U.S. patent application number 09/746345 was filed with the patent office on 2001-08-09 for oxetanone derivatives.
Invention is credited to Mullins, John Jason Gentry.
Application Number | 20010012852 09/746345 |
Document ID | / |
Family ID | 27496670 |
Filed Date | 2001-08-09 |
United States Patent
Application |
20010012852 |
Kind Code |
A1 |
Mullins, John Jason Gentry |
August 9, 2001 |
Oxetanone derivatives
Abstract
This invention relates to novel oxetanone derivative compounds
and processes for producing such derivatives that are useful as
lipase inhibitors. Further the invention relates to processes for
producing salts and for producing pharmaceutical compositions
compounds comprising at least one such oxetanone derivative or
salt, as well as methods for using such compounds and compositions
for inhibiting lipases.
Inventors: |
Mullins, John Jason Gentry;
(San Francisco, CA) |
Correspondence
Address: |
Robert G. Lev
c/o Lev Intellectual Property Consulting
4766 Michigan Boulevard
Youngstown
OH
44505
US
|
Family ID: |
27496670 |
Appl. No.: |
09/746345 |
Filed: |
December 21, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09746345 |
Dec 21, 2000 |
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09698307 |
Oct 27, 2000 |
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09698307 |
Oct 27, 2000 |
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09618328 |
Jul 18, 2000 |
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09618328 |
Jul 18, 2000 |
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09431551 |
Oct 29, 1999 |
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60165960 |
Nov 17, 1999 |
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Current U.S.
Class: |
514/449 ;
549/328 |
Current CPC
Class: |
C07D 305/12 20130101;
A61K 31/715 20130101; A61K 31/722 20130101 |
Class at
Publication: |
514/449 ;
549/328 |
International
Class: |
A61K 031/335; C07D
305/12 |
Claims
What is claimed is:
1. A novel oxetanone derivative of the formula: 19wherein: t is an
integer from 0 to 1 X-L-Q is an ether or amino linkage wherein: X
of the ether or amino linkage is a bridging group, L is --O-- or
--NH--, and Q of the ether or amino linkage is a polysaccharide of
a sufficient molecular weight or property that such polysaccharide
is not absorbed by the digestive system of a mammal such as a dog,
cat, non-human primate or a human primate; R is a member selected
from the group consisting of: a straight or branched chained
C.sub.1-17-alkyl group which is saturated or optionally interrupted
by up to eight double or triple bonds; a straight or branched
chained C.sub.1-17-alkyl group which is saturated or optionally
interrupted by one or more members selected from the group
consisting of an oxygen atom, a sulfur atom, a sulfonyl group or a
sulfinyl group; a straight or branched chained C.sub.1-17-alkyl
group which is saturated or optionally interrupted by up to eight
double or triple bonds and is interrupted in a position other than
alpha to an unsaturated carbon atom by one or more members selected
from the group consisting of an oxygen atom, a sulfur atom, a
sulfonyl group or a sulfinyl group atoms; phenyl substituted by 0-4
members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; benzyl substituted by 0-4 members selected
from the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; biphenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C-.sub.1-6-alkyl-SH; phenoxyphenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; phenylthiophenylene substituted by 0-6
members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6
hydrogen atoms on one or more of the phenyl ring and
--C.sub.1-6-alkyl- group is/are replaced independently by a member
selected from the group consisting
of--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; R.sup.1 is a member selected from the group
consisting of: Hydrogen, Ar, Ar-- C.sub.1-5-alkyl and
C.sub.1-10-alkyl interrupted by 0-3 members independently selected
from the group consisting of an oxygen atom, a sulfur atom, a
sulfinyl group, a sulfonyl group, a-N(--R.sup.4)-- group, a
--C(.dbd.O)--N(--R.sup.4)-- group, and a
--N(--R.sup.4)--C(.dbd.O)-- group, wherein 0-3 carbon atoms of the
C.sub.1-10-alkyl group can be substituted independently by a member
selected from the group consisting of a hydroxy group, thiol group,
C.sub.1-10-alkoxy group, a C.sub.1-10-alkylthio group, a
--N(--R.sup.5,--R.sup.6) group, a --C(.dbd.O)--N(--R.sup.7,
--R.sup.8) group, and a --N(--R.sup.9)--C(.dbd.O)--R.sup.10 group;
R.sup.2 is a member selected from the group consisting of: hydrogen
and C.sub.1-6-alkyl, or R.sup.2 taken with R.sup.1 forms a 4-6
membered saturated ring containing 0-4 nitrogen atoms wherein the
ring may be substituted by 0-4 R.sup.11 groups; R.sup.3 is a member
selected from the group consisting of: a straight or branched
chained C.sub.1-17-alkyl group which is saturated or optionally
interrupted by up to eight double or triple bonds; a straight or
branched chained C.sub.1-17-alkyl group which is saturated or
optionally interrupted by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group; a straight or branched chained
C.sub.1-17-alkyl group which is saturated or optionally interrupted
by up to eight double or triple bonds and is interrupted in a
position other than alpha to an unsaturated carbon atom by one or
more members selected from the group consisting of an oxygen atom,
a sulfur atom, a sulfonyl group or a sulfinyl group atoms; phenyl
substituted by 0-4 members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; benzyl substituted by 0-4 members selected
from the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; biphenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; phenoxyphenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; phenylthiophenylene substituted by 0-6
members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6
hydrogen atoms on one or more of the phenyl ring and
--C.sub.1-6-alkyl- group is/are replaced independently by a member
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; R.sup.4-R.sup.10 are each independently a
member selected from the group consisting of: hydrogen and
C.sub.1-6-alkyl; n is an integer of 0-3; and all pharmaceutically
acceptable isomers, salts, hydrates, solvates and prodrug
derivatives thereof.
2. A compound according to claim 1, wherein L is --NH--, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
3. A compound according to claim 1, wherein X is the group
--(C(.dbd.O)).sub.0-1--X.sub.a--, wherein X.sub.a is a member
selected from the group consisting of: a straight or branched
chained divalent C.sub.1-17-alkylene group which is saturated or
optionally interrupted by up to eight double or triple bonds; a
straight or branched chained divalent C.sub.1-17-alkylene group
which is saturated or optionally interrupted by one or more members
selected from the group consisting of: an oxygen atom, a sulfur
atom, a sulfonyl group, a sulfinyl group, a substituted or
unsubstituted 6-10 member monocyclic or bicyclic aryl or heteroaryl
group having from 1-4 ring hetero atoms selected from the group
consisting of O, N, S, a --NH-- group, wherein the hydrogen atom
may be replaced with a C.sub.1-10 alkyl group a --C(.dbd.O)--
group, a --NH--C(.dbd.O)-- group, wherein the hydrogen atom may be
replaced with a C.sub.1-10 alkyl group and a --C(.dbd.O)--NH--
group, wherein the hydrogen atom may be replaced with a C.sub.1-10
alkyl group a straight or branched chained divalent
C.sub.1-17-alkylene group which is saturated or optionally
interrupted by up to eight double or triple bonds and is
interrupted in a position other than alpha to an unsaturated carbon
atom by one or more members selected from the group consisting
optionally interrupted by one or more members selected from the
group consisting of: an oxygen atom, a sulfur atom, a sulfonyl
group, a sulfinyl group, a substituted or unsubstituted 6-10 member
monocyclic or bicyclic aryl or heteroaryl group having from 1-4
ring hetero atoms selected from the group consisting of O, N, S, a
--NH-- group, wherein the hydrogen atom may be replaced with a
C.sub.1-10 alkyl group a --C(.dbd.O)-- group, a --NH--C(.dbd.O)--
group, wherein the hydrogen atom may be replaced with a C.sub.1-10
alkyl group and a --C(.dbd.O)--NH-- group, wherein the hydrogen
atom may be replaced with a C.sub.1-10 alkyl group divalent
phenylene or divalent naphthylene substituted on the ring structure
by 0-4 members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.- sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; divalent biphenylene substituted by 0-6
members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; phenoxyphenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alky- l,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; divalent phenylthiophenylene substituted by
0-6 members selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.- 1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and and all pharmaceutically acceptable
isomers, salts, hydrates, solvates and prodrug derivatives
thereof.
4. The compound of claim 3, wherein R is
--(CH.sub.2).sub.3-6--CH.sub.3 and R.sup.3 is a member selected
from the group consisting of --(CH.sub.2).sub.8-14--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.d-
bd.CH--(CH.sub.2).sub.2-8--CH.sub.3, and all pharmaceutically
acceptable isomers, salts, hydrates, solvates and prodrug
derivatives thereof.
5. The compound of claim 3, wherein R is
--(CH.sub.2).sub.5--CH.sub.3 and R.sup.3 is a member selected from
the group consisting of --(CH.sub.2).sub.10--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd-
.CH--(CH.sub.2).sub.4--CH.sub.3, and all pharmaceutically
acceptable isomers, salts, hydrates, solvates and prodrug
derivatives thereof.
6. The compound of claim 3, wherein n is zero to provide compounds
of the formula: 20wherein: X, L, t, Q, R, R.sup.1, R.sup.2 and
R.sup.3 are defined as in claim 2, and isomers, salts, hydrates,
solvates and prodrug derivatives thereof.
7. The compound of claim 6, wherein R is
--(CH.sub.2).sub.3-6--CH.sub.3 and R.sup.3 is a member selected
from the group consisting of --(CH.sub.2).sub.8-14--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.d-
bd.CH--(CH.sub.2).sub.2-8--CH.sub.3, and isomers, salts, hydrates,
solvates and prodrug derivatives thereof.
8. The compound of claim 6, wherein R is
--(CH.sub.2).sub.5--CH.sub.3 and R.sup.3 is a member selected from
the group consisting of --(CH.sub.2).sub.10--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd-
.CH--(CH.sub.2).sub.4--CH.sub.3, and isomers, salts, hydrates,
solvates and prodrug derivatives thereof.
9. The compound of claim 6, wherein t is 0, and isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
10. The compound of claim 3, wherein t is 0 or 1 and X is a member
selected from the group consisting of: 21wherein R.sup.1a is
independently defined the same as defined for R.sup.1, R.sup.2a is
independently defined the same as for R.sup.2, m is a integer from
0 to 10, preferably from 0-5, and more preferred from 0-2, and
wherein z is an integer from 1 to 20, preferably 2 to 10, and more
preferably, 2-4, and all pharmaceutically acceptable isomers,
salts, hydrates, solvates and prodrug derivatives thereof.
11. The compound of claim 10, wherein X is a member selected from
the group consisting of: 22and wherein z is a integer from 0 to 10,
preferably from 0-5, and more preferred from 0-2, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
12. The compound of claim 10, wherein X is a member selected from
the group consisting of: 23and wherein z is a integer from 0 to 18,
and all pharmaceutically acceptable isomers, salts, hydrates,
solvates and prodrug derivatives thereof.
13. The compound of claim 10, wherein X is a member selected from
the group consisting of: 24and wherein z is a integer 6-12, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
14. The compound of claim 10, wherein X is a member selected from
the group consisting of: 25and wherein z is a integer 6-12, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
15. The compound of claim 2, wherein the Q group is a chitosan
compound modified by attaching a sufficient number of organic acyl
groups to hydroxyl groups, amino groups or amino and hydroxyl
groups, to cause the modified chitosan to absorb or associate both
lipids and water and to form a substantially homogenous gel with
lipids and water.
16. A method for producing a compound of claim 1, comprising
reacting a compound of the formula: 26with a compound of the
formula 27wherein t is 0 or 1 and Y is a leaving group for an
etherification or esterification reaction with the hydroxy group to
produce a compound of the formula: 28or a salt thereof.
17. A pharmaceutical composition comprising at least one
pharmaceutically acceptable carrier excipient and an amount of at
least one compound according to claim 1 in a therapeutically
effective amount with respect to limiting or preventing the
absorption of some dietary fat.
18. A pharmaceutical composition according to claim 17, further
comprising a therapeutically effective amount of an oil absorbing
effective amount of polysaccharide such as chitosan.
19. A method of using a compound according to claim 1 as a
therapeutic agent for disease states in a mammal having at least
one disorder that is due to undesired absorption of dietary fat or
for reducing the effective caloric intake of a mammal who consumes
dietary fat.
20. A method according to claim 18 as part of a treatment method
for managing or controlling undesired weight gain or obesity.
21. A method of using a composition according to claim 16 as a
therapeutic agent for disease states in a mammal having at least
one disorder that is due to undesired absorption of dietary fat or
for reducing the effective caloric intake of a mammal who consumes
dietary fat.
22. A compound according to claim 2, wherein organic acyl groups
are present on the modified chitosan chain of the Q group in a
molar ratio from 1 to 8 times the number of the molar ratio of
esterified lipase inhibitor alcohol groups.
22. A compound according to claim 2, wherein the hydroxyl groups,
amino groups or both hydroxyl and amino groups of Q are modified by
the attachment of a sufficient number of organic acyl groups to
cause Q to absorb or associate with both lipids and water and to
form a substantially homogeneous gel with lipids and water.
Description
[0001] The present application is a continuation-in-part of Ser.
No. 09/698,307 Oct. 27, 2000, which is a continuation-in-part of
Ser. No. 09/618,328, filed Jul. 18, 2000, which is a
continuation-in-part of Ser. No. 09/431,551 filed Oct. 29, 1999,
which is a continuation-in-part of Ser. No. 60/165,960, filed Nov.
17, 1999.
FIELD OF THE INVENTION
[0002] This invention relates to novel oxetanone derivative
compounds and processes for producing such derivatives which are
useful as lipase inhibitors. Further the invention relates to
processes for producing salts and for producing pharmaceutical
compositions compounds comprising at least one such oxetanone
derivative or salt, as well as methods for using such compounds and
compositions for inhibiting lipases. In one aspect the invention
relates to lipase inhibitors which include on the same molecule an
oxetanone derivative portion capable of inhibiting a lipase and a
non-absorbable moiety such a polysaccharide, which are covalently
linked or are in the form of a salt. In a preferred aspect of the
invention the non-absorbable moiety is lipophilic and will
associate with oils or fats. An absorbable oxetanone lipase
inhibitor may be rendered non-absorbable by covalent linking it
directly or indirectly to a non-absorbable moiety and thereby
producing a novel non-absorbable lipase inhibitor.
BACKGROUND OF THE INVENTION
[0003] Some lipase-inhibiting oxetanones and intermediates for
making them are well known. See for example, U.S. Pat. Nos.
5,931,463, 4,189,438 and 4,202,824. However, there is a need for
improved oxetanones that are have low toxicity and are essentially
not absorbable by the digestive system of mammals such as dogs,
cats, non-human primates and human primates.
[0004] Lipase inhibitors such as esterastin (see U.S. Pat. No.
4,189,438), tetrahydroesterastin
(3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone),
3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,
3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, are
well-known as lipase inhibitors and as pancreatic cholesterol
esterase inhibitors. However, such lipase inhibitors are, inter
alia, also substantially orally active as immunosuppressants (see
U.S. Pat. No. 4,189,438 and U.S. Pat. No. 4,202,824), which can be
a highly undesired side activity in a normal or immunosuppressed
person. Such lipase inhibitor compounds are 3,5 dihydroxy 1,3
lactone derivative compounds, wherein the 5-hydroxyl group may be
esterified at the 5 position or is hydrolyzed to the free hydroxyl
group.
[0005] A popular lipase inhibiting compound which is substantially
non-absorbable is known as Orlistat
((2S,3S,5S)-5-[(S)-2-formamido-4-meth-
yl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, see
U.S. Pat. No. 5,643,874). This compound is a steric isomer
derivative of tetrahydroesteratin and its 5-hydroxyl group is
esterified with a [S-2-formamido-4-methyl-valeryloxy] group.
Orlistat has been used to inhibit lipases in the body and thereby
prevent the absorption of dietary fat. At a 120 mg dose of
Orlistat, taken before consuming a fat-containing meal (or up to
one hour after eating such a meal), up to one-third of the fat
eaten at a given meal will not be absorbed by the average person
and utilized as dietary fat calories. The undigested fat passes
directly through the digestive system as an oil and is eliminated
from the bowel in its oily undigested form.
[0006] Certain polysaccharides are non-absorbable and some
polysaccharides have the side benefit of reducing lipid absorption
by the body. Defatted rice germ polysaccharides and sulfated
polysaccharides are also lipase inhibitors, which are high
molecular weight compounds that do not appear to have any lactone
moieties and seem to work by a different mechanism, binding the
lipase and removing it from the digestive system when they are
discharged from the digestive system. The super fiber Chitosan,
which is a deacylated polysaccharide derived from shellfish chitan,
has an ability to absorb fat and cholesterol, particularly in
combination with vitamin C. Chitosan compositions may actually
absorb up to 6 to 8 times their weight in fat and oils. While the
polysaccharide from shellfish is similar to crude cellulose plant
fiber, it has the ability to significantly bind fat in the
digestive system as compared to plant fiber. Further, since
polysaccharides, including those which do not preferentially bind
oils over water, are not absorbed by the digestive systems of
animals such as humans, non-human primates, dogs and cats, there is
no caloric value to such polysaccharides and they pass through the
such digestive systems unabsorbed and substantially intact.
Examples of non-absorbable polysaccharides are polysaccharides
having a molecular weight of greater than 8 kDa such as dextrans,
molecular microcrystalline cellulose, wheat bran, oat bran,
defatted rice germ, alginic acid, pectin, amylopectin, chitin,
crude cellulose, argar, chitosan and the like.
[0007] There is a need in the art for non-absorbable lipase
inhibitors, as well as for improved antiadiposity compositions and
methods which do not require an absolute low-fat diet in order to
lower the absorption of dietary fat as calories.
SUMMARY OF THE INVENTION
[0008] In one aspect the present invention relates to novel
derivatives of lipase inhibitors which are non-absorbable compounds
comprising at least one lipase inhibitor moiety and at least one
non-absorbable polymeric moiety in the same molecule or salt. The
lipase inhibitor moiety is preferably present in the non-absorbable
compound in a weight ratio of from about 1:10 to about 1:60 with
respect to the weight of the polymeric moiety, preferably from
about 1:20 to about 1:40, and more preferably from about 1:25 to
1:35. In one aspect, such lipase inhibitors comprise at least one
lipase inhibitor moiety (or moieties) linked directly or indirectly
to such a polymeric moiety. The invention also includes
pharmaceutical compositions comprising an effective amount of such
lipase inhibitors in combination with a pharmaceutically acceptable
carrier or diluent, which compositions may further comprise an
effective amount of a lipophilic, non-absorbable biocompatible,
pharmaceutically acceptable oil absorbing polymer.
[0009] In another aspect the present invention relates to novel
salts of non-absorbable lipase inhibitors and a non-absorbable
biocompatible, pharmaceutically acceptable oil absorbing polymer.
The invention also includes pharmaceutical compositions comprising
an effective amount of such lipase inhibitors in combination with a
pharmaceutically acceptable carrier or diluent, which compositions
may further comprise an effective amount of a lipophilic,
non-absorbable biocompatible, pharmaceutically acceptable oil
absorbing polymer.
[0010] In a preferred aspect the present invention relates to novel
non-absorbable derivatives of a 1,3 oxetanone lipase inhibitor,
which include at least one 1,3 oxetanone lipase inhibiting moiety
that is covalently or non-covalently linked to a non-absorbable
biocompatible, pharmaceutically acceptable polymer moiety to
provide a novel lipase inhibitor compound. Preferred compounds have
the dual function of inhibiting lipases and absorbing fat, in that
the non-absorbable biocompatible, pharmaceutically acceptable
polymer moiety of the novel lipase inhibitor will bind to fat,
carry the bound fat with it through portions of the digestive
system and cause the non-absorbed fat to be eliminated removed from
the digestive system as undigested fat. The 1,3 oxetanone moiety
that is derivatized directly or indirectly with the polymer moiety
according to the invention may be initially an absorbable or
non-absorbable moiety and is derivatized by directly or indirectly
linking it to the polymer moiety to form a novel non-absorbable
lipase inhibitor, preferably at the 5 hydroxyl position of a 1,3
oxetanone moiety.
[0011] In a preferred aspect the invention provides compounds
having either non-covalent linkages of such two moieties or
covalent linkages that are hydrolyzed or digested in the digestive
system, providing that the lipase inhibiting 1,3 oxetanone
derivative moiety that is released in the digestive system is
substantially non-absorbable.
[0012] In another preferred aspect the invention provides compounds
having either a non-covalent linkage of such two moieties or a
covalent linkage that is not hydrolyzed or digested in the
digestive system, whereby the lipase inhibiting 1,3 oxetanone
derivative moiety remains linked to the polymer moiety via such
non-covalent or covalent linkage and is not released in the
digestive system.
[0013] In one aspect of the invention, an absorbable lipases such
as esterastin moiety, tetrahydroestrastin, or a similar moiety, is
rendered non-absorbable by coupling it directly or indirectly to a
non-absorbable biocompatible, pharmaceutically acceptable polymer
moiety, such as a polysaccharide, to render the lipase essentially
non-absorbable by the digestive system of an animal such as a dog,
cat, non-human primate or humans. Preferred lipase inhibitor
moieties that are coupled to the polysaccharide include at least
one lipase inhibitor which is a member selected from the group
consisting of esterastin, tetrahydro-esterastin
(3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone),
3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,
3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like.
Preferably, such lipase inhibitor is coupled to a non-absorbable
biocompatible, pharmaceutically acceptable polymer moiety, such as
a polysaccharide, to render the lipase non-absorbable by the
digestive system of an animal such as a dog, cat, non-human primate
or humans. Particularly preferred polysaccharides have at least one
member selected from the group consisting of dextrans, molecular
microcrystalline cellulose, wheat bran, oat bran, defatted rice
germ, alginic acid, pectin, amylopectin, chitin, crude cellulose,
argar, chitosan, a chitosan methylbenzoic acid ester ether
derivative, and the like. Particularly preferred bound lipase
inhibitors are lipase inhibitors bound via a derivatized group on
the lipase such as a derivatized nitrogen, acid or alcohol group to
a group on the polymer moiety such as a derivatized alcohol, acid
or amino group. Preferably, a divalent bridging group is attached
at one portion of the bridging group to an amino group on the
polysaccharide and attached at a second portion of the bridging
group to a lipase inhibitor and the moiety. Further preferred are
such compounds wherein further amino groups, alcohol groups or
amino groups and alcohol groups on the polysaccharide are modified
to present open organic acyl group sufficient to render the
polysaccharide capable of associating with both organic neutral to
acid groups and polar inorganic groups such as water such that a
homogeneous gel can be formed. Also preferred are compounds wherein
the lipase inhibitor is an oxetanone moiety which is derivatized to
provide an amino group which is further derivatized to form a
carboxamide group, followed by linking the carboxamide group to an
acid group, alcohol group or amino group on the polymer moiety via
a bridging group, which polymer moiety may have been derivativized
in order to provide such an acid or alcohol group for attachment.
Examples of such attachments are illustrated below by a preferred
embodiment of the invention.
[0014] In another aspect the present invention relates to
pharmaceutical compositions comprising a lipase inhibiting
effective amount of at least one lipase inhibitor which is coupled
to a digestively non-absorbable moiety. Preferred are such
pharmaceutical compositions comprising an effective amount of a
lipases coupled to a non-absorbable biocompatible, pharmaceutically
acceptable polymer moiety, such as a polysaccharide, wherein the
lipase is essentially non-absorbable by the digestive system of an
animal such as a dog, cat, non-human primate or humans.
[0015] In still another aspect, the present invention relates to a
method for treating adiposity or obesity by administering to a
patient before a fat-contain meal, or up to one hour after such a
meal is consumed, an amount of at least one lipase inhibitor which
is bound to a non-absorbable polymer moiety in an amount effective
to inhibit the absorption of up to one-third of the dietary fat in
such a meal. In particular, a preferred method comprises
administering at one lipase inhibitor which is a member selected
from the group consisting of esterastin, tetrahydro-esterastin
(3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone),
3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,
3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like,
wherein such lipase inhibitor is coupled to a non-absorbable
biocompatible, pharmaceutically acceptable polymer moiety, such as
a polysaccharide, to render the lipase non-absorbable by the
digestive system of an animal such as a dog, cat, non-human primate
or humans. Particularly preferred polysaccharides are at least one
member selected from the group consisting of dextrans, molecular
microcrystalline cellulose, wheat bran, oat bran, defatted rice
germ, alginic acid, pectin, amylopectin, chitin, crude cellulose,
argar, chitosan and the like. Particularly preferred bound lipase
inhibitors are lipase inhibitors bound via a derivatized nitrogen,
acid or alcohol group to a derivatized alcohol, acid or amino group
on the polymer moiety.
[0016] A divalent bridge terminal amino attachment/terminal ester
bridge, between the lipase inhibitor moiety and the polymer moiety
which is derived from an alcohol group on the lipase inhibitor
moiety and an amino group on the polymer moiety, respectively
reacting with a bridging group is a preferred coupling of the
lipase inhibitor to the moiety.
[0017] Another preferred bridge between the lipase inhibitor moiety
and the polymer moiety includes at least amino terminal bridge
formed from an amino group on the polymer moiety and at least one
carboxamide bond terminal bridge attachment to the lipase inhibitor
derivative. Further preferred are compounds wherein at least one
amino acid derivative is located in the bridge, and is bound
directly or indirectly to the 5 hydroxyl position on the 1,3
oxetanone lipase inhibitor moiety via an ester linkage.
[0018] The preferred compounds also include their pharmaceutically
acceptable isomers, hydrates, solvates, salts and prodrug
derivatives.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Definitions
[0020] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0021] The term "alkenyl" refers to a trivalent straight chain or
branched chain unsaturated aliphatic radical. The term "alkinyl"
(or "alkynyl") refers to a straight or branched chain aliphatic
radical that includes at least two carbons joined by a triple bond.
If no number of carbons is specified alkenyl and alkinyl each refer
to radicals having from 2-12 carbon atoms.
[0022] The term "alkyl" refers to saturated aliphatic groups
including straight-chain, branched-chain and cyclic groups having
the number of carbon atoms specified, or if no number is specified,
having up to 12 carbon atoms. The term "cycloalkyl" as used herein
refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14
carbon atoms and preferably 3 to 7 carbon atoms.
[0023] The term "bridging group" refers to a bifunctional chain or
spacer group capable of reacting with one or more functional groups
on a lipase inhibitor compound and then react with a second same or
different functional group on a polymer compound in order to form a
linked structure or conjugate between the two compounds. The bond
formed between the bridging group and each of the two moieties is
preferably of a type that is resistant to cleavage by the digestive
environment when the linked lipase moiety would be absorbable upon
cleavage of the bond. In one aspect, the bridging group is of the
formula X-R-X, wherein R is a member selected from a
straight-chained or branched alkyl group, a straight-chained or
branched alkenyl group, a straight-chained or branched alkynyl
group, a mono acyl group, a diacyl group and the like, which R
portion of the chain may include a cycloalkyl or an aryl group, and
X is a functionally reactive group such as a halogen, or acid
group, under special reaction conditions as described hereinafter.
Particularly preferred bridging groups form a ester terminal and
amino terminal, ether terminal/acyl terminal bridge that is
resistant to cleavage by the digestive environment. In one aspect
bridging groups that are cleaved by the digestive group to release
an essentially non-absorbable lipase inhibitor are preferred.
Examples of alkylene halogen terminal/acyl terminal bridging group
forming compounds are a C.sub.2 to C.sub.20 n-haloalkanoic acid or
an ester thereof, such as 6-bromohexanoic acid, 12-bromolauric
acid, haloloweralkylbenzoic acid, and the like.
[0024] As used herein, the terms "carbocyclic ring structure" and
"C.sub.3-16 carbocyclic mono, bicyclic or tricyclic ring structure"
or the like are each intended to mean stable ring structures having
only carbon atoms as ring atoms wherein the ring structure is a
substituted or unsubstituted member selected from the group
consisting of: a stable monocyclic ring which is aromatic ring
("aryl") having six ring atoms; a stable monocyclic non-aromatic
ring having from 3 to 7 ring atoms in the ring; a stable bicyclic
ring structure having a total of from 7 to 12 ring atoms in the two
rings wherein the bicyclic ring structure is selected from the
group consisting of ring structures in which both of the rings are
aromatic, ring structures in which one of the rings is aromatic and
ring structures in which both of the rings are non-aromatic; and a
stable tricyclic ring structure having a total of from 10 to 16
atoms in the three rings wherein the tricyclic ring structure is
selected from the group consisting of: ring structures in which
three of the rings are aromatic, ring structures in which two of
the rings are aromatic and ring structures in which three of the
rings are non-aromatic. In each case, the non-aromatic rings when
present in the monocyclic, bicyclic or tricyclic ring structure may
independently be saturated, partially saturated or fully saturated.
Examples of such carbocyclic ring structures include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl,
phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl
(tetralin). Moreover, the ring structures described herein may be
attached to one or more indicated pendant groups via any carbon
atom which results in a stable structure. The term "substituted" as
used in conjunction with carbocyclic ring structures means that
hydrogen atoms attached to the ring carbon atoms of ring structures
described herein may be substituted by one or more of the
substituents indicated for that structure if such substitution(s)
would result in a stable compound.
[0025] The term "aryl" which is included with the term "carbocyclic
ring structure" refers to an unsubstituted or substituted aromatic
ring, substituted with one, two or three substituents selected from
loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano,
hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,
carboalkoxy and carboxamide, including but not limited to
carbocyclic aryl, heterocyclic aryl, and biaryl groups and the
like, all of which may be optionally substituted. Preferred aryl
groups include phenyl, halophenyl, loweralkylphenyl, napthyl,
biphenyl, phenanthrenyl and naphthacenyl.
[0026] The term "arylalkyl" which is included with the term
"carbocyclic aryl" refers to one, two, or three aryl groups having
the number of carbon atoms designated, appended to an alkyl group
having the number of carbon atoms designated. Suitable arylalkyl
groups include, but are not limited to, benzyl, picolyl,
naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all
of which may be optionally substituted.
[0027] As used herein, the term "heterocyclic ring" or
"heterocyclic ring system" is intended to mean a substituted or
unsubstituted member selected from the group consisting of stable
monocyclic ring having from 5-7 members in the ring itself and
having from 1 to 4 hetero ring atoms selected from the group
consisting of N, O and S; a stable bicyclic ring structure having a
total of from 7 to 12 atoms in the two rings wherein at least one
of the two rings has from 1 to 4 hetero atoms selected from N, O
and S, including bicyclic ring structures wherein any of the
described stable monocyclic heterocyclic rings is fused to a hexane
or benzene ring; and a stable tricyclic heterocyclic ring structure
having a total of from 10 to 16 atoms in the three rings wherein at
least one of the three rings has from 1 to 4 hetero atoms selected
from the group consisting of N, O and S. Any nitrogen and sulfur
atoms present in a heterocyclic ring of such a heterocyclic ring
structure may be oxidized. Unless indicated otherwise the terms
"heterocyclic ring" or "heterocyclic ring system" include aromatic
rings, as well as non-aromatic rings which can be saturated,
partially saturated or fully saturated non-aromatic rings. Also,
unless indicated otherwise the term "heterocyclic ring system"
includes ring structures wherein all of the rings contain at least
one hetero atom as well as structures having less than all of the
rings in the ring structure containing at least one hetero atom,
for example bicyclic ring structures wherein one ring is a benzene
ring and one of the rings has one or more hetero atoms are included
within the term "heterocyclic ring systems" as well as bicyclic
ring structures wherein each of the two rings has at least one
hetero atom. Moreover, the ring structures described herein may be
attached to one or more indicated pendant groups via any hetero
atom or carbon atom which results in a stable structure. Further,
the term "substituted" means that one or more of the hydrogen atoms
on the ring carbon atom(s) or nitrogen atom(s) of the each of the
rings in the ring structures described herein may be replaced by
one or more of the indicated substituents if such replacement(s)
would result in a stable compound. Nitrogen atoms in a ring
structure may be quaternized, but such compounds are specifically
indicated or are included within the term "a pharmaceutically
acceptable salt" for a particular compound. When the total number
of O and S atoms in a single heterocyclic ring is greater than 1,
it is preferred that such atoms not be adjacent to one another.
Preferably, there are no more that 1 O or S ring atoms in the same
ring of a given heterocyclic ring structure.
[0028] Examples of monocylic and bicyclic heterocylic ring systems,
in alphabetical order, are acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl,
pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preferred
heterocyclic ring structures include, but are not limited to,
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl,
imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolinyl, or
isatinoyl. Also included are fused ring and spiro compounds
containing, for example, the above heterocylic ring structures.
[0029] As used herein the term "aromatic heterocyclic ring system"
has essentially the same definition as for the monocyclic and
bicyclic ring systems except that at least one ring of the ring
system is an aromatic heterocyclic ring or the bicyclic ring has an
aromatic or non-aromatic heterocyclic ring fused to an aromatic
carbocyclic ring structure.
[0030] The terms "halo" or "halogen" as used herein refer to Cl,
Br, F or I substituents. The term "haloalkyl", and the like, refer
to an aliphatic carbon radicals having at least one hydrogen atom
replaced by a Cl, Br, F or I atom, including mixtures of different
halo atoms. Trihaloalkyl includes trifluoromethyl and the like as
preferred radicals, for example.
[0031] The term "methylene" refers to --CH.sub.2--.
[0032] The term "pharmaceutically acceptable salts" includes salts
of compounds derived from the combination of a compound and an
organic or inorganic acid. These compounds are useful in both free
base and salt form. In practice, the use of the salt form amounts
to use of the base form; both acid and base addition salts are
within the scope of the present invention.
[0033] "Pharmaceutically acceptable acid addition salt" refers to
salts retaining the biological effectiveness and properties of the
free bases and which are not biologically or otherwise undesirable,
formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as acetic acid, propionic acid, glycolic acid,
pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicyclic acid and the like.
[0034] "Pharmaceutically acceptable base addition salts" include
those derived from inorganic bases such as sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum salts and the like. Particularly preferred are
the ammonium, potassium, sodium, calcium and magnesium salts. Salts
derived from pharmaceutically acceptable organic nontoxic bases
include salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglucamine, theobromine, purines, piperizine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic nontoxic bases are isopropylamine, diethylamine,
ethanolamine, trimethamine, dicyclohexylamine, choline, and
caffeine.
[0035] "Biological property" for the purposes herein means an in
vivo effector or antigenic function or activity that is directly or
indirectly performed by a compound of this invention that are often
shown by in vitro assays. Effector functions include receptor or
ligand binding, any enzyme activity or enzyme modulatory activity,
any carrier binding activity, any hormonal activity, any activity
in promoting or inhibiting adhesion of cells to an extracellular
matrix or cell surface molecules, or any structural role. Antigenic
functions include possession of an epitope or antigenic site that
is capable of reacting with antibodies raised against it.
[0036] In the compounds of this invention, carbon atoms bonded to
four non-identical substituents are asymmetric. Accordingly, the
compounds may exist as diastereoisomers, enantiomers or mixtures
thereof. The syntheses described herein may employ racemates,
enantiomers or diastereomers as starting materials or
intermediates. Diastereomeric products resulting from such
syntheses may be separated by chromatographic or crystallization
methods, or by other methods known in the art. Likewise,
enantiomeric product mixtures may be separated using the same
techniques or by other methods known in the art. Each of the
asymmetric carbon atoms, when present in the compounds of this
invention, may be in one of two configurations (R or S) and both
are within the scope of the present invention.
[0037] Preferred Embodiments
[0038] In one aspect the present invention relates to novel
derivatives of lipase inhibitors which are non-absorbable and have
a lipase inhibitor moiety and polymeric moiety in the same
molecule. The invention also includes pharmaceutical compositions
comprising an effective amount of such lipase inhibitors in
combination with a pharmaceutically acceptable carrier or diluent,
and may further comprise an effective amount of a lipophilic,
non-absorbable biocompatible, pharmaceutically acceptable oil
absorbing polymer. The lipase inhibitor moiety is present in a
weight ratio of from about 1:10 to about 1:60 with respect to the
weight of the polymeric moiety, preferably from about 1:20 to about
1:40, and more preferably from about 1:25 to 1:35. In one aspect,
such lipase inhibitors comprise at least one lipase inhibitor
moiety (or moieties) linked directly or indirectly to such
polymeric moiety.
[0039] In another aspect the present invention relates to novel
salts of non-absorbable lipase inhibitors and a non-absorbable
biocompatible, pharmaceutically acceptable oil absorbing polymer.
The invention also includes pharmaceutical compositions comprising
an effective amount of such lipase inhibitors in combination with a
pharmaceutically acceptable carrier or diluent, which compositions
may further comprise an effective amount of a lipophilic,
non-absorbable biocompatible, pharmaceutically acceptable oil
absorbing polymer.
[0040] In a preferred aspect the present invention relates to novel
essentially non-absorbable derivatives of a 1,3 oxetanone lipase
inhibitor, which include at least one 1,3 oxetanone lipase
inhibiting moiety that is covalently or non-covalently linked to a
non-absorbable biocompatible, pharmaceutically acceptable polymer
moiety to provide a novel lipase inhibitor compound. Preferred
compounds have the dual function of inhibiting lipases and
absorbing fat, in that the non-absorbable biocompatible,
pharmaceutically acceptable polymer moiety of the novel lipase
inhibitor will bind to fat, carry the bound fat with it through
portions of the digestive system and cause the non-absorbed fat to
be eliminated removed from the digestive system as undigested fat.
Further preferred are such compounds wherein the compound is
capable of associating with both oil and water to form an
essentially homogeneous gel. The 1,3 oxetanone moiety that is
derivatized directly or indirectly with the polymer moiety
according to the invention may be initially an absorbable or
non-absorbable moiety and is derivatized by directly or indirectly
linking it to the polymer moiety to form a novel non-absorbable
lipase inhibitor, preferably at the 5 hydroxyl position of a 1,3
oxetanone moiety.
[0041] In a preferred aspect the invention provides compounds
having either non-covalent linkages of such two moieties or
covalent linkages that are hydrolyzed or digested in the digestive
system, providing that the lipase inhibiting 1,3 oxetanone
derivative moiety that is released in the digestive system is
substantially non-absorbable.
[0042] In one aspect of the invention, lipases such as esterastin
moiety, tetrahydroestrastin, or a similar moiety, is coupled
directly or indirectly to a non-absorbable biocompatible,
pharmaceutically acceptable polymer moiety, such as a
polysaccharide, to render the lipase essentially non-absorbable by
the digestive system of an animal such as a dog, cat, non-human
primate or humans. Preferred absorbable lipase inhibitor moieties
that are rendered non-absorbable by such coupling include at least
one lipase inhibitor which is a member selected from the group
consisting of esterastin, tetrahydro-esterastin
(3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone),
3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,
3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like.
Preferably, such lipase inhibitor is coupled to a non-absorbable
biocompatible, pharmaceutically acceptable polymer moiety, such as
a polysaccharide, to render the lipase non-absorbable by the
digestive system of an animal such as a dog, cat, non-human primate
or humans. Particularly preferred polysaccharides have at least one
member selected from the group consisting of dextrans, molecular
microcrystalline cellulose, wheat bran, oat bran, defatted rice
germ, alginic acid, pectin, amylopectin, chitin, crude cellulose,
argar, chitosan, a chitosan methylbenzoic acid ester ether
derivative, and the like. Particularly preferred bound lipase
inhibitors are lipase inhibitors bound via a derivatized group on
the lipase such as a derivatized nitrogen, acid or alcohol group to
a group on the polymer moiety such as a derivatized alcohol, acid
or amino group. Preferably, amino groups, alcohol groups or both
amino and alcohol groups on the polysaccharide has been derivitized
with a sufficient number of organic acyl groups to render the
polysaccharide capable of associating with both oil and water and
thereby form an essentially homogeneous gel. Preferably, a terminal
ether/terminal acyl ester bridge or a terminal amino/terminal acyl
ester bridge is formed between the lipase inhibitor and the moiety,
wherein the bridge is derived from an alcohol group on the lipase
and an alcohol or amino group on the polysaccharide moiety, each
reacting the polysaccharide with an etherizing or amino forming
bridging group to present an acyl group, which may be a free acyl
group or ester group. Also preferred are compounds wherein the
oxetanone moiety of lipase inhibitor is derivatized to provide an
amino group which is further derivatized to form a carboxamide
group, followed by linking the carboxamide group to an acid, amino
or alcohol group on the polymer moiety via a bridging group, which
polymer moiety may have been derivativized in order to provide such
an acid, alcohol or amino group for attachment. Examples of such
attachments are illustrated below by preferred embodiments of the
invention.
[0043] An ether terminal/ester terminal or amino terminal/ester
terminal, between the lipase inhibitor moiety and the polymer
moiety which is derived from an alcohol group on the lipase
inhibitor moiety and an alcohol or amino group on the
polysaccharidemoiety, respectively reacting with a bridging group
is a preferred coupling of the lipase inhibitor to the moiety.
[0044] Another preferred bridge between the lipase inhibitor moiety
and the polymer moiety includes at least one ether bridge or amino
bridge formed from an alcohol group or amino group, respectively,
on the polymer moiety and at least one carboxamide bond. Further
preferred are compound wherein at least one amino acid derivative
is located in the bridge, and is bound directly or indirectly to
the 5 hydroxyl position on the 1,3 oxetanone lipase inhibitor
moiety via an ester linkage.
[0045] The preferred compounds also include their pharmaceutically
acceptable isomers, hydrates, solvates, salts and prodrug
derivatives.
[0046] A preferred aspect of the present invention relates to novel
oxetanone derivatives of the formula I, as follows: 1
[0047] wherein:
[0048] t is an integer from 0 to 1
[0049] X-L-Q is an ether or amino linkage wherein:
[0050] X of the ether or amino linkage is a bridging group,
[0051] L is --O-- or --NH--, and
[0052] Q of the ether or amino linkage is a polysaccharide of a
sufficient molecular weight or property that such polysaccharide is
not absorbed by the digestive system of a mammal such as a dog,
cat, non-human primate or a human primate, particularly preferred
is wherein the hydroxyl groups, amino groups or hydroxyl and amino
groups of Q are modified by the attachment of a sufficient number
of organic acyl groups to cause Q to absorb or associate with both
lipids and water and to form a substantially homogeneous gel with
lipids and water;
[0053] R is a member selected from the group consisting of:
[0054] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds;
[0055] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by one or more members
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfonyl group or a sulfinyl group;
[0056] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds and is interrupted in a position other than alpha to
an unsaturated carbon atom by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group atoms;
[0057] phenyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0058] benzyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0059] biphenylene substituted by 0-6 members selected from the
group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0060] phenoxyphenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0061] phenylthiophenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and
[0062] phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6 hydrogen atoms on
one or more of the phenyl ring and --C.sub.1-6-alkyl- group is/are
replaced independently by a member selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alk- yl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0063] R.sup.1 is a member selected from the group consisting
of:
[0064] Hydrogen,
[0065] Ar,
[0066] Ar-- C.sub.1-5-alkyl and
[0067] C.sub.1-10-alkyl interrupted by 0-3 members independently
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a-N(--R.sup.4)-- group, a
--C(.dbd.O)--N(--R.sup.4)-- group, and a
--N(--R.sup.4)--C(.dbd.O)-- group, wherein 0-3 carbon atoms of the
C.sub.1-10-alkyl group can be substituted independently by a member
selected from the group consisting of a hydroxy group, thiol group,
C.sub.1-10-alkoxy group, a C.sub.1-10-alkylthio group, a
--N(--R.sup.5,--R.sup.6) group, a --C(.dbd.O)--N(--R.sup.7,
--R.sup.8) group, and a --N(--R.sup.9)--C(.dbd.- O)--R.sup.10
group;
[0068] R.sup.2 is a member selected from the group consisting
of:
[0069] hydrogen and C.sub.1-6-alkyl, or R.sup.2 taken with R.sup.1
forms a 4-6 membered saturated ring containing 0-4 nitrogen atoms
wherein the ring may be substituted by 0-4 R.sup.11 groups;
[0070] R.sup.3 is a member selected from the group consisting
of:
[0071] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds;
[0072] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by one or more members
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfonyl group or a sulfinyl group;
[0073] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds and is interrupted in a position other than alpha to
an unsaturated carbon atom by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group atoms;
[0074] phenyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0075] benzyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0076] biphenylene substituted by 0-6 members selected from the
group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0077] phenoxyphenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0078] phenylthiophenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and
[0079] phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6 hydrogen atoms on
one or more of the phenyl ring and --C.sub.1-6-alkyl- group is/are
replaced independently by a member selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alk- yl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0080] R.sup.4-R.sup.10 are each independently a member selected
from the group consisting of:
[0081] hydrogen and C.sub.1-6-alkyl;
[0082] n is an integer of 0-3;
[0083] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
[0084] Another preferred aspect of the present invention relates to
novel oxetanone derivatives of the formula Ia, as follows: 2
[0085] wherein:
[0086] t is an integer from 0 to 1
[0087] X--N(--H)-Q is an amino linkage of X to Q wherein:
[0088] X of the amino linkage is a bridging group, and
[0089] Q of the amino linkage is a polysaccharide of a sufficient
molecular weight or property that such polysaccharide is not
absorbed by the digestive system of a mammal such as a dog, cat,
non-human primate or a human primate, particularly preferred is
wherein the hydroxyl groups, amino groups or hydroxyl and amino
groups of Q are modified by the attachment of a sufficient number
of organic acyl groups to cause Q to absorb or associate with both
lipids and water and to form a substantially homogeneous gel with
lipids and water;
[0090] R is a member selected from the group consisting of:
[0091] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds;
[0092] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by one or more members
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfonyl group or a sulfinyl group;
[0093] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds and is interrupted in a position other than alpha to
an unsaturated carbon atom by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group atoms;
[0094] phenyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0095] benzyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0096] biphenylene substituted by 0-6 members selected from the
group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0097] phenoxyphenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0098] phenyithiophenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and
[0099] phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6 hydrogen atoms on
one or more of the phenyl ring and --C.sub.1-6-alkyl- group is/are
replaced independently by a member selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alk- yl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0100] R.sup.1 is a member selected from the group consisting
of:
[0101] Hydrogen,
[0102] Ar,
[0103] Ar-- C.sub.1-5-alkyl and
[0104] C.sub.1-10-alkyl interrupted by 0-3 members independently
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a-N(--R.sup.4)-- group, a
--C(.dbd.O)--N(--R.sup.4)-- group, and a
--N(--R.sup.4)--C(.dbd.O)-- group, wherein 0-3 carbon atoms of the
C.sub.1-10-alkyl group can be substituted independently by a member
selected from the group consisting of a hydroxy group, thiol group,
C.sub.1-10-alkoxy group, a C.sub.1-10-alkylthio group, a
--N(--R.sup.5,--R.sup.6) group, a --C(.dbd.O)--N(--R.sup.7,
--R.sup.8) group, and a --N(--R.sup.9)--C(.dbd.- O)--R.sup.10
group;
[0105] R.sup.2 is a member selected from the group consisting
of:
[0106] hydrogen and C.sub.1-6-alkyl, or R.sup.2 taken with R.sup.1
forms a 4-6 membered saturated ring containing 0-4 nitrogen atoms
wherein the ring may be substituted by 0-4 R.sup.11 groups;
[0107] R.sup.3 is a member selected from the group consisting
of:
[0108] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds;
[0109] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by one or more members
selected from the group consisting of an oxygen atom, a sulfur
atom, a sulfonyl group or a sulfinyl group;
[0110] a straight or branched chained C.sub.1-17-alkyl group which
is saturated or optionally interrupted by up to eight double or
triple bonds and is interrupted in a position other than alpha to
an unsaturated carbon atom by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group atoms;
[0111] phenyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0112] benzyl substituted by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0113] biphenylene substituted by 0-6 members selected from the
group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0114] phenoxyphenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0115] phenylthiophenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and
[0116] phenyl-C.sub.1-6-alkyl-phenyl wherein 0-6 hydrogen atoms on
one or more of the phenyl ring and --C.sub.1-6-alkyl- group is/are
replaced independently by a member selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alk- yl, --C.sub.1-6-alkyl-OH and
-C.sub.1-6-alkyl-SH;
[0117] R.sup.4-R.sup.10 are each independently a member selected
from the group consisting of:
[0118] hydrogen and C.sub.1-6-alkyl;
[0119] n is an integer of 0-3;
[0120] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
[0121] A preferred compound according to formula I, or formula Ia,
is a compound wherein X is a member selected from the group
consisting of:
--(C(.dbd.O)).sub.0-1--X.sub.a--,
[0122] wherein X.sub.a is a member selected from the group
consisting of:
[0123] a straight or branched chained divalent C.sub.1-17-alkylene
group which is saturated or optionally interrupted by up to eight
double or triple bonds;
[0124] a straight or branched chained divalent C.sub.1-17-alkylene
group which is saturated or optionally interrupted by one or more
members selected from the group consisting of:
[0125] an oxygen atom,
[0126] a sulfur atom,
[0127] a sulfonyl group,
[0128] a sulfinyl group,
[0129] a substituted or unsubstituted 6-10 member monocyclic or
bicyclic aryl or heteroaryl group having from 1-4 ring hetero atoms
selected from the group consisting of O, N, S,
[0130] a --NH-- group, wherein the hydrogen atom may be replaced
with a C.sub.1-10 alkyl group
[0131] a --C(.dbd.O)-- group,
[0132] a --NH--C(.dbd.O)-- group, wherein the hydrogen atom may be
replaced with a C.sub.1-10 alkyl group and
[0133] a --C(.dbd.O)--NH-- group, wherein the hydrogen atom may be
replaced with a C.sub.1-10 alkyl group
[0134] a straight or branched chained divalent C.sub.1-17-alkylene
group which is saturated or optionally interrupted by up to eight
double or triple bonds and is interrupted in a position other than
alpha to an unsaturated carbon atom by one or more members selected
from the group consisting optionally interrupted by one or more
members selected from the group consisting of:
[0135] an oxygen atom,
[0136] a sulfur atom,
[0137] a sulfonyl group,
[0138] a sulfinyl group,
[0139] a substituted or unsubstituted 6-10 member monocyclic or
bicyclic aryl or heteroaryl group having from 1-4 ring hetero atoms
selected from the group consisting of O, N, S,
[0140] a --NH-- group, wherein the hydrogen atom may be replaced
with a C.sub.1-10 alkyl group
[0141] a --C(.dbd.O)-- group,
[0142] a --NH--C(.dbd.O)-- group, wherein the hydrogen atom may be
replaced with a C.sub.1-10 alkyl group and
[0143] a --C(.dbd.O)--NH-- group, wherein the hydrogen atom may be
replaced with a C.sub.1-10 alkyl group
[0144] divalent phenylene or divalent naphthylene substituted on
the ring structure by 0-4 members selected from the group
consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alk- yl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0145] divalent biphenylene substituted by 0-6 members selected
from the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0146] phenoxyphenylene substituted by 0-6 members selected from
the group consisting of --C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH;
[0147] divalent phenylthiophenylene substituted by 0-6 members
selected from the group consisting of
--C.sub.1-6-alkyloxy-C.sub.1-6-alkyl,
--C.sub.1-6-alkylthio-C.sub.1-6-alkyl, --C.sub.1-6-alkyl-OH and
--C.sub.1-6-alkyl-SH; and
[0148] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
[0149] Preferred sub-groups of such compounds are compounds wherein
R is --(CH.sub.2).sub.3-6--CH.sub.3 and R.sup.3 is a member
selected from the group consisting of
--(CH.sub.2).sub.8-14--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.2-8--CH.sub.3.
Even more preferred are such compounds wherein R is
--(CH.sub.2).sub.5--CH.sub.3 and R.sup.3 is a member selected from
the group consisting of --(CH.sub.2).sub.10--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.4--CH.sub.3.
[0150] In a preferred embodiment, the present invention relates to
novel oxetanone derivatives wherein n of the above formula is zero
to provide compounds of the formula: 3
[0151] wherein:
[0152] X, L, t, Q, R, R.sup.1, R.sup.2 and R.sup.3 are defined as
above, and isomers, salts, hydrates, solvates and prodrug
derivatives thereof. Preferred sub-groups of such compounds are
compounds wherein R is --(CH.sub.2).sub.3-6--CH.sub.3 and R.sup.3
is a member selected from the group consisting of
--(CH.sub.2).sub.8-14--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.2-8--CH.sub.3.
More preferred are such compounds wherein R is
--(CH.sub.2).sub.5--CH.sub- .3 and R.sup.3 is a member selected
from the group consisting of --(CH.sub.2).sub.10--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd-
.CH--(CH.sub.2).sub.4--CH.sub.3. Further preferred are compounds
wherein t is 0 and X is --C(.dbd.O)--X.sub.a-- as set forth
above.
[0153] Even further preferred are such compounds wherein t is 1 and
X is a member selected from the group consisting of: 4
[0154] wherein R.sup.1a is independently defined the same as
defined for R.sup.1, R.sup.2a is independently defined the same as
for R.sup.2, m is a integer from 0 to 10, preferably from 0-5, and
more preferred from 0-2, and wherein z is an integer from 1 to 20,
preferably 2 to 10, and more preferably, 2-4, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
[0155] In another preferred embodiment, the present invention
relates to such novel oxetanone derivatives of formula 1 having the
following formula: 5
[0156] wherein:
[0157] X, L, Q, R, and R.sup.3 are defined as above, and isomers,
salts, hydrates, solvates and prodrug derivatives thereof.
Preferred sub-groups of such compounds are compounds wherein R is
--(CH.sub.2).sub.3-6--CH.sub- .3 and R.sup.3 is a member selected
from the group consisting of --(CH.sub.2).sub.8-14--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.d-
bd.CH--(CH.sub.2).sub.2-8--CH.sub.3. More preferred are such
compounds wherein R is --(CH.sub.2).sub.5--CH.sub.3 and R.sup.3 is
a member selected from the group consisting of
--(CH.sub.2).sub.10--CH.sub.3 and
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.4--CH.sub.3.
[0158] Even further preferred are such compounds wherein X is a
member selected from the group consisting of: 6
[0159] wherein z is a integer from 0 to 10, preferably from 0-5,
and more preferred from 0-2.
[0160] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
[0161] Other preferred compounds are compounds, wherein t is 0 or 1
and X is a member selected from the group consisting of: 7
[0162] wherein R.sup.1a is independently defined the same as
defined for R.sup.1, R.sup.2a is independently defined the same as
for R.sup.2, m is a integer from 0 to 10, preferably from 0-5, and
more preferred from 0-2, and wherein z is an integer from 1 to 20,
preferably 2 to 10, and more preferably, 2-4, and all
pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof. One preferred group of compounds are
such compounds wherein L is --NH-- and another preferred group of
compounds are such compounds wherein L is --O--.
[0163] The above compound, wherein X is a member selected from the
group consisting of: 8
[0164] and wherein z is a integer from 0 to 10, preferably from
0-5, and more preferred from 0-2,
[0165] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof.
[0166] Further preferred are such compounds, wherein X is a member
selected from the group consisting of: 9
[0167] and wherein z is a integer from 0 to 18,
[0168] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof. One preferred
group of such compounds is wherein L is --NH-- and another
preferred group of such compound is wherein L is --O--.
[0169] Additionally preferred are such compounds wherein X is a
member selected from the group consisting of: 10
[0170] and wherein z is a integer 6-12,
[0171] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof. One preferred
group of such compounds is wherein L is --NH-- and another
preferred group of such compound is wherein L is --O--.
[0172] More preferred are such compounds wherein X is a member
selected from the group consisting of: 11
[0173] and wherein z is a integer 6-12,
[0174] and all pharmaceutically acceptable isomers, salts,
hydrates, solvates and prodrug derivatives thereof. One preferred
group of such compounds is wherein L is --NH-- and another
preferred group of such compound is wherein L is --O--.
[0175] Particularly preferred Q groups for the above compounds are
non-absorbable biocompatable, pharmaceutically acceptable polymers,
such as a polysaccharide, which are preferably lipophilic and bind
to fat and are non-absorbable by the digestive system of an animal
such as a dog, cat, non-human primate or humans. Particularly
preferred polysaccharides have at least one member selected from
the group consisting of dextrans, molecular microcrystalline
cellulose, wheat bran, oat bran, defatted rice germ, alginic acid,
pectin, amylopectin, chitin, crude cellulose, argar, chitosan and
the like. Particularly preferred Q groups have an alcohol, acyl
group or amino group, or can be derivitized to present such an
alcohol, acyl or amino group, which can be bound to the R moiety or
the X--R--X group Preferably, at least one and or two ether bridges
can be formed between a lipase inhibitor moiety and the polymer
moiety via an X--R--X bridge, wherein the bridge is derived from an
alcohol group or amine group on the lipase and an alcohol group,
acyl group or amino group on the Q group. Even more preferred are Q
groups which are chitosan derivatives that have been modified by an
ether group or amino group which is terminated by an organic acid
group. Further preferred are such modified chitosan Q groups
wherein the organic acyl groups appended from the modified alcohol
or amino group of the polysaccharide are independently a straight
or branched chained alkanoyl group. Most preferred are such
modified chitosan Q groups wherein the polarity resulting from the
modification of chitosan alcohol or amino groups with organic acyl
groups allows the modified chitosan to absorb both lipids and water
and to form a substantially homogenous gel with lipids and
water.
[0176] Most preferred are the compounds as set forth above, wherein
the Q group is a chitosan compound modified with a sufficient
number of organic acyl groups to cause the modified chitosan to
absorb or associate both lipids and water and to form a
substantially homogenous gel with oil and water. The number of
organic acyl groups present on the modified chitosan chains are
present in a molar ratio from 1 to 8 times the number of the molar
ratio of esterified lipase inhibitor alcohol groups, and more
preferably a ratio from 2 to 5 times, and most preferably a ratio
of from 3 to 4 times the number of esterified lipase inhibitor
alcohol groups.
[0177] Preparation of Compounds
[0178] The lipase inhibitor compounds, polymer moieties and
bridging groups of the present invention may be synthesized or
readily obtained from commercially available sources. Polymer
bridging groups, bridge coupling processes and compound
purification methods are described and referenced in standard
textbooks, particularly the coupling of alcohol groups via diether
bridges, ether/ester bridges, ether/ketone bridges and the like.
Standard polymer textbooks reference typical bifunctional bridging
groups and coupling procedures.
[0179] Starting materials used in any of these methods are
commercially available from chemical vendors such as Aldrich,
Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may
be readily synthesized by known procedures.
[0180] Reactions are carried out in standard laboratory glassware
and reaction vessels under reaction conditions of standard
temperature and pressure, except where otherwise indicated.
[0181] During the synthesis of these compounds, the functional
groups may be protected by blocking groups to prevent cross
reaction during the coupling procedure. Examples of suitable
blocking groups and their use are described in "The Peptides:
Analysis, Synthesis, Biology", Academic Press, Vol. 3 (Gross, et
al., Eds., 1981) and Vol. 9 (1987), the disclosures of which are
incorporated herein by reference.
[0182] Lipase inhibitor moieties having a free hydroxy group such
as tetrahydro-esterastin (3,5-hydroxy-2-hexadeca-7,10-dienoic
1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic
1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and
the like, are easily coupled to a polymer moiety having free
hydroxy groups such as cellulose, chitosan and other
polysaccharides having free hydroxyl groups. One or both of the
lipase inhibitor moiety and the polymer moiety may be derivitized
to form part of the linking bridge prior to reacting with the other
moiety. For example, the lipase inhibitor molecule may be condensed
with a dihalide group or a terminal halide terminal acyl (acyl
group may be protected with an acid group) to form an ether or
ester linkage and then condensed with a polymer moiety having a
free hydroxyl group or free amino group by methods shown in polymer
chemistry. In one procedure a polymer moiety such as chitosan can
be reacted with a compound such as a halomethylbenzoic acid ester,
C.sub.2 to C.sub.20 n-haloalkanoic acid, C.sub.2 to C.sub.20
n-alkanoic acid ester or the like, and optionally de-esterified to
present a free acid group which may be reacted to form an ester,
ketone, carboxamide or the like with the derivitized or
underivatized lipase inhibitor moiety. In one preferred aspect of
the invention, the amino or alcohol groups of the polysaccharide
moiety, such as chitosan, is reacted with one or more types of
n-haloalkanoic acid (or an acyl ester derivative) such as
n-bromohexanoic acid, n-chlorolauric acid in a molar ratio 1:1 to
1:10, or the like, sufficient to attach an organic acyl side chain
to 1 to 10%, preferably from 1 to 5% and more preferably from 2 to
4%, of the free alcohol groups, amino groups or alcohol and amino
groups on the polysaccharide chain to provide an organic acyl group
modified polysaccharide, such as an organic acyl group modified
chitosan derivative. In such case, the n-haloalkanoic acid, or
other halo derivative organic acyl group, etherizes free hydroxyl
groups, replaces a hydrogen atom on an amino group, or forms a
ketone with an acid group or a previously modified polysaccharide
compound, and the resulting intermediate can then be reacted with
the lipase inhibitor to form an ester group with a free alcohol
group, replace a hydrogen atom on a amino group to form a
carboxamide, and the like. Particularly preferred polymer moieties
to be modified are polysaccharides having multiple free hydroxyl
groups or amino groups for coupling, such as chitosan or a chitosan
that has optionally been sulfonated to render the lipase moiety
itself a lipase inhibitor compound. Etherification, amination and
ketone formation procedures are well-known in the art and well
within the routine skill of the ordinary practitioner. Further,
other bridging groups and the techniques for binding a compound
having a reactive functional group to a polymer moiety are
well-known in the art. The preferred compounds also include their
pharmaceutically acceptable isomers, hydrates, solvates, salts and
prodrug derivatives.
[0183] The bridging group refers to a bifunctional chain or spacer
group capable of reacting with one or more functional groups on a
lipase inhibitor compound and then react with a second same or
different functional group on a polymer compound in order to form a
linked structure or conjugate between the two compounds. The bond
formed between the bridging group and each of the two compounds is
preferably of a type that is resistant to cleavage by the digestive
environment, except that the lipase inhibitor may optionably be
cleavable by a digestive lipase. In one aspect, the bridging group
is of the formula X--R--X, wherein R is a member selected from a
straight-chained or branched alkyl group, a straight-chained or
branched alkenyl group, a straight-chained or branched alkynyl
group, a mono acyl group, a diacyl group and the like, and X is a
functionally reactive group such as a halogen or an acid group,
preferably on X is bromo and the other is an acyl or acyl ester
group, which react under the special reaction conditions as
described hereinafter. Particularly preferred bridging groups form
a terminal ether or a terminal amino alkyl bond with the
polysaccharide and an acyl ester or carboxamide bond with the
lipase inhibitor.
[0184] Examples of alkylene dichloride bridging group forming
compounds are dichloromethane, 1,2-dichloroethane, 1,2- and
1,3-dichloropropane, 1,2-, 1,3- and 1,4-dichlorobutane,
1,2-bromochloroethane, 1,2-and 1,3-bromochloropropane, and the
like.
[0185] Examples of acyldichloride bridging group forming compounds
are oxalic acid dichloride, malonic acid dichloride, succinic acid
dichloride, glutaric acid dichloride, adipic acid dichloride,
pimelic acid dichloride, suberic acid dichloride, fumaric acid
dichloride, malic acid dichloride, glutamic acid dichloride,
terephthalic acid dichloride, isophthalic acid dichloride, and the
like.
[0186] Examples of haloacyl bridging groups include
chloromethylbenzoic acid or an ester thereof, 3-bromopropanoic
acid, 2-chloroacetic acid, 6-bromohexanoic acid or an ester
thereof, 12-bromododecanoic acid or an ester thereof, other
n-haloalkanoic acids or esters thereof, and the like.
[0187] Other such bridging group reagents are compounds such as
epichlorhydrin, phosphorus oxychloride, and diphosphoryl
tetrachloride, and the like.
[0188] Preferred bridging groups terminated with at least one bromo
or chlorine group and the other terminus is an acyl group or an
acyl derivative. Even more preferred bridging groups are
n-halo(preferably n-bromo)-C.sub.4-C.sub.20 (preferably
C.sub.6-C.sub.14) alkanoic acids or esters thereof. The reaction is
reacting the bridging group with the polysaccharide under either
etherification or amino alkylation conditions in a substantially
water immiscible organic solvent, such as THF substantially 1:1 to
1:10 molecular ratio of polysaccharide chain to bridging group
reactant. The reaction may proceed at the interface between the two
immiscible solutions, or in solution, to provide a condensation and
produce the polysaccharide derivative or analogue. It has been
discovered that this reaction at the interface of the organic
solution and the aqueous solution imparts a specificity to the
reaction for primary alcohol groups of the polysaccharide. A
miscible solvent such as THF, an ether or the like, favors
alkylation of the amino groups. It should be understood that
equivalent reactants such as diepoxides and balohydrocarbyloxiranes
such as epichlorohydrin also react in the process to provide new
and useful ether bridges.
[0189] By appropriate selection of the type of bridging group
reactant and reaction conditions, different structural groups with
various chemical properties can be incorporated into the resulting
bridge and various types of lipase inhibitors can be connected to a
nonabsorbable polymer moiety, such as a polysaccharide, and
preferably to chitosan or modified chitosan. Reaction temperatures
and other reactions conditions, as well are reactant proportions
are well within the skill of the ordinary polymer chemist
practitioner in view of the present description of the invention.
Other groups and modifications will be apparent to one of ordinary
skill in the art from the above discussion.
[0190] The lipase inhibitor functionality of the coupled lipase
inhibitors may be determined by well-known lipase inhibitor assays.
A therapeutically effective amount of the bound lipase inhibitor
may be administered to a patient. Additional fat binding polymers
may optionally be added to the composition.
[0191] The following non-limiting reaction Schemes I, II, III and
IV illustrate preferred embodiments of the invention with respect
to making compounds according to the invention. 12 13 14 15
[0192] Therefore, in a preferred aspect the invention provides a
method for producing a compound of claim 1, comprising reacting a
compound of the formula: 16
[0193] with a compound of the formula 17
[0194] wherein L is --O-- or --NH--, t is 0 or 1 and Y is a leaving
group for an etherification or esterification reaction with the
hydroxy group to produce a compound of the formula: 18
[0195] or a salt thereof.
[0196] Pharmaceutical Compositions and Edible Compositions
[0197] In one aspect, the present invention provides a sports
drink, snack, nutrient supplement, food or power which may be
formulated to contain a lipase inhibiting therapeutically effective
amount of the lipase inhibitor composition according to the
invention.
[0198] In another aspect the present invention relates to
pharmaceutical compositions comprising a lipase inhibiting
effective amount of at least one lipase inhibitor which is coupled
to a digestively non-absorbable moiety. Preferred are such
pharmaceutical compositions comprising an effective amount of a
lipases coupled to a non-absorbable biocompatable, pharmaceutically
acceptable polymer moiety, such as a polysaccharide, wherein the
lipase is essentially non-absorbable by the digestive system of an
animal such as a dog, cat, non-human primate or humans. The
pharmaceutical composition can be administrated to a patent prior
to or within one hour of consuming a fat-containing meal to prevent
absorption of up to one-third of the dietary fat consumed at the
meal.
[0199] In still another aspect, the present invention relates to a
method for treating adiposity or obesity by administering to a
patient before a fat-contain meal, or up to one hour after such a
meal is consumed, an amount of at least one lipase inhibitor which
is bound to a non-absorbable polymer moiety in an amount effective
to inhibit the absorption of up to one-third of the dietary fat in
such a meal. In particular, a preferred method comprises
administering at one lipase inhibitor which is a member selected
from the group consisting of esterastin, tetrahydro-esterastin
(3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone),
3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,
3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like,
wherein such lipase inhibitor is coupled to a non-absorbable
biocompatable, pharmaceutically acceptable polymer moiety, such as
a polysaccharide, to render the lipase non-absorbable by the
digestive system of an animal such as a dog, cat, non-human primate
or humans. Particularly preferred polysaccharides are at least one
member selected from the group consisting of dextrans, molecular
microcrystalline cellulose, wheat bran, oat bran, defatted rice
germ, alginic acid, pectin, amylopectin, chitin, crude cellulose,
argar, chitosan and the like. Particularly preferred bound lipase
inhibitors are lipase inhibitors bound via a derivatized nitrogen,
acid or alcohol group to a derivatized alcohol, acid or amino group
on the polymer moiety. Preferred bound polymer moities are
derivatized to have an excess of acyl organic acid side chains
which are adequate to cause the compound to absorb both oil and
water or associate with both oil and water to provide a
substantially homogeneous gel. A ether bond or alkylamino bond at
one bridge terminus and an acyl ester or carboxamide bridge
terminus connecting the lipase inhibitor and the polysaccharide
moiety is preferred which is derived from an alcohol group on the
lipase and an alcohol or amino group on the polysaccharide moiety,
respectively reacting with a bridging group is the preferred
coupling of the lipase inhibitor to the moiety.
[0200] The compounds of this invention may be isolated as the free
acid or base or converted to salts of various inorganic and organic
acids and bases. Such salts are within the scope of this invention.
Non-toxic and physiologically compatible salts are particularly
useful although other less desirable salts may have use in the
processes of isolation and purification.
[0201] Numerous methods are useful for the preparation of the salts
described above and are known to those skilled in the art. For
example, free acid or free base forms of a compound of one of the
above compounds can be reacted with one or more molar equivalents
of the desired acid or base in a solvent or solvent mixture in
which the salt is insoluble, or in a solvent like water after which
the solvent is removed by evaporation, distillation or freeze
drying.
[0202] Alternatively, the free acid or base form of the product may
be passed over an ion exchange resin to form the desired salt or
one salt form of the product may be converted to another using the
same general process.
[0203] Prodrug Derivatives of Compounds
[0204] This invention also encompasses prodrug derivatives of the
compounds contained herein. The term "prodrug" refers to a
pharmacologically inactive derivative of a parent drug molecule
that requires biotransformation, either spontaneous, acid/base
reaction, or enzymatic, within the organism to release the active
drug. Prodrugs are variations or derivatives of the compounds of
this invention which have groups cleavable under digestive system
conditions. Prodrugs become the compounds of the invention which
are pharmaceutically active in vivo, when they undergo solvolysis
under physiological conditions or undergo enzymatic degradation.
Prodrug compounds of this invention may be called single, double,
triple etc., depending on the number of biotransformation steps
required to release the active drug within the organism, and
indicating the number of functionalities present in a
precursor-type form. Prodrug forms often offer advantages of
solubility, digestive compatibility, or delayed release in the
mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,
21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic
Chemistry of Drug Design and Drug Action, pp. 352-401, Academic
Press, San Diego, Calif., 1992). Prodrugs commonly known in the art
include acid derivatives well known to practitioners of the art,
such as, for example, esters prepared by reaction of the parent
acids with a suitable alcohol, or amides prepared by reaction of
the parent acid compound with an amine, or basic groups reacted to
form an acylated base derivative. Moreover, the prodrug derivatives
of this invention may be combined with other features herein taught
to enhance bioavailability.
[0205] Formulations of the compounds of this invention are prepared
for storage or administration by mixing the compound having a
desired degree of purity with physiologically acceptable carriers,
excipients, stabilizers etc., and may be provided in sustained
release or timed release formulations. Acceptable carriers or
diluents for therapeutic use are well known in the pharmaceutical
field, and are described, for example, in Remington's
Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit.
1985). Such materials are nontoxic to the recipients at the dosages
and concentrations employed, and include buffers such as phosphate,
citrate, acetate and other organic acid salts, antioxidants such as
ascorbic acid, low molecular weight (less than about ten residues)
peptides such as polyarginine, proteins, such as serum albumin,
gelatin, or immunoglobulins, hydrophilic polymers such as
polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,
aspartic acid, or arginine, monosaccharides, disaccharides, and
other carbohydrates including cellulose or its derivatives,
glucose, mannose or dextrins, chelating agents such as EDTA, sugar
alcohols such as mannitol or sorbitol, counterions such as sodium
and/or nonionic surfactants such as Tween, Pluronics or
polyethyleneglycol.
[0206] Dosage formulations of the compounds of this invention to be
used for therapeutic administration must be sterile. Sterility is
readily accomplished by filtration through sterile membranes such
as 0.2 micron membranes, or by other conventional methods.
Formulations typically will be stored in lyophilized form or as an
aqueous solution. The pH of the preparations of this invention
typically will be 3-11, more preferably 5-9 and most preferably
7-8. It will be understood that use of certain of the foregoing
excipients, carriers, or stabilizers will result in the formation
of cyclic polypeptide salts.
[0207] Therapeutically effective dosages may be determined bv
either in vitro or in vivo methods. For each particular compound of
the present invention, individual determinations may be made to
determine the optimal dosage required. The range of therapeutically
effective dosages will be influenced by the route of
administration, the therapeutic objectives and the condition of the
patient. Accordingly, it may be necessary for the therapist to
titer the dosage and modify the means of administration as required
to obtain the optimal therapeutic effect. The determination of
effective dosage levels, that is, the dosage levels necessary to
achieve the desired result, will be readily determined by one
skilled in the art. Typically, applications of compound are
commenced at lower dosage levels, with dosage levels being
increased until the desired effect is achieved.
[0208] The compounds of the invention can be administered orally in
an effective amount within the dosage range of about 10 to 400
mg/kg, preferably about 20 to 200 mg/kg and more preferably about
20 to 50 mg/kg per fat containing meal on a regimen in a single or
2 to 4 divided daily doses. A preferred dosage is an amount (e.g.
about 20 to 40 mg/kg) that has a similar lipase inhibiting effect
to the lipase inhibition of 120 mg (approximately 1-2 mg/kg dosage)
of orally taken Orlistat. The determination of such equivalent
lipase inhibition can be determined via well-known lipase
inhibition assays, and may be either an in vivo assay, an in vitro
assay, or both. The fat absorption properties of the lipophilic
lipase inhibitor of the invention can be observed by comparing the
amount of anal oil discharged in a patient taking an lipase
inhibitor equivalent amount of the lipase inhibitor according to
the invention as compared to a patient taking only Orlistat. The
grooming of mice with anal oil is one comparison as compared to
Orlistat or the actual comparison of anal discharge in animals or
patients also will show a reduction in the amount of oily anal
discharge when a lipophilic lipase inhibitor according to the
invention is administered.
[0209] Typically, for a unit dose form, about 500 mg to 2 g of a
compound or mixture of compounds of this invention, as the free
acid or base form or as a pharmaceutically acceptable salt, is
compounded with a physiologically acceptable vehicle, carrier,
excipient, binder, preservative, stabilizer, dye, flavor etc., as
called for by accepted pharmaceutical practice. The amount of
active ingredient in these compositions is such that a suitable
dosage in the range indicated is obtained.
[0210] Typical adjuvants which may be incorporated into tablets,
capsules and the like are binders such as acacia, corn starch or
gelatin, and excipients such as microcrystalline cellulose,
disintegrating agents like corn starch or alginic acid, lubricants
such as magnesium stearate, sweetening agents such as sucrose or
lactose, or flavoring agents. When a dosage form is a capsule, in
addition to the above materials it may also contain liquid carriers
such as water, saline, or a fatty oil. Other materials of various
types may be used as coatings or as modifiers of the physical form
of the dosage unit. Sterile compositions for injection can be
formulated according to conventional pharmaceutical practice. For
example, dissolution or suspension of the active compound in a
vehicle such as an oil or a synthetic fatty vehicle like ethyl
oleate, or into a liposome may be desired. Buffers, preservatives,
antioxidants and the like can be incorporated according to accepted
pharmaceutical practice.
[0211] In certain aspects of this invention, compounds are provided
which are useful as diagnostic reagents to determine lipase
activity. In another aspect, the present invention includes
pharmaceutical compositions comprising a pharmaceutically effective
amount of the compounds of this invention and a pharmaceutically
acceptable carrier. In yet another aspect, the present invention
includes methods comprising using the above compounds and
pharmaceutical compositions for preventing or treating disease
states characterized by undesired lipid or fat absorption such as
obesity, hyperlipaemia, atherosclerosis and ateioscherosis
disorders of the blood coagulation process in mammals, or for
stabilizing fats by preventing lipase function in stored fat
products and samples. Optionally, the methods of this invention
comprise administering the pharmaceutical composition in
combination with an additional therapeutic agent such as an
anticholesterol agent, appetite suppressant, metabolic stimulant
and the like.
[0212] The preferred compounds also include their pharmaceutically
acceptable isomers, hydrates, solvates, salts and prodrug
derivatives.
[0213] In one embodiment the present invention provides a
pharmaceutical composition comprising at least one pharmaceutically
acceptable carrier excipient and an amount of at least one of the
above described compounds according to the invention in a
therapeutically effective amount with respect to limiting or
preventing the absorption of some dietary fat. In a preferred
embodiment, the pharmaceutical composition comprises a
therapeutically effective amount of slow-release lipoprotein
lipase, preferably from a microbial or plant source, which
selectively hydrolyzes terminal triglyceride groups in combination
with an oil absorbing effective amount of polysaccharide such as
chitosan, wherein the lipoprotein lipase is present in a ratio of
less that 25% with respect to the oil absorbing polysaccharide.
[0214] In another embodiment the present invention provides a
pharmaceutical composition comprising at least one pharmaceutically
acceptable carrier excipient, an amount of at least one of the
above described compounds according to the invention in a
therapeutically effective amount with respect to limiting or
preventing the absorption of some dietary fat, and an oil absorbing
effective amount of polysaccharide such as chitosan, wherein such
lipase inhibitor is selectively effective to inhibit lipases other
than lipases involved in the hydrolysis of terminal triglyceride
groups and such lipase inhibitor does not substantially inhibit the
absorption of vitamins A, D and E.
[0215] In another embodiment the present invention provides a
method of using such compounds and pharmaceutical compositions as
therapeutic agents for disease states in a mammal having at least
one disorder that is due to undesired absorption of dietary fat or
for reducing the effective caloric intake of a mammal who consumes
dietary fat, which method may be useful in the treatment of
undesired weight gain or obesity.
[0216] The compounds of this invention also find utility as
intermediates for producing therapeutic agents or as therapeutic
agents for disease states in mammals which have disorders that are
due to undesired absorption of dietary fat. Methods for making
starting materials may be found in U.S. Pat. No. 4,931,463, which
is incorporated fully herein. Preferred oxetanones of the invention
are compounds wherein R is methyl, ethyl, propyl, hexyl, decyl,
hexadecyl, allyl and benzyl, and most preferably hexyl; R.sup.1 is
hydrogen, methyl, ethyl, propyl, 2-butyl, isobutyl, benzyl and
methylthio-ethyl, most preferably, hydrogen or isobutyl; R.sup.2 is
hydrogen, methyl or ethyl, most preferably hydrogen; n is 0 or 1,
and when t is 1, then X is preferably attached to N via an amino
acid, such as valine, alanine and the like, preferably alanine; and
R.sup.3 is preferably a straight or branched chained
C.sub.1-17-alkyl group which is saturated or optionally interrupted
by up to eight double or triple bonds, or R.sup.3 is a straight or
branched chained C.sub.1-17-alkyl group which is saturated or
optionally interrupted by one or more members selected from the
group consisting of an oxygen atom, a sulfur atom, a sulfonyl group
or a sulfinyl group or R.sup.3 is a straight or branched chained
C.sub.1-17-alkyl group which is saturated or optionally interrupted
by up to eight double or triple bonds and is interrupted in a
position other than alpha to an unsaturated carbon atom by one or
more members selected from the group consisting of an oxygen atom,
a sulfur atom, a sulfonyl group or a sulfinyl group atoms.
[0217] The compounds produced according to the present invention,
particularly, the modified polysaccharides, may also be used as
intermediates in the formation of compounds that may be
administered in combination or in concert with other therapeutic or
diagnostic agents, however, they may be useful as oil absorbing
polymers that are capable of dispersing in water after oil
absorption. Such may be useful food additives. In certain preferred
embodiments, the compounds produced by the intermediates according
to the present invention may be co-administered along with other
compounds typically prescribed for these conditions according to
generally accepted medical practice such as other dietary
maintenance medicaments and for diseases related to or impacted by
the absorption of dietary fat. The compounds produced from the
intermediates according to the present invention may act in a
synergistic fashion with other such medicaments. Such compounds may
also allow for reduced doses of other cholesterol inhibiting,
appetite inhibiting and metabolic stimulating medicaments, and the
like. Such compounds can be utilized in vivo, ordinarily in mammals
such as primates, (non-human and humans), sheep, horses, cattle,
pigs, dogs, cats, rats and mice, or in vitro.
[0218] The starting materials used in above processes are
commercially available from chemical vendors such as Aldrich,
Sigma, Lancaster, TCI, and the like, or may be readily synthesized
by known procedures, for example, by using procedures such as
indicated above.
[0219] Reactions are carried out in standard laboratory glassware
and reaction vessels under reaction conditions of standard
temperature and pressure, except where otherwise indicated, or is
well-known in literature available in the art. Further, the above
procedures of the claimed invention processes my be carried out on
a commercial scale by utilizing reactors and standard scale-up
equipment available in the art for producing large amounts of
compounds in the commercial environment. Such equipment and
scale-up procedures are well-known to the ordinary practitioner in
the field of commercial chemical production.
[0220] During the synthesis of these compounds, amino or acid
functional groups may be protected by blocking groups to prevent
undesired reactions with the amino group or acid group during
certain procedures. Procedures for such protection and removal of
protecting groups are routine in this art and well-known to the
ordinary practitioner in this field.
[0221] Four non-limiting exemplary synthesis schemes were shown
above, which are each a preferred embodiment of the invention,
comprise the process steps outlined above which may also include
further initial starting steps such as those set forth in J. Med.
Chem., Vol. 15, No. 8 (1972) or further processing steps which
modify the amino group to comprise a desired functional group such
as groups described in the lipase inhibiting field. Amino coupling
reactions are well-known in the art. Moreover, specific steps that
are set forth in the preferred embodiment reaction scheme described
above. The reaction products are isolated and purified by
conventional methods, typically by solvent extraction into a
compatible solvent. Preferred solvents are lower alkane ethers and
alcohols; ethyl ether and isopropyl alcohol are preferred for
solvent extraction or recrystallization procedures. Esters of
carboxylic acid side groups may be formed that permit selective
separation of the R and S enantiomers by solvent extraction or
recrystallization. D-alaninol is the preferred enantiomer resolving
agent, but other resolving agents or analogous procedures may be
used, e.g., tartartic acid derivatives and the like. The products
may be further purified by column chromatography or other
appropriate methods.
[0222] Enantiomeric Resolution and Acid Salt Formation
[0223] As is clear from the above formulae and the discussion
above, by using the above reactions racemic chromane acetic acid is
obtained which may optionally be resolved to produce a racemic
mixture enriched in either the R or S enantiomers or completely
resolved into a substantially pure composition of one of the
enantiomers. The literature in this field describes examples of
conventional processes whereby the enantiomers may be resolved.
[0224] Coupling Reaction of the Hydrochloride Salt Intermediate
Compounds
[0225] The above compounds produced according to the above
invention may be isolated and further reacted to substitute a
desired group for one or more of the hydrogen atoms on an amino
group, on a free hydroxyl group or on a free acyl group by a
coupling reaction with the desired group.
[0226] Compositions and Formulations
[0227] The compounds of this invention may be isolated as the free
acid or base or converted to salts of various inorganic and organic
acids and bases. Such salts are within the scope of this invention.
Non-toxic and physiologically compatible salts are particularly
useful although other less desirable salts may have use in the
processes of isolation and purification.
[0228] A number of methods are useful for the preparation of the
salts described above and are known to those skilled in the art.
For example, reaction of the free acid or free base form of a
compound of the structures recited above with one or more molar
equivalents of the desired acid or base in a solvent or solvent
mixture in which the salt is insoluble, or in a solvent like water
after which the solvent is removed by evaporation, distillation or
freeze drying. Alternatively, the free acid or base form of the
product may be passed over an ion exchange resin to form the
desired salt or one salt form of the product may be converted to
another using the same general process.
[0229] Diagnostic applications of the compounds of this invention
will typically utilize formulations such as solution or suspension.
In the management of undesired fat absorption the compounds of this
invention may be utilized in compositions such as tablets, capsules
or elixirs for oral administration, sterile solutions or
suspensions, and the like, or incorporated into shaped articles.
Subjects in need of treatment (typically mammalian) using the
compounds of this invention can be administered dosages that will
provide optimal efficacy. The dose and method of administration
will vary from subject to subject and be dependent upon such
factors as the type of mammal being treated, its sex, weight, diet,
concurrent medication, overall clinical condition, the particular
compounds employed, the specific use for which these compounds are
employed, and other factors which those skilled in the medical arts
will recognize.
[0230] Formulations of the compounds of this invention are prepared
for storage or administration by mixing the compound having a
desired degree of purity with physiologically acceptable carriers,
excipients, stabilizers etc., and may be provided in sustained
release or timed release formulations. Acceptable carriers or
diluents for therapeutic use are well known in the pharmaceutical
field, and are described, for example, in Remington's
Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit.
1985). Such materials are nontoxic to the recipients at the dosages
and concentrations employed, and include buffers such as phosphate,
citrate, acetate and other organic acid salts, antioxidants such as
ascorbic acid, low molecular weight (less than about ten residues)
peptides such as polyarginine, proteins, such as serum albumin,
gelatin, or immunoglobulins, hydrophilic polymers such as
polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,
aspartic acid, or arginine, monosaccharides, disaccharides, and
other carbohydrates including cellulose or its derivatives,
glucose, mannose or dextrins, chelating agents such as EDTA, sugar
alcohols such as mannitol or sorbitol, counterions such as sodium
and/or nonionic surfactants such as Tween, Pluronics or
polyethyleneglycol.
[0231] Dosage formulations of the compounds of this invention to be
used for therapeutic administration must be sterile. Sterility is
readily accomplished by filtration through sterile membranes such
as 0.2 micron membranes, or by other conventional methods.
Formulations typically will be stored in lyophilized form or as an
aqueous solution. The pH of the preparations of this invention
typically will be between 3 and 11, more preferably from 5 to 9 and
most preferably from 7 to 8. It will be understood that use of
certain of the foregoing excipients, carriers, or stabilizers will
result in the formation of cyclic polypeptide salts. While the
preferred route of administration is by oral tablets, capsules or
other unit dose mechanisms, such as liquids, other methods of
administration are also anticipated such as in food stuffs,
employing a variety of dosage forms. The compounds of this
invention are desirably incorporated into food articles which may
include fats to prevent their absorption.
[0232] The compounds of this invention may also be coupled with
suitable polymers to enhance their therapeutic effects. Such
polymers can include lipophilic polymers, such as polysaccharides
and the like.
[0233] Therapeutically effective dosages may be determined by
either in vitro or in vivo methods. For each particular compound of
the present invention, individual determinations may be made to
determine the optimal dosage required. The range of therapeutically
effective dosages will naturally be influenced by the route of
administration, the therapeutic objectives, and the condition of
the patient. For routes of administration, the lipase inhibitor
activity, in view of the amount of fat consumed, must be
individually determined for each inhibitor by methods well known in
pharmacology. Accordingly, it may be necessary for the therapist to
titer the dosage and modify the route of administration as required
to obtain the optimal therapeutic effect. The determination of
effective dosage levels, that is, the dosage levels necessary to
achieve the desired result, will be within the ambit of one skilled
in the art. Typically, applications of compound are commenced at
lower dosage levels, with dosage levels being increased until the
desired effect is achieved.
[0234] Typically, about 500 mg to 3 g of a lipase inhibitor
compound or mixture of lipase inhibitor compounds of this
invention, as the free acid or base form or as a pharmaceutically
acceptable salt, is compounded with a physiologically acceptable
vehicle, carrier, excipient, binder, preservative, stabilizer, dye,
flavor etc., as called for by accepted pharmaceutical practice. The
amount of active ingredient in these compositions is such that a
suitable dosage in the range indicated is obtained. The addition,
one or more other therapeutic ingredients such as a fat absorbing
polysaccharide or fiber, a fat-specific lipase inhibitor or lipase,
as well as other dietary agents may be utilized in therapeutically
effective amounts.
[0235] Typical adjuvants which may be incorporated into tablets,
capsules and the like are a binder such as acacia, corn starch or
gelatin, and excipient such as microcrystalline cellulose, a
disintegrating agent like corn starch or alginic acid, a lubricant
such as magnesium stearate, a sweetening agent such as sucrose or
lactose, or a flavoring agent. When a dosage form is a capsule, in
addition to the above materials it may also contain a liquid
carrier such as water, saline, a fatty oil. Other materials of
various types may be used as coatings or as modifiers of the
physical form of the dosage unit. Sterile compositions for
injection can be formulated according to conventional
pharmaceutical practice. Buffers, preservatives, antioxidants and
the like can be incorporated according to accepted pharmaceutical
practice.
[0236] In practicing the methods of this invention, the compounds
of this invention may be used alone or in combination, or in
combination with other therapeutic or diagnostic agents. In certain
preferred embodiments, the compounds of this inventions may be
coadministered along with other compounds typically prescribed for
these conditions according to generally accepted medical practice,
such as
[0237] The compounds of this invention can be utilized in vivo,
ordinarily in mammals such as non-human primates, humans, sheep,
horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
[0238] The following non-limiting examples are provided to better
illustrate the present invention.
EXAMPLE 1
[0239] 10 grams of low viscosity chitosan is dissolved in a 500
milliliter flask equipped with a stirrer thermometer and electrical
heater, in a mixture of 190 g of dimethylsulfoxide and 10 g of
paraformaldehyde, at 50.degree. C. At this temperature, after the
addition of 0.1 g of finely powdered sodium hydroxide, a solution
of 400 mg of p-chloromethyl benzoic acid methyl ester in 10 g of
dimethylsolfoxide is added over a period of about 30 minutes. The
mixture is stirred for four hours at 50.degree. C. The reaction
mixture is cooled to room temperature, then poured into ethanol
while the latter is being stirred vigorously. The solid is suction
filtered, suspended repeatedly in ethanol until all the soluble
substances are removed to yield a crude product. The crude product
is stirred in an aqueous basic 1 N sodium hydroxide ethanol
solution, which is then acidified with HCl until neutral pH for
chitosan. The solid is washed twice with cold ethanol and cold
water, and the solid is then dried to yield about 10 grams of ether
functionalized chitosan. Analysis indicates that from 1% to 3% of
the free hydroxyl groups on the chitosan polymeric backbone are
etherified by the entry of the p-methylbenzoic acid group.
EXAMPLE 2
[0240] A colorless power of 3,5-dihydroxy-2-hexyl-hexadecanoic
1,3-lactone (6 g, produced as described on pages 11 and 12 of U.S.
Pat. No. 4,202,824) is dissolved in 500 mL of THF to which is added
Boc-(L) 2-amino-4-methylpentanoic acid chloride (3 g,
Boc-(L)-Leucine). The reaction mixture is stirred and heated to
reflux until HPLC indicates that the esterification is essentially
complete. The organic phase is evaporated and the residue purified
by chromatography on silica gel with toluene-ethyl acetate to yield
5-[Boc-(L) 2-amido-4-methylvaleryloxy]-2-h- exyl-hexadecanoic
1,3-lactone (6 g).
EXAMPLE 3
[0241] The BOC group of the product (6 mg) of Example 2 is removed
by hydrogenation at room temperature in 120 mL of THF in the
presence of 10% Pd/C. After hydrogenation is completed, the
catalyst is filtered off and the filtrate is evaporated to yield a
crude free amino group product, which is taken up in 100 mL of THF.
The functionalized chitosan product produced in Example 1 is taken
up in 200 mL of THF and stirred while the crude free amino product
is added dropwise at room temperature. The mixture is gradually
heated to 40.degree. C. with stirring until HPLC indicates the
formation of the carboxamide linked product. Yielded is
5-[2-{(4-chitosan methyl ether)
benzoylamido}-4-methylvaleryloxy]-2-hexyl- -hexadecanoic
1,3-lactone (about 15 grams).
EXAMPLE 4
[0242] To a 1 liter flask was added 20 g of chitosan that had been
dissolved in 350 mL of DMF (N,N-dimethylformamide), with stirring
and the temperature was raised to 50.degree. C. A mixture of 0.2 g
of NaOH and 1 g of 6-bromohexanoic acid in 20 mL of DMF was added
slowly over 30 minutes with stirring. The reaction mixture was
stirred at 50.degree. C. for 4 hours. The reaction mixture was
cooled to room temperature and poured into 500 mL of ethanol. The
solid is suction filtered and washed three times with cold ethanol.
The crude precipitate was treated in 1N NaOH ethanol solution for 3
hours, then the pH was reduced to neutral by the addition of 1N
HCl. The solid was washed with cold ethanol and H.sub.2O (4:1
ratio) 3 times and dried to provide 19.7 g of functionalized
chitosan.
EXAMPLE 6
[0243] To 200 mL of THF (tetrahydrofuran) was added 9 g of the
functionalized chitosan from Example 5, with stirring. To this
mixture was added 10 mmol of HBTU (1H-benzotriazolium-1-[bis,
(dimethylamino)methylene]-hexafluorophosphate(1-)-3-oxide)
dissolved in 10 mL of DMF with stirring over a 10 minute period.
Tetrahydrostatin L-leucine ester (about 525 mg) dissolved in 100 mL
of THF was added dropwise with stirring. The pH was then adjusted
to about 8.5 by the addition of DIEA (disopropylethylamine) and the
mixture was stirred at room temperature overnight. The reaction
mixture was reduced in volume by evaporated under vacuum to about
50% volume and 500 mL of hexane was added. The mixture was filtered
and the solid cake was washed with cold hexane three times and then
with a cold ethanol/water (3:1) solution 3 times. The filter cake
was dried under a lyophilizer to yield 9.3 grams of final product
2S, 3S, 4S [2-{(hexanoic acid modified chitosan
6-hexanoylamido}-4-methylvaleryloxy]-2-hexyl-hexadecanoic
1,3-lactone (Compound A).
EXAMPLE 7
[0244] To 200 mL of THF was dissolved with stirring 10.65 g of the
functionalized chitosan from Example 5, above, followed by 2 mmoles
of HBTU. The mixture was stirred together for 15 minutes and then
350 mg of 2S, 3S, 4S 2-hexyl-4-hydroxy-hexadecanoic 1,3 lactone
that was dissolved in 30 mL of THF (tetrahydrofuran) was added. The
pH was adjusted to about 8.5 by the addition of DIEA and the
mixture was stirred overnight. The reaction mixture was filtered
and the solid was washed with cold hexane 3 times and then washed 3
times with a cold ethanol/water (3:1) mixture. The filter cake was
dried under a lyophilizer to yield 11.1 g of final product
4-[{(hexanoic acid modified chitosan 6-hexanoyloxy}-2-hexyl-hexad-
ecanoic 1,3-lactone (Compound B).
BIOLOGICAL AND OTHER PROPERTIES ASSAY EXAMPLES
EXAMPLE 8
[0245] Lipase inhibition assays were performed essentially as
follows using each of Compounds A and B.
[0246] A 1 L stock solution of 1N NaOH was made and a 500 mL stock
solution of 0.025 N NaOH was made by diluting a portion of the
stock 1N solution. Also a stock solution of 0.2 N HCl was made. A
100 mL TRIZMA solution (from Aldrich Lipase Assay Kit Cat. No.
800B) was diluted with 100 mL of denatured EtOH and 300 mL of water
to form a 500 mL TEW solution. Compound A from Example 6 (100 mg)
was added to a portion of the 0.2 N HCl stock solution and diluted
to a final volume of 300 mL with the same HCl stock solution to
form a compound A stock solution. Compound B from Example 7 was
added to a portion of the 0.2 N HCl stock solution and diluted to a
final volume of 80 mL with the same HCl stock solution to produce a
compound B stock solution. Aldrich Lipase PS Standard (human lipase
3 mL.times.3) Aldrich Product No. 8054 was diluted with isotonic
saline solution to a 25 mL volume (Lipase #1 solution). Likewise
Aldrich Pork Pancreas Lipase [EC 3.1.1.3] Product No. 32313 was
diluted to a final volume of 25 mL with isotonic saline (Lipase #2
solution). Aldrich Sigma Lipase Substrate Standard Cat. Product No.
62314 (3.times.100, 300 mL) was obtained to use as the lipid
source.
[0247] In a 500 mL beaker equipped with a heat source and a
magnetic stirrer was added 100 mL of distilled water, 10 mL of TEW
solution, 10 mL of Sigma Lipase Substrate and a 20 mL sample
(sample control was 20 mL of the stock 0.2 N HCl solution, sample A
was 20 mL of the compound A stock solution, and sample B was 20 mL
of the compound B stock solution). The pH was adjusted to about 8
with 1N NaOH using a pH meter, whose reading was noted and recorded
as a baseline reading after the pH adjustment. The temperature was
brought to 37.5.degree. C. and 1 mL of either Lipase #1 or Lipase
#2 was added and a timer was started for 30 minutes. The mixture
was stirred and the temperature maintained between 35.degree. C.
and 37.degree. C. At the end of the time period, the mixture was
stirred and triturated with 0.025 N NaOH. The volume of NaOH
solution used to return to the baseline pH reading was noted and
recorded. The percent inhibition by the Sample A or Sample B was
calculated by subtracting the volume of NaOH used to return from
baseline pH for either of Sample A or Sample B from the average
volume of NaOH used to return from baseline pH for the control
sample (three runs), the difference is divided by the average
volume of NaOH used to return to baseline pH for the control
sample, and the result was multiplied by 100% to obtain the percent
inhibition of Sample A or Sample B (two runs each).
[0248] Each of Sample A and B showed a percent inhibition of about
50% with respect to the control for each of Lipase #1 and Lipase
#2.
EXAMPLE 9
[0249] Oil binding assay were performed using each of Compounds A
and B using the procedures essentially as follows.
[0250] Six controls were obtained by adding Star Brand Olive Oil
(extra virgin light colored olive oil) to 4 or 7 mL sample bottles,
which were photographed at a distance of 10 inches by using an
IZONE POLAROID camera as follows. Control 1 was obtained by adding
3 mL of olive oil to a 7 mL bottle, which showed the clear but
light reflective oil. Control 2 was obtained by adding 3 mL of
olive oil to a 7 mL bottle and adding 10 drops of McCormick
Schilling Red Food Coloring (RFC), which showed the oil insoluble
food color at the bottom of the bottle and floating on top of the
red food coloring is the 3 mL of light reflective olive oil.
Control 3 was obtained by adding 3 mL of olive oil to a 7 mL bottle
and adding 3 mL of water followed by 5 drops RFC, which showed of
the clear separation of the red aqueous layer on the bottom of the
bottle and floating on top was the light reflective olive oil.
Control 4 was obtained by adding 1.5 g of olive oil to 1 g of
chitosan (Natural Max Brand, greater than 90% deacylated chitin)
and the two were mixed with a stirrer, followed by the addition of
4 mL of water and 5 drops of RFC, which showed the oil tightly
bound to the chitosan in the bottom of the bottle, upon which was
floating the aqueous red food color layer (a clean red meniscus
with substantially no floating oil was observed). Control 5 was
obtained by adding 1.5 g of olive oil to 1 g of cellulose (Avicel)
and the two were mixed with a stirrer, followed by the addition of
4 mL of water and 5 drops of RFC, which showed some oil bound in
the bottom to the cellulose, upon which was floating the aqueous
red food color layer, further upon which was floating a clear layer
of oil, about 3/4 mL (a clear floating oily layer meniscus was
observed to show that cellulose does not tightly bind an excess of
its weight in oil. Control 6 was obtained by adding 8 g of olive
oil to 1 g of chitosan and the two were mixed together with a
stirrer, followed by the addition of 1 mL of water and 5 drops of
RFC, which shows an hour-glass shape of oil bound by chitosan
surrounded in the middle of the bottle at the narrow point with the
aqueous red food color solution (chitosan binds oil and
substantially excludes water from the bound mixture).
[0251] For comparison with Control 4 (oil/chitosan 1.5/1 ratio)
each of Compounds A and B were mixed with oil in the same
ratio(oil/compound 1.5/1 ratio, green food coloring was added to
the aqueous portion of the compound A sample bottle and blue food
coloring was added to the aqueous portion of the compound B sample
bottle). The same results occurred with each of Compounds A and B
as for the chitosan Control 4, in that the oil is bound tightly at
the bottom of the bottle and there is substantially no floating
oil, i.e., the meniscus for each is a clean green and blue
meniscus. However, Compound B appeared to perhaps bind the oil more
tightly than either chitosan or compound A.
[0252] For comparison with Control 6 (oil/chitosan 8:1 ratio and 1
mL of aqueous solution with food coloring), compound B was added to
8 times its weight of oil and stirred to a uniform consistency. The
1 mL of water was added and 5 drops of red food coloring were
added. Upon mixing, the oil and compound B swelled to form a grainy
gel-like consistency and uniformly absorbed the 1 mL of aqueous
food coloring solution to form a homogenous layer which was present
even after 24 hours. This shows that compound B has the ability to
bind oil and then absorb at least its weight in water to form
grainy gel-like homogeneous mixture, and continues to tightly bind
the oil while being hydrated with water.
[0253] In view of the above description it is believed that one of
ordinary skill can practice the invention. The examples given above
are non-limiting in that one of ordinary skill in view of the above
will readily envision other permutations and variations on the
invention without departing from the principal concepts. Such
permutations and variations are also within the scope of the
present invention.
* * * * *