Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-28
2003-12-23
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S022000, C546S024000
Reexamination Certificate
active
06667315
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pyridoxine phosphonate analogues, to pyridoxine malonate analogues, to their preparation, to pharmaceutical compositions thereof, and to treatments for cardiovascular and related diseases, for example, hypertrophy, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated; and treatments for diabetes mellitus and related diseases, for example, hyperinsulinemia, diabetes-induced hypertension, obesity, insulin resistance, and damage to blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin connective tissue, or immune system.
BACKGROUND
Pyridoxal-5′-phosphate (PLP), an end product of vitamin B
6
metabolism, plays a vital role in mammalian health. In previous patents (U.S. Pat. Nos. 6,051,587 and 6,043,259, herein incorporated by reference) the role of pyridoxal-5′-phosphate, and its precursors pyridoxal and pyridoxine (vitamin B
6
), in mediating cardiovascular health and in treating cardiovascular related diseases is disclosed.
The major degradation pathway for pyridoxal-5′-phosphate in vivo is the conversion to pyridoxal, catalysed by alkaline phosphatase. Thus, there is a need to identify and administer drugs that are functionally similar to pyridoxal-5′-phosphate such as pyridoxine phosphonate analogues or pyridoxine malonate analogues, that elicit similar or enhanced cardiovascular benefits, and that beneficially affect PLP-related conditions, but are stable to degradation by phosphatase.
SUMMARY OF THE INVENTION
The present invention provides for pyridoxine phosphonate analogues and to pyridoxine malonates. In one aspect, the present invention includes a compound of formula I:
in which
R
1
is hydrogen or alkyl;
R
2
is —CHO, —CH
2
OH, —CH
3
, —CO
2
R
6
in which R
6
is hydrogen, alkyl, or aryl; or
R
2
is —CH
2-
O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R
1
;
R
3
is hydrogen and R
4
is hydroxy, halo, alkoxy, alkylcarbonyloxy, alkylamino or arylamino; or
R
3
and R
4
are halo; and
R
5
is hydrogen, alkyl, aryl, aralkyl, or —CO
2
R
7
in which R
7
is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention includes a compound of formula II:
in which
R
1
is hydrogen or alkyl;
R
2
is —CHO, —CH
2
OH, —CH
3
or —CO
2
R
5
in which R
5
is hydrogen, alkyl, or aryl; or
R
2
is —CH
2-
O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R
1
;
R
3
is hydrogen, alkyl, aryl, or aralkyl;
R
4
is hydrogen, alkyl, aryl, aralkyl, or —CO
2
R
6
in which R
6
is hydrogen, alkyl, aryl, or aralkyl; and
n is 1 to 6;
or a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention includes a compound of formula III:
in which
R
1
is hydrogen or alkyl;
R
2
is —CHO, —CH
2
OH, —CH
3
or —CO
2
R
8
in which R
8
is hydrogen, alkyl, or aryl; or
R
2
is —CH
2-
O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R
1
;
R
3
is hydrogen and R
4
is hydroxy, halo, alkoxy or alkylcarbonyloxy; or
R
3
and R
4
can be taken together to form ═O;
R
5
and R
6
are hydrogen; or
R
5
and R
6
are halo; and
R
7
is hydrogen, alkyl, aryl, aralkyl, or —CO
2
R
8
in which R
8
is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention includes a compound of formula IV:
in which
R
1
is hydrogen or alkyl;
R
2
is —CHO, —CH
2
OH, —CH
3
or CO
2
R
5
in which R
5
is hydrogen, alkyl, or aryl; or
R
2
is —CH
2-
O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R
1
;
R
3
and R
3
′ are independently hydrogen or halo; or
R
3
and R
3
′ taken together constitute a second covalent bond between the carbons to which they are substituent; and
R
4
is hydrogen or alkyl;
or a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the invention is directed to pharmaceutical compositions that include a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of formula I, II, III or IV.
In another aspect, the invention is directed to a method of treating cardiovascular and related diseases, for example, hypertension, hypertrophy, arrhythmia, congestive heart failure, myocardial ischemia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated by administering a therapeutically effective amount of at least one compound of formula I, II, III or IV in a unit dosage form. For such a method, a compound of formula I, II, III or IV can be administered alone or concurrently with a known therapeutic cardiovascular agent, for example, angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a vasodilator, a diuretic, an &agr;-adrenergic receptor antagonist, a &bgr;-adrenergic receptor antagonist, an antioxidant, or a mixture thereof.
In still another aspect, the invention is directed to a method of treating diabetes mellitus and related diseases, for example, hyperinsulinemia, insulin resistance, obesity, diabetes-induced hypertension, and damage to eyes, kidneys, blood vessels, nerves, autonomic nervous system, skin, connective tissue, or immune system, by administering a therapeutically effective amount of a compound of formula I, II, III or IV in a unit dosage form. For such a method, a compound of formula I, II, III or IV can be administered alone or concurrently with known medicaments suitable for treating diabetes mellitus and related diseases, for example, insulin, hypoglycemic drugs, or a mixture thereof.
DESCRIPTION OF THE INVENTION
The present invention provides for pyridoxine phosphonate analogues such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates, and (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) and to pyridoxine malonate analogues, such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates), pharmaceutical compositions, and methods for treatment of cardiovascular and related diseases, and diabetes mellitus and related diseases.
It is to be understood that the recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).
It is to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.”
It is to be understood that “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds.
It is to be understood that some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diasteriomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)— or (S)—. The present invention is meant to imclude all such possible diasteriomers and enantiomers as well as their racemic and optically pure forms. Optically active (R)— and (S)— isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. Likewise all tautomeric forms are intended to be included.
The general definitions used herein have the following meanings within the scope of the present invention.
As used herein the term “alkyl” includes a stra
Desai Rita
Medicure International Inc.
Merchant & Gould P.C.
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