Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-11
2001-08-07
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S360000
Reexamination Certificate
active
06271234
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel 1,4-disubstituted piperazines that bind to serotonergic receptors, to pharmaceutical compositions containing them, and to uses for such derivatives and compositions.
BACKGROUND OF THE INVENTION
In mammals, micturition (urination) is a complex process that requires the integrated actions of the bladder, its internal and external sphincters, the musculature of the pelvic floor, and neurological control over these muscles at three levels (in the bladder wall or sphincter itself, in the autonomic centers of the spinal cord, and in the central nervous system at the level of the pontine micturition center (PMC) in the brainstem (Pons) under the control of cerebral cortex) (De Groat,
Neurobiology of Incontinence
, (Ciba Foundation Symposium 151:27, 1990). Micturition results from contraction of the detrusor muscle, which consists of interlacing smooth muscle fibers under parasympathetic autonomic control from the sacral spinal cord. A simple voiding reflex is formed by sensory nerves for pain, temperature, and distension that run from the bladder to the sacral cord. However, sensory tracts from the bladder also reach the PMC, resulting in the generation of nerve impulses that normally suppress the sacral spinal reflex arc controlling bladder emptying. Thus, normal micturition is initiated by voluntary suppression of cortical inhibition of the reflex arc and by relaxation of the muscles of the pelvic floor and the external sphincter. Finally, the detrusor muscle contracts and voiding occurs.
Abnormalities of lower urinary tract function, e.g., dysuria, incontinence, and enuresis, are common in the general population. Dysuria includes urinary frequency, nocturia, and urgency, and may be caused by cystitis, prostatitis or benign prostatic hypertrophy (BPH) (which affects about 70% of elderly males), or by neurological disorders. Incontinence syndromes include stress incontinence, urgency incontinence, and overflow incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep.
Prior to the work of the present inventors, treatment of neuromuscular dysfunction of the lower urinary tract has involved administration of compounds that act directly on the bladder muscles, such as flavoxate, a spasmolytic drug (Ruffman,
J. Int.Med.Res.
16:317, 1988) also active on the PMC (Guarneri et al.,
Drugs of Today
30:91, 1994), or anticholinergic compounds such as oxybutynin (Andersson,
Drugs
35:477, 1988). The use of &agr;
1
-adrenergic receptor antagonists for the treatment of BPH is also common but is based on a different mechanism of action. (Lepor,
Urology,
42:483, 1993).
However, treatments that involve direct inhibition of the pelvic musculature (including the detrusor muscle) may have unwanted side effects such as incomplete voiding or accommodation paralysis, tachycardia and dry mouth (Andersson,
Drugs
35:477, 1988). Thus, it would be preferable to utilize compounds that act via the peripheral or central nervous system to, for example, affect the sacral spinal reflex arc and/or the PMC inhibition pathways in a manner that restores normal functioning of the micturition mechanism. N-(2-pyridyl)-N,2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylcyclohexanecarboxamide (compound A, below) is described in GB 2255 337 A and is reported to possess 5-HT
1A
antagonistic properties. It is also disclosed that it can be used for the treatment of central nervous system disorders, for example as an anxiolytic agent in the treatment of anxiety.
The compounds of the present invention, described below, are structurally different from compound A because of the novel substitutions on the aromatic ring bound to the piperazine moiety and because of the insertion of a series of spacer moieties (Z) between the piperazine and phenyl rings. These structural variations are not disclosed by GB 2255337 A, particularly with regard to compounds that can be used to improve urinary tract function. These novel compounds also have a longer duration of action than does compound A in pharmacological tests predictive of activity on the lower urinary tract. This is especially true with respect to the activity of the compounds of the invention against urinary incontinence, which is a novel therapeutic indication for this class of compounds acting at the 5-HT
1A
receptor.
SUMMARY OF THE INVENTION
In one aspect, the invention is directed to compounds of formula I:
wherein
n is 1 or 2,
Het is a monocyclic heteroaryl radical,
R is a cycloalkyl or a monocyclic heteroaryl radical,
R
3
is a hydrogen atom or a lower alkyl group,
Z is a bond, —CH
2
—, —CH
2
CH
2
—, —CH
2
C(O)—, —CH
2
CH(OH)—, —O—, —OCH
2
— or —C(O)— each of which is depicted with left end being the end which attaches to the piperazine ring and the right end being the end which attaches to group B,
wherein B is selected from the group consisting of a heteroaryl radical, an unsubstituted aryl radical, and a substituted aryl radical, where the substituted aryl radical is represented by the following formula:
where R
1
is a single substituent selected from the group consisting of hydrogen, alkoxy, halogen, nitro, amino, acylamino, alkylamino, dialyklamino and alkylsulfonylamino, and R
2
is selected from the group consisting of an alkoxy, polyfluoroalkoxy, cyano, halogen and aminocarbonyl radical, and where the heteroaryl radical is selected from the group consisting of a mono or a bicyclic aromatic radical comprising from 5 to 12 ring atoms, where one or more of the ring atoms are selected from the group consisting of nitrogen, oxygen, and sulfur; with the proviso that when the compound of formula I has the formula
then R
2
is not halogen when R
1
is H, and R
2
is not alkoxy, cyano, or aminocarbonyl when R
1
is hydrogen, halogen, nitro or amino.
The invention also includes the enantiomers, diastereomers, N-oxides, crystalline forms, hydrates and pharmaceutically acceptable salts of these compounds, as well as metabolites of these compounds having the same type of activity (hereafter sometimes referred to as “active metabolites”).
The invention further provides pharmaceutical compositions comprising a compound of formula I or an enantiomer, diastereomer, N-oxide, crystalline form, hydrate or pharmaceutically acceptable salt of the compound, in admixture with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention is directed to methods for reducing the frequency of bladder contractions due to bladder distension 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 a further aspect, the present invention is directed to methods for treating disorders of the urinary tract in a subject in need of such treatment, comprising administering an effective amount of a compound of formula 1 to ameliorate at least one of urinary urgency, increased urinary frequency, incontinence, urine leakage, enuresis, dysuria, urinary hesitancy, and difficulty in emptying bladder.
In yet another aspect, the invention is directed to methods for binding compounds to 5-HT
1A
serotonergic receptors, and, by virtue of this binding activity, to methods for the treatment of CNS disorders due to serotonergic dysfunction such as anxiety, depression, hypertension, sleep/wake cycle disorders, feeding behavior, sexual function and cognition disorders in mammals, particularly in humans, by delivering to the environment of the 5-HT
1A
serotonergic receptors, e.g., to the extracellular medium (or by administering to a mammal possessing such receptors) an effective amount of a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The activity of the compounds of the invention as inhibitors of frequency of mict
Guarneri Luciano
Leonardi Amedeo
Motta Gianni
Poggesi Elena
Riva Carlo
Bernhardt Emily
Darby & Darby
Recordati S.A. Chemical and Pharmaceutical Company
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