Benzopyran derivatives

Details Benzopyran derivatives Benzopyran derivatives

2000-10-18

2002-06-11

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S376000

Reexamination Certificate

active

06403594

ABSTRACT:

Applicants also claim priority under 35 U.S.C. §119(a-d) of Italian patent application no. MI99A 002174, filed Oct. 18, 1999, which is hereby incorporated by reference
SCOPE OF THE INVENTION
This invention relates to benzopyran derivatives, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
BACKGROUND OF THE INVENTION
Flavoxate, 3-methyl-4-oxo-2-phenyl-8-(2,N-piperidinylethoxycarbonyl)-4H-1-benzopyran, has the formula:
and is used as a pharmaceutical agent for urinary-tract disturbances as it possesses a smooth-muscle relaxing activity attributable to its calcium antagonist activity. This activity is exerted on the bladder-neck smooth muscles or can be related to an effect on the micturition centre in the central nervous system (Guarneri L. el al.,
Drugs of Today,
30:91-98, 1994).
U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations in part (U.S. Pat. No. 5,474,994, Leonardi et al., and U.S. Pat. No. 5,605,896, Leonardi et al.) claim more complex amino functions in place of the piperidinyl group of flavoxate. Further claimed changes include alternatives to the ethoxycarbonyl group which links the amino moiety to position 8 of the benzopyran ring, alternative substitutions at positions 2, 3, 6 and 7 of the benzopyran ring, replacement of the ring heteroatom by a sulphur atom or by a sulphinyl or sulphonyl group, or by a nitrogen atom or an amino group, and/or hydrogenation at position 2-3 of the benzopyran ring. Further variations of the heterocyclic ring were also described. These structural variations gave the new compounds the ability to interact with different biological systems, as supported by the affinity of the new compounds for the &agr;
1
-adrenergic and 5HT
1A
-serotoninergic receptors. Flavoxate is practically devoid of affinity for these receptors. One of the most interesting of the compounds of U.S. Pat. No. 5,403,842, Leonardi et al., was Compound A (Ex. 11).
The compounds of the present invention retain the 3-methyl-4-oxo-8-[(&ohgr;-(4-phenyl-1-piperazinyl)alkylcarbamoyl]-4H-1-benzopyran structure of Compound A, but introduce alternative substituents in place of the phenyl group at position 2 of the benzopyran ring and new patterns of substitution for the phenyl group linked to the piperazine ring. These new compounds are endowed with selective antagonistic activity for the &agr;
1
receptor (in particular if compared to affinity for the 5-HT
1A
receptor) and are able to reduce the contractility of prostatic urethra in mammals with little or no effect on 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), female lower urinary tract symptoms (LUTS), and neurogenic lower urinary tract dysfunction (NLUTD), without side effects associated with hypotensive activity. Some of the new compounds also have a longer duration of action on the urethra than Compound A.
SUMMARY OF THE INVENTION
The invention describes compounds of the general formula I:
wherein
R is selected from the group consisting of a phenyl, alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group;
R
1
is selected from the group consisting of an alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulphonyloxy group;
each of R
2
and R
3
independently is selected from a group consisting of a hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl group; and
n is 0, 1 or 2;
with the proviso that, if R represents a phenyl group and both R
2
and R
3
represent hydrogen and/or halogen atoms, then R
1
represents a polyfluoroalkoxy or trifluoromethanesulphonyloxy group.
The invention also includes the N-oxides and pharmaceutically acceptable salts of these compounds.
When R does not represent a phenyl group, each of R
2
and R
3
preferably independently represents a hydrogen or halogen atom or a polyfluoroalkoxy group.
Alkyl and alkoxy groups preferably have from 1 to 4 carbon atoms; complex groups such as alkoxycarbonyl, alkylcarbonyl, alkylcarbamoyl, dialkylcarbamoyl, polyfluoroalkyl, polyfluoroalkoxy and alkoxycarbonylamino, are preferably construed accordingly. Preferred polyfluoroalkoxy groups are trifluoromethoxy and 2,2,2-trifluoroethoxy. The preferred value for n is 1.
Further preferred is where R is selected from the group consisting of phenyl, alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino; R
1
is selected from the group consisting of alkoxy and hydroxy; each of R
2
and R
3
is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl and carbamoyl; and n=0, 1 or 2.
Further preferred is where R is selected from the group consisting of carbamoyl, alkylcarbamoyl and dialkylcarbamoyl; R
1
is selected from the group consisting of alkoxy, polyfluroalkoxy, hydroxy and trifluoromethanesulphonyloxy; each R
2
and R
3
is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl; and n=0, 1 or 2.
Further preferred is where R is carbomoyl; R
1
is selected from the group consisting of alkoxy; polyfluoroalkoxy, hydroxy, and trifluoromethanesulphonyloxy; each R
2
and R
3
is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl; and n=0, 1 or 2.
The compounds of the invention include those compounds where, independently, R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R
1
is selected from a group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group, R
2
is selected from the group consisting of hydrogen and fluorine, R
3
is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; 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 an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R
1
is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R
2
is selected from the group consisting of hydrogen and fluorine; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R
3
is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and 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 methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R
2
is selected from the group consisting of hydrogen and fluorine; or R
1
is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R
3
is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
Also included within the invention compounds with combinations of substituents where, together, R
2
is selected from the group consisting of hydrogen and fluorine and R
3
is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or

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