Pharmaceutical aminophosphonic acid derivatives

Details Pharmaceutical aminophosphonic acid derivatives Pharmaceutical aminophosphonic acid derivatives

1999-06-18

2001-10-16

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S022000, C568S054000, C568S054000

Reexamination Certificate

active

06303784

ABSTRACT:

The present invention relates to novel aminophosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, in particular for lowering lipoprotein(a) in plama and in tissues.
Lipoprotein(a) [Lp(a)] is a LDL-like lipoprotein where its major lipoprotein, apoB-100 is covalently linked to an unusual glycoprotein, apoprotein(a). Due to its structural similarity to plasminogen, apo(a) interfers with the normal physiological thrombosis-hemostasis process. The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombolytic 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 (see for instance: “Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger”; A. G. Bostom, L. A. Cupples, J. L. Jenner, J. M. Ordovas, L. J. Seman, P. W. F. Wilson, E. J. Schaefer and W. P. Castelli; 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 as potent hypocholesterolemic agents such as the HMGCoA reductase inhibitors do not affect Lp(a). Until recently, the only compound shown to lower Lp(a) was niacin. The high doses necessary for activity however entail unacceptable side-effects. There is therefore an unmet therapeutic need for agents that effectively reduce elevated levels of Lp(a).
International application WO97/02037 (Symphar SA; SmithKline Beecham plc, published Jan. 23, 1997), published after the priority date of the present application, describes a group of aminophosphonates alpha substituted by phenol groups of the formula (A):
in which X
a
is H, C
(1-8)
alkyl, hydroxy or C
(1-8)
alkoxy; X
b
is C
(1-8)
alkyl or C
(1-8)
alkoxy; X
c
is H, C
(1-4)
alkyl, or X
3
O and one of the two other substituents X
a
or X
b
may form an alkylidene dioxy ring having from 1 to 4 carbon atoms; R
a
and R
b
which may be identical or different, are H or C
(1-6)
alkyl; B is CH
2
CH
2
, CH═CH, or CH
2
; n is zero or 1; Z is H or a C
(1-8)
alkyl group; m is 0 or an integer from 1 to 5; X
d
is H, or C
(1-8)
alkyl, C
(1-8)
alkoxy or halo; and the pyridyl ring is attached by the ring carbon &agr;- or &bgr;- to the nitrogen (2- or 3-pyridyl). These have Lp(a) lowering activity. Compounds of formula (A) fall within scope of the generic disclosure of EP-A-0 559 079. This is directed towards aminophosponates alpha substituted by phenol groups which are said to be of use in decreasing plasma cholesterol and blood peroxides. Compounds of formula (A) are characterised by having either no substituents (X
d
is H) or a single substituent on the pyridyl ring. It has now been found that further substitution on the pyridyl ring provides compounds with an improved biological profile.
Accordingly, the present invention provides a compound of the formula (I):
in which:
X
1
and X
2
, which may be the same or different, are H, a straight or branched C
(1-8)
alkyl or C
(1-8)
alkoxy group, a hydroxy group or a nitro group;
X
3
is H, a C
(1-4)
alkyl group, X
3
O and one of the two other substituents X
1
or X
2
may form a C
(1-4)
alkylidene dioxy ring;
R
1
and R
2
, which may be the same or different, are H, a straight or branched C
(1-6)
alkyl group;
B is CH
2
, CH
2
—CH
2
or CH═CH;
n is zero or 1;
Z is H, or a straight or branched C
(1-8)
alkyl group;
m is 0 or an integer from 1 to 5; and
Y
1
, Y
2
, Y
3
and Y
4
, which may be the same or different, are H, a straight or branched C
(1-8)
alkyl or C
(1-8)
alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxymethyl, C
(1-4)
alkoxymethyl, amino, C
(1-4)
alkylamino, C
(1-4)
dialkylamino group, a halogen atom (F, Cl, Br, I), or any two adjacent Y
1
, Y
2
, Y
3
and Y
4
may form an optionally substituted C
(1-6)
alkylidene or C
(1-4)
alkylidenedioxy ring, with the proviso that at least two of the Y
1
, Y
2
, Y
3
and Y
4
groups are not H;
or a pharmaceutically acceptable salt thereof.
Preferably, X
1
is H, hydroxy, C
(1-4)
alkyl or C
(1-4)
alkoxy, preferably C
(1-3)
alkyl or C
(1-3)
alkoxy, more preferably hydrogen, hydroxy, methyl, methoxy or ethoxy.
Preferably, X
2
is C
(1-4)
alkyl or C
(1-4)
alkoxy, preferably C
(1-3)
alkyl or C
(1-3)
alkoxy, more preferably methyl, methoxy or ethoxy.
Preferably, X
1
and X
2
is each C
(1-4)
alkyl, preferably C
(1-3)
alkyl, or C
(1-4)
alkoxy; or or one of X
1
and X
2
is C
(1-4)
alkyl and the other is C
(1-4)
alkoxy or C
(1-3)
alkyl; or X
1
is hydroxy and X
2
is C
(1-4)
alkyl or C
(1-4)
alkoxy.
Preferred combinations of X
1
and X
2
include methoxy and methoxy, methoxy and methyl, ethoxy and methyl, methyl or t-butyl and methyl, ethoxy and ethoxy and ethoxy, hydroxy and methyl, and hydroxy and methoxy, respectively.
Preferably, X
3
is hydrogen or methyl.
A particularly preferred phenyl group is 4-hydroxy-3- methoxy-5-methylphenyl.
Preferably, (B)
n
is a direct bond.
Preferably, m is zero
Preferably, R
1
and R
2
is each a C
(1-3)
alkyl group, more preferably, a C
2
or C
3
alkyl group, in particular R
1
and R
2
is ethyl or isopropyl.
Preferably, Z is hydrogen.
Representative values for Y
1
to Y
4
include alkyl, for instance methyl or t-butyl, methoxy, chloro, hydroxy, hydroxymethyl or two adjacent substituents form an optionally substituted alkylidene or alkyldenedioxy ring having 1 to 6 carbon atoms.
Preferably, Y
1
and Y
2
is each methyl, preferably as 2,6-substituents of the pyridyl ring, and Y
3
and Y
4
is each hydrogen,.
Preferably, the pyridyl ring is attached by the ring carbon &bgr;- to the nitrogen (3/5-pyridyl). A particularly preferred pyridyl ring is (2,6-dimethyl)pyrid-3-yl.
Pharmaceutically acceptable salts are well know in the art and include inorganic and organic salts, for instance salts with HCl, H
2
SO
4
, oxalic acid, maleic acid, sulfonic acid, etc.
Preferred compounds of formula (I) include:
Diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate; and
Diethyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;
and pharmaceutically acceptably salts;
in particular:
(+)-diisopropyl &agr;-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate; and
pharmaceutically acceptable salts thereof, in particular, the hydrochloride salt.
Compounds of formula (I) are found to be effective in decreasing Lp(a) production by primary cultures of Cynomolgus monkey hepatocytes. The Lp(a) of these primates is similar in immunologic properties to human Lp(a) and occurs in an almost identical frequency distribution of plasma concentrations (see “Plasma Lipoprotein(a) Concentration is Controlled by Apolipoprotein(a) Protein Size and the Abundance of Hepatic Apo(a) mRNA in a Cynomolgus Monkey Model”, N. Azrolan et al, J. Biol. Chem., 266, 13866-13872, 1991). The compounds of formula (I) are thus potentially useful for decreasing Lp(a) in man and thereby providing a therapeutic benefit. Accordingly, in a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, in particular as an Lp(a) lowering agent. Elevated plasma and tissue levels of lipoprotein(a) is associated with accelerated atherosclerosis, abnormal proliferation of smooth muscle cells and increased thrombogenesis and expressed in disease states such as, for instance: coronary heart disease, peripheral artery disease: intermittent claudication, thrombosis, restenosis after angioplasty, extracranial carotid ather

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