Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-21
2002-06-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253060, C514S253090, C544S333000, C544S359000, C544S363000
Reexamination Certificate
active
06399614
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring, 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 advantageous if compounds were available 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.
1-(N-phenyl-N-cyclohexylcarbonyl-2-aminoethyl)-4-(2-methoxyphenyl)piperazine (compound A)
is described in GB 2 263110 A and is reported to be a 5-HT
1A
receptor antagonist. 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 substituents present on the aniline ring at the 2 position. Other differences between the compounds of the present invention and those disclosed in GB 2 263110 A are the substitutions on the aromatic ring at position 4 of the piperazine ring. These structural variations are neither disclosed nor suggested by GB 2 263110 A, particularly with regard to compounds that can be used to improve urinary tract function. These structural variations result in compounds that are more potent than compound A in pharmacological tests predictive of activity on the lower urinary tract, in particular for activity against urinary incontinence.
Other compounds which have been found by the present inventors to be useful in the methods of the present invention, e.g., treatment of disorders of the urinary tract, are disclosed in U.S. Pat. No. 4,205,173; EP 711,757; DE patent 2,405,441;
Chem. Pharm. Bull.
33:1823-1835 (1985), and
J. Med. Chem.
7:721-725 (1964), all of which are incorporated by reference.
SUMMARY OF THE INVENTION
In one aspect the invention is directed to compounds of formula I:
wherein
R is hydrogen
R
1
is chosen from the group consisting of hydrogen and lower alkyl;
R
2
is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulphonylamino, alkoxycarbonyl, N-acylaminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, aminocarbonyl, halo, trifluoromethyl or polyfluroalkoxy group,
n=1or 2;
B is chosen from the group consisting of optionally substituted aryl, optionally substituted bicyclic aryl group, optionally substituted 9-member bicyclic heteroaromatic containing one heteroatom, and an optionally substituted benzyl group,
with the proviso that if B is aryl and is substituted by an alkoxy group, the alkoxy group must be at the two position, and
if R
1
is hydrogen and R
2
is a nitro group and n=1, then B cannot be a phenyl, 2methoxyphenyl 4-chlorophenyl, 3 acetylphenyl, 3,4,5 trimethoxyphenyl, 2-chloro-4-methylphenyl or 2-pyridyl group; and
if R and R
1
are hydrogen and B is optionally substituted phenyl, then R
2
cannot be acyl, acylamino, alkoxycarbonyl, N-acylaminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl,
and enantiomers N-oxides hydrates and pharmaceutically acceptable salts thereof.
Preferred is when n=1. Further preferred is when B is optionally substituted phenyl. Further preferred is when B is indolyl.
Also preferred is when R
1
is hydrogen; R
2
is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, amino, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is substituted phenyl.
Also preferred is when R
1
is hydrogen; R
2
is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, amino, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is indolyl.
Also preferred is when R
1
is hydrogen; R2 is chosen from the group consisting of alkoxy, nitro, halo, trifluoromethyl or polyfluroalkoxy; n=1, and B is substituted phenyl.
Also preferred is when R
1
is hydrogen; R
2
is chosen from the group consisting of alkoxy, nitro, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is substituted indolyl.
In another aspect, the invention is directed to compounds chosen from the group consisting of List I A:
1-[N-cyclohexylcarbonyl-N-(2-methanesulphonylaminophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-methoxyphenyl)-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-benzyloxycarbonylpheny)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-(2-nitrophenyl)-N-(2-pyrazinecarbonyl)-2-aminoethyl)]-4-(4-indolyl)piperazine,
1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-amino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-acetylamino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-trifluoroacetylamino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(
Leonardi Amedeo
Motta Gianni
Riva Carlo
Testa Rodolfo
Raymond Richard L.
Recordati S.A. Chemical and Pharmaceutical Company
Truong Tamthom N.
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