1-(4-Arylpiperazin-1-yl)-&ohgr;-[N-(&agr;,&ohgr;-dicarb...

Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

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C544S372000

Reexamination Certificate

active

06812344

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to certain novel piperazine derivatives having protracted uro-selective &agr;
1
-adrenoceptor antagonistic activity exceeding those of previously described compounds. The compounds of the present invention hold promise for treating benign prostatic hyperplasia (BPH). This invention also relates to methods for making the novel compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hyperplasia using the compounds.
2. DESCRIPTION OF THE RELATED ART
A review in
J.Med.Chem
. 1997, V.40, No.9, pp.1292-1315, describes the most important pharmacological options available at present in the treatment of benign prostatic hyperplasia. The two most successful therapies are based on &agr;-adrenergic receptor antagonism and androgen levels modulation by 5&agr;-reductase inhibitors. 5&agr;-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. &agr;
1
-antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore the preferred modalities of treatment in the control of benign prostrate hypertrophy. &agr;
1
-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus, &agr;
1
-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
The more important of the &agr;
1
-adrenoceptor antagonists which are currently used in the management of BPH are shown below.
However, most of these known drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headaches, etc.) due to lack of selectivity of action between prostatic and vascular &agr;
1
-adrenoceptors. Clearly, &agr;
1
-adrenoceptor antagonists which have inherently greater selectivity for prostatic &agr;
1
-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective &agr;
1
-adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
Recently, it has been demonstrated that the prostate tissue of higher species like man and dog is overvalued by low affinity &agr;
1A
-adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel &agr;
1
-antagonists, namely, a new class of piperazine if compounds, with greater selectivity of action against &agr;
1A
-adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.
There are many descriptions in the literature of the pharmacological activities associated with penyl piperazines.
Eur. J. Med, Chem
. -
Chimica Therapeuetica
, 1977, V. 12, No. 2, pp. 173-176, describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below as anorectic agents with no CNS side effects.
The synthesis and pharmacology of some 2-[3-4aryi-1-piperazinyl)propyl]-1H-benz[de]isoquinolin- 1,3(2H)-diones/2,5-pynolidinediones (
J. Indian Chem. Soc
., 1986, V. LXIII, pp. 529-530), of N
4
-aryl-N
1
-piperozinyhnethyl)4-(4′-methoxyphenyl)piperidine-2,6-diones(
J. Indian Chem. Soc
., 1978, v. LV, pp.819-821), and of N(N
4
-arylpiperazinylalkyl)- phthalimides (
J. Indi an Chem. Soc
., 1979, V. LVI, pp. 1002-1005), as shown below, have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals.
However, in those papers there is no mention of the adrenoceptor blocking activity of these compounds, and thus their usefulness in the treatment of benign prostate hyperplasia did not arise.
The earlier synthesis of various 1-(4-aryl-piperazine-1-yl)-3-(2-oxo-pyrrolidin-1-yl/piperidin-1-yl) alkanes and their usefulness as hypotensive and antisehemic agents is disclosed in unpublished Indian patent applications DEL 496/95 (Mar. 3, 1995), DEL500/95 (Mar. 21, 1995) and DEL/96/96 (Mar. 29, 1996) by the inventors herein. These compounds had low &agr;
1
-adrenergic blocking activity (pKi~6 as compared to >8 of the known &agr;
1
-antagonists such as prazosin), and practically no adrenoceptor subclass selectivity for &agr;
1A
vs &agr;
1B
or
60 1D
adrenoceptors. It has now been discovered that structural modification of these compounds from lactam to dioxo compounds, i.e., from 2-oxopyrrolidin to 2,5- dioxopyrrolidin and 2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for &agr;
1A
in comparison to &agr;
1B
-adrenoceptor blocking activity, an essential requirement A for compounds to be good candidates for treatment of BPH.
3. OBJECTS OF INVENTION
An object of the present invention, therefore, is to provide novel arylpiperazine derivatives that exhibit significantly greater &agr;
1A
-adrenergic blocking potency the available with the known compounds in order to provide specific treatment for benign prostatic hyperplasia.
It is also an object of the invention to provide a method for synthesis of the novel compounds.
It is a further object of the invention to provide compositions containing the novel compounds which are useful in the treatment of benign prostatic hyperplasia.
4. SUMMARY OF THE INVENTION
The above-mentioned objectives are achieved by a novel class of piperazine derivatives of general Formula I below
wherein Y is O or S; Q, X, Z and Z′ are independently CH or N; m=0-3; n=0-4; R
1
, R
2
are independently selected from: H, F, Cl, Br, OCH
3
, OC2H
5
, OCH
2
CF
3
, SCF
3
, CH
3
, C2H
5
, CF
3
, isopropyloxy, and cyclopropyl; R
3
is H, R
6
, OH or OR
6
; R
6
is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R
4
, R
5
are H, C
1-3
alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring. Preferably, R
1
is H, R
2
is H, Cl or CF
3
, R
3
, R
4
, and R
5
=H Y=O and Q=CH when m=0 and n=1; or R
1
is H, R
2
is OCH
3
, R
3
, R
4
and R
5
=H, Y=O and Q=CH when m=0 and n=2.
Compounds within the scope of Formula I but having the structure of Formula II below
wherein n, X, Z, Z″ R′
1
, R
2
and R
3
are as defined for Formula I, and wherein m′=1-4, are preferred as selective and potent &agr;
1A
-adrenoceptor antagonistic activity over the &agr;
1B
- and &agr;
1D
-adrenoceptors. In Formula II, preferably R
1
is H, R
2
is H, Cl or CF
3
, and R
3
is H when m′=1 and n=1; or R
1
is H, R
2
is OCH
3
, and R
3
is H when m′=1 and n=2.
The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia These compositions comprise an effective amount of at least one of the above compounds of Formula I, or preferably of Formula II, and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier.
An illustrative list of particular compounds of the invention is given below:
Compound Chemical Name
No.
1. 1-[4-(4-Fluorophenyl)piperazine-1-yl]-3-(2,5-dixopyrrolidin-1-yl)propane
2. 1-[4-(2-Methox phenyl)piper azin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
3. 1-[4-(3-Trifluoromethylphenyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
4. 1-[4-(2-Pyridyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
5. 1-[4(3-Chlorophenyl)piperazine-1-yl]-3-(2,5dioxopyrrolidin-1-yl)propane
6. 1-[4(2-Pyrimidyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
7. 1-[4(3,4-Dimethylphenyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin- 1-yl)propane
8. 1-[

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