U.S. patent application number 10/881864 was filed with the patent office on 2004-11-25 for treatment of diabetes and related pathologies.
This patent application is currently assigned to Medicure, Inc.. Invention is credited to Haque, Wasimul, Sethi, Rajat.
Application Number | 20040235907 10/881864 |
Document ID | / |
Family ID | 22504214 |
Filed Date | 2004-11-25 |
United States Patent
Application |
20040235907 |
Kind Code |
A1 |
Sethi, Rajat ; et
al. |
November 25, 2004 |
Treatment of diabetes and related pathologies
Abstract
Methods for treating diabetes mellitus and related conditions
and symptoms are described. The methods are directed to
administering a therapeutically effective amount of a compound.
Compounds suitable for the invention include
pyridoxal-5'-phosphate, pyridoxal, pyridoxamine, pyridoxine, a
3-acylated pyridoxal analogue, a pharmaceutically acceptable acid
addition salt thereof, or a mixture thereof. Also disclosed are
methods directed to concurrently administering a therapeutically
effective amount of a compound with other compounds known in the
treatment of diabetes mellitus. In one embodiment, a
therapeutically effective amount of a compound is administered
concurrently with a therapeutically effective amount of insulin. In
another embodiment, a therapeutically effective amount of a
compound is administered concurrently with a therapeutically
effective amount of a hypoglycemic compound.
Inventors: |
Sethi, Rajat; (Winnipeg,
CA) ; Haque, Wasimul; (Edmonton, CA) |
Correspondence
Address: |
MERCHANT & GOULD PC
P.O. BOX 2903
MINNEAPOLIS
MN
55402-0903
US
|
Assignee: |
Medicure, Inc.
Winnipeg
CA
|
Family ID: |
22504214 |
Appl. No.: |
10/881864 |
Filed: |
June 30, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10881864 |
Jun 30, 2004 |
|
|
|
10215739 |
Aug 8, 2002 |
|
|
|
10215739 |
Aug 8, 2002 |
|
|
|
09615201 |
Jul 13, 2000 |
|
|
|
6489345 |
|
|
|
|
60143466 |
Jul 13, 1999 |
|
|
|
Current U.S.
Class: |
514/350 |
Current CPC
Class: |
A61K 31/435 20130101;
A61K 31/4355 20130101; A61K 31/44 20130101; A61K 31/675 20130101;
A61K 31/715 20130101; A61P 3/10 20180101; A61K 31/675 20130101;
A61K 31/435 20130101; A61K 31/715 20130101; A61K 31/675 20130101;
A61K 31/715 20130101; A61K 31/435 20130101; A61K 31/4355 20130101;
A61K 31/44 20130101; A61K 31/675 20130101; A61K 45/06 20130101;
A61K 31/4415 20130101; A61K 31/715 20130101; A61K 31/5375 20130101;
A61K 31/64 20130101; A61K 31/675 20130101; A61K 31/5375 20130101;
A61K 31/64 20130101; Y10S 514/866 20130101; A61K 31/44 20130101;
A61K 31/64 20130101; A61K 31/64 20130101; A61K 31/44 20130101; A61K
2300/00 20130101; A61K 31/155 20130101; A61K 31/44 20130101; A61K
31/675 20130101; A61K 31/64 20130101; A61K 2300/00 20130101; A61K
31/155 20130101; A61K 2300/00 20130101; A61K 31/155 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/435 20130101; A61K 31/435
20130101 |
Class at
Publication: |
514/350 |
International
Class: |
A61K 031/4415 |
Claims
1-75. (Canceled)
76. A method of treating insulin-dependent diabetes mellitus in a
mammal comprising: administering to the mammal a therapeutically
effective amount of pyridoxal-5'-phosphate, pharmaceutically
acceptable acid addition salts thereof, or mixtures thereof.
77. A method according to claim 76, further comprising concurrently
administering to the mammal a therapeutically effective amount of
insulin.
78. A method according to claim 76, further comprising concurrently
administering to the mammal a therapeutically effective amount of a
hypoglycemic compound.
79. A method according to claim 78, wherein the hypoglycemic
compound is acarbose, acetohexamide, chlorpropamide, glimepiride,
glipizide, glyburide, metformin, tolazamide, tolbutamide, or
mixtures thereof.
80. A method according to claim 78, wherein the hypoglycemic
compound is tolbutamide.
81. A method according to claim 78 comprising: concurrently
administering to the mammal the pyridoxal-5'-phosphate and the
hypoglycemic compound in combination with a therapeutically
effective amount of insulin.
82. A method of treating noninsulin-dependent diabetes mellitus in
a mammal comprising: concurrently administering to the mammal a
therapeutically effective amount of a first compound selected from
the group consisting of pyridoxal-5'-phosphate, pyridoxamine,
pyridoxal, pyridoxine, a pharmaceutically acceptable acid addition
salt thereof, and mixtures thereof; and a second compound selected
from the group consisting of: a hypoglycemic compound, insulin, and
a combination thereof.
83. A method according to claim 82, wherein the second compound is
a hypoglycemic compound.
84. A method according to claim 83, wherein the hypoglycemic
compound is acarbose, acetohexamide, chlorpropamide, glimepiride,
glipizide, glyburide, metformin, tolazamide, tolbutamide, or
mixtures thereof.
85. A method according to claim 83, wherein the hypoglycemic
compound is tolbutamide.
86. A method according to claim 82, wherein the second compound is
insulin.
87. A method according to claim 82, wherein the second compound is
a combination of insulin and a hypoglycemic compound.
Description
[0001] This application claims priority to provisional application
Serial No. 60/143,466, filed on Jul. 13, 1999.
FIELD OF THE INVENTION
[0002] This invention relates to methods of treating
insulin-dependent diabetes mellitus, noninsulin-dependent diabetes
mellitus, and related conditions and symptoms.
BACKGROUND
[0003] 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. Type II diabetes is often
associated with hyperglycemia (high plasma glucose levels due to
decreased glucose utilization) and hyperinsulinemia (high plasma
insulin levels due to decreased insulin receptors available),
factors that contribute to insulin resistance.
[0004] 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 in combination with the hypoglycemic
drugs, will usually be administered.
[0005] Although many of the symptoms of diabetes mellitus may be
controlled by insulin therapy, the long-term complications of both
type I and type II diabetes mellitus are severe and may reduce life
expectancy by as much as one third. Over time, elevated blood
glucose levels damage blood vessels, eyes, kidneys, nerves,
autonomic nervous system, skin, connective tissue, and white blood
cell function.
[0006] Moreover, insulin therapy may result in insulin allergy,
insulin resistance, atrophy of the subcutaneous fat at the site of
insulin injection (i.e., lipoatrophy), enlargement of subcutaneous
fat deposit (i.e., lipohypertrophy) due to lipogenic action of high
local concentration of insulin, and insulin adema.
[0007] Thus, it would be desirable to find an alternative to the
above-described therapies or to administer a drug therapy that may
reduce the amount of insulin or hypoglycemic drug required, yet
maintain the effectiveness of the insulin or hypoglycemic drug
administered.
SUMMARY OF THE INVENTION
[0008] The present invention provides methods for treating
insulin-dependent diabetes mellitus, noninsulin-dependent diabetes
mellitus, and related conditions and symptoms. One embodiment
includes a method of treating diabetes mellitus in a mammal by
administering a therapeutically effective amount of a compound,
such as pyridoxal-5'-phosphate, pyridoxal, pyridoxamine,
pyridoxine, a 3-acylated pyridoxal analogue, a pharmaceutically
acceptable acid addition salt thereof, or a mixture thereof.
[0009] In another embodiment, the invention provides a method of
treating diabetes mellitus in a mammal by concurrently
administering a therapeutically effective amount of a combination
of insulin and a compound, such as pyridoxal-5'-phosphate,
pyridoxal, pyridoxamine, pyridoxine, a 3-acylated pyridoxal
analogue, a pharmaceutically acceptable acid addition salt thereof,
or a mixture thereof.
[0010] In still another embodiment, the invention provides a method
of treating noninsulin-dependent diabetes mellitus in a mammal by
concurrently administering a therapeutically effective amount of a
combination of a hypoglycemic compound and a compound, such as
pyridoxal-5'-phosphate, pyridoxal, pyridoxamine, pyridoxine, a
3-acylated pyridoxal analogue, a pharmaceutically acceptable acid
addition salt thereof, or a mixture thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows the effect of P-5-P and insulin alone or in
combination on plasma glucose levels in rats induced with Type I
diabetes.
[0012] FIG. 2 shows the effect of P-5-P and insulin alone or in
combination on plasma insulin levels in rats induced with Type I
diabetes.
[0013] FIG. 3 shows the effect of P-5-P and tolbutamide alone or in
combination on plasma glucose levels in rats induced with Type II
diabetes.
[0014] FIG. 4 shows the effect of P-5-P and tolbutamide alone or in
combination on plasma insulin levels in rats induced with Type II
diabetes.
[0015] FIG. 5 shows the effect of P-5-P and tolbutamide alone or in
combination on increased systolic blood pressure in rats induced
with Type II diabetes.
DETAILED DESCRIPTION
[0016] The present invention provides methods for treatment of
diabetes mellitus and related conditions and symptoms. Such
diabetes mellitus and related conditions include insulin-dependent
diabetes mellitus (type I diabetes), noninsulin-dependent diabetes
mellitus (type II diabetes), insulin resistance, hyperinsulinemia,
and diabetes-induced hypertension. Other diabetes-related
conditions include obesity and damage to blood vessels, eyes,
kidneys, nerves, autonomic nervous system, skin, connective tissue,
and immune system.
[0017] In accordance with the present invention, it has been found
that compounds, such as, for example, pyridoxal-5'-phosphate,
pyridoxal, pyridoxamine, a 3-acylated pyridoxal analogue, a
pharmaceutically acceptable acid addition salt thereof, or a
mixture thereof, either alone or in combination with insulin and/or
hypoglycemic compounds can be used in the treatment of the
above-identified diseases and conditions. As used herein,
"treatment" and "treating" include preventing inhibiting, and
alleviating diabetes mellitus and related conditions and symptoms.
In some instances, the treatment may be carried out by
administering a therapeutically effective amount of a compound
suitable for use in methods of the invention. In other instances,
the treatment may be carried out by concurrently administering a
therapeutically effective amount of a combination of insulin and a
compound suitable for use in methods of the invention. In still
other instances, the treatment may involve concurrently
administering a therapeutically effective amount of a combination
of a hypoglycemic compound and a compound suitable for use in
methods of the invention when the diabetes mellitus and related
conditions to be treated is type II diabetes, insulin resistance,
hyperinsulinemia, diabetes-induced hypertension, obesity, or damage
to blood vessels, eyes, kidneys, nerves, autonomic nervous system,
skin, connective tissue, or immune system.
[0018] A "therapeutically effective amount" as used herein includes
a prophylactic amount, for example, an amount effective for
preventing or protecting against diabetes mellitus and related
conditions and symptoms, and amounts effective for alleviating or
healing diabetes mellitus and related conditions and symptoms.
Generally, by administering a compound suitable for use in methods
of the invention concurrently with insulin and/or a hypoglycemic
compound the insulin and/or hypoglycemic compound may be
administered in a dosage amount that is less than the dosage amount
required when the insulin and/or hypoglycemic compound is the sole
active ingredient. By administering lower dosage amounts of insulin
and/or a hypoglycemic compound, the side effects associated
therewith should accordingly be reduced and/or the onset of the
long-term complications that arise from diabetes mellitus and
related conditions may be delayed.
[0019] Compounds suitable for use in the methods of the invention
include pyridoxal-5'-phosphate, pyridoxal, pyridoxamine,
pyridoxine, 3-acylated pyridoxal analogues, pharmaceutically
acceptable acid addition salts thereof, or a mixture thereof.
3-Acylated pyridoxal analogues include prodrugs of pyridoxal that
provide for slower metabolism to pyridoxal in vivo. For example,
one suitable 3-acylated analogue of pyridoxal
(2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine) is a compound
of the formula I: 1
[0020] or a pharmaceutically acceptable acid addition salt thereof,
wherein
[0021] R.sub.1 is a straight or branched alkyl group, a straight or
branched alkenyl group, in which an alkyl or alkenyl group may be
interrupted by a nitrogen or oxygen atom; an alkoxy group; a
dialkylamino group; or an unsubstituted or substituted aryl
group.
[0022] The term "alkyl" group includes a straight or branched
saturated aliphatic hydrocarbon chain having from 1 to 8 carbon
atoms, such as, for example, methyl, ethyl, propyl, isopropyl
(1-methylethyl), butyl, tert-butyl (1,1-dimethylethyl), and the
like.
[0023] The term "alkenyl" group includes an unsaturated aliphatic
hydrocarbon chain having from 2 to 8 carbon atoms, such as, for
example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,
2-methyl-1-propenyl, and the like.
[0024] The above alkyl or alkenyl groups may optionally be
interrupted in the chain by a heteroatom, such as, for example, a
nitrogen or oxygen atom, forming an alkylaminoalkyl or alkoxyalkyl
group, for example, methylaminoethyl or methoxymethyl, and the
like.
[0025] The term "alkoxy" group includes an alkyl group as defined
above joined to an oxygen atom having preferably from 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.
[0026] The term "dialkylamino" group includes two alkyl groups as
defined above joined to a nitrogen atom, in which the alkyl group
has preferably 1 to 4 carbon atoms, such as, for example,
dimethylamino, diethylamino, methylethylamino, methylpropylamino,
diethylamino, and the like.
[0027] The term "aryl" group includes an aromatic hydrocarbon
group, including fused aromatic rings, such as, for example, phenyl
and naphthyl. Such groups may be unsubstituted or substituted on
the aromatic ring by, for example, an alkyl group of 1 to 4 carbon
atoms, an alkoxy group of 1 to 4 carbon atoms, an amino group, a
hydroxy group, or an acetyloxy group.
[0028] Preferred R.sub.1 groups for compounds of formula I are
toluyl or naphthyl. Such R.sub.1 groups when joined with a carbonyl
group form an acyl group 2
[0029] which preferred for compounds of formula I include toluoyl
or .beta.-naphthoyl. Of the toluoyl group, the p-isomer is more
preferred.
[0030] Examples of 3-acylated analogues of pyridoxal include, but
are not limited to,
2-methyl-3-toluoyloxy-4-formyl-5-hydroxymethylpyridine and
2-methyl-.beta.-naphthoyloxy-4-formyl-5-hydroxymethylpyridine.
[0031] Another suitable analogue is a 3-acylated analogue of
pyridoxal-4,5-aminal (1-secondary
amino-1,3-dihydro-7-hydroxy-6-methylfur- o(3,4-c)pyridine) of the
formula II: 3
[0032] or a pharmaceutically acceptable acid addition salt thereof,
wherein
[0033] R.sub.1 is a straight or branched alkyl group, a straight or
branched alkenyl group, in which an alkyl or alkenyl group may be
interrupted by a nitrogen or oxygen atom; an alkoxy group; a
dialkylamino group; or an unsubstituted or substituted aryl group;
and
[0034] R.sub.2 is a secondary amino group.
[0035] The terms "alkyl," "alkenyl," "alkoxy," "dialkylamino," and
"aryl" are as defined above.
[0036] The term "secondary amino" group includes a group of the
formula III: 4
[0037] derived from a secondary amine R.sub.3R.sub.4NH, in which
R.sub.3 and R.sub.4 are each independently alkyl, alkenyl,
cycloalkyl, aryl, or, when R.sub.3 and R.sub.4 are taken together,
may form a ring with the nitrogen atom and which may optionally be
interrupted by a heteroatom, such as, for example, a nitrogen or
oxygen atom. The terms "alkyl," "alkenyl," and "aryl" are used as
defined above in forming secondary amino groups such as, for
example, dimethylamino, methylethylamino, diethylamino,
dialkylamino, phenylmethylamino, diphenylamino, and the like.
[0038] The term "cycloalkyl" refers to a saturated hydrocarbon
having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms,
such as, for example, cyclopropyl, cyclopentyl, cyclohexyl, and the
like.
[0039] When R.sub.3 and R.sub.4 are taken together with the
nitrogen atom, they may form a cyclic secondary amino group, such
as, for example, piperidino, and, when interrupted with a
heteroatom, includes, for example, piperazino and morpholino.
[0040] Preferred R.sub.1 groups for compounds of formula II include
toluyl, e.g., p-toluyl, naphthyl, tert-butyl, dimethylamino,
acetylphenyl, hydroxyphenyl, or alkoxy, e.g., methoxy. Such R.sub.1
groups when joined with a carbonyl group form an acyl group 5
[0041] which preferred for compounds and formula II include
toluoyl, .beta.-naphthoyl, pivaloyl, dimethylcarbamoyl,
acetylsalicyloyl, salicyloyl, or alkoxycarbonyl. A preferred
secondary amino group may be morpholino.
[0042] Examples of 3-acylated analogues of pyridoxal-4,5-aminal
include, but are not limited to,
1-morpholino-1,3-dihydro-7-(p-toluoyloxy)-6-methy-
lfuro(3,4-c)pyridine;
1-morpholino-1,3-dihydro-7-(.beta.-naphthoyloxy)-6-m-
ethylfuro(3,4-c)pyridine;
1-morpholino-1,3-dihydro-7-pivaloyloxy-6-methylf-
uro(3,4-c)pyridine;
1-morpholino-1,3-dihydro-7-carbamoyloxy-6-methylfuro(3-
,4-c)pyridine; and
1-morpholino-1,3-dihydro-7-acetylsalicyloxy-6-methylfur-
o(3,4-c)pyridine.
[0043] The compounds of formula I may be prepared by reacting
pyridoxal hydrochloride with an acyl halide in an aprotic solvent.
A suitable acyl group is 6
[0044] wherein R.sub.1 is as defined above. A particularly suitable
acyl halide includes p-toluoyl chloride or .beta.-naphthoyl
chloride. A suitable aprotic solvent includes acetone,
methylethylketone, and the like.
[0045] The compounds of formula II may be prepared by reacting
1-secondary amino-1,3-dihydro-7-hydroxy-6-methylfuro(3,4-c)pyridine
with an acyl halide in an aprotic solvent. An acyl group is 7
[0046] wherein R.sub.1 is as defined above. A particularly suitable
acyl halide includes p-toluoyl chloride, .beta.-naphthoyl chloride,
trimethylacetyl chloride, dimethylcarbamoyl chloride, and
acetylsalicyloyl chloride. A particularly suitable secondary amino
group includes morpholino.
[0047] The compound
1-morpholino-1,3-dihydro-7-hydroxy-6-methylfuro(3,4-c)- pyridine
may be prepared by methods known in the art, for example, by
reacting morpholine and pyridoxal hydrochloride at a temperature of
about 100.degree. C. in a solvent. A suitable solvent includes, for
example, toluene. Similarly, other secondary amines as defined for
R.sub.2 may be used as reactants to prepare the appropriate
1-secondary amino compounds.
[0048] The compounds of formula I may alternatively be prepared
from the compounds of formula II by reacting a compound of formula
II with an aqueous acid, such as, for example, aqueous acetic
acid.
[0049] One skilled in the art would recognize variations in the
sequence and would recognize variations in the appropriate reaction
conditions from the analogous reactions shown or otherwise known
that may be appropriately used in the above-described processes to
make the compounds of formulas I and II herein.
[0050] The products of the reactions described herein are isolated
by conventional means such as extraction, distillation,
chromatography, and the like.
[0051] Pharmaceutically acceptable acid addition salts of the
compounds suitable for use in methods of the invention include
salts derived from nontoxic inorganic acids such as hydrochloric,
nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric,
phosphorous, and the like, as well as the salts derived from
nontoxic organic acids, such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. Such salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate,
trifluoroacetate, propionate, caprylate, isobutyrate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
mandelate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate,
phenylacetate, citrate, lactate, maleate, tartrate,
methanesulfonate, and the like. Also contemplated are salts of
amino acids such as arginate and the like and gluconate,
galacturonate, n-methyl glutamine, etc. (see, e.g., Berge et al.,
J. Pharmaceutical Science, 66: 1-19 (1977).
[0052] The acid addition salts of the basic compounds are prepared
by contacting the free base form with a sufficient amount of the
desired acid to produce the salt in the conventional manner. The
free base form may be regenerated by contacting the salt form with
a base and isolating the free base in the conventional manner. The
free base forms differ from their respective salt forms somewhat in
certain physical properties such as solubility in polar solvents,
but otherwise the salts are equivalent to their respective free
base for purposes of the present invention.
[0053] A physician or veterinarian of ordinary skill readily
determines a subject who is exhibiting symptoms of any one or more
of the diseases described above. Regardless of the route of
administration selected, the compounds suitable for use in methods
of the invention are formulated into pharmaceutically acceptable
unit dosage forms by conventional methods known to the
pharmaceutical art. An effective but nontoxic quantity of the
compound is employed in treatment. The compounds can be
administered in enteral unit dosage forms, such as, for example,
tablets, sustained release tablets, enteric coated tablets,
capsules, sustained release capsules, enteric coated capsules,
pills, powders, granules, solutions, and the like. They may also be
administered parenterally, such as, for example, subcutaneously,
intramuscularly, intradermally, intramammarally, intravenously, and
other administrative methods known in the art.
[0054] Although it is possible for a compound suitable for use in
methods of the invention to be administered alone in a unit dosage
form, preferably the compound is administered in admixture as a
pharmaceutical composition suitable for use in methods of the
invention. A pharmaceutical composition comprises a
pharmaceutically acceptable carrier and a compound. A
pharmaceutically acceptable carrier includes, but is not limited
to, physiological saline, ringers, phosphate buffered saline, and
other carriers known in the art. Pharmaceutical compositions may
also include additives, for example, stabilizers, antioxidants,
colorants, excipients, binders, thickeners, dispersing agents,
readsorpotion enhancers, buffers, surfactants, preservatives,
emulsifiers, isotonizing agents, and diluents. Pharmaceutically
acceptable carriers and additives are chosen such that side effects
from the pharmaceutical compound are minimized and the performance
of the compound is not canceled or inhibited to such an extent that
treatment is ineffective.
[0055] Methods of preparing pharmaceutical compositions containing
a pharmaceutically acceptable carrier and a compound suitable for
use in methods of the invention are known to those of skill in the
art. All methods may include the step of bringing the compound in
association with the carrier and additives. In general, the
formulations are prepared by uniformly and intimately bringing the
compound of the invention into association with a liquid carrier or
a finely divided solid carrier or both, and then, if necessary,
shaping the product into the desired unit dosage form.
[0056] The ordinarily skilled physician or veterinarian will
readily determine and prescribe the therapeutically effective
amount of the compound to treat the disease for which treatment is
administered. In so proceeding, the physician or veterinarian could
employ relatively low dosages at first, subsequently increasing the
dose until a maximum response is obtained. Typically, the
particular disease, the severity of the disease, the compound to be
administered, the route of administration, and the characteristics
of the mammal to be treated, for example, age, sex, and weight, are
considered in determining the effective amount to administer.
Generally, a therapeutically effective amount of a compound to
treat diabetes mellitus and related conditions and symptoms is in a
range of about 0.1-100 mg/kg of a patient's body weight, more
preferably in the range of about 0.5-50 mg/kg of a patient's body
weight, per daily dose. The compound may be administered for
periods of short and long duration.
[0057] A therapeutically effective amount of a compound for
treating diabetes mellitus and related conditions and symptoms can
be administered prior to, concurrently with, or after the onset of
the disease or symptom. The compound can be administered to treat
diabetes mellitus type I, diabetes mellitus type II, or obesity.
Preferably, the compound can be administered to treat damage to
blood vessels, eyes, kidneys, nerves, autonomic nervous system,
skin, connective tissue, or immune system. Still preferably, the
compound can be administered to treat insulin resistance or
hyperinsulinemia. Also preferably, the compound can be administered
to treat diabetes-induced hypertension.
[0058] Moreover, the compound may be administered concurrently with
insulin and/or a hypoglycemic compound to treat diabetes mellitus
and related conditions and symptoms. The compound can be
administered concurrently with insulin and/or a hypoglycemic
compound to treat type I diabetes, type II diabetes, or obesity.
Preferably, the compound can be administered concurrently with
insulin and/or hypoglycemic compound to treat damage to blood
vessels, eyes, kidneys, nerves, autonomic nervous system, skin,
connective tissue, or immune system. Still preferably, the compound
can be administered concurrently with insulin and/or hypoglycemic
compound to treat insulin resistance or hyperinsulinemia. Also
preferably, the compound can be administered concurrently with
insulin and/or hypoglycemic compound to treat diabetes-induced
hypertension.
[0059] Typically, a compound may be administered concurrently with
insulin to treat type I diabetes, type II diabetes, and related
conditions and symptoms. For type II diabetes, insulin resistance,
hyperinsulinemia, diabetes-induced hypertension, obesity, or damage
to blood vessels, eyes, kidneys, nerves, autonomic nervous system,
skin, connective tissue, or immune system, a compound may be
administered concurrently with a hypoglycemic compound instead of
insulin. Alternatively, a compound may be administered concurrently
with insulin and a hypoglycemic compound to treat type II diabetes,
insulin resistance, hyperinsulinemia, diabetes-induced
hypertension, obesity, or damage to blood vessels, eyes, kidneys,
nerves, autonomic nervous system, skin, connective tissue, or
immune system.
[0060] "Concurrent administration" and "concurrently administering"
as used herein includes administering a compound suitable for use
in methods of the invention and insulin and/or a hypoglycemic
compound in admixture, such as, for example, in a pharmaceutical
composition, or as separate compounds, such as, for example,
separate pharmaceutical compositions administered consecutively,
simultaneously, or at different times. Preferably, if the compound
and insulin and/or hypoglycemic compound are administered
separately, they are not administered so distant in time from each
other that the compound and the insulin and/or hypoglycemic
compound cannot interact and a lower dosage amount of insulin
and/or hypoglycemic compound cannot be administered.
[0061] Suitable hypoglycemic compounds include, for example,
metformin, acarbose, acetohexamide, glimepiride, tolazamide,
glipizide, glyburide, tolbutamide, chlorpropamide,
thiazolidinediones, alpha glucosidase inhibitors, biguanindine
derivatives, and troglitazone, and a mixture thereof. Preferably,
the hypoglycemic compound is tolbutamide.
[0062] A physician or veterinarian of ordinary skill readily
determines a subject who is exhibiting symptoms of diabetes
mellitus and related conditions and symptoms. Regardless of the
route of administration selected, the compound and the insulin
and/or hypoglycemic compound are formulated into pharmaceutically
acceptable unit dosage forms by conventional methods known to the
pharmaceutical art. An effective but nontoxic quantity of the
compound and the insulin and/or hypoglycemic compound is employed
in the treatment of diabetes mellitus and related conditions and
symptoms. The compound and the insulin may be concurrently
administered parenterally in admixture or may be concurrently
administered enterally and/or parenterally separately. Similarly,
the compound and the hypoglycemic compound may be concurrently
administered enterally in admixture or may be administered
enterally and/or parenterally separately. In some instances, the
compound may be concurrently administered with insulin and a
hypoglycemic compound. Such administration would involve enteral
and/or parenteral administration as described above.
[0063] Parenteral administration includes subcutaneous,
intramuscular, intradermal, intramammary, intravenous, and other
administrative methods known in the art. Enteral administration
includes tablets, sustained release tablets, enteric coated
tablets, capsules, sustained release capsules, enteric coated
capsules, pills, powders, granules, solutions, and the like.
[0064] A pharmaceutical composition suitable for administration
includes a pharmaceutically acceptable carrier and a compound
suitable for use in methods of the invention and, optionally,
insulin and/or a hypoglycemic compound. A pharmaceutically
acceptable carrier includes, but is not limited to, physiological
saline, ringers, phosphate buffered saline, and other carriers
known in the art. Pharmaceutical compositions may also include
stabilizers, antioxidants, colorants, and diluents.
Pharmaceutically acceptable carriers and additives are chosen such
that side effects from the pharmaceutical compound are minimized
and the performance of the compound is not canceled or inhibited to
such an extent that treatment is ineffective.
[0065] Methods of preparing pharmaceutical compositions containing
a pharmaceutically acceptable carrier and a compound suitable for
use in methods of the invention and, optionally, insulin and/or a
hypoglycemic compound, are known to those of skill in the art. All
methods may include the step of bringing the compound and,
optionally, a hypoglycemic compound in association with the carrier
or additives. In general, the formulations are prepared by
uniformly and intimately bringing the compound into association
with a liquid carrier or a finely divided solid carrier or both,
and then, if necessary, shaping the product into the desired unit
dosage form.
[0066] The ordinarily skilled physician or veterinarian will
readily determine and prescribe the therapeutically effective
amount of the compound to treat the disease for which treatment is
administered as described above.
[0067] When concurrently administering a compound with insulin
and/or a hypoglycemic compound, the compound is administered in a
range of about 0.1-100 mg per daily dose, typically 0.5-50 mg/kg of
body weight per daily dose. A hypoglycemic compound is administered
in a range of about 1 to 300 mg per daily dose, typically 1 to 200
mg per daily dose. Insulin is typically administered in a range of
about 0.1 to 2 units/kg of a patient's body weight per daily dose.
A "unit" of insulin refers to that amount of insulin necessary to
lower the blood-sugar level in a rabbit by 50% in 1 to 3 hours.
[0068] The invention is further elaborated by the representative
examples as follows. Such examples are not meant to be limiting but
only illustrative of the invention.
EXAMPLES
Example 1
Synthesis of Morpholine Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-h-
ydroxy-6-methylfuro(3,4-c)pyridine)
[0069] A mixture of morpholine (20 g) and toluene (100 mL) was
stirred and heated using an oil bath set to 100.degree. C. for 15
minutes. Pyridoxal hydrochloride (10 g) was then added and the
reaction mixture was stirred at 100.degree. C. for two hours. The
reaction mixture was then concentrated by distillation of the
toluene and morpholine. The concentrated reaction mixture was
washed three times by adding toluene (100 mL) and removing the
toluene by distillation. After washing, the residue was dissolved
in toluene and filtered, and then hexane was added until
precipitation began, at which time the reaction mixture was left
overnight at room temperature. Crystals were collected and washed
thoroughly with hexane.
[0070] Nuclear magnetic resonance spectroscopy (NMR) and mass
spectroscopy confirmed the identity of the synthesized compound.
The purity of the compound was analyzed by high performance liquid
chromatography (HPLC) using a C-18 reverse phase column and
water/acetonitrile as solvent (1-100% acetonitrile over 25
minutes).
Example 2
Synthesis of the 3-toluate of the Morpholine Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-(p-toluoyloxy)-6-methylfuro(3,4-c)pyridine)
[0071] Anhydrous powdered potassium carbonate (5 g), acetone (100
mL), and morpholine pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-hydroxy-6-met- hylfuro(3,4-c)pyridine)
(1.11 g, 5 mmoles) were mixed in a nitrogen-cooled, dry flask. The
reaction mixture was cooled to between 0 and 5.degree. C. and then
p-toluoyl chloride (1.06 g, 6 mmoles) in acetone (20 mL) was added.
This mixture was stirred for two hours, followed by filtering out
the solid and evaporating the solution to dryness under vacuum. The
residue was chromatographed on silica gel using a mixture of ethyl
acetate and hexane as solvent.
[0072] The purified solid was analyzed by thin layer chromatography
(TLC), NMR, and mass spectroscopy. The purity of the synthesized
compound was confirmed by HPLC as described in Example 1.
Example 3
Synthesis of the 3-toluate of Pyridoxal
(2-methyl-3-toluoyloxy-4-formyl-5-- hydroxymethylpyridine)
[0073] Anhydrous potassium carbonate (10 g), acetone (100 mL), and
pyridoxal hydrochloride (2.03 g, 10 mmoles) were mixed in a
nitrogen-cooled, dry flask. The mixture was cooled to between 0 and
5.degree. C. and then p-toluoyl chloride (2.12 g, 12 mmoles) in
acetone (20 mL) was added. The reaction mixture was stirred for two
hours followed by filtering out the solid and evaporating the
solution to dryness under vacuum. The residue was chromatographed
on silica gel as described in Example 2.
[0074] The purified solid was analyzed by TLC, NMR, and mass
spectroscopy. The purity of the compound was confirmed by HPLC as
described in Example 1.
[0075] Alternative to the above-described method, the 3-toluate of
pyridoxal is synthesized by reacting the compound of Example 2 with
80% aqueous acetic acid at 60.degree. C. for 30 minutes, and then
diluting with water and extracting by ethyl acetate. The ethyl
acetate layer is washed with 5% aqueous sodium bicarbonate, dried
with magnesium sulfate, and evaporated to dryness. The compound is
also analyzed as described supra.
Example 4
Synthesis of 3-.beta.-naphthoate of the Morpholine
Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-(.beta.-naphthoyloxy)-6-methylfuro(3,4-c)pyri-
dine)
[0076] Anhydrous powdered potassium carbonate (5 g), acetone (100
mL), and morpholine pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-hydroxy-6-met- hylfuro(3,4-c)pyridine)
(1.11 g, 5 mmoles) were mixed in a nitrogen-cooled, dry flask. The
mixture was cooled to between 0 and 5.degree. C. and then
.beta.-naphthoyl chloride (1.06 g, 6 mmoles) in acetone (20 mL) was
added. The reaction mixture was stirred for two hours, and then the
solid was filtered out and the solution was evaporated to dryness
under vacuum. The residue was chromatographed according to Example
2.
[0077] The purified solid was analyzed according to Example 2, and
the purity was confirmed according to Example 1.
Example 5
Synthesis of the 3-.beta.-naphthoate of Pyridoxal
(2-methyl-3-.beta.-napht-
hoyloxy-4-formyl-5-hydroxymethylpyridine)
[0078] Anhydrous potassium carbonate (10 g), acetone (100 mL), and
pyridoxal hydrochloride (2.03 g, 10 mmoles) were mixed in a
nitrogen-cooled, dry flask. The mixture was cooled to between 0 and
5.degree. C. and then .beta.-naphthoyl chloride (2.12 g, 12 mmoles)
in acetone (20 mL) was added and the mixture was stirred for two
hours. The solid was filtered out and the solution was evaporated
to dryness under vacuum. The residue was chromatographed according
to Example 2.
[0079] The purified solid was analyzed according to Example 2, and
the purity was confirmed according to Example 1.
[0080] Alternative to the above-described synthesis, the
3-.beta.-naphthoate of pyridoxal is prepared by reacting the
compound of Example 4 with 80% aqueous acetic acid at 60.degree. C.
for 30 minutes, followed by diluting with water and extracting by
ethyl acetate. The ethyl acetate layer is then washed with 5%
aqueous sodium bicarbonate, dried with magnesium sulfate, and
evaporated to dryness. The compound is also analyzed as described
supra.
Example 6
Synthesis of 3-pivaloyl of the Morpholine Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-pivaloyloxy)-6-methylfuro(3,4-c)pyridine)
[0081] Anhydrous powdered potassium carbonate (5 g), acetone (100
mL), and morpholine pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-hydroxy-6-met- hylfuro(3,4-c)pyridine)
(1.11 g, 5 mmoles) were mixed in a nitrogen-cooled, dry flask. The
mixture was cooled to between 0 and 5.degree. C. and then pivaloyl
chloride (trimethylacetyl chloride) (720 mg, 6 mmoles) in acetone
(20 mL) was added. The reaction mixture was stirred for two hours.
The solid was then filtered out and the solution was evaporated to
dryness under vacuum. The residue was chromatographed according to
Example 2.
[0082] The purified solid was analyzed according to Example 2, and
the purity was confirmed according to Example 1.
Example 7
Synthesis of 3-dimethylcarbamoyl of the Morpholine
Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-(dimethylcarbamoyloxy)-6-methylfuro(3,4-c)pyr-
idine)
[0083] Anhydrous powdered potassium carbonate (5 g), acetone (100
mL), and morpholine pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-hydroxy-6-met- hylfuro(3,4-c)pyridine)
(1.11 g, 5 mmoles) were mixed in a nitrogen-cooled, dry flask. The
mixture was cooled to between 0 and 5.degree. C. and then
dimethylcarbamoyl chloride (642 mg, 6 mmoles) in acetone (20 mL)
was added. The reaction mixture was stirred for two hours. The
solid was then filtered out and the solution was evaporated to
dryness under vacuum. The residue was chromatographed according to
Example 2.
[0084] The purified solid was analyzed according to Example 2, and
the purity was confirmed according to Example 1.
Example 8
Synthesis of 3-acetylsalicyloyl of the Morpholine
Pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-acetylsalicyloxy)-6-methylfuro(3,4-c)pyridine-
)
[0085] Anhydrous powdered potassium carbonate (5 g), acetone (100
mL), and morpholine pyridoxal-4,5-aminal
(1-morpholino-1,3-dihydro-7-hydroxy-6-met- hylfuro(3,4-c)pyridine)
(1.11 g, 5 mmoles) were mixed in a nitrogen-cooled, dry flask. The
mixture was cooled to between 0 and 5.degree. C. and then
acetylsalicyloyl chloride (1.09 g, 6 mmoles) in acetone (20 mL) was
added. The reaction mixture was stirred for two hours. The solid
was then filtered out and the solution was evaporated to dryness
under vacuum. The residue was chromatographed according to Example
2.
[0086] The purified solid was analyzed according to Example 2, and
the purity was confirmed according to Example 1.
Example 9
Control of Glucose and Insulin Levels in Subjects Having Type I
Diabetes by Administration of Pyridoxal-5'-Phosphate
[0087] To determine the effect of a compound suitable for use in
methods of the invention on glucose and insulin levels, rats are
administered pyridoxal-5'-phosphate, either alone or in combination
with insulin, after being experimentally induced with type I
diabetes, and their urine and blood glucose and insulin levels are
determined.
[0088] Male Sprague-Dawley (Charles River Laboratories, Montreal,
Canada) rats weighing approximately 200 g are randomly separated
into control and experimental groups. All experimental animals are
given an intravenous injection of 0.1 M citrate buffered
streptozotocin (pH 4.5) at a dosage of 65 mg/kg of body weight to
induce diabetes mellitus. All control animals receive an
intravenous injection of 0.1 M citrate buffer (pH 4.5) alone.
[0089] One experimental group of rats also receives daily doses of
pyridoxal-5'-phosphate (25 mg/kg body weight) (Aldrich Canada Ltd.,
Ontario, Canada). A second experimental group receives daily
subcutanteous injections of Humulin.RTM. N (3 units per day)
(insulin isophene, human biosynthetic; Eli Lilly and Co.,
Indianapolis, Ind.). A third experimental group receives both daily
subcutaneous injections of Humulin.RTM. N (3 units per day) and a
daily dose of pyridoxal-5'-phosphate (25 mg/kg body weight). A
fourth experimental group receives daily subcutaneous injections of
Humulin.RTM. N (1.5 units per day). A fifth experimental group
receives both daily subcutaneous injections of Humulin.RTM. N (1.5
units per day) and a daily dose of pyridoxal-5'-phosphate (25 mg/kg
body weight).
[0090] All animals are fed rat chow and water ad libitum. Plasma
glucose levels were done using the Infinity Glucose Reagent.RTM.
(Sigma Diagnostics, St. Louis, Mo.).
[0091] The experimental group of rats that receive daily doses of
pyridoxal-5'-phosphate and daily injections of Humulin.RTM. N show
reduced levels of glucose and insulin in blood and urine samples
when compared with the group of rats that receive daily injections
of Humulin.RTM. N without receiving daily doses of
pyridoxal-5'-phosphate.
[0092] FIG. 1 demonstrates the effect of P-5-P and insulin alone or
in combination on increased plasma glucose levels in a Type I
diabetes indication of hyperglycemia. It can be seen in FIG. 1 that
Insulin (1 unit and 3 unit) and P-5-P significantly reduced the
plasma glucose levels when compared to diabetic group. Moreover a
decreased dose of insulin was needed in the presence of P-5-P to
produce the same effect as with a full dose of 3 units of
insulin.
[0093] FIG. 2 demonstrates the effect of P-5-P and insulin alone or
in combination on plasma glucose levels in a Type I diabetes
indication of hyperglycemia. It can be seen in FIG. 2 that Insulin
(1 unit and 3 unit) and P-5-P significantly increased the plasma
insulin levels when compared to diabetic group. Moreover a
decreased dose of insulin was needed in the presence of P-5-P to
produce the same effect as with a full dose of 3 units of
insulin.
Example 10
Control of Glucose and Insulin Levels in Subjects Having Type II
Diabetes by Administration of Pyridoxal-5'-Phosphate
[0094] To determine the effect of a compound suitable for use in
methods of the invention on glucose and insulin levels, as well as
increases in systolic blood pressure, rats having type II diabetes
are administered pyridoxal-5'-phosphate, either alone or in
combination with sucrose and/or tolbutamide, and their systolic
blood pressure, urine and blood glucose and insulin levels are
determined. Acarbose reduces blood pressure in sucrose induced
hypertension in rats. Madar Z et al: Isr J Med Sci; 33:153-159.
[0095] As described by Madar et al., Acarbose reduces blood
pressure in sucrose induced hypertension in rats. Madar Z et al:
Isr J Med Sci; 33:153-159, a high sucrose or fructose diet for a
prolonged period is one technique used to induce Type II diabetes,
specifically hypertension associated with hyperglycemia and
hyperinsulinemia in animals.
[0096] Male Sprague-Dawley (Charles River Laboratories, Montreal,
Canada) rats weighing approximately 200 g are randomly separated
into the following groups with each group having 5 amimals:
[0097] a) The control group that was fed a normal diet and provided
with drinking water
[0098] b) The sucrose group that was fed 35% sucrose (35 gm
sucrose/100 ml of drinking water/day) with an average intake of 150
ml/rat/day
[0099] c) The sucrose+P-5-P group that was fed sucrose as stated in
b above and 25 mg/kg orally/day of P-5-P
[0100] d) The sucrose+tolbutamide group that was fed sucrose as
stated in b above and administered 40 mg/kg orally/day of
tolbutamide
[0101] e) The sucrose+P-5-P+tolbutamide group that was fed sucrose
as stated in b above, 25 mg/kg orally/day of P-5-P, and
administered 40 mg/kg orally/day of tolbutamide
[0102] f) The sucrose+P-5-P+tolbutamide group that was fed sucrose
as stated in b above, 25 mg/kg orally/day of P-5-P, and
administered 20 mg/kg, orally/day of tolbutamide
[0103] g) The sucrose+tolbutamide group that was fed sucrose as
stated in b above and 20 mg/kg orally/day of tolbutamide.
[0104] Total duration of the study was 16 weeks. Plasma insulin
levels were measured using Rat Insulin RIA Kit (Linco Research
Inc., St. Charles, Mo.). Plasma glucose levels were done using the
Infinity Glucose Reagent.RTM. (Sigma Diagnostics, St. Louis, Mo.).
Blood pressure was measured using the tail cuff method, (see, Madar
et al., Acarbose reduces blood pressure in sucrose induced
hypertension in rats. Madar Z et al: Isr J Med Sci;
33:153-159).
[0105] FIG. 3 demonstrates the effect of P-5-P and tolbutamide
alone or in combination on increased plasma glucose levels in a
Type II diabetes indication of hyperglycemia. It can be seen in
FIG. 3 that tolbutamide (40 and 20 mg/kg) and P-5-P significantly
decreased the plasma glucose levels when compared to diabetic
group. Moreover a decreased dose of tolbutamide was needed in the
presence of P-5-P to produce the same effect as with a full dose of
40 mg/kg tolbutamide.
[0106] FIG. 4 demonstrates the effect of P-5-P and tolbutamide
alone or in combination on increased plasma insulin levels in a
Type II diabetes indication of hyperglycemia. It can be seen in
FIG. 4 that tolbutamide (40 and 20 mg/kg) and P-5-P significantly
decreased the plasma insulin levels when compared to diabetic
group. Moreover a decreased dose of tolbutamide was needed in the
presence of P-5-P to produce the same or better effect as with a
full dose of 40 mg/kg tolbutamide.
[0107] FIG. 5 demonstrates the effect of P-5-P and tolbutamide
alone or in combination on increased systolic blood pressure in a
Type II diabetes indication of hyperglycemia. It can be seen in
FIG. 5 that that P-5-P significantly decreased the rise in systolic
blood pressure when compared to diabetic and tolbutamide treatment
groups. Moreover when the rats were treated with P-5-P and
tolbutamide (40 mg/kg), the decrease in systolic blood pressure was
significantly greater when compared to rats treated with P-5-P or
tolbutamide alone.
[0108] It should be noted that, as used in the specification and
the appended claims, the singular forms "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.
Similarly, reference to "a compound" includes a mixture having more
than one compound.
[0109] Although embodiments of the invention have been described
above, it is not limited thereto, and it will be apparent to
persons skilled in the art that numerous modifications and
variations form part of the present invention insofar as they do
not depart from the spirit, nature, and scope of the claimed and
described invention.
* * * * *