Title: Cardioprotective phosphonates and malonates
Abstract: 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.
Patent Number: 6,867,215 Issued on 03/15/2005 to Haque
| Inventors:
|
Haque; Wasimul (Edmonton, CA)
|
| Assignee:
|
Medicure International Inc. (St. James, BB)
|
| Appl. No.:
|
377507 |
| Filed:
|
February 28, 2003 |
| Current U.S. Class: |
514/277; 546/22; 546/23 |
| Intern'l Class: |
A61K 031//43.5; C07F 009//30; C07F 009//34 |
| Field of Search: |
546/22,23
514/277
|
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|
Primary Examiner: Desai; Rita
Attorney, Agent or Firm: Merchant & Gould P.C.
Parent Case Text
PRIORITY OF INVENTION
This application is a continuation of U.S. application Ser. No. 09/795,689
filed on Feb. 28, 2001, now U.S. Pat. No. 6,605,612, which claims priority
of invention under 35 U.S.C. .sctn.119(e) from U.S. provisional
application No. 60/185,899, filed Feb. 29, 2000.
Claims
We claim:
1. A compound of the formula I
##STR45##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is CHO,
R.sub.3 is hydrogen and R.sub.4 is hydroxy, halo, alkoxy, alkylcarbonyloxy,
alkylamino or arylamino; and
R.sub.5 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.7 in which
R.sub.7 is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, wherein R.sub.1 is hydrogen.
3. A compound according to claim 1, wherein R.sub.3 is hydrogen and R.sub.4
is F, MeO--, or CH.sub.3 C(O)O--.
4. A compound according to claim 1, wherein R.sub.5 is alkyl or aralkyl.
5. A compound according to claim 4, wherein R.sub.5 is t-butyl or benzyl.
6. A pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a therapeutically effective amount of a compound according to
claim 1.
7. A pharmaceutical composition of claim 6, wherein the pharmaceutical
composition is in a form suitable for enteral or parenteral
administration.
8. A method of treating hypertension in a mammal comprising administering
to the mammal a therapeutically effective amount of a compound according
to claim 1 in a unit dosage form.
9. The method of claim 8, wherein the compound is administered enterally or
parenterally.
10. A method of treating myocardial infarction, ischemia reperfusion
injury, myocardial ischemia, congestive heart failure, or arrhythmia in a
mammal comprising administering to the mammal a therapeutically effective
amount of a compound according to claim 1 in a unit dosage form.
11. The method of claim 10, wherein the compound is administered enterally
or parenterally.
Description
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.sub.6 metabolism,
plays a vital role in mammalian health. In previous patents (U.S. Pat. No.
6,051,587 and U.S. Pat. No. 6,043,259, herein incorporated by reference)
the role of pyridoxal-5'-phosphate, and its precursors pyridoxal and
pyridoxine (vitamin B.sub.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:
##STR1##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3, --CO.sub.2 R.sub.6 in which
R.sub.6 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen and R.sub.4 is hydroxy, halo, alkoxy, alkylcarbonyloxy,
alkylamino or arylamino; or
R.sub.3 and R.sub.4 are halo; and
R.sub.5 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.7 in which
R.sub.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:
##STR2##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3 or --CO.sub.2 R.sub.5 in which
R.sub.5 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen, alkyl, aryl, or aralkyl; R.sub.4 is hydrogen, alkyl,
aryl, aralkyl, or --CO.sub.2 R.sub.6 in which R.sub.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:
##STR3##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3 or --CO.sub.2 R.sub.8 in which
R.sub.8 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen and R.sub.4 is hydroxy, halo, alkoxy or
alkylcarbonyloxy; or
R.sub.3 and R.sub.4 can be taken together to form .dbd.O;
R.sub.5 and R.sub.6 are hydrogen; or
R.sub.5 and R.sub.6 are halo; and
R.sub.7 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.8 in which
R.sub.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:
##STR4##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3 or CO.sub.2 R.sub.5 in which
R.sub.5 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 and R.sub.3 ' are independently hydrogen or halo; or
R.sub.3 and R.sub.3 ' taken together constitute a second covalent bond
between the carbons to which they are substituent; and
R.sub.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 .alpha.-adrenergic receptor
antagonist, a .beta.-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 include 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 straight or branched saturated
aliphatic hydrocarbon redicals, such as, for example, methyl, ethyl,
propyl, isopropyl (1-methylethyl),
##STR5##
butyl, tert-butyl (1,1-dimethylethyl), and the like.
As used herein the term "alkoxy" refers to --O-alkyl with alkyl as defined
above. Alkoxy groups include those with 1 to 4 carbon atoms in a straight
or branched chain, such as, for example, methoxy, ethoxy, propoxy,
isopropoxy (1-methylethoxy), butoxy, tert-butoxy (1,1-dimethylethoxy), and
the like.
As used herein the term "aryl" refers to unsaturated aromatic carbocyclic
radicals having a single ring, such as phenyl, or multiple condensed
rings, such as naphthyl or anthryl. The term "aryl" also includes
substituted aryl comprising aryl substituted on a ring by, for example,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, hydroxy, phenyl, nitro, halo,
carboxyalkyl or alkanoyloxy. Aryl groups include, for example, phenyl,
naphthyl, anthryl, biphenyl, methoxyphenyl, halophenyl, and the like.
As used herein the term "alkylamino" refers to --N-alkyl with alkyl as
defined above. Alkylamino groups include those with 1-6 carbons in a
straight or branched chain, such as, for example, methylamino, ethylamino,
propylamino, and the like.
As used herein the term "arylamino" refers to --N-aryl with aryl as defined
above. Arylamino includes --NH-phenyl, --NH-biphenyl,
--NH-4-methoxyphenyl, and the like.
As used herein the term "aralkyl" refers to an aryl radical defined as
above substituted with an alkyl radical as defined above (e.g.
aryl-alkyl-). Aralkyl groups include, for example, phenethyl, benzyl, and
naphthylmethyl.
As used herein the term "halo" includes bromo, chloro, and fluoro.
Preferably halo is fluoro.
As used herein the term "alkylcarbonyloxy" includes alkyl as defined above
bonded to carbonyl bonded to oxygen, such as, for example, acetate,
propionate and t-butylcarbonyloxy.
Cardiovascular and related diseases include, for example, hypertension,
hypertrophy, congestive heart failure, heart failure subsequent to
myocardial infarction, arrhythmia, myocardial ischemia, myocardial
infarction, ischemia reperfusion injury, and diseases that arise from
thrombotic and prothrombotic states in which the coagulation cascade is
activated.
Heart failure is a pathophysiological condition in which the heart is
unable to pump blood at a rate commensurate with the requirement of the
metabolizing tissues or can do so only from an elevated filling pressure
(increased load). Thus, the heart has a diminished ability to keep up with
its workload. Over time, this condition leads to excess fluid
accumulation, such as peripheral edema, and is referred to as congestive
heart failure.
When an excessive pressure or volume load is imposed on a ventricle,
myocardial hypertrophy (i.e., enlargement of the heart muscle) develops as
a compensatory mechanism. Hypertrophy permits the ventricle to sustain an
increased load because the heart muscle can contract with greater force.
However, a ventricle subjected to an abnormally elevated load for a
prolonged period eventually fails to sustain an increased load despite the
presence of ventricular hypertrophy, and pump failure can ultimately
occur.
Heart failure can arise from any disease that affects the heart and
interferes with circulation. For example, a disease that increases the
heart muscle's workload, such as hypertension, will eventually weaken the
force of the heart's contraction. Hypertension is a condition in which
there is an increase in resistance to blood flow through the vascular
system. This resistance leads to increases in systolic and/or diastolic
blood pressures. Hypertension places increased tension on the left
ventricular myocardium, causing it to stiffen and hypertrophy, and
accelerates the development of atherosclerosis in the coronary arteries.
The combination of increased demand and lessened supply increases the
likelihood of myocardial ischemia leading to myocardial infarction, sudden
death, arrhythmias, and congestive heart failure.
Ischemia is a condition in which an organ or a part of the body fails to
receive a sufficient blood supply. When an organ is deprived of a blood
supply, it is said to be hypoxic. An organ will become hypoxic even when
the blood supply temporarily ceases, such as during a surgical procedure
or during temporary artery blockage. Ischemia initially leads to a
decrease in or loss of contractile activity. When the organ affected is
the heart, this condition is known as myocardial ischemia, and myocardial
isehemia initially leads to abnormal electrical activity. This can
generate an arrhythmia. When myocardial isehemia is of sufficient severity
and duration, cell injury can progress to cell death--i.e., myocardial
infarction--and subsequently to heart failure, hypertrophy, or congestive
heart failure.
When blood flow resumes to an organ after temporary cessation, this is
known as ischemic reperfusion of the organ. For example, reperfusion of an
ischemic myocardium can counter the effects of coronary occlusion, a
condition that leads to myocardial ischemia. Ischemic reperfusion to the
myocardium can lead to reperfusion arrhythmia or reperfusion injury. The
severity of reperfusion injury is affected by numerous factors, such as,
for example, duration of ischemia, severity of ischemia, and speed of
reperfusion. Conditions observed with ischemia reperfusion injury include
neutrophil infiltration, necrosis, and apoptosis.
Drug therapies, using known active ingredients such as vasodilators,
angiotensin II receptor antagonists, angiotensin converting enzyme
inhibitors, diuretics, antithrombolytic agents, .alpha. or
.beta.-adrenergic receptor antagonists, .alpha.-adrenergic receptor
antagonists, calcium channel blockers, and the like, are available for
treating cardiovascular and related diseases.
Diabetes mellitus and related diseases include hyperinsulinemia, insulin
resistance, obesity, diabetes-induced hypertension, and damage to blood
vessels, eyes, kidneys, nerves, autonomic nervous system, skin, connective
tissue, and immune system. Diabetes mellitus is a condition in which blood
glucose levels are abnormally high because the body is unable to produce
enough insulin to maintain normal blood glucose levels or is unable to
adequately respond to the insulin produced. Insulin-dependent diabetes
mellitus (often referred to as type I diabetes) arises when the body
produces little or no insulin. About 10% of all diabetics have type I
diabetes. Noninsulin-dependent diabetes mellitus (often referred to as
type II diabetes) arises when the body cannot adequately respond to the
insulin that is produced in response to blood glucose levels.
Available treatments include weight control, exercise, diet, and drug
therapy. Drug therapy for type I diabetes mellitus requires the
administration of insulin; however, drug therapy for type II diabetes
mellitus usually involves the administration of insulin and/or oral
hypoglycemic drugs to lower blood glucose levels. If the oral hypoglycemic
drugs fail to control blood sugar, then insulin, either alone or
concurrently with the hypoglycemic drugs, will usually be administered.
The invention is generally directed to pyridoxine phosphonate analogues
such as, for example,
((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates,
(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),
compositions including these analogues, and methods of administering
pharmaceutical compositions containing a therapeutically effective amount
of at least one of these analogues to treat cardiovascular and related
diseases or diabetes and related diseases.
To enhance absorption from the digestive tract and across biological
membranes, polar groups on a drug molecule can be blocked with lipophilic
functions that will be enzymatically cleaved off from the drug after
absorption into the circulatory system. Lipophilic moieties can also
improve site-specificity and biovailability of the drug. The speed at
which the blocking groups are removed can be used to control the rate at
which the drug is released. The blocking of polar groups on the drug can
also slow first-pass metabolism and excretion. An ester is a common
blocking group that is readily hydrolyzed from the drug by endogenous
esterases. Bundgaard, Design and Application of Prodrugs in A Textbook of
Drug Design and Development (Krogsgaard-Larson & Bundgaard, eds., Hardwood
Academic Publishers, Reading, United Kingdom 1991).
In one embodiment, the compounds of the present invention are analogues of
pyridoxal phosphonate. The compounds of the invention include, for
example, (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)methylphosphonate
analogues. Such compounds are represented by the formula I:
##STR6##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3, --CO.sub.2 R.sub.6 in which
R.sub.6 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen and R.sub.4 is hydroxy, halo, alkoxy, alkylcarbonyloxy,
alkylamino or arylamino; or
R.sub.3 and R.sub.4 are halo; and
R.sub.5 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.7 in which
R.sub.7 is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
Examples of compounds of formula I include those where R.sub.1 is hydrogen,
or those where R.sub.2 is --CH.sub.2 OH, or --CH.sub.2 --O-alkyl- in which
alkyl is covalently bonded to the oxygen at the 3-position instead of
R.sub.1, or those where R.sub.3 is hydrogen and R.sub.4 is F, MeO-- or
CH.sub.3 C(O)O--, or those where R.sub.5 is alkyl or aralkyl. Additional
examples of compounds of formula I include those where R.sub.3 and R.sub.4
are F, or those where R.sub.5 is t-butyl or benzyl.
In another aspect, the compounds of the invention include
(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonate
analogues. Such compounds are represented by formula II:
##STR7##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3 or --CO.sub.2 R.sub.5 in which
R.sub.5 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen, alkyl, aryl, or aralkyl;
R.sub.4 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.6 in which
R.sub.6 is hydrogen, alkyl, aryl, or aralkyl; and
n is 1 to 6;
or a pharmaceutically acceptable acid addition salt thereof.
Examples of compounds of formula II include those where R.sub.1 is
hydrogen, or those where R.sub.2 is --CH.sub.2 OH, or --CH.sub.2
--O-alkyl- in which alkyl is covalently bonded to the oxygen at the
3-position instead of R.sub.1, or those where R.sub.3 is hydrogen, or
those where R.sub.4 is alkyl or hydrogen. Additional examples of compounds
of formula II include those where R.sub.4 is ethyl.
In still another aspect, the compounds of the invention include
(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)ethylphosphonate analogues.
Such compounds are represented by formula III:
##STR8##
in which
R.sub.1 is hydrogen or alkyl;
R.sub.2 is --CHO, --CH.sub.2 OH, --CH.sub.3 or --CO.sub.2 R.sub.8 in which
R.sub.8 is hydrogen, alkyl, or aryl; or
R.sub.2 is --CH.sub.2 --O-alkyl- in which alkyl is covalently bonded to the
oxygen at the 3-position instead of R.sub.1 ;
R.sub.3 is hydrogen and R.sub.4 is hydroxy, halo, alkoxy or
alkylcarbonyloxy; or
R.sub.3 and R.sub.4 can be taken together to form .dbd.O;
R.sub.5 and R.sub.6 are hydrogen; or
R.sub.5 and R.sub.6 are halo; and
R.sub.7 is hydrogen, alkyl, aryl, aralkyl, or --CO.sub.2 R.sub.8 in which
R.sub.8 is hydrogen, alkyl, aryl, or aralkyl;
or a pharmaceutically acceptable acid addition salt thereof.
Examples of compounds of formula III include those where R.sub.1 is
hydrogen, or those where R.sub.2 is --CH.sub.2 OH, or --CH.sub.2
--O-alkyl- in which alkyl is covalently bonded to the oxygen at the
3-position instead of R.sub.1, or those where R.sub.3 and R.sub.4 taken
together form .dbd.O, or those where R.sub.5 and R.sub.6 are F, or those
where R.sub.7 is alkyl. Additional examples of compounds of formula III
include those where R.sub.4 is OH or CH.sub.3 C(O)O--, those where R.sub.7
is ethyl.
In yet another aspect, the compounds of the invention include pyridoxine
malonate analogues such as, for example,
((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates). Such
compounds are represented by the formula IV:
##STR9##
in which
