U.S. patent application number 13/701630 was filed with the patent office on 2013-06-20 for tocopherol derivatives and methods of use.
This patent application is currently assigned to THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPARTMENT OF VETERAN AFFAIRS. The applicant listed for this patent is Philip J. Breen, Cesar Compadre, Martin Hauer-Jensen, K. Sree Kumar, Kottayil Varughese. Invention is credited to Philip J. Breen, Cesar Compadre, Martin Hauer-Jensen, K. Sree Kumar, Kottayil Varughese.
Application Number | 20130158106 13/701630 |
Document ID | / |
Family ID | 45067073 |
Filed Date | 2013-06-20 |
United States Patent
Application |
20130158106 |
Kind Code |
A1 |
Breen; Philip J. ; et
al. |
June 20, 2013 |
TOCOPHEROL DERIVATIVES AND METHODS OF USE
Abstract
Tocol derivative compounds, compositions comprising these tocol
derivatives and methods of using the tocol derivatives are provided
herein. Specifically the tocol derivatives have a partially
unsaturated hydrocarbon tail and are thus distinct from the
tocopherols. The hydrocarbon tails do not have a trans
carbon-carbon double bond in the second isoprene unit of the
hydrocarbon tail and are distinct from the tocotrienols. The
compounds are expected to allow improved interaction with the
.alpha.-tocopherol transfer protein receptor than the tocotrienols
and better bioactivity than the tocopherols.
Inventors: |
Breen; Philip J.; (Little
Rock, AR) ; Kumar; K. Sree; (Rockville, MD) ;
Compadre; Cesar; (Little Rock, AR) ; Hauer-Jensen;
Martin; (Little Rock, AR) ; Varughese; Kottayil;
(Little Rock, AR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Breen; Philip J.
Kumar; K. Sree
Compadre; Cesar
Hauer-Jensen; Martin
Varughese; Kottayil |
Little Rock
Rockville
Little Rock
Little Rock
Little Rock |
AR
MD
AR
AR
AR |
US
US
US
US
US |
|
|
Assignee: |
THE UNITED STATES OF AMERICA AS
REPRESENTED BY THE DEPARTMENT OF VETERAN AFFAIRS
Washington
DC
THE BOARD OF TRUSTEES FOR THE UNIVERSITY OF ARKANSAS
Little Rock
AR
|
Family ID: |
45067073 |
Appl. No.: |
13/701630 |
Filed: |
June 2, 2011 |
PCT Filed: |
June 2, 2011 |
PCT NO: |
PCT/US11/38933 |
371 Date: |
January 24, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61350740 |
Jun 2, 2010 |
|
|
|
Current U.S.
Class: |
514/456 ;
549/408 |
Current CPC
Class: |
C07D 311/72 20130101;
C07D 311/58 20130101 |
Class at
Publication: |
514/456 ;
549/408 |
International
Class: |
C07D 311/72 20060101
C07D311/72 |
Claims
1. A tocol derivative compound comprising a chroman group and a
hydrocarbon tail, the hydrocarbon tail having three isoprene units,
wherein at least one isoprene unit is unsaturated between carbon 2
and 3 of the isoprene unit and wherein the second isoprene unit in
the hydrocarbon tail does not include a trans carbon-carbon double
bond.
2.-3. (canceled)
4. The compound of claim 1, wherein the compound has formula (I)
##STR00013## or a salt thereof, wherein R.sup.1, R.sup.3, R.sup.4
and R.sup.5 are each independently --H, halogen, --OH, --OCH.sub.3,
or a branched or unbranched, substituted or unsubstituted,
saturated or unsaturated C.sub.1-C.sub.20 alkyl; R.sup.2 is an
ester, --OH, --NHR.sup.6, --CO.sub.2H, --C(R.sup.6).sub.2CO.sub.2H
or a branched or =branched, substituted or unsubstituted, saturated
or unsaturated C.sub.1-C.sub.6 alkyl; R.sup.6 is --H, halogen,
--OH, or a branched or unbranched, substituted or unsubstituted,
saturated or unsaturated C.sub.1-C.sub.20 alkyl; Y is O, S or NH;
and Z is a hydrocarbon side chain having 1 to 3 carbon-carbon
double bonds and represented by formula (II) ##STR00014## wherein
the numerals represent the numbering of the carbons in the chain,
wherein the dotted lines between carbons 1', 2', 3', 4' and 16',
and between 15', 8', 9 10', 11', 12', 13', and 14' represent a
position for an optional carbon-carbon bond and the dotted line
between carbon 7' and 8' represent a single bond, a cis
carbon-carbon double bond or a cyclopropyl group including both
carbon 7' and 8' and an additional carbon not shown in formula
II.
5. The compound of claim 4, wherein the Torsion A angle between
carbons 5', 6', 7', and 8' of the hydrocarbon tail of formula II
and the Torsion B angle between carbons 6', 7', 8, and 9' of the
hydrocarbon tail of formula II can adopt conformations between
30.degree. and 90.degree..
6. The compound of claim 4, wherein Z includes two double
bonds.
7. The compound of claim 6, wherein Z includes a double bond
between the 3' and 4' carbons.
8. The compound of claim 4, wherein Z includes a cis double bond
between the 7' and 8' carbons.
9. The compound of claim 8, wherein Z includes three double
bonds.
10. The compound of claim 4, wherein Z includes a cyclopropyl group
including the 7' and 8' carbons.
11. The compound of claim 10, wherein Z has one of the two
following structures: ##STR00015##
12. The compound of claim 1, wherein the compound is a racemic
mixture of stereoisomers.
13. The compound of claim 1, wherein either isomer is in
enantiomeric excess of over 50% the compound is over 80% in the RS
structure.
14. The compound of claim 4, wherein R.sup.2 is an ester selected
from --O(CO)CH.sub.3, --O(CO)heterocyclic, O(CO) carbocyclic,
--O(CO)(R.sup.7)COOH, --O(CO)R.sup.8, wherein R.sup.7 is selected
from a branched or unbranched, saturated or unsaturated,
substituted or unsubstituted C.sub.1-C.sub.20 alkyl and R.sup.8 is
selected from --H, and a branched or unbranched, saturated or
unsaturated, substituted or unsubstituted C.sub.1-C.sub.20
alkyl.
15. The compound of claim 4, wherein R.sup.2 is --OH and wherein
R.sup.5 is --H.
16. (canceled)
17. The compound of claim 4, wherein R.sup.1, R.sup.3 and R.sup.4
are all CH.sub.3.
18. The compound of claim 4, wherein R.sup.3 and R.sup.4 are
CH.sub.3 and R.sup.1 is H.
19. The compound of claim 4, wherein R.sup.1 and R.sup.4 are
CH.sub.3 and R.sup.3 is H.
20. The compound of claim 4, wherein R.sup.1, R.sup.3 and R.sup.4
are H.
21. The compound of claim 1, wherein the hydrocarbon tail allows
farnesyl recognition.
22. The compound of claim 1, wherein the hydrocarbon tail confers
HMGCoA reductase inhibition activity.
23. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable carrier.
24. A method of treating a subject comprising administering an
effective amount of a composition comprising the compound of claim
1 to the subject.
25. The method of claim 24, wherein the subject is in need of
treatment with an antioxidant agent, an anti-inflammatory agent, an
inn unoregulatory agent, an anti-thromobotic agent, an
anti-atherogenic agent, a hypocholesterolemic agent or an HMG-CoA
reductase inhibitor.
26. The method of claim 24, wherein the subject has a condition
selected from the group consisting of radiation exposure, cancer,
cardiovascular disease including but not limited to coronary artery
disease, decreasing lipoprotein levels, decreasing cholesterol
levels, decreasing triglycerides, age-related macular degeneration,
cataracts, glaucoma, chronic pain, chronic fatigue syndrome, fever,
edema, diabetes mellitus, signs of aging, rheumatoid diseases,
septic shock, and Alzheimer's disease.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefit of priority of
U.S. Provisional Patent Application No. 61/350,740, filed Jun. 2,
2010, which is incorporated herein by reference in its
entirety.
INTRODUCTION
[0002] Vitamin E is composed of eight naturally occurring tocols.
Four are tocopherols, which possess a saturated hydrocarbon tail,
and four are tocotrienols, which possess three trans double bonds
in the hydrocarbon tail. The tocols are known to have beneficial
health effects when provided as a dietary supplement. Efficient
transport out of the liver is necessary for the tocols to deliver
the beneficial health effects. The tocols are transported out of
the liver and into the blood stream by a protein called .alpha.TTP
(tocopherol transfer protein). Some tocols, specifically the
tocopherols, are more efficiently transported out of the liver and
into the blood stream than the tocotrienols and have a longer
half-life in the body which allows for decreased doses and possibly
increased biological activity.
SUMMARY
[0003] The tocotrienols have recently been shown to have some
beneficial health effects not seen with the tocopherols. Provided
herein are tocol derivatives with modifications to the hydrocarbon
tail to allow more efficient binding and uptake of tocols with
unsaturated hydrocarbon tails by the .alpha.TTP receptor. The
derivatives are called tocoflexols to indicate the increased
flexibility of the hydrocarbon tail as compared to tocotrienols and
differentiate this class of compounds from the tocopherols and
tocotrienols. Tocopherol and tocotrienol derivatives with one to
three double bonds in the hydrocarbon tail are described
herein.
[0004] In one aspect, tocol derivative compounds with a chroman
group and a hydrocarbon tail having three isoprene units are
described herein. The hydrocarbon tail is distinct from that of
tocopherol and tocotrienol in that at least one isoprene unit is
unsaturated, suitably between carbon 2 and 3 of the isoprene unit
and the second isoprene unit in the hydrocarbon tail does not
include a trans carbon carbon double bond.
[0005] In another aspect, the compounds described herein have
formula (I):
##STR00001##
or a salt thereof, wherein R.sup.1, R.sup.3, R.sup.4 and R.sup.5
are each independently --H, halogen, --OH, --OCH.sub.3, or a
branched or unbranched, substituted or unsubstituted, saturated or
unsaturated C.sub.1-C.sub.20 alkyl; R.sup.2 is an ester, --OH,
--NHR.sup.6, --CO.sub.2H, C(R.sup.6).sub.2CO.sub.2H or a branched
or unbranched, substituted or unsubstituted, saturated or
unsaturated C.sub.1-C.sub.6 alkyl; R.sup.6 is --H, halogen, --OH,
or a branched or unbranched, substituted or unsubstituted,
saturated or unsaturated C.sub.1-C.sub.20 alkyl; Y is O, S or NH;
and Z is a hydrocarbon side chain having 1 to 3 carbon-carbon
double bonds represented by formula (II):
##STR00002##
wherein the numerals represent the numbering of the carbons in the
chain, wherein the dotted lines between carbons 1', 2', 3', 4' and
16', and between 15', 8', 9', 10', 11', 12', 13', and 14' represent
a position for an optional carbon-carbon bond and the dotted line
between carbons 7' and 8' represent a single bond, a cis
carbon-carbon double bond or a cyclopropyl group including carbon
7' and 8' and a third carbon that is not shown in the formula.
[0006] In one aspect, the compounds have a chroman head group of
any of the tocol derivatives and a partially unsaturated
hydrocarbon tail with a carbon-carbon double bond between carbons
11' and 12' or alternatively between any of the carbons in the
third isoprene unit. In another aspect, the compounds have a
hydrocarbon tail with two carbon-carbon double bonds. In one
embodiment, the carbon-carbon double bonds are between carbons 15',
8', 9', 10', 11', 12', 13', and 14' and at least one of carbons
1'-2', 2'-3',3'-4', '-8' and 4'-16'. In yet another aspect, the
compounds have a hydrocarbon tail with three carbon-carbon double
bonds. In one embodiment, the carbon-carbon double bonds are
between at least one of carbons 15', 8', 9', 10', 11', 12', 13',
and 14' and between carbons 7' and 8' and one of carbons 2'-3',
3'-4', and 4'-16'. In still another embodiment, the hydrocarbon
tail has a double bond between at least one of carbons 15', 8', 9',
10', 11', 12', 13', and 14' and between one of carbons 1'-2',
2'-3',3'-4', and 4'-16' and contains a cyclopropyl group including
carbons 7' and 8' and a carbon 17' not shown in formula II.
[0007] In still another aspect, methods of treating a subject with
a condition are provided. The methods include administering an
effective amount of at least one of the described compounds to the
subject to ameliorate the condition. The subject may be in need of
treatment with an antioxidant, an anti-inflammatory agent, an
immunoregulatory agent, an anti-thromobotic agent, an
anti-atherogenic agent, a hypocholesterolemic agent or an HMG-CoA
reductase inhibitor. The subject may have a condition selected from
radiation exposure, cancer, cardiovascular disease including but
not limited to coronary artery disease, decreasing lipoprotein
levels, decreasing cholesterol levels, decreasing triglycerides,
age-related macular degeneration, cataracts, glaucoma, chronic
pain, chronic fatigue syndrome, fever, edema, diabetes mellitus,
signs of aging, rheumatoid diseases, septic shock, and Alzheimer's
disease.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a schematic of RRR-.alpha.-tocopherol as it would
appear when bound to the .alpha.-TTP receptor.
[0009] FIG. 2 is a schematic of the in silico analysis of the
Torsion angles A and B for tocopherol, tocotrienol and the RS and
RR configuration of tocoflexol compounds of the invention. The
circle represents a key contact between the TTP receptor and the
tocol.
[0010] FIG. 3 is a synthetic scheme for producing a compound of the
invention.
[0011] FIG. 4 is a graph showing the results of a gas
chromatography-mass spectrometry experiment demonstrating the
ability to detect and differentiate tocol compounds in plasma.
DETAILED DESCRIPTION
[0012] Provided herein are tocol derivatives with modifications to
the hydrocarbon tail to allow more efficient binding and uptake by
the .alpha.TTP receptor and methods of using these compounds. The
derivatives are called tocoflexols to indicate the increased
flexibility of the hydrocarbon tail relative to the tocotrienols
and differentiate this class of compounds from the tocopherols and
tocotrienols. Tocopherol and tocotrienol derivatives with one to
three double bonds in the hydrocarbon tail are described
herein.
[0013] Tocol derivative compounds with a chroman group and a
hydrocarbon tail having three isoprene units are described herein.
The chroman group has the basic structure shown in formula I. Many
alterations to the chroman head group of the tocols have been
described elsewhere and are known to those of skill in the art. The
chroman head group of any tocol may be used to generate the
compounds descried herein. The hydrocarbon tail is distinct from
that of tocopherol in that at least one isoprene unit is
unsaturated. Suitably the double bond is between carbon 2 and 3 of
the isoprene unit as shown below. The hydrocarbon tail is also
distinct from that of the tocotrienols because the second (middle)
isoprene unit in the hydrocarbon tail does not include a trans
carbon-carbon double bond.
##STR00003##
[0014] Suitably, at least one of the isoprene units has a double
bond. Suitably, the double bond is between carbons 2 and 3 of the
isoprene unit as shown by the dotted line in the formula above.
Suitably, the third isoprene unit (the farthest from the chroman
head group) has a carbon-carbon double bond between carbon 2 and 3.
Suitably the hydrocarbon tail has a cis carbon-carbon double bond
between carbons 2 and 3 of the second or middle isoprene unit.
Suitably the compound has a carbon-carbon double bond between
carbon 2 and 3 of the third isoprene unit and a cis carbon-carbon
double bond between carbons 2 and 3 of the second or middle
isoprene unit. Alternatively, the compound may have a cyclopropyl
group involving carbons 2 and 3 of the second or middle isoprene
unit and an additional carbon that is not part of the basic
isoprene unit. This compound may also have a carbon-carbon double
bond between carbons 2 and 3 of the third isoprene unit.
Alternatively, the second isoprene unit of the hydrocarbon tail may
be saturated and the first or first and third isoprene units may be
unsaturated.
[0015] As described in the Examples, the inventors found that in
order to efficiently bind to the .alpha.TTP receptor the
hydrocarbon tail of tocols must be flexible and able to fold and
bend. Tocotrienols, because of the unsaturated hydrocarbon tail, do
not bind as efficiently to .alpha.TTP and have lower
bioavailability than tocopherols. The hydrocarbon tail of the
tocoflexols of the present invention may be folded such that the
Torsion angle between carbon 4 of the first isoprene unit and
carbons 1, 2, and 3 of the second isoprene unit is about
61.0.degree. and the Torsion angle between carbons 1, 2, 3, and 4
of the second isoprene unit is about 58.4.degree.. Suitably the
hydrocarbon tail is flexible and can adopt conformations with
Torsion angles between 30.degree. and 90.degree., suitably between
45.degree. and 75.degree., suitably between 50.degree. and
70.degree., suitably between 53.degree. and 65.degree. at these
positions.
[0016] Tocopherol and tocotrienol derivatives having one to three
unsaturated carbon-carbon bonds on the hydrocarbon tail are
provided herein. The compounds provided herein may have the
following structural formula:
##STR00004##
or a salt thereof, wherein R.sup.1, R.sup.3, R.sup.4 and R.sup.5
are each independently --H, halogen, --OH, --OCH.sub.3, or a
branched or unbranched, substituted or unsubstituted, saturated or
unsaturated C.sub.1-C.sub.20 alkyl; R.sup.2 is an ester, --OH,
--NHR.sup.6, --CO.sub.2H, --C(R.sup.6).sub.2CO.sub.2H or a branched
or unbranched, substituted or unsubstituted, saturated or
unsaturated C.sub.1-C.sub.6 alkyl or hydroxyalkyl; R.sup.6 is --H,
halogen, --OH, or a branched or unbranched, substituted or
unsubstituted, saturated or unsaturated C.sub.1-C.sub.20 alkyl; Y
is O, S or NH; and Z is a hydrocarbon side chain having 1 to 3
carbon-carbon double bonds represented by formula (II).
##STR00005##
The numerals represent the numbering of the carbons in the chain.
The dotted lines between carbons 1', 2', 3', 4' and 16', and
between 15', 8', 9', 10', 11', 12', 13', and 14' represent a
position for an optional carbon-carbon double bond and the dotted
line between carbon 7' and 8' represent a single bond, an optional
cis carbon-carbon double bond or a cyclopropyl group including both
carbon 7' and 8' and an additional carbon 17' not shown in this
formula.
[0017] The compound may have the Torsion angles described above
such that the Torsion A angle between carbons 5', 6', 7', and 8' of
the hydrocarbon tail of formula II is about 61.0.degree. and the
Torsion B angle between carbons 6', 7', 8', and 9' of the
hydrocarbon tail of formula II is about 58.4.degree.. Suitably the
hydrocarbon tail is flexible and can adopt conformations with
Torsion angles between 30.degree. and 90.degree., suitably between
45.degree. and 75.degree., suitably between 50.degree. and
70.degree., suitably between 53.degree. and 65.degree. at these
positions. A tocol compound having these torsion angles is depicted
in FIG. 1. In a straight line drawing the torsion angles are
depicted as follows:
##STR00006##
[0018] The compounds have a hydrocarbon tail with a carbon-carbon
double bond. The double bond may be between one of carbons 15', 8',
9', 10', 11', 12', 13', and 14', suitably the double bond is
between carbons 11' and 12'. The compounds may have a hydrocarbon
tail with two or three carbon-carbon double bonds. The
carbon-carbon double bonds may be between at least one of carbons
15', 8', 9', 10', 11', 12', 13', and 14', suitably carbons 11' and
12' and at least one of carbons 1'-2', 2'-3',3'-4', 4'-16', 8'-15',
8'-9' or 9'-10'. The hydrocarbon tails do not have a carbon-carbon
double bond between carbons 5'-6', 6'-7' or 7'-8' in the trans
configuration. In another aspect, the compounds have a hydrocarbon
tail with two carbon-carbon double bonds. In one embodiment, the
carbon-carbon double bonds are between at least one of carbons 15',
8', 9', 10', 11', 12', 13', and 14', suitably carbons 11' and 12'
and at least one of carbons 1'-2', 2'-3',3'-4', 7'-8' (in cis) and
4'-16'. In yet another aspect, the compounds have a hydrocarbon
tail with three carbon-carbon double bonds. In one embodiment, the
carbon-carbon double bonds are between at least one of carbons 15',
8', 9', 10', 11', 12', 13', and 14', suitably carbons 11' and 12',
and 7'-8' (in cis) and one of carbons 1'-2', 2'-3',3'-4', and
4'-16'. In still another embodiment, the hydrocarbon tail has a
double bond between at least one of carbons 15', 8', 9', 10', 11',
12', 13', and 14', suitably carbons 11' and 12' and between one of
carbons 1'-2', 2'-3',3'-4', and 4'-16' and contains a cyclopropyl
group including carbons 7' and 8' and a carbon 17' not shown in
formula II. The hydrocarbon tail with the optional cyclopropyl
group may have one of the following configurations with the
carbon-double bond shown between carbons 3' and 4' as an optional
double bond:
##STR00007##
[0019] The hydrocarbon tails described herein may have at least one
stereocenter. Thus the compounds of the invention may be present as
a racemic mixture of compounds or stereoisomers. As shown in FIG. 2
and described further in the examples, certain isomers may be more
effective in terms of binding and transport by the .alpha.TTP
receptor or may have different or distinct bioactivity,
bioavailability or pharmacokinetics. The RS configuration is
expected to bind and be transported more efficiently than other
isomers. Thus preparation and isolation of the most effective
stereoisomers may result in relative pure preparations. If either
isomer is in enantiomeric excess of over 50%, the compound is
suitably over 80% in the RS structure. Suitably, the compound is
over 80%, 85%, 90%, 95%, 98%, 99% a single stereoisomer, such as
the RS stereoisomer.
[0020] The chroman head group of the tocols of formula I may be any
of those known or readily available to those of skill in the art.
In some embodiments, R.sup.2 is an --OH. In other embodiments
R.sup.2 is an ester. If R.sup.2 is an ester it may be an ester
selected from --O(CO)CH.sub.3, --O(CO)heterocyclic,
O(CO)carbocyclic, --O(CO)(R.sup.7)COOH, --O(CO)R.sup.8, wherein
R.sup.7 is selected from a branched or unbranched, saturated or
unsaturated, substituted or unsubstituted C.sub.1-C.sub.20 alkyl
and R.sup.8 is selected from --H, and a branched or unbranched,
saturated or unsaturated, substituted or unsubstituted
C.sub.1-C.sub.20 alkyl. Suitably R.sup.2 is --NHR.sup.6,
--CO.sub.2H, --C(R.sup.6).sub.2CO.sub.2H or a branched or
unbranched, substituted or unsubstituted, saturated or unsaturated
C.sub.1-C.sub.6 alkyl or hydroxyalkyl. R.sup.6 is suitably a --H,
--OH or --CH.sub.3.
[0021] In other embodiments, Y is an --O--. R.sup.5 is suitably
either a --H or a --CH.sub.3. R.sup.1, R.sup.3 and R.sup.4 are
suitably a C.sub.1-C.sub.6 branched or unbranched, saturated or
unsaturated, substituted or unsubstituted alkyl. In one embodiment,
R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are selected from --H and
--CH.sub.3, R.sup.2 is --OH or an ester, Y is --O--, and the
hydrocarbon tail (Z) has at least a double bond between carbons 11'
and 12'. In one embodiment, R.sup.5 is --H. In one embodiment,
R.sup.1, R.sup.3 and R.sup.4 are all CH.sub.3. In one embodiment,
R.sup.3 and R.sup.4 are CH.sub.3 and R.sup.1 is H. In another
embodiment, R' and R.sup.4 are CH.sub.3 and R.sup.3 is H. In
another embodiment, R.sup.1, R.sup.3 and R.sup.4 are H. Each R
group is independently selected and may be combined in any manner
and with any of the hydrocarbon tails described herein. One
exemplary embodiment of the compounds of the invention is as shown
below:
##STR00008##
[0022] "Substituted" means that one or more of the hydrogen atoms
bonded to carbon atoms in the chain or ring have been replaced with
other substituents. Suitable substituents include monovalent
hydrocarbon groups including alkyl groups such as methyl groups and
monovalent heterogeneous groups including alkoxy groups such as
methoxy groups. "Unsubstituted" means that the carbon chain or ring
contains no other substituents other than carbon and hydrogen.
[0023] "Branched" means that the carbon chain is not simply a
linear chain. "Unbranched" means that the carbon chain is a linear
carbon chain.
[0024] "Saturated" means that the carbon chain or ring does not
contain any double or triple bonds. "Unsaturated" means that the
carbon chain or ring contains at least one double bond. An
unsaturated carbon chain or ring may include more than one double
bond.
[0025] "Heterogeneous group" means a saturated or unsaturated chain
of non-hydrogen member atoms comprising carbon atoms and at least
one heteroatom.
[0026] "Hydrocarbon group" means a chain of 1 to 25 carbon atoms,
suitably 1 to 12 carbon atoms, more suitably 1 to 10 carbon atoms,
and most suitably 1 to 8 carbon atoms. Hydrocarbon groups may have
a linear or branched chain structure. Suitably the hydrocarbon
groups have one branch.
[0027] "Carbocyclic group" means a saturated or unsaturated
hydrocarbon ring. Carbocyclic groups are not aromatic. Carbocyclic
groups are monocyclic or polycyclic. Polycyclic carbocyclic groups
can be fused, spiro, or bridged ring systems. Monocyclic
carbocyclic groups contain 4 to 10 carbon atoms, suitably 4 to 7
carbon atoms, and more suitably 5 to 6 carbon atoms in the ring.
Bicyclic carbocyclic groups contain 8 to 12 carbon atoms,
preferably 9 to 10 carbon atoms in the rings.
[0028] "Heteroatom" means an atom other than carbon e.g., in the
ring of a heterocyclic group or the chain of a heterogeneous group.
Preferably, heteroatoms are selected from the group consisting of
sulfur, phosphorous, nitrogen and oxygen atoms. Groups containing
more than one heteroatom may contain different heteroatoms.
[0029] "Heterocyclic group" means a saturated or unsaturated ring
structure containing carbon atoms and 1 or more heteroatoms in the
ring. Heterocyclic groups are not aromatic. Heterocyclic groups are
monocyclic or polycyclic. Polycyclic heteroaromatic groups can be
fused, spiro, or bridged ring systems. Monocyclic heterocyclic
groups contain 4 to 10 member atoms (i.e., including both carbon
atoms and at least 1 heteroatom), suitably 4 to 7, and more
suitably 5 to 6 in the ring. Bicyclic heterocyclic groups contain 8
to 18 member atoms, suitably 9 or 10 in the rings.
[0030] Methods of making the compounds described herein are
provided in the Examples. The compounds may be synthesized using
conventional chemical technologies available to those skilled in
the art. Salts of the compounds described herein are also provided.
Suitably the salts are pharmaceutically acceptable. Acceptable
salts of the compounds include, but are not limited to
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate.
[0031] The compounds described have enhanced binding to the
.alpha.-TTP receptor and enhanced transport out of the liver and
into the circulation after administration to a subject. The
enhanced transport is expected to lead to enhanced biological
activity of the compounds as compared to tocotrienol after
administration to a subject. The elimination half-life from the
subject is also expected to be enhanced. This enhancement of uptake
into the blood stream combined with decreased clearance from the
body may result in increased effectiveness of administration of the
compound or may allow for the therapeutically effective dose of the
compounds described herein to be lower than that of tocotrienol or
other tocols. The subject may be any mammal, including but not
limited to a human, mouse, or domesticated animal.
[0032] In addition, the compounds may have other activities in
addition to increased receptor mediated uptake into the blood
stream. For example the hydrocarbon tail may allow farnesyl
recognition or confer HMGCoA reductase inhibition activity. Thus
the hydrocarbon tail composition may also affect the bioactivity of
the compound.
[0033] The compounds may be used to make pharmaceutical
compositions. Pharmaceutical compositions comprising the compound
of formula (I) or any of the compounds described above and a
pharmaceutically acceptable carrier are provided. A
pharmaceutically acceptable carrier is any carrier suitable for in
vivo administration. Examples of pharmaceutically acceptable
carriers suitable for use in the composition include, but are not
limited to, water, buffered solutions, glucose solutions, oil-based
or bacterial culture fluids. Additional components of the
compositions may suitably include, for example, excipients such as
stabilizers, preservatives, diluents, emulsifiers and lubricants.
Examples of pharmaceutically acceptable carriers or diluents
include stabilizers such as carbohydrates (e.g., sorbitol,
mannitol, starch, sucrose, glucose, dextran), proteins such as
albumin or casein, protein-containing agents such as bovine serum
or skimmed milk and buffers (e.g., phosphate buffer). Especially
when such stabilizers are added to the compositions, the
composition is suitable for freeze-drying or spray-drying. The
composition may also be emulsified.
[0034] The compounds described herein may be used to treat a
subject with a condition selected from radiation exposure, cancer,
cardiovascular disease including but not limited to coronary artery
disease, decreasing lipoprotein levels, decreasing cholesterol
levels, decrease triglyceride levels and the like, age-related
macular degeneration, cataracts, glaucoma, chronic pain, chronic
fatigue syndrome, fever, edema, diabetes mellitus, signs of aging,
rheumatoid diseases, septic shock, or Alzheimer's disease. In the
case of radiation exposure, the compounds may be delivered as a
radioprotective agent to a subject prior to potential exposure to
radiation, such as to a patient receiving radiation therapy, or a
person working with or cleaning up radiation. The compounds may
also be given after radiation exposure as a radiomitigator, such as
after an accident involving the release of radiation.
[0035] Treatment of a condition includes but is not limited to,
prophylaxis of symptoms or indicators of the condition, reduction
in disease severity, or reversal, reduction or slowing in disease
progression as compared to an untreated subject. The compounds
described herein may be used to treat subjects in need of treatment
with an antioxidant, an anti-inflammatory, immunoregulatory,
antithromobotic, antiatherogenic, hypocholesterolemic or an HMG-CoA
reductase inhibitor.
[0036] In addition, the compounds may be useful to increase the
feed conversion efficiency of domesticated animals including
livestock. Combination therapy with a known antioxidant,
anti-inflammatory or HMG-CoA reductase inhibitor may result in
increased effectiveness of the combination treatment as compared to
treatment with either compound alone.
[0037] The compounds described herein may be administered by any
means known to those skilled in the art, including, but not limited
to, oral, topical, intranasal, intraperitoneal, parenteral,
intravenous, intramuscular, or subcutaneous. Thus the compounds may
be formulated as an ingestable, injectable, topical or suppository
formulation. The compounds may also be delivered with in a
liposomal or time-release vehicle. Administration of the compounds
to a subject in accordance with the invention appears to exhibit
beneficial effects in a dose-dependent manner. Thus, within broad
limits, administration of larger quantities of the compounds is
expected to achieve increased beneficial biological effects than
administration of a smaller amount. Moreover, efficacy is also
contemplated at dosages below the level at which toxicity is
seen.
[0038] It will be appreciated that the specific dosage administered
in any given case will be adjusted in accordance with the compound
or compounds being administered, the disease to be treated or
inhibited, the condition of the subject, and other relevant medical
factors that may modify the activity of the compound or the
response of the subject, as is well known by those skilled in the
art. For example, the specific dose for a particular subject
depends on age, body weight, general state of health, diet, the
timing and mode of administration, the rate of excretion,
medicaments used in combination and the severity of the particular
disorder to which the therapy is applied. Dosages for a given
patient can be determined using conventional considerations, e.g.,
by customary comparison of the differential activities of the
compound of the invention and of a known agent such as tocopherol,
such as by means of an appropriate conventional pharmacological or
prophylactic protocol.
[0039] The maximal dosage for a subject is the highest dosage that
does not cause undesirable or intolerable side effects. The number
of variables in regard to an individual prophylactic or treatment
regimen is large, and a considerable range of doses is expected.
The route of administration will also impact the dosage
requirements. It is anticipated that dosages of the compound will
reduce symptoms of the condition at least 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90% or 100% compared to pre-treatment symptoms or
symptoms is left untreated. It is specifically contemplated that
pharmaceutical preparations and compositions may palliate or
alleviate symptoms of the disease without providing a cure, or, in
some embodiments, may be used to cure the disease or disorder.
[0040] Suitable effective dosage amounts for administering the
compounds may be determined by those of skill in the art, but
typically range from about 1 microgram to about 100,000 micrograms
per kilogram of body weight weekly, although they are typically
about 1,000 micrograms or less per kilogram of body weight weekly.
Like other vitamin E compounds, large doses may be required for
therapeutic effect and toxicity of the compounds is likely low. In
some embodiments, the effective dosage amount ranges from about 10
to about 10,000 micrograms per kilogram of body weight weekly. In
another embodiment, the effective dosage amount ranges from about
50 to about 5,000 micrograms per kilogram of body weight weekly. In
another embodiment, the effective dosage amount ranges from about
75 to about 1,000 micrograms per kilogram of body weight weekly.
The effective dosage amounts described herein refer to total
amounts administered, that is, if more than one compound is
administered, the effective dosage amounts correspond to the total
amount administered. The compound can be administered as a single
dose or as divided doses. For example, the composition may be
administered two or more times separated by 4 hours, 6 hours, 8
hours, 12 hours, a day, two days, three days, four days, one week,
two weeks, or by three or more weeks.
[0041] The following examples are meant only to be illustrative and
are not meant as limitations on the scope of the invention or of
the appended claims. All references cited herein are hereby
incorporated by reference in their entireties.
EXAMPLES
Predicted Binding of Tocoflexols to .alpha.TTP
[0042] In silico analysis of the .alpha.TTP receptor interaction
with .alpha.TTP demonstrated that the hydrocarbon tail of
tocopherol folds over in order to efficiently bind the receptor as
shown in FIG. 1. FIG. 1 demonstrates that the hydrocarbon tail must
fold at two torsion points. Torsion angle A is suitably about
61.degree. and Torsion B is suitably at about 58.4.degree.. Thus
tocols with a flexible tail capable of conforming to these angles
are contemplated. The central location of the torsion is shown in
the drawing below.
##STR00009##
[0043] The heat map of the interaction between various tocols and
the .alpha.TTP receptor is shown in FIG. 2. The circled area on the
heat map shows the key interaction distinction between
RRR-.alpha.-tocopherol and R-.gamma.-tocotrienol. The heat map for
RS-.gamma.-tocoflexol is quite similar to that of tocopherol and
thus binding to .alpha.TTP receptor is expected to be similar to
that of tocopherol. The heat map for RR-.gamma.-tocoflexol lacks
this key predicted interaction and thus is expected to bind
.alpha.TTP less efficiently.
Synthesis of Compounds of Formula I
##STR00010##
[0044] Compound 1 is synthesized by a reaction between a chiral
chromanyl group and C15 alkyl chain built as shown below.
##STR00011## ##STR00012##
Alternative Synthesis Scheme for Compounds of Formula I
[0045] An alternative synthesis scheme to make the compounds of
formula I is depicted in FIG. 3.
Ability to Monitor Tocol Levels in Samples
[0046] Gas chromatography-mass spectrometry (GC/MS) will be used to
monitor tocol in plasma and other tissues of subjects treated with
or administered tocols. The tracings shown in FIG. 4 demonstrate
our ability to use GC/MS to differentiate and determine the
presence, pharmacokinetics and bioavailability of tocols. In the
top tracing .gamma.-tocotrienol was detected and in the bottom
tracing .alpha.-tocotrienol was detected. In both cases standard
methods for GC/MS were used based on single-ion monitoring under
electron impact conditions after the samples were derivatized using
MSTFA (N-methyltrimethylsilytrifluoracetamide) as the Silylation
reagent.
Tests for In Vitro Binding to .alpha.TTP
[0047] The ability of the compounds described herein to bind
.alpha.-TTP will be measured as described in Panagabko et al, 2003
Biochemistry 42:6467-74. The Vitamin E activity of the compounds
will be assessed by the method of Leth et al, 1977 J. Nutr.
107:2236-43. Specific activity, for example, as radioprotectors,
will be assessed in vitro and in vivo using standard assays. For
example, the compounds will be used in the following assays: in
vitro radiation toxicity assays (clonogenic cell survival,
cytogenetics, and measurement of oxidative stress) and in vivo
studies (hematopoietic, gastrointestinal, pulmonary, cutaneous, and
neurovascular subsyndromes of the acute radiation syndrome). We
expect the compounds will offer greater radioprotection, greater
Vitamin E activity and have higher affinity for .alpha.TTP as
compared to tocotrienol.
[0048] The compounds described herein and .alpha.-tocopherol and
.alpha.-tocotrienol will be combined with food or provided in
tablet form to subjects over a period of four weeks. At various
times post-administration blood samples will be harvested from the
subjects and the amount of the compound present in the blood will
be compared. Subjects will be tested for blood lipoprotein levels
prior to receiving the compounds and after 4 weeks of treatment.
After 4 weeks of treatment we expect the compounds of the invention
will cause a significant reduction in the levels of lipoproteins in
the blood of treated individuals as compared to untreated controls
and as compared to those treated with .alpha.-tocopherol or
.alpha.-tocotrienol.
* * * * *