Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-28
2001-10-23
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...
C544S377000
Reexamination Certificate
active
06306861
ABSTRACT:
SCOPE OF THE INVENTION
The present invention relates to thienopyranecarboxamide 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 in part (U.S. Pat. Nos. 5,474,994 and 5,605,896) claim heterobicyclic derivatives bearing substituted phenylpiperazines as basic moieties linked to the heterocyclic ring by a variety of spacer groups. Among said derivatives, compound A (Ex. 11) is of relevant interest due its very high uroselective activity.
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.)
7-Oxo-7H-thieno[3,2-b]pyran-3-carboxylic acid and its N,&ohgr;-aminoalkylamides are compounds not yet reported in the literature. The present invention is directed to the new structural class of the N-(substituted phenyl)-N′-[&ohgr;-(5-substituted-7-oxo-7H-thieno[3,2-b]pyran-3-carbonylamino)alkyl]piperazines.
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 &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), and of lower urinary tract symptoms (LUTS) as well as of neurogenic lower urinary tract dysfunction (NLUTD), without side-effects associated with hypotensive activity.
SUMMARY OF THE INVENTION
In one aspect, the invention is directed to compounds of Formula I:
wherein
R is an aryl, cycloalkyl or polyhaloalkyl group,
R
1
is chosen from the group consisting of alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulfonyloxy; each of R
2
and R
3
independently is chosen from the group consisting of a hydrogen, halogen, alkoxy and polyfluoroalkoxy group, and n is 0, 1 or 2.
The preferred aryl group which R may represent without limitation is phenyl. The preferred cycloalkyl group that R may represent without limitation is cyclohexyl. The preferred polyhaloalkyl group that R may represent without limitation is trifluoromethyl. The preferred alkyl group which R
1
may represent without limitation is C
1-4
lower alkyl. Preferred alkoxy groups (C
1-4
) which R
1
, R
2
, and R
3
may represent without limitation are lower alkoxy groups, most preferably methoxy. Preferred polyfluoroalkoxy which R
1
, R
2
, and R
3
may represent without limitation are trifluoromethoxy or 2,2,2-trifluoroethoxy.
The preferred value for n is 1.
Also preferred is where R
1
is chosen from the group consisting of alkoxy and hydroxy; R
2
is chosen from the group consisting of hydrogen and halogen; R
3
is chosen from the group consisting of hydrogen and halogen; and n is 0, 1 or 2.
Also preferred is where R
1
is chosen from a group consisting of alkoxy, hydroxy and polyfluoroalkoxy; R
2
is chosen from the group consisting of hydrogen, halogen and alkoxy; R
3
is chosen from the group consisting of hydrogen, halogen and alkoxy; and n is 0, 1 or 2.
Also preferred is where R
1
is chosen from the group consisting of alkoxy, polyfluoroalkoxy, hydroxy; R
2
is halogen; R
3
is hydrogen; and n is 0, 1 or 2.
The invention also includes the N-oxides and pharmaceutically acceptable salts of these compounds.
The invention further provides pharmaceutical compositions comprising a compound of Formula I or a N-oxide or pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention is directed to methods for selectively preventing contractions (including noradrenaline-mediated contractions) of the urethra and lower urinary tract, without substantially affecting blood pressure, by administering one or more selected compounds of Formula I to a mammal (including a human) in need of such treatment in an amount or amounts effective for the particular use.
In yet another aspect, the invention is directed to methods for blocking a, receptors, by delivering to the environment of said receptors, e.g., to the extracellular medium, (or by administering to a mammal possessing said receptors) an effective amount of a compound of the invention, in this way relieving diseases associated to overactivity of said receptors.
The very high uroselectivity of the compounds of this invention has been tested in the dog model described in Example 10, where their efficacy in antagonizing the contractions of prostatic urethra in the presence of very limited effects on blood pressure has been shown, in comparison to compound A and to another well-known &agr;
1
-antagonist, prazosin.
Accordingly, it is a primary object of the present invention to provide a method of treating BPH which avoids any undue side effects due to acute hypotension (i.e., limited effects on blood pressure).
It is another object of the present invention to provide pharmaceutical compositions comprising 7-oxo-7H-thieno[3,2-b]pyran compounds which are selective a, adrenoceptor antagonists, which compositions are effective for the treatment of BPH optionally including a carrier or diluent.
It is another object of the present invention to provide a method of treating BPH using 7-oxo-7H-thieno[3,2-b]pyran compounds which are selective &agr;
1
adrenoceptor antagonists.
Another aspect of the invention is the use of new compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, reducing sympathetically-mediated pain, the treatment of cardiac arrhythmia and erectile dysfunction, as well as treatment of LUTS and NLUTD.
An object of the present invention is to provide a method of preventing contractions of the urethra and lower urinary tract comprising administering to a mammal including a human in need of such treatment an effective amount of compounds of the present invention and/or pharmaceutical compositions comprising compounds of the present invention.
A further object of the present invention is a method of administration of compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention to mammals including humans which causes very limited effects on the blood pressure of said mammal.
A further object of the present invention is a method for blocking a, adrenergic receptors comprising releasing in the environment of said receptors compounds of the present inventions or pharmaceutical compositions of the present invention to relieve diseases associated with overactivity of said receptor.
A further object of the present invention is the release of compounds of the present invention or pharmaceutical compositions containing compounds of the present invention in the environment of &agr;
1
adrenergic receptors wherein said release is effected by administering compounds of the present invention or pharmaceutical compositions containing compounds of the present invention to a mammal including a human possessing said receptors.
A further object of the present invention is the method of treatment of a patient suffering from benign prostatic hyperplasia, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from excessive intraocular pressure, the method comprising administering an effective amount of a compound of the present invention or
Leonardi Amedeo
Motta Gianni
Riva Carlo
Testa Rodolfo
Darby & Darby
Liu Hong
Recordati S.A. Chemical and Pharmaceutical Company
Shah Mukund J.
LandOfFree
Thienopyrancecarboxamide derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thienopyrancecarboxamide derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thienopyrancecarboxamide derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2593692