Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-09-26
2004-03-16
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S080000, C514S085000, C514S086000, C514S089000, C514S091000, C514S092000, C514S096000, C544S232000, C544S243000, C544S337000, C546S022000, C546S026000, C548S112000, C548S113000
Reexamination Certificate
active
06706698
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to substituted aminoethylphosphonate compositions and therapeutic uses thereof. More specifically, the present invention relates to novel &agr;-substituted-&bgr;-aminoethylphosphonate and &agr;-substituted-&bgr;-aminovinylphosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, for lowering plasma levels of apo (a) and apo (a) associated lipoprotein (lipoprotein(a) or “Lp(a)”), for lowering plasma levels of apo B and apo B associated lipoproteins (low density lipoproteins and very low density lipoproteins), and for lowering plasma levels of total cholesterol.
BACKGROUND OF THE INVENTION
Lp(a) is a LDL-like lipoprotein wherein the major lipoprotein, apo B-100, is covalently linked to an unusual glycoprotein, apoprotein(a). The covalent association between apo(a) and apo B to form Lp(a) is a secondary event which is independent of the plasma concentration of apo B. Due to its structural similarity to plasminogen, apo(a) interferes with the normal physiological thrombosis-hemostasis process by preventing thrombolysis, that is clot dissolution (see e.g., Biemond B J, Circulation 1997, 96(5) 1612-1615). The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombogenic activities.
Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, restenosis following balloon angioplasty and stroke. A recent epidemiologic study has provided the clinical proof of a positive correlation between plasma Lp(a) concentrations and the incidence of heart disease (A. G. Bostom, et al., Journal of American Medical Association 1996, 276, p. 544-548).
Patients that have Lp(a) levels in excess of 20-30 mg/dl run a significantly increased risk of heart attacks and stroke. An effective therapy for lowering Lp(a) does not exist at present because cholesterol lowering agents such as the HMGCoA reductase inhibitors do not lower Lp(a) plasma concentrations. The only compound that lowers Lp(a) is niacin, but the high doses necessary for activity are accompanied with unacceptable side-effects. There is, therefore, an unmet therapeutic need for agents that effectively reduce elevated levels of Lp(a).
International applications WO 97/20307, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar, SmithKline Beecham) describe a series of &agr;-amino phosphonates which have Lp(a) lowering activity. There however remains the need to identify further compounds having Lp(a) lowering activity.
SUMMARY OF THE INVENTION
The present invention provides, in a first aspect, a compound of formula (Ia):
or a compound of formula (Ib):
in which:
X
1
, X
2
, X
3
, X
4
and X
5
are independently hydrogen, hydroxy, hydroxymethyl, C
1
-C
3
alkoxymethyl, straight or branched C
1
-C
8
alkyl, straight or branched C
1
-C
8
alkoxy, C
3
-C
6
cycloalkyl, C
3
-C
6
cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C
1
-C
3
alkyl, cyano, halogen (F, Cl, Br, I), and nitro; or
X
2
may be combined with X
3
, or X
4
may be combined with X
5
, to form a 5- to 6-membered alkylidenedioxy ring optionally substituted with a C
1
-C
4
alkyl group; or
X
4
may be combined with X
5
to form a 5- to 6-membered alkylidene ring optionally substituted with a C
1
-C
4
alkyl group;
R
1
and R
2
which may be the same or different, are independently hydrogen or a straight or branched C
1
-C
6
alkyl;
B is CH
2
or CH
2
—CH
2
;
n is zero or 1;
Z
0
is H, straight or branched C
1
-C
4
alkyl, C
1
-C
4
alkylcarbonyl, or C
1
-C
4
perfluoroalkylcarbonyl;
m is zero or an integer from 1 to 4;
Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom, or a pharmaceutically acceptable salt thereof;
for a compound of formula (Ia), Y
1
, Y
2
and Y
3
are independently hydrogen or C
1
-C
4
alkyl and for a compound of formula (Ib), Y
3
is hydrogen or C
1
-C
4
alkyl.
The compound of formula (Ib) may be the Z-isomer, the E-isomer, or a mixture thereof.
Compounds of the present invention include:
(Z)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(Z)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(Z)-diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-Diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl)-amino]-vinylphosphonate;
diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-pyridyl)-amino]-ethylphosphonate;
diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-pyridyl)-amino]-ethylphosphonate;
diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl)-amino]-ethylphosphonate;
diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-pyridyl) amino]-ethylphosphonate;
(Z)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(Z)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
(E)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(5-(2-methyl)pyridyl))-amino]-vinylphosphonate;
diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(5-(2-methyl)pyridyl))-amino]-ethylphosphonate;
(E)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(5-(2-methoxy)pyridyl))-amino]-vinylphosphonate;
diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(5-(2-methoxy)pyridyl))-amino]-ethylphosphonate;
(Z)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(pyrazinyl)-amino]-vinylphosphonate;
(Z)-diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(pyrazinyl)-amino]-vinylphosphonate;
(Z)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(pyrazinyl)-amino]-vinylphosphonate;
(E)-diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(pyrazinyl)-amino]-vinylphosphonate;
(E)-diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(pyrazinyl)-amino]-vinylphosphonate;
diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(pyrazinyl)-amino]-ethylphosphonate;
diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(pyrazinyl)-amino]-ethylphosphonate;
diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-&bgr;-[N-(pyrazinyl)-amino]-ethylphosphonate;
(Z)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(Z)-diisopropyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(E)-diethyl &agr;-(3,5-dimethoxy-4-hydroxyphenyl)-&bgr;-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(E)-diisopropyl &agr
Azoulay Raymond
Bentzen Craig Leigh
Diep Vinh Van
Eschenhof Harald
Ife Robert John
Fulbright & Jaworski L.L.P
ILEX Products, Inc.
Shah Mukund J.
Tucker Zachary C.
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