrogen, cyano, amino, C
1-6
alkylsulfonylamino, C
3-6
cycloalkyl, oxoC
5-6
cycloalkyl, aryl or Het
1
;
R
7
is hydrogen, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
cycloalkyl, aryl 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, hydroxy or aryl;
Y is a direct bond, NR
10
, O, S, O—(CH
2
)
n
—, S—(CH
2
)
n
—, or —NR
10
—(CH
2
)
n
—, wherein n is an integer from 1 to 6, and 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
each aryl represents 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, amino-sulfonyl, 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; tetrahydrofuran substituted with C
1-6
alkyl; dioxolane; dioxolane substituted with C
1-6
alkyl; dioxane; dioxane substituted with C
1-6
alkyl; tetrahydropyran; 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
4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 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-methyl-butyl, 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
1-12
alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl and the branched isomers thereof. C
1-6
alkanediyl is defined in an analogous way as C
1-12
alkanediyl.
The —OR
4
radical is preferably situated at the 3- or 4-position of the piperidine moiety.
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 term prodrug as used throughout this text means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8
th
ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15) describing prodrugs generally, is hereby incorporated.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the fr
Bosmans Jean-Paul Rene Marie Andre
De Cleyn Michel Anna Jozef
Gijsen Henricus Jacobus Maria
Meulemans Ann Louise Gabriëlle
Janssen Pharmaceutica N.V.
Liu Hong
Shah Mukund J.
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