Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-07-20
2001-02-27
Berhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000, C549S366000
Reexamination Certificate
active
06194411
ABSTRACT:
The invention relates to the compounds R-2-[3-([1,4]-benzodioxan-2-ylmethylamino)-1-propyl]-3(2H)-pyridazinone of formula (1)
and S-2-[3-)[1,4]benzodioxan-2-ylmethylamino)-1-propyl]-3(2H)-pyridazinone of formula (2)
as well as their acid-addition salts. The invention relates also to pharmaceutical compositions containing these compounds as well as to a process for the preparation of these compounds.
Antihypertensive 2-(aminoalkyl)-3(2H)-pyridazinone derivatives are published in the Hungarian patent specification No. 195,645. A typical example of these substances is 2-[3-([1,4]benzodioxan-2-ylmethylamino)-1-propyl]-3(2H)-pyridazinone of formula (3),
i.e. racemic form of the compounds of formulae (1) and (2), a very low dose of which significantly decreases the arterial blood pressure in animal experiments under in vivo conditions. According to the description, these pyridazinone derivatives selectively inhibit &agr;
1
-adrenoceptors and possess a calcium antagonistic effect. Thus, they meet the demands of a multicomponent antihypertensive action; no comments are made about any other possible pharmacological effects of these compounds.
Recently, the possibilities of drug treatment of benign prostatic hypertrophy (hereinafter abbreviated: BPH; the benign tissue hyperplasia of the prostate). Till now, a surgical intervention has nearly exclusively been performed to overcome this disorder affecting about 50% of men above 50 years. Due to the higher risk in the elderly and high costs of surgical intervention, drug therapy has called an increased attention.
It has been stated that a major part of symptoms accompanying BPH are related to a increased tone of the smooth muscles of the prostatic zone of urethra and the bladder neck, which leads to an increase in the intraurethral pressure. Furthermore, it has been proven that in these tissues the smooth musculature, having an &agr;-adrenergic innervation containing both &agr;
1
- and &agr;
1
-adrenoceptors, can be relaxed by &agr;-adrenergic blocking agents. Thus, the symptoms of BPH can be favourably influenced by &agr;-adrenergic blocking drugs [see, e.g.: E. Shapiro et al.: J. Urol. 137, 565 (1987); H. Lepor, J. Androl. 12, 356 (1991); as well as S. Heda et al.: Eur. J. Pharm. 103, 249 (1994). However, for the treatment of BPH, such &agr;-adrenoceptor blocking compounds can only be taken preferably into account, which do not exert any considerable cardiovascular side effects, e.g. a decrease in blood pressure, orthostatic hypotension or syncope.
Due to the inhibition of presynaptic &agr;
2
-receptors by using nonselective &agr;
1
- and &agr;
2
-adrenoceptor blocking agents, other side effects could also appear (e.g. the heart rate is increased). Therefore, exclusively &agr;
1
-adrenoceptor blocking drugs are therapeutically employed at present.
Conclusively, the urogenital selectivity of the active agents, i.e. its selectivity for the prostate-urethra-bladder system is a very important requirement; nevertheless, the selectivity of available drugs (e.g. prazosin, terazosin, alfuzosin) is low or moderate and as a consequence, they show adverse effects. Thus novel urogenitally selective &agr;-adrenoceptor blocking agents are really needed, which are able to favourably influence the symptoms of BPH and are free of untoward side effects.
During our investigations it has been surprisingly found that the &agr;-adrenoceptor blocking compounds of formulae (1) and (2) of the invention also have a significant urogenital selectivity; while these compounds diminish the intraurethral pressure at very low doses, they simultaneously exhibit a very weak influence only on other cardiovascular parameters. Thus, they meet the above requirements.
The efficacy and selectivity of the compounds were proven under in vivo conditions as well as by in vitro experiments on isolated organs and receptor-binding assays.
In an in vivo animal model, in anaesthetized cat, intraurethral hypertension can be induced by &agr;
1
-adrenoceptor agonists [e.g. phenylephrine, which is chemically (−)-1-(3-hydroxyphenyl)-2-(methylamino)ethanol]. This hypertension-inducing effect can be antagonized by &agr;
1
-adrenoceptor antagonists. The antihypertensive effect is expressed by reduction of the diastolic pressure. Results of this experiment are summarized in Table 1 (the experiment is described in detail in the Pharmacological part).
TABLE 1
Effects of compounds of formulae (1) and (2) on phenyl-
ephrine-induced intraurethral hypertension and diastolic
pressure, respectively
ED
50
(&mgr;g/kg, iv.)
diastolic
Compound
urethra
a
pressure
b
D/U
c
(1)
13.9
>888
>63.9
(2)
3.4
90
26.5
(3)
28.4
130
4.6
Prazosin
18.7
25
1.3
Remarks:
a
Dose decreasing by 50% the hypertension induced by a 15 &mgr;g/kg/min intravenous dose of phenylephrine
b
Dose decreasing by 50% the diastolic total pressure increased by phenylephrine
c
ED
50
(diastolic pressure)/ED
50
(urethra)
It is obvious from the above data that the intraurethral pressure-decreasing effects of compounds of formulae (1) and (2) of the invention appear in a low dose; moreover their urogenital selectivity (expressed as D/U) considerably exceeds the selectivity of the racemic compound of formula (3) and that of prazosin.
In addition, investigations were performed on blood vessel and human hyperplasic prostate tissue preparations. In these experiments, a mesenteric artery was used as a model of resistance vessels which affect the blood pressure. We measured the extent of inhibition of the compounds of the invention and that of the reference drugs, respectively, on the contraction-inducing action of the &agr;
1
-agonist (phenylephrine). The &agr;
1
-adrenoceptor antagonism was then characterized by pA
2
values. The results are shown in Table 2.
TABLE 2
Evaluation of &agr;
1
-adrenoceptor antagonistic efffect in
isolated organ experiments
pA
2
human hyper-
Selectivity
a
rat mesen-
plasic pros-
(prostate/
Compound
teric artery
tate tissue
/artery)
(1)
6.56
7.20
4.37
(2)
7.68
8.23
3.55
(3)
7.16
7.51
2.24
Alfuzosin
8.60
8.01
0.26
Terazosin
8.45
8.39
0.87
Remark:
a
Antilogarithmic ratio of pA
2
value
The data of Table 2 show that the compounds of formulae (1) and (2) possess a strong &agr;
1
-adrenoceptor antagonistic effect, which is more pronounced on the prostate tissue than on the resistance artery preparation. It is also remarkable that the prostate selectivity of the compounds according to the invention is more favourable than that of any reference drugs including the racemic compound of formula (3).
As mentioned above, an &agr;
2
-adrenoceptor blocking component may also be of importance in treatment of BPH if inhibition of the postsynaptic &agr;
2
-adrenoceptors is more pronounced than that of presynaptic &agr;
2
-receptors.
Moreover, as shown more recently, &agr;
2
-antagonists, besides their capacity of reducing the overactivity of sympathetic control in the prostate, may be able to effectively reduce hormonally induced prostatic stiffness [see, in R. R. Ruffolo et al.: Eur. J. Med. Chem., 30S, 269 (1995)].
The pre- and post-synaptic &agr;
2
-adrenoceptor antagonistic effects of the compounds according to the invention were determined on rat vas deferens and dog vena saphena preparations by using xylazine [chemically 5,6-dihydro-2-(2,6-dimethylphenylamino)-1,3-thiazine] or UK 14304 [chemically 5-bromo-5-(2-imidazolin-2-ylamino)-quinoxaline] as agonists. The antagonism was characterized by the pA
2
values. The results are summarized in Table 3.
TABLE 3
Pre- and postsynaptic &agr;
2
-adrenoceptor antagonistic ef-
fects on vas deferens and vena saphena preparations
Selectivity
a
pA
2
postsynaptic/
Compound
presynaptic
postsynaptic
presynaptic
(1)
5.81
7.87
115.0
(2)
6.81
8.14
21.4
Yohimbine
6.93
8.05
13.2
Remark:
a
Antilogarithmic ratio of pA
2
values
On the basis of the above data it can be stated that both compounds of formulae (1) and (2) do have a strong &agr;
2
-adrenoceptor antagonistic activity and,
Druga Alice
Harsing Laszlo
Horvath Edit
Horvath Katalin
Karpati Egon
Berhardt Emily
Gyogyszerkutato Intezet Kft.
Keil & Weinkauf
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