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
2002-05-14
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
06387909
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, 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), 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.
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 &agr;
1
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 &agr;
1
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, and the treatment of cardiac arrhythmia and erectile dysfunction.
Other features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications and literature references cited in this application are incorporated by reference in their entirety.
The adrenergic antagonistic activity of the compounds of the invention renders them useful as agents acting on body tissues particularly rich in &agr;
1
-adrenergic receptors (such as prostate and urethra). Accordingly, the anti-adrenergic compounds within the invention, established as such on the basis of their receptor binding profile, can be useful therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including but not limited to benign prostatic hypertrophy (BPH).
BPH is a progressive condition, which is characterised by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urinary stream and hesitancy or delay in starting urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of a prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the ageing male population. BPH is observed in approximately 70% of males over the age of 70. Currently, the worldwide stated method of choice for treating BPH is surgery. A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
&agr;-Adrenergic receptors (McGrath et al., Med. Res. Rev., 9:407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many &agr;-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). &agr;-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter noradrenaline, and antagonists (phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin are antagonists), which act to block the effects of noradenaline. Many of
Leonardi Amedeo
Motta Gianni
Riva Carlo
Testa Rodolfo
Darby & Darby
Liu Hong
Recordati S.A. Chemical and Pharmaceutical Company
Shah Mukund J.
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