Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-09-21
2003-09-30
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S529000, C514S534000, C514S651000
Reexamination Certificate
active
06627662
ABSTRACT:
This application is a 371 of PCT/AU96/00638 filed Oct. 10, 1996.
The present invention relates to potent, &bgr;
1
-specific beta adrenoreceptor blockers w a short duration of action and to a method for the treatment and/or prophylaxis of conditions for which potent, &bgr;
1
-specific beta adrenoreceptor blockers with a short duration of action in the systemic circulation would be particularly advantageous.
The class of drugs known as &bgr;-blockers are well known in the art for treatment of cardiac disorders and particular ophthalmological conditions. However, the optimum combination of properties of such agents depends critically on the condition being treated. Thus, in the long-term treatment of cardiovascular diseases such as hypertension and cardiac arrhythmias, the combination of &bgr;
1
-selectivity with high potency, good oral bioavailability and long plasma half-life and duration of action are usually considered optimal, since &bgr;
1
-selective compounds have a low incidence of side-effects associated with blockade of &bgr;
2
-receptors, such as asthma, and the remaining properties permit treatment by oral administration usually on a once a day basis.
In other conditions where &bgr;
1
-selectivity is preferred, some of these properties are not optimal. In ocular administration for the treatment of glaucoma oral availability and long plasma half-life may lead to unwanted systemic side-effects. In the management of cardiac arrhythmias which may arise during induction of anaesthesia or in the care of critically ill patients, short systemic half-life permits rapid control of arrhythmias without the risk of inducing long acting beta blockade. Treatment of glaucoma requires a drug which is well absorbed into the eye. However rapid clearance from the systemic circulation by metabolism to inactive metabolites, after passing through the eye or being swallowed via the naso-lachrymal duct, ensures that treatment is limited to the eye and side-effects are minimised For short-term systemic administration a combination of &bgr;
1
-selectivity and short half-life is ideal. For both conditions high potency is required as there is a limit to the practical concentrations which may be formulated into eyedrops, and high potency reduces the dose needed for systemic administration, which tends to be greater for compounds with short half-lives than conventional beta blockers.
Accordingly there is a need to develop &bgr;
1
-specific blockers with high potency and a short duration of action in the systemic circulation.
Short acting beta blockers have been described in U.S. Pat. No. 4,966,914, U.S. Pat. No. 4,455,317, U.S. Pat. No. 4,810,717, U.S. Pat. No. 4,593,119, U.S. Pat. No. 5,013,734 and European Patent 041491. All of the short acting beta blocking drugs described in these patents incorporate an easily hydrolysed ester function in their structures.
However, it is difficult to say that the compounds of the above inventions are entirely adequate with regard to the optimum combination of properties required. These may be summarised as (1) adequate blocking effect on the receptor (2) specificity for the &bgr;
1
receptor and (3) a short duration of action in the systemic circulation.
Accordingly there is a need to develop &bgr;-blocking drugs which satisfactorily combine the aforementioned properties (1) to (3).
U.S. Pat. No. 4,816,604 describes the group of compounds of formula (I) as &bgr;
1
-selective beta blockers.
wherein
R is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35,
R
1
is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alklythio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 35, trifluoromethyl, 1-pyrrolyl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, or alkanoyl of 1 to 5 carbon atoms,
R
2
is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted or independently trisubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35.
A is alkylene of 2 to 5 carbon atoms.
X is a bond, an oxygen or a sulfur atom
Y is an oxygen or a sulfur atom, and either Z is an oxygen atom and n is 2 or 3 or Z is a bond and n is 1, 2 or 3, with the provisos, that
(a) when R
2
is alkyl, then Z is an oxygen atom and the group —NH—A—X—R is other than the moiety of formula
—NHCH(CH
3
)CH
2
CH
2
Ph
—NHCH(CH
3
)CH
2
CH
2
OPh
—NHCH(CH
3
)CH
2
CH
2
CH
2
OPh
or
—NHCH(CH
3
)CH
2
CH(CH
3
)OPh
(b) when R
2
is alkyl and X is a bond or an oxygen atom, then Y is an oxygen atom, and
(c) when
R
2
is unsubstituted or monosubstituted phenyl,
X is a bond and
Z is an oxygen atom, or
when R
2
is cycloalkyl or cycloalkylalkyl and
X is a bond,
then R
1
is other than hydrogen, and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form, or a pharmaceutically acceptable acid addition salt form thereof.
We have now surprisingly found that a small group of compounds selected from the class generally described in U.S. Pat. No. 4,816,604 have the desirable combination of the aforementioned characteristics (1) to (3). They are particularly active, &bgr;
1
-specific and exhibit a short duration of action in the systemic circulation. Such a short duration of action in the systemic circulation is unexpected and could not be predicted as the compounds of the invention are not dependant upon the easily hydrolysed ester groups associated with prior art &bgr;-blockers with a short plasma half-life.
Accordingly the present invention provides compounds of formula (Ia) as potent, &bgr;
1
-specific beta blockers with a short duration of action in the systemic circulation,
wherein
R is 3′,4′-dimethoxyphenyl, R
1
is hydrogen, and R
2
is selected from methyl, ethyl, propyl, isobutyl and isopropyl; or
R is 3′,4′-dimethoxyphenyl, R
1
is selected from fluorine, chlorine and bromine, and R
2
is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 4′-methoxyphenoxy, R
1
is selected from hydrogen, fluorine, chlorine and bromine, and R
2
is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 3′,4′-dimethoxyphenyl, R
1
is cyano, and R
2
is cyclopropylmethyl or isobutyl; or
R is 4′-methoxyphenoxy, R
1
is cyano, and R
2
is isobutyl; and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2-position of the 3-aminopropoxy side chain in esterified form,
in their racemic and optically active forms, and their pharmaceutically acceptable acid addition salts.
In accordance with a preferred aspect, the present invention provides compounds of formula (Ia) as stated above,
wherein
R is 3′,4′-dimethoxyphenyl, R
1
is hydrogen, and R
2
is selected from methyl, ethyl, propyl, isobutyl and isopropyl; or
R is 4′-methoxyphenoxy, R
1
is hydrogen and R
2
is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 3′,4′-dimethoxyphenyl, R
1
is cyano, and R
2
is cyclopropylmethyl; or
R is 4′-methoxyphenoxy, R
1
is cyano, and R
2
is isobutyl;
R is 3′,4′-dimethoxyphenyl, R
1
is bromine, and R
2
is methyl;
and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2-position of the 3-aminopropoxy side chain in esterified form,
in their racemic and optically active forms, and their pharmaceutically a
Drummer Olaf Heino
Iakovidis Dimitrios
Jackman Graham Paul
Louis Simon Nicholas Stewart
Louis William John
Barts Samuel
Sughrue & Mion, PLLC
William John Louis, Austin and Repatriation Medical Centre
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