Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-17
2004-01-20
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S367000, C514S382000, C514S428000, C514S534000, C514S649000
Reexamination Certificate
active
06680319
ABSTRACT:
SCOPE OF THE INVENTION
The present invention relates to isoxazolecarboxamide derivatives, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations (U.S. Pat. Nos. 5,474,994, Leonardi et al. and 5,605,896, Leonardi et al.) claim heterobicyclic derivatives bearing substituted phenylpiperazines linked to the heterocyclic ring by a variety of spacer groups. Among said derivatives, compound A (Ex. 11) is of particular interest due its high activity and uroselectivity.
Compound A is endowed with good affinity for the &agr;
1A
adrenoceptor and is able to selectively inhibit contractility of the prostatic urethra in a dog model without substantial effects on blood pressure (Leonardi et al., J. Pharmacol. Exp. Therap., 281:1272-1283, 1997).
N,&ohgr;-Aminoalkylamides of 3-phenyl-4-isoxazolecarboxylic acid are known compounds, but prior-art molecules possess quite diverse molecular structures as compared to those claimed in this patent and a completely different pharmacological effect. For example, European patent EP 0573883, Jeschke et al., includes, as a representative compound, 3-(2-chloro-6-fluorophenyl)-N-[3-(2-chlorophenylamino) propyl]-5-methyl-isoxazole-4-carboxamide and other similar derivatives and their claimed therapeutic application is the care of endoparasitoses. European patent EP 0428434, Emonds-Alt et al., claims 3-(2-chlorophenyl)-N-{2-(3,4-dichlorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]butyl}-5-methylisoxazole-4-carboxamide as substance P antagonists. Neither of these patents claim arylpiperazinyl derivatives active at the &agr;
1
adrenergic receptor.
The present invention is directed to the structural class of N-(substituted phenyl)-N′-[&ohgr;-(3-substituted phenyl-4-isoxazolecarbonylamino)alkyl]piperazines. The compounds of this class are endowed with enhanced selectivity toward the &agr;
1
adrenergic receptor (with or without further selectivity for the &agr;
1A
receptor or for both the &agr;
1A
and &agr;
1D
), in particular with respect to the 5-HT
1A
receptor, and improved in vivo uroselectivity even compared to compound A, with remarkable effects on relaxation of prostatic urethra and very low activity in lowering blood pressure. This activity profile suggests the safer use of the compounds of the invention in the therapy of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH); of lower urinary tract symptoms (LUTS); and neurogenic lower urinary tract dysfunction (NLUTD), without side-effects associated with hypotensive activity.
SUMMARY OF THE INVENTION
The invention provides compounds of the general formula I:
wherein:
R is selected from the group consisting of alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulfonyloxy group;
each of R
1
and R
2
independently is selected from the group consisting of a hydrogen, halogen, polyfluoroalkoxy and alkoxy group;
R
3
represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl, carboxamido group;
R
4
is selected from the group consisting of a hydrogen atom, an alkyl group and an arylalkyl group; and
n is 0, 1 or 2.
The invention also includes the N-oxides and pharmaceutically acceptable salts of these compounds.
Preferred alkyl groups which R and R
4
may represent are without limitation lower (C
1-4
) alkyl groups, most preferably methyl (CH
3
). Preferred alkoxy groups which R, R
1
, R
2
and R
3
may represent without limitation are lower (C
1-4
) alkoxy groups, most preferably methoxy. Preferred polyfluoroalkoxy groups which R, R
1
and R
2
may represent are without limitation trifluoromethoxy or 2,2,2-trifluoroethoxy groups. The preferred value for n is 1.
A preferred arylalkyl group that R
4
may represent without limitation is phenyl, optionally substituted with one or more substituent selected from the group consisting of hydrogen, halogen, C
1-4
alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl and carboxamido group.
A preferred group that R
3
may represent without limitation is carboxamido.
Also preferred is where R is selected from the group consisting of alkoxy and hydroxy; R
1
is selected from the group consisting of hydrogen and halogen; R
2
is selected from the group consisting of hydrogen and halogen; R
3
represents one or more substitutents consisting of hydrogen, halogen, alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl and carboxamido group; R
4
is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
Also preferred is where R is selected from a group consisting of alkoxy, alkyl and polyfluoroalkoxy; R
1
is selected from the group consisting of hydrogen, halogen and alkoxy; R
2
is selected from the group consisting of hydrogen, halogen and alkoxy; R
3
represents one or more substitutents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, and amino; R
4
is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
Also preferred is where R is selected from the group consisting of alkoxy, alkyl and polyfluoroalkoxy, R
1
is halogen; R
2
is hydrogen; R
3
represents one or more substitutents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and amino; R
4
is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
The compounds of the invention include those compounds where, independently, R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R
1
is selected from a group consisting of hydrogen and fluorine, R
2
is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R
3
is carboxamido, R
4
is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; and n is 0, 1 or 2.
Other compounds within the invention are those compounds with combinations of substituents where, together, R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R
1
is selected from the group consisting of hydrogen and fluorine; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R
2
is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R
3
is carboxamido; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R
4
is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
Compounds of the invention also include those compounds with combinations of substituents where, together, R
1
is selected from the group consisting of hydrogen and fluorine and R
2
is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy; or R
1
is selected from the group consisting of hydrogen and fluorine and R
3
is carboxamido; or R
1
is selected from the group consisting of hydrogen and fluorine and R
4
is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
Also included within the invention are compounds with combinations of substituents where, together, R
2
is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R
3
is carboxamido; or R
2
is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R
4
is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R
3
is carboxamido and R
4
is selected from the group cons
Leonardi Amedeo
Motta Gianni
Poggesi Elena
Riva Carlo
Jones Dwayne C.
Recordati S.A.
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