U.S. patent application number 17/828627 was filed with the patent office on 2022-09-22 for method for improving digestive health.
The applicant listed for this patent is Brightseed, Inc., Sanford-Burnham Medical Research Institute. Invention is credited to Lee Heil Chae, Fred Levine.
Application Number | 20220296542 17/828627 |
Document ID | / |
Family ID | 1000006377706 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220296542 |
Kind Code |
A1 |
Chae; Lee Heil ; et
al. |
September 22, 2022 |
METHOD FOR IMPROVING DIGESTIVE HEALTH
Abstract
Disclosed herein are methods for improving digestive health by
providing a consumable composition. Some embodiments provided
include, for example, administering a compound of Formula (I) or
compound of Formula (II). Some embodiments provide the composition
is formulated as a dietary supplement, food ingredient or additive,
a medical food, nutraceutical or pharmaceutical composition.
Inventors: |
Chae; Lee Heil; (South San
Francisco, CA) ; Levine; Fred; (La Jolla,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Brightseed, Inc.
Sanford-Burnham Medical Research Institute |
South San Francisco
La Jolla |
CA
CA |
US
US |
|
|
Family ID: |
1000006377706 |
Appl. No.: |
17/828627 |
Filed: |
May 31, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17140979 |
Jan 4, 2021 |
11382880 |
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17828627 |
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PCT/US2020/043753 |
Jul 27, 2020 |
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17140979 |
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62879727 |
Jul 29, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A23L 33/40 20160801;
A61K 36/899 20130101; A61K 36/758 20130101; A61K 2236/333 20130101;
A61K 36/31 20130101; A61K 36/21 20130101; A23L 33/105 20160801;
A61K 31/165 20130101; A61K 36/67 20130101; A23V 2002/00 20130101;
A61K 36/185 20130101; A61K 36/815 20130101; A61K 36/69 20130101;
A61K 36/39 20130101; A61P 1/14 20180101; A61K 36/81 20130101; A61K
36/725 20130101; A61K 36/8962 20130101; A61K 36/47 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A23L 33/105 20060101 A23L033/105; A23L 33/00 20060101
A23L033/00; A61P 1/14 20060101 A61P001/14; A61K 36/185 20060101
A61K036/185; A61K 36/21 20060101 A61K036/21; A61K 36/31 20060101
A61K036/31; A61K 36/39 20060101 A61K036/39; A61K 36/47 20060101
A61K036/47; A61K 36/67 20060101 A61K036/67; A61K 36/69 20060101
A61K036/69; A61K 36/725 20060101 A61K036/725; A61K 36/758 20060101
A61K036/758; A61K 36/81 20060101 A61K036/81; A61K 36/815 20060101
A61K036/815; A61K 36/8962 20060101 A61K036/8962; A61K 36/899
20060101 A61K036/899 |
Claims
1. A method for improving digestive health comprising providing a
consumable composition comprising at least one carrier and an
effective amount of an extract comprising a compound of Formula
(I), or an isomer, salt, homodimer, heterodimer, or conjugate
thereof: ##STR00010## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each
independently selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; X is CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and
R.sup.a is selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl, thereby improving
digestive health.
2. The method of claim 1, wherein said compound has the structure
of Formula II: ##STR00011## wherein: R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are each independently selected from hydrogen, deuterium,
hydroxyl, halogen, cyano, nitro, optionally substituted amino,
optionally substituted C-amido, optionally substituted N-amido,
optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; Z is CHR.sup.a, NR.sup.a, or O; and R.sup.a is selected
from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
3. The method of claim 1, wherein said extract is an ethanol
extract of a member of the genus Allium, Amoracia, Chenopodium,
Spinacia, Fagopyrum, Annona, Jatropha, Hibiscus, Piper, Eragrostis,
Zea, Nelumbo, Cannabis, Ziziphus, Zanthoxylum, Ipomea, Capsicum,
Lycium, Solanum, or Tribulus.
4. The method of claim 1, wherein the composition is formulated as
a dietary supplement, food ingredient or additive, a medical food,
nutraceutical or pharmaceutical composition.
5. The method of claim 1, wherein R.sup.1, R.sup.2, R.sup.3, and
R.sup.8 are each independently selected from hydrogen, deuterium,
hydroxyl, halogen, cyano, nitro, optionally substituted amino,
optionally substituted C-amido, optionally substituted N-amido,
optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.9 are each independently hydrogen, deuterium,
hydroxyl, or halogen; dashed bond is present; X is O; Z is
CHR.sup.a, NR.sup.a, or O; and R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
6. The method of claim 1, wherein R.sup.1, R.sup.2, and R.sup.8 are
each independently selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.9 are each independently hydrogen,
deuterium, hydroxyl, or halogen; the dashed bond is present; X is
CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and R.sup.a is
selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
7. The method of claim 2, wherein R.sup.4 is selected from
hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally
substituted amino, optionally substituted C-amido, optionally
substituted N-amido, optionally substituted ester, optionally
substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.1 and R.sup.2 are
--OH; R.sup.3 is H; the dashed bond is present; Z is CHR.sup.a,
NR.sup.a, or O; and R.sup.a is selected from hydrogen, deuterium,
hydroxyl, halogen, cyano, nitro, optionally substituted amino,
optionally substituted C-amido, optionally substituted N-amido,
optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
8. The method of claim 2, wherein R.sup.2 and R.sup.4 is selected
from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.1 is --OH; R.sup.3
is H; the dashed bond is present; Z is CHR.sup.a, NR.sup.a, or O;
and R.sup.a is selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
9. The method of claim 2, R.sup.1, R.sup.2, and R.sup.4 are --OH;
R.sup.3 is H; the dashed bond is present; Z is CHR.sup.a, NR.sup.a,
or O; and R.sup.a is selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
10. The method of claim 1 or 2, wherein the compound of Formula (I)
or Formula (II) is selected from the group consisting of:
N-trans-caffeoyltyramine, N-cis-caffeoyltyramine,
N-trans-feruloyltyramine, N-cis-feruloyltyramine,
p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and
5-hydroxyferuloyltyramine, or a pharmaceutically acceptable salt,
solvates, and combinations of the foregoing.
11. The method of claim 1 or 2, wherein the compound of Formula (I)
or Formula (II) is selected from the group consisting of: a
compound of Formula (II) is selected from
(E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acry-
lamide,
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)aceti-
c acid, ethyl
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate,
(E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamid-
e,
(E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylam-
ide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)phenethyl)a-
crylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acryla-
mide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl-
)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide,
(E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acr-
ylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methox-
y)phenethyl)acrylamide,
(E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl
hydrogen carbonate,
(E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acryla-
mide,
(E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-y-
l)phenoxy)acetic acid,
(E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenethyl)acr-
ylamide,
(E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphene-
thyl)acrylamide,
(E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide-
,
(E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)glycine,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)-
acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide,
(E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide,
3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide,
or pharmaceutical salts, solvates, and combination of the
foregoing.
12. The method of claim 1 or 2, wherein the compound of Formula (I)
or Formula (II) is in the form of a pharmaceutically acceptable
salt.
13. The method of claim 1 or 2, wherein the composition of Formula
(I) or Formula (II) is in a unit dosage form and is configured for
administration between 0.1 and 100 mg/kg of the body weight of the
subject of Formula (I) or Formula (II) per administration.
14. The method of claim 1 or 2, wherein administering the compound
of Formula (I) or Formula (II) increases HNF4.alpha.
expression.
15. The method of claim 1 or 2, wherein administering the compound
of Formula (I) or Formula (II) reverses the loss of Paneth cells
that occur from a high fat diet.
16. The method of claim 1 or 2, wherein improving digestive health
is treating or ameliorating digestive health in the subject.
17. The method of claim 1 or 2, wherein improving digestive health
is treating or ameliorating inflammation.
18. The method of claim 1 or 2, wherein improving digestive health
is increasing HNF4.alpha. expression in the subject.
19. The method of claim 1 or 2, wherein improving digestive health
reverses the loss of Paneth cells.
20. The method of claim 1 or 2, wherein improving digestive health
improves digestive health in a subject by at least 30%.
21. The method of claim 1 or 2, wherein improving digestive health
reduces a disease or condition by about 30%.
22. The method of claim 1 or 2, wherein improving digestive health
improves intestinal villus levels.
23. A method of treating or preventing a disease or disorder in a
subject, comprising: administering a therapeutically effective
amount of a compound of Formula I, or a pharmaceutically acceptable
salt, to a subject in need thereof, ##STR00012## wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and
R.sup.9 are each independently selected from hydrogen, deuterium,
hydroxyl, halogen, cyano, nitro, optionally substituted amino,
optionally substituted C-amido, optionally substituted N-amido,
optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; X is CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and
R.sup.a is selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; wherein the disease or
disorder is associated with the intestines.
24. The method of claim 23, wherein administering the compound of
Formula (I) induces a large increase in HNF4.alpha..
25. The method of claim 23 or 24, wherein administering the
compound of Formula (I) increases intestinal villus.
26. The method of any one of claims 23 to 25, wherein administering
the compound of Formula (I) increases Paneth cell formation.
27. The method of any one of claims 23 to 26, wherein the disease
or disorder associated with the intestines is inflammation.
28. The method of any one of claims 23 to 27, wherein the disease
or disorder associated with the intestines is a condition
associated with an allergic response.
29. The method of any one of claims 23 to 28, wherein the
composition is formulated as a dietary supplement, food ingredient
or additive, a medical food, nutraceutical or pharmaceutical
composition.
30. The method of any one of claims 23 to 29, wherein R.sup.1,
R.sup.2, R.sup.3, and R.sup.8 are each independently selected from
hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally
substituted amino, optionally substituted C-amido, optionally
substituted N-amido, optionally substituted ester, optionally
substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.9 are each independently hydrogen, deuterium,
hydroxyl, or halogen; dashed bond is present; X is O; Z is
CHR.sup.a, NR.sup.a, or O; and R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
31. The method of any one of claims 23 to 30, wherein R.sup.1,
R.sup.2, and R.sup.8 are each independently selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.9 are each independently hydrogen,
deuterium, hydroxyl, or halogen; the dashed bond is present; X is
CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and R.sup.a is
selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
32. The method of any one of claims 23 to 31, wherein the compound
of Formula (I) is selected compound is selected from the group
consisting of: N-trans-caffeoyltyramine, N-cis-caffeoyltyramine,
N-trans-feruloyltyramine, N-cis-feruloyltyramine,
p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and
5-hydroxyferuloyltyramine.
33. The method of any one of claims 23 to 32, wherein the compound
of Formula (I) is in the form of a pharmaceutically acceptable
salt.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 17/140,979 filed Jan. 4, 2021, which is a
continuation of PCT/US2020/043753 filed Jul. 27, 2020, which claims
the priority benefit of U.S. Provisional Application No. 62/879,727
filed Jul. 29, 2019, the entire content of each of which is hereby
incorporated by reference herein in its entirety.
BACKGROUND
[0002] HNF4.alpha. is a nuclear receptor that acts as a
transcriptional regulator of many genetic programs in humans,
including those underlying sugar and lipid metabolism. It is
expressed in a number of tissues including the liver, pancreas, and
kidney, as well as the intestine. HNF4.alpha. is known to have a
diverse role in epithelial biology, cells, including the central
regulation architecture of epithelial morphogenesis, and
homeostasis and barrier functioning of the intestinal epithelium
(Cattin, et al. (2009) Mol. Cell. Biol. 29(23):6294-6308; Spath
& Weiss (1998) J. Cell Biol. 140: 935-946). In addition, the
HNF4.alpha. gene is highly expressed in the small intestine and
colon and the HNF4.alpha. protein is abundant in the nucleus of
mucosal epithelial cells (Jiang, et al. (2003) Nucl. Recept. 1:5).
Further, it has been suggested that HNF4.alpha. has a protective
role in inflammatory bowel disease (IBD), and that HNF4.alpha.
agonists may be of use in the treatment of IBD (Chahar, et al.
(2014) Mol. Cell. Biol. 34:3291-3304).
[0003] Studies have shown that HNF4.alpha. is critical to the
expression and proper localization of tight and adherens junction
proteins (Chiba, et al. (2003) Exp. Cell Res. 286:288-297; Parviz,
et al. (2003) Nat. Genet. 34:292-296), and the formation of
microvilli within the intestine (Chiba, et al. (2006) J. Cell Biol.
175(6):971-980). Further, HNF4.alpha. has also been described as a
central regulator protecting the intestinal epithelium against
inflammation (Babeu & Boudreau (2014) World J. Gastroenterol.
20(1):22-30). Moreover, HNF4.alpha. expression has been shown to be
drastically reduced in intestinal tissues from patients with
Crohn's disease (CD) and ulcerative colitis (UC) (Darsigny, et al.
(2009) PLoS One 4:e7609; Ahn, et al. (2008) Inflamm. Bowel Dis.
14:908-920).
[0004] Studies with intestine-specific HNF4.alpha. null mice have
shown that the null mice are more susceptible to dextran sulfate
sodium (DSS)-induced colitis, and exhibit an increase in intestinal
permeability compared to control mice (Ahn, et al. (2008) Inflamm.
Bowel Dis. 14: 908-920). In another study, mice lacking intestinal
expression of both HNF4.alpha. P1 and P2 isoforms developed
progressive, chronic gut inflammation similar to human IBD,
suggesting that long-term reduction of HNF4.alpha. activity is
likely to promote IBD (Darsigny, et al. (2009) PLoS One
4:e7609).
[0005] It is estimated that three million US adults have received
the IBD diagnosis, equaling just over 1% of the population, and
prevalence is increasing. Direct treatment costs for IBD are
estimated to be near $7 billion. Given that many conditions go
undiagnosed and IBD can also afflict children, it is likely that
the actual prevalence of IBD is much higher and exceeds current
cost estimates. Accordingly, there is a need in the art to improve
the digestive health of these individuals in a manner which has a
high acceptance by patients, efficacy, relative safety, and
relatively low cost. The present disclosure addresses this need in
the art.
SUMMARY OF THE DISCLOSURE
[0006] The present disclosure provides a method for improving
digestive health by providing a consumable composition composed of
at least one carrier and an effective amount of an extract
comprising a compound of Formula I, or an isomer, salt, homodimer,
heterodimer, or conjugate thereof:
##STR00001##
[0007] In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each
independently selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; X is CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and
R.sup.a is selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl, thereby improving
digestive health.
[0008] In some embodiments, the compound has the structure of
Formula II:
##STR00002##
[0009] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are each independently selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; Z is CHR.sup.a, NR.sup.a, or O; and R.sup.a is selected
from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0010] In some embodiments, the extract is an ethanol extract of a
member of the genus Allium, Amoracia, Chenopodium, Spinacia,
Fagopyrum, Annona, Jatropha, Hibiscus, Piper, Eragrostis, Zea,
Nelumbo, Cannabis, Ziziphus, Zanthoxylum, Ipomea, Capsicum, Lycium,
Solanum, or Tribulus.
[0011] In some embodiments, the composition is formulated as a
dietary supplement, food ingredient or additive, a medical food,
nutraceutical or pharmaceutical composition.
[0012] In some embodiments, the compound of Formula (I) or Formula
(II) is selected from the group consisting of:
N-trans-caffeoyltyramine, N-cis-caffeoyltyramine,
N-trans-feruloyltyramine, N-cis-feruloyltyramine,
p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and
5-hydroxyferuloyltyramine, or a pharmaceutically acceptable salt,
solvates, and combinations of the foregoing.
[0013] In some embodiments, the compound of Formula (I) or Formula
(II) is selected from the group consisting of: a compound of
Formula (II) is selected from
(E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acry-
lamide,
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)aceti-
c acid, ethyl
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate,
(E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamid-
e,
(E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylam-
ide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)phenethyl)a-
crylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acryla-
mide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl-
)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide,
(E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acr-
ylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methox-
y)phenethyl)acrylamide,
(E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl
hydrogen carbonate,
(E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acryla-
mide,
(E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-y-
l)phenoxy)acetic acid,
(E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenethyl)acr-
ylamide,
(E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphene-
thyl)acrylamide,
(E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide-
,
(E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)glycine,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)-
acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide,
(E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide,
3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide,
or pharmaceutical salts, solvates, and combination of the
foregoing.
[0014] In some embodiments, the composition of Formula (I) or
Formula (II) is in a unit dosage form and is configured for
administration between 0.1 and 100 mg/kg of the body weight of the
subject per administration.
[0015] In some embodiments, administering the compound of Formula
(I) or Formula (II) increases HNF4.alpha. expression.
[0016] In some embodiments, administering the compound of Formula
(I) or Formula (II) reverses the loss of Paneth cells that occur
from a high fat diet.
[0017] In some aspects, a method of treating or preventing a
disease or disorder in a subject, comprising: administering a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt, to a subject in need thereof,
##STR00003##
[0018] wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently
selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted amino, optionally substituted C-amido,
optionally substituted N-amido, optionally substituted ester,
optionally substituted --(O)C.sub.1-6alkyl, optionally substituted
--(O)C.sub.1-6alkenyl, optionally substituted --(O)C.sub.1-6alkynl,
optionally substituted, --(O)C.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally
substituted --(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; the dashed bond is present
or absent; X is CH.sub.2 or O; Z is CHR.sup.a, NR.sup.a, or O; and
R.sup.a is selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl; wherein the disease or
disorder is associated with the intestines.
[0019] In some embodiments, administering a compound of Formula (I)
induces a large increase in HNF4.alpha..
[0020] In some embodiments, administering a compound of Formula (I)
increases intestinal villus.
[0021] In some embodiments, administering a compound of Formula (I)
increases Paneth cell formation.
[0022] In some embodiments, the disease or disorder associated with
the liver or intestines is inflammation.
[0023] In some embodiments, the disease or disorder associated with
the intestines is a condition associated with an allergic
response.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The features and advantages of the compositions and methods
described herein will become apparent from the following
description, taken in conjunction with the accompanying drawings.
These drawings depict certain aspects of the compositions and
methods described in the present application, and thus, are not to
be considered limiting. In the drawings, similar reference numbers
or symbols typically identify similar components, unless context
dictates otherwise. The drawings may not be drawn to scale.
[0025] FIG. 1 illustrates a dose-response analysis of
N-trans-caffeoyltyramine, N-trans-feruloyltyramine and
p-coumaroyltyramine in an assay measuring insulin promoter
activity. Dimethylsulfoxide (DMSO) and alverine (20 .mu.M) were
used as negative and positive controls, respectively.
[0026] FIG. 2 illustrates the effect of N-trans-caffeoyltyramine,
N-trans-feruloyltyramine and p-coumaroyltyramine on HNF4.alpha.
mRNA levels as determined by quantitative PCR. DMSO and alverine
(20 .mu.M) were used as negative and positive controls,
respectively.
[0027] FIG. 3 illustrates the amounts of N-trans-caffeoyltyramine,
N-trans-feruloyltyramine and p-coumaroyl tyramine present in
ethanol extracts (% of extract, w/w) from a variety of sources
including Tribulus terrestris seed (1), Cannabis (hemp) seed hull
(2), Annona spp. (atemoya) seed (3), Annona muricata (Guanabana)
seed (4), A. cherimola (Cherimoya) leaf (5), Zea mays stalk (6),
Tribulus terrestris (Goat Head) seed (7), A. cherimola hardwood
(bark and core) (8), Solanum lycopersicum ground pomace (9), S.
tuberosum (yellow potato) peel (10), Piper nigrum (black
peppercorn) fruit (11), S. tuberosum (purple potato) peel (12), S.
tuberosum (red potato) peel (13), S. lycopersicum pomace (14), S.
lycopersicum extruded pomace (15), A. muricata (Guanabana) leaves
(16), Allium sativum (garlic) bulb (17), S. tuberosum (purple
potato) peel (18), A. montana (Mountain soursop) leaves (19), Z.
mays leaves (20), S. tuberosum (purple potato) sprouts (21), A.
cherimola (Cherimoya) seed (22), Allium fistulosum (green onion)
whole plant (23), S. tuberosum (white potato) peel (24), A.
cherimola (Cherimoya) greenwood (25), Cannabis (hemp) leaves (26),
S. tuberosum (white potato) peel (27), S. lycopersicum seed (28),
S. lycopersicum (Beefsteak) whole fruit (29), A. muricata
(Guarabana) skin of unripe fruit (30), A. muricata (Guanabana) ripe
fresh fruit (31), A. squamosa (sweetsop) whole fruit (32), Capsicum
annuum (serrano pepper) fruit (33), S. tuberosum (Russet potato)
peel (34), Lycium barbarum (goji/wolf berry) fruit (35), S.
tuberosum (purple potato) core (36), Chenopodium quinoa (quinoa)
seed (37), Ipomoea batatas (sweet potato) whole potato (38),
Ipomoea batatas (sweet potato) peel (39), Armoracia rusticana
(horseradish) root (40), S. tuberosum (Colorado potato) peel (41),
Fagopyrum esculentum (buckwheat) hulls (42), Capsicum frutescens
(piri piri pepper) fruit (43), S. tuberosum (purple potato) core
(44), C. annuum (Thai chili) stems and leaves (45), A. muricata
(Guanabana) unripe fruit flesh (46), S. tuberosum (yellow potato)
core (47), and Eragrostis tef (teff) seed (48).
[0028] FIG. 4 illustrates HNF4.alpha. is increased in the intestine
of DIG mice treated with NCT.
[0029] FIG. 5 illustrates paneth cells are increased in the
intestine of DIG mice treated with NCT.
DETAILED DESCRIPTION
[0030] It has now been shown that tyramine containing
hydroxycinnamic acid amides and extracts containing the same, which
are isolated from natural sources, increase or enhance HNF4.alpha.
expression/activity. Given that decreased expression of HNF4.alpha.
within the intestinal epithelial layer has been shown to be
associated with IBD pathogenesis and other chronic conditions
linked to gut inflammation, these natural compounds and extracts
are of use in restoring digestive health in IBD and other chronic
gastrointestinal conditions. Advantageously, the compounds and
extracts of this disclosure have a number of potential benefits
including acceptance by patients, relative safety, low cost and use
as a complementary approach to conventional Western medicine
approaches.
[0031] The tyramine containing hydroxycinnamic acid amide of this
disclosure are analogs of lead compounds identified in traditional
screening assays for agents that modulate known signaling pathways.
The tyramine containing hydroxycinnamic acid amides exhibit
dose-response HNF4.alpha. activity, as initially determined in a
T6PNE engineered pancreatic cell, and increase HNF4.alpha. mRNA
levels. While not wishing to be bound by theory, it is believed
that the tyramine containing hydroxycinnamic acid amides of this
disclosure increase HNF4.alpha. activity as a result of higher
affinity for the HNF4.alpha. binding site than the natural ligand,
palmitic acid, which down regulates HNF4.alpha. activity.
Accordingly, by increasing HNF4.alpha. activity, the compounds of
this disclosure are of use in improving heal thy digestive
function, thereby addressing the underlying pathogenesis of
gastrointestinal disorders such as IBD, UC, and CD. Using the
composition of this disclosure, health and well-being are improved
and promoted.
Compositions
[0032] In some aspects, the disclosure provided herein disclosure
provides plant-derived aromatic metabolites with one or more acidic
hydroxyl groups attached to aromatic arenes, and their use in
modulating metabolism. In one embodiment, the plant-derived
aromatic metabolite is a structural analog of compound 1:
##STR00004##
[0033] In particular, the disclosure encompasses a compound of
Formula (I), or an isomer, salt, homodimer, heterodimer, or
conjugate thereof:
##STR00005##
[0034] In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each
independently selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0035] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.8
are each independently selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl, and R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.9 are each independently hydrogen,
deuterium, hydroxyl, or halogen;
[0036] In some embodiments, R.sup.1, R.sup.2, and R.sup.8 are each
independently selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl, and R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, and R.sup.9 are each independently
hydrogen, deuterium, hydroxyl, or halogen.
[0037] In some embodiments, the dashed bond is present or
absent.
[0038] In some embodiments, X is CH.sub.2 or O.
[0039] In some embodiments, Z is CHR.sup.a, NR.sup.a, or O.
[0040] In some embodiments, R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0041] In some embodiments, a compound of Formula (I) is provided
as a pharmaceutically acceptable salt or solvate thereof.
[0042] In some embodiments, a compound of Formula (I) is selected
from (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acry-
lamide,
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)aceti-
c acid, ethyl
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate,
(E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamid-
e,
(E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylam-
ide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)phenethyl)a-
crylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acryla-
mide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl-
)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide,
(E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acr-
ylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methox-
y)phenethyl)acrylamide,
(E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl
hydrogen carbonate,
(E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acryla-
mide,
(E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-y-
l)phenoxy)acetic acid,
(E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenethyl)acr-
ylamide,
(E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphene-
thyl)acrylamide,
(E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide-
,
(E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)glycine,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)-
acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide,
(E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide,
3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide,
or pharmaceutical salts, solvates, and combination of the
foregoing.
[0043] In some embodiments, the disclosure encloses a compound of
Formula (II):
##STR00006##
[0044] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are each independently selected from hydrogen, deuterium, hydroxyl,
halogen, cyano, nitro, optionally substituted amino, optionally
substituted C-amido, optionally substituted N-amido, optionally
substituted ester, optionally substituted --(O)C.sub.1-6alkyl,
optionally substituted --(O)C.sub.1-6alkenyl, optionally
substituted --(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0045] In some embodiments, the dashed bond is present or
absent.
[0046] In some embodiments, Z is CHR.sup.a, NR.sup.a, or O.
[0047] In some embodiments, R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0048] In some embodiments, a compound of Formula (II) is selected
from (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acry-
lamide,
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)aceti-
c acid, ethyl
(E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate,
(E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamid-
e,
(E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylam-
ide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)phenethyl)a-
crylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamid-
e,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acryla-
mide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acryl-
amide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy-
)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl-
)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide-
,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide,
(E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acr-
ylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methox-
y)phenethyl)acrylamide,
(E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl
hydrogen carbonate,
(E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide,
(E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acryla-
mide,
(E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-y-
l)phenoxy)acetic acid,
(E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenethyl)acr-
ylamide,
(E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphene-
thyl)acrylamide,
(E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide,
(E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide-
,
(E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)glycine,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)-
acrylamide,
(E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide,
(E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylam-
ide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide,
3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide,
or pharmaceutical salts, solvates, and combination of the
foregoing.
[0049] In some embodiments, a compound of Formula (II) is provided
as a pharmaceutically acceptable salt or solvate thereof.
[0050] In some embodiments, the disclosure encloses a compound of
Formula (III):
##STR00007##
[0051] In some embodiments, R.sup.3 and R.sup.4 are each
independently selected from hydrogen, deuterium, hydroxyl, halogen,
cyano, nitro, optionally substituted amino, optionally substituted
C-amido, optionally substituted N-amido, optionally substituted
ester, optionally substituted --(O)C.sub.1-6alkyl, optionally
substituted --(O)C.sub.1-6alkenyl, optionally substituted
--(O)C.sub.1-6alkynl, optionally substituted,
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.2-12heterocyclyl, optionally substituted
--(O)C.sub.5-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0052] In some embodiments, the each independently selected dashed
bond is present or absent.
[0053] In some embodiments, Z is CHR.sup.a, NR.sup.a, or O.
[0054] In some embodiments, R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally substituted
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12heteroaryl.
[0055] In some embodiments, Q.sup.a, Q.sup.b, Q.sup.c, Q.sup.d are
each independently selected from a bond, CHR.sup.a, NR.sup.a,
C.dbd.O, and --O--.
[0056] In some embodiments, R.sup.a is selected from hydrogen,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C-amido, optionally substituted
N-amido, optionally substituted ester, optionally substituted
--(O)C.sub.1-6alkyl, optionally substituted --(O)C.sub.1-6alkenyl,
optionally substituted --(O)C.sub.1-6alkynl, optionally
substituted, --(O)C.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12cycloalkyl, optionally substituted
--(O)C.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.1-6alkylC.sub.4-12heterocyclyl, optionally substituted
--(O)C.sub.4-12aryl, optionally substituted
--(O)C.sub.1-6alkylC.sub.5-12aryl, optionally substituted
--(O)C.sub.1-12heteroaryl, and optionally substituted
--(O)C.sub.1-6alkylC.sub.1-12heteroaryl.
[0057] In some embodiments, Q.sup.c, Q.sup.d are absent. In some
embodiments, Q.sup.d is absent.
[0058] In some embodiments, n is 1, 2, 3, or 4
[0059] In some embodiments, a compound of Formula (II) is provided
as a pharmaceutically acceptable salt or solvate thereof.
[0060] "Isomer" refers to especially optical isomers (for example
essentially pure enantiomers, essentially pure diastereomers, and
mixtures thereof) as well as conformation isomers (i.e., isomers
that differ only in their angles of at least one chemical bond),
position isomers (particularly tautomers), and geometric isomers
(e.g., cis-trans isomers).
[0061] In certain embodiments, a compound of Formula (I) or Formula
(II) is selected from:
##STR00008## ##STR00009##
[0062] A salt of a compound of this disclosure refers to a compound
that possesses the desired pharmacological activity of the parent
compound and includes: (1) an acid addition salt, formed with an
inorganic acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with an organic acid such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic camphorsulfonic
acid, acid, 4-toluenesulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) a salt formed when an acidic proton
present in the parent compound is replaced.
[0063] As is known in the art, a homodimer is a molecule composed
of two identical tyramine containing hydroxycinnamic acid amide
subunits. By comparison, a heterodimer is a molecule composed of
two different tyramine containing hydroxycinnamic acid amide
subunits. Examples of homodimers of this disclosure include but are
not limited to a cross-linked N-trans-feruloyltyramine dimer, a
cross-linked N-trans-caffeoyl tyramine dimer and a cross-linked
p-coumaroyltyramine dimer. See, for example, King & Calhoun
(2005) Phytochemistry 66(20): 2468-73, which teaches the isolation
of a cross-linked N-transferuloyltyramine dimer from potato common
scab lesions.
[0064] Conjugates of monomers of tyramine containing
hydroxycinnamic acid amide and other compounds, such as lignan
amides. Examples of conjugates include, but are not limited to
cannabisin A, cannabisin B, cannabisin C, cannabisin D, cannabisin
E, cannabisin F and grossamide.
[0065] Whenever a group is described as being "optionally
substituted" that group may be unsubstituted or substituted with
one or more of the indicated substituents. Likewise, when a group
is described as being "unsubstituted or substituted" if
substituted, the substituent may be selected from one or more the
indicated substituents. If no substituents are indicated, it is
meant that the indicated "optionally substituted" or "substituted"
group may be individually and independently substituted with one or
more group(s) individually and independently selected from alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl,
(heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy,
aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen,
thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,
C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl,
haloalkyl, haloalkoxy, trihalomethanesulfonyl,
trihalomethanesulfonamido, amino, mono-substituted amino group and
di-substituted amino group, and protected derivatives thereof.
[0066] For the groups herein, the following parenthetical
subscripts further define the groups as follows: "(C.sub.n)"
defines the exact number (n) of carbon atoms in the group. For
example, "C.sub.1-C.sub.6-alkyl" designates those alkyl groups
having from 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or any
range derivable therein (e.g., 3-6 carbon atoms)).
[0067] In addition to isomers, salts, homodimers, heterodimers, and
conjugates, the tyramine containing hydroxycinnamic acid amide may
also be glycosylated. A glycosylated tyramine containing
hydroxycinnamic acid amide may be produced by transglycosylating
the tyramine containing hydroxycinnamic acid amide to add glucose
units, for example, one, two, three, four, five, or more than five
glucose units, to the tyramine containing hydroxycinnamic acid
amide. Transglycosylation can be carried out with any suitable
enzyme including, but not limited to, a pullulanase and isomaltase
(Lobov, et al. (1991) Agric. Biol. Chem. 55:2959-2965),
.about.-galactosidase (Kitahata, et al. (1989) Agric. Biol. Chem.
53:2923-2928), dextrine saccharase (Yamamoto, et al. (1994) Biosci.
Biotech. Biochem. 58: 1657-1661) or cyclodextrin
gluconotransferase, with pullulan, maltose, lactose, partially
hydrolyzed starch and maltodextrin being donors.
[0068] As used herein, "alkyl" refers to a straight or branched
hydrocarbon chain that comprises a fully saturated (no double or
triple bonds) hydrocarbon group. The alkyl group may have 1 to 20
carbon atoms (whenever it appears herein, a numerical range such as
"1 to 20" refers to each integer in the given range; e.g., "1 to 20
carbon atoms" means that the alkyl group may consist of 1 carbon
atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20
carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is
designated). The alkyl group may also be a medium size alkyl having
1 to 10 carbon atoms. The alkyl group could also be a lower alkyl
having 1 to 6 carbon atoms. The alkyl group of the compounds may be
designated as "C1-C4 alkyl" or similar designations. By way of
example only, "C1-C4 alkyl" indicates that there are one to four
carbon atoms in the alkyl chain, i.e., the alkyl chain is selected
from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and t-butyl. Typical alkyl groups include, but are in no
way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tertiary butyl, pentyl, and hexyls. The alkyl group may be
substituted or unsubstituted.
[0069] The term "halogen atom" or "halogen" as used herein, means
any one of the radio-stable atoms of column 7 of the Periodic Table
of the Elements, such as chloro (Cl), fluoro (F), bromo (Br) and
iodo (I) groups.
[0070] In any of the groups described herein, an available hydrogen
may be replaced with an alkyl, alkenyl, alkynyl, aryl, heteroaryl,
aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, alkoxyalkoxy, alkoxycarbonyl, acyl, halo, nitro,
aryloxycarbonyl, cyano, carboxy, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, or
heterocyclyl.
[0071] Any undefined valency on an atom of a structure shown in
this application implicitly represents a hydrogen atom bonded to
the atom.
[0072] As used herein, "alkenyl" refers to an alkyl group, as
defined herein, that contains in the straight or branched
hydrocarbon chain one or more double bonds. An alkenyl group may be
unsubstituted or substituted.
[0073] As used herein, "alkynyl" refers to an alkyl group as
defined herein, that contains in the straight or branched
hydrocarbon chain one or more triple bonds. An alkynyl group may be
unsubstituted or substituted.
[0074] As used herein, "cycloalkyl" refers to a completely
saturated (no double or triple bonds) mono- or multi-cyclic
hydrocarbon ring system. When composed of two or more rings, the
rings may be joined together in a fused fashion. Cycloalkyl groups
can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the
ring(s). A cycloalkyl group may be unsubstituted or substituted.
Typical cycloalkyl groups include, but are in no way limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
[0075] As used herein, "aryl" refers to a carbocyclic (all carbon)
monocyclic or multicyclic aromatic ring system (including, e.g.,
fused, bridged, or spiro ring systems where two carbocyclic rings
share a chemical bond, e.g., one or more aryl rings with one or
more aryl or non-aryl rings) that has a fully delocalized
pi-electron system throughout at least one of the rings. The number
of carbon atoms in an aryl group can vary. For example, the aryl
group can be a C.sub.6-C.sub.14 aryl group, a C.sub.6-C.sub.10 aryl
group, or a C.sub.6 aryl group. Examples of aryl groups include,
but are not limited to, benzene, naphthalene, and azulene. An aryl
group may be substituted or unsubstituted.
[0076] As used herein, "heterocyclyl" refers to mono- or polycyclic
ring systems including at least one heteroatom (e.g., O, N, S).
Such systems can be unsaturated, can include some unsaturation, or
can contain some aromatic portion, or be all aromatic. A
heterocyclyl group can contain from 3 to 30 atoms. A heterocyclyl
group may be unsubstituted or substituted.
[0077] In particular embodiments, R.sup.1 is present and represents
a hydroxy group at the para position and R.sup.2 is a hydroxy or
lower alkoxy group at the meta position. In certain embodiments,
the tyramine containing hydroxycinnamic acid amide having the
structure of Formula (I) is in the trans configuration.
[0078] As used herein, "heteroaryl" refers to a monocyclic or
multicyclic aromatic ring system (a ring system having a least one
ring with a fully delocalized pi-electron system) that contain(s)
one or more heteroatoms, that is, an element other than carbon,
including but not limited to, nitrogen, oxygen, and sulfur, and at
least one aromatic ring. The number of atoms in the ring(s) of a
heteroaryl group can vary. For example, the heteroaryl group can
contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s)
or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl"
includes fused ring systems where two rings, such as at least one
aryl ring and at least one heteroaryl ring, or at least two
heteroaryl rings, share at least one chemical bond. Examples of
heteroaryl rings include, but are not limited to, furan, furazan,
thiophene, benzothiophene, phthalazine, pyrrole, oxazole,
benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,
benzimidazole, indole, indazole, pyrazole, benzopyrazole,
isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole,
thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,
purine, pteridine, quinoline, isoquinoline, quinazoline,
quinoxaline, cinnoline, and triazine. A heteroaryl group may be
substituted or unsubstituted.
[0079] The term "amino" as used herein refers to a --NH.sub.2
group.
[0080] As used herein, the term "hydroxy" refers to a --OH
group.
[0081] A "cyano" group refers to a "--CN" group.
[0082] A "carbonyl" group refers to a C.dbd.O group.
[0083] A "C-amido" group refers to a "--C(.dbd.O)N(R.sub.AR.sub.B)"
group in which R.sub.A and R.sub.B can be independently hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroaryl, heteroalicyclyl, aralkyl, or
(heteroalicyclyl)alkyl, as defined above. A C-amido may be
substituted or unsubstituted.
[0084] An "N-amido" group refers to a "RC(.dbd.O)N(R.sub.A)--"
group in which R and R.sub.A can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as
defined above. An N-amido may be substituted or unsubstituted.
[0085] A "urea" group refers to a
"--N(R.sub.AR.sub.B)--C(.dbd.O)--N(R.sub.AR.sub.B)--" group in
which R.sub.A and R.sub.B can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as
defined above. A urea group may be substituted or
unsubstituted.
[0086] The term "pharmaceutically acceptable salt" as used herein
is a broad term, and is to be given its ordinary and customary
meaning to a person of ordinary skill in the art (and is not to be
limited to a special or customized meaning), and refers without
limitation to a salt of a compound that does not cause significant
irritation to an organism to which it is administered and does not
abrogate the biological activity and properties of the compound. In
some embodiments, the salt is an acid addition salt of the
compound. Pharmaceutical salts can be obtained by reacting a
compound with inorganic acids such as hydrohalic acid (e.g.,
hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid,
and phosphoric acid. Pharmaceutical salts can also be obtained by
reacting a compound with an organic acid such as aliphatic or
aromatic carboxylic or sulfonic acids, for example formic acid,
acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid,
malonic acid, maleic acid, fumaric acid, trifluoroacetic acid
(TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid,
lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,
nicotinic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid,
butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid,
1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid, or
naphthalenesulfonic acid. Pharmaceutical salts can also be obtained
by reacting a compound with a base to form a salt such as an
ammonium salt, an alkali metal salt, such as a lithium, sodium or a
potassium salt, an alkaline earth metal salt, such as a calcium,
magnesium or aluminum salt, a salt of organic bases such as
dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, C.sub.1-C.sub.7 alkylamine,
cyclohexylamine, dicyclohexylamine, triethanolamine,
ethylenediamine, ethanolamine, diethanolamine, triethanolamine,
tromethamine, and salts with amino acids such as arginine and
lysine; or a salt of an inorganic base, such as aluminum hydroxide,
calcium hydroxide, potassium hydroxide, sodium carbonate, sodium
hydroxide, or the like.
[0087] It is understood that, in any compound described herein
having one or more chiral centers, if an absolute stereochemistry
is not expressly indicated, then each center may independently be
of R-configuration or S-configuration or a mixture thereof. Thus,
the compounds provided herein may be enantiomerically pure,
enantiomerically enriched, or may be stereoisomeric mixtures, and
include all diastereomeric, and enantiomeric forms. In addition it
is understood that, in any compound described herein having one or
more double bond(s) generating geometrical isomers that can be
defined as E or Z, each double bond may independently be E or Z a
mixture thereof. Stereoisomers are obtained, if desired, by methods
such as, stereoselective synthesis and/or the separation of
stereoisomers by chiral chromatographic columns.
[0088] Likewise, it is understood that, in any compound described,
all tautomeric forms are also intended to be included.
[0089] It is understood that the compounds described herein can be
labeled isotopically or by another other means, including, but not
limited to, the use of chromophores or fluorescent moieties,
bioluminescent labels, or chemiluminescent labels. Substitution
with isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, such as, for
example, increased in vivo half-life or reduced dosage
requirements. Each chemical element as represented in a compound
structure may include any isotope of said element. For example, in
a compound structure a hydrogen atom may be explicitly disclosed or
understood to be present in the compound. At any position of the
compound that a hydrogen atom may be present, the hydrogen atom can
be any isotope of hydrogen, including but not limited to hydrogen-1
(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,
reference herein to a compound encompasses all potential isotopic
forms unless the context clearly dictates otherwise.
[0090] It is understood that the compounds described herein can be
labeled isotopically or by another other means, including, but not
limited to, the use of chromophores or fluorescent moieties,
bioluminescent labels, or chemiluminescent labels. Substitution
with isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, such as, for
example, increased in vivo half-life or reduced dosage
requirements. Each chemical element as represented in a compound
structure may include any isotope of said element. For example, in
a compound structure a hydrogen atom may be explicitly disclosed or
understood to be present in the compound. At any position of the
compound that a hydrogen atom may be present, the hydrogen atom can
be any isotope of hydrogen, including but not limited to hydrogen-1
(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,
reference herein to a compound encompasses all potential isotopic
forms unless the context clearly dictates otherwise.
[0091] It is understood that the methods and formulations described
herein include the use of crystalline forms, amorphous phases,
and/or pharmaceutically acceptable salts, solvates, hydrates, and
conformers of compounds of some embodiments, as well as metabolites
and active metabolites of these compounds having the same type of
activity. A conformer is a structure that is a conformational
isomer. Conformational isomerism is the phenomenon of molecules
with the same structural formula but different conformations
(conformers) of atoms about a rotating bond. In specific
embodiments, the compounds described herein exist in solvated forms
with pharmaceutically acceptable solvents such as water, ethanol,
or the like. In other embodiments, the compounds described herein
exist in unsolvated form. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent and may be formed during
the process of crystallization with pharmaceutically acceptable
solvents such as water, ethanol, or the like. Hydrates are formed
when the solvent is water, or alcoholates are formed when the
solvent is alcohol. In addition, the compounds provided herein can
exist in unsolvated as well as solvated forms. In general, the
solvated forms are considered equivalent to the unsolvated forms
for the purposes of the compounds and methods provided herein.
Other forms in which the compounds of some embodiments can be
provided include amorphous forms, milled forms and nano-particulate
forms.
[0092] Likewise, it is understood that the compounds described
herein, such as compounds of some embodiments, include the compound
in any of the forms described herein (e.g., pharmaceutically
acceptable salts, prodrugs, crystalline forms, amorphous form,
solvated forms, enantiomeric forms, tautomeric forms, and the
like).
Sources of Active Compound
[0093] A compound of this disclosure can be obtained from any
suitable botanical species and/or botanical raw material known to
possess a compound of Formula (I). Preferably, the compound is
provided as an extract comprising the compound or a substantially
pure compound.
[0094] An "extract" refers to a composition containing a compound
of Formula (I), which is separated from other unwanted substances
present in the natural source material from which the extract was
obtained. In some embodiments, the natural source material is a
plant. Plant extracts can be obtained from any plant tissue
including a whole plant; a plant part such as shoot vegetative
organs/structures (for example, leaves, stems and tubers), roots,
flowers and floral organs/structures (for example, bracts, sepals,
petals, stamens, carpels, anthers and ovules), a seed (including
embryo, endosperm, and seed coat) or fruit (the mature ovary); a
plant tissue (for example, vascular tissue, ground tissue, and the
like); cells (for example, guard cells, egg cells, and the like),
or exudates as well as progeny and cultures or cell lines of the
same. Preferably, the extract contains compounds that will be found
to be generally recognized as safe (GRAS) for human consumption.
Accordingly, in certain embodiments the extract is from an edible
source. In this respect, the extract is an edible extract.
[0095] Extracts can be prepared by freezing, grinding, macerating,
pulverizing, fermenting, percolation, decoction, solvent extraction
(e.g., partitioning) or precipitation, treatment with activated
charcoal, evaporation, filtration, and/or chromatographic
fractionation of the source material of interest. In this respect,
an "extract" of the disclosure can be crude, fractionated,
sub-fractionated, separated, isolated, enriched or purified,
without being limited thereto. The term "crude" means compounds or
molecules that have not been entirely separated from the components
of the original composition in which it was present. In embodiments
pertaining to fractions or sub-fractions, a molecule in crude
extract may be subjected to partial separation to provide a less
crude extract containing other substances. In some embodiments, the
compound is isolated. The term "isolated" means that a compound or
molecule is substantially enriched or purified with respect to the
complex cellular milieu in which it naturally occurs, such as in a
crude extract. When an isolated molecule is enriched or purified,
the absolute level of purity is not critical and those skilled in
the art can readily determine appropriate levels of purity
according to the use to which the material is to be put. In some
circumstances, the isolated molecule forms part of a composition
(for example a more or less crude extract containing many other
substances), which may for example contain other components. In
other circumstances, the isolated molecule may be purified to
essential homogeneity, for example as determined
spectrophotometrically, by NMR or by chromatography (for example
LC-MS).
[0096] Suitable solvents for preparing an extract include, e.g.,
n-pentane, hexane, butane, chloroform, dichloromethane, di-ethyl
ether, acetonitrile, water, butanol, isopropanol, ethanol,
methanol, glacial acetic acid, acetone, butanone, pentanone,
norflurane (HFA134a), ethyl acetate, dimethyl sulfoxide,
heptafluoropropane (HFA227), and subcritical or supercritical
fluids such as liquid carbon dioxide and water, or a combination
thereof in any proportion. When solvents such as those listed above
are used, the resultant extract typically contains non-specific
lipid-soluble material. This can be removed by a variety of
processes including "winterization", which involves chilling to a
specified temperature, typically -20.degree. C. followed by
filtration or centrifugation to remove waxy ballast, extraction
with subcritical or supercritical carbon dioxide or non-polar
solvents (e.g., hexane) and by distillation.
[0097] Extracts enriched for a compound of the disclosure are
ideally obtained by chromatographic fractionation. Chromatographic
fractionation typically includes column chromatography and may be
based on molecular sizing, charge, solubility and/or polarity.
Depending on the type of chromatographic method, column
chromatography can be carried out with matrix materials composed
of, for example, dextran, agarose, polyacrylamide, silica, C18, C8,
polyvinylpyrrolidone, polystyrene, celite, and phenyl-hexy and can
include solvents such as dimethyl sulfoxide, pyridine, water,
dimethylformamide, methanol, saline, ethylene dichloride,
chloroform, propanol, ethanol, isobutanol, formamide, methylene
dichloride, butanol, acetonitrile, isopropanol, tetrahydrofuran,
dioxane, chloroform/dichloromethane, methanol, hexane, and ethyl
acetate.
[0098] Typically, the product of the chromatographic step is
collected in multiple fractions, which may then be tested for the
presence of the desired compound using any suitable analytical
technique (e.g. `thin layer chromatography, mass spectrometry, and
ultraviolet absorption). Fractions enriched in the desired compound
may then be selected for further purification.
[0099] As an alternative, or in conjunction with chromatography,
crystallization may be performed to obtain high purity amides. The
hydroxycinnamic tyramine solubility containing of the acid amide is
hydroxycinnamic acid tyramine adjusted by containing changing
temperature and/or the composition of the solution, for instance by
removing ethanol, and/or adjusting the pH to facilitate
precipitation, followed by filtration or centrifugation of the
precipitated crystals or oils. Other suitable methods include, but
are not limited to, liquid-liquid extraction, centrifugal partition
chromatography or adsorption onto a resin or removal of impurities
with resin.
[0100] A "substantially pure" preparation of a compound is defined
as a preparation having a chromatographic purity (of the desired
compound) of greater than 95%, more preferably greater than 96%,
more preferably greater than 97%, more preferably greater than 98%,
more preferably greater than 99% and most preferably greater than
99.5%, as determined by area normalization of an HPLC profile.
[0101] The term "extract comprising a compound" encompasses
preparations having at least 2%, preferably greater than 5%, more
preferably greater than 10% chromatographic purity for the desired
compound. Such an extract will generally contain a greater
proportion of impurities, non-target materials and other molecules
than a "substantially pure" preparation.
[0102] In particular embodiments, an "extract comprising a
compound" is a "botanical" product or substance. In this context,
"botanical" refers to "products that include plant materials,
algae, macroscopic fungi and combinations thereof." Botanicals are
defined by the process steps used to prepare the extract (e.g., by
pulverization, decoction, expression, aqueous and/or ethanol
extraction) and provide a quantified amount of one or more of the
compounds of interest.
[0103] Ideally, a compound of this disclosure is extracted and/or
purified from a plant. Exemplary plants sources include, but are
not limited to, plants in the genera, family, order, genus, species
listed in Table 1.
TABLE-US-00001 TABLE 1 Order Family Genus Common name Asparagales
Amaryllidaceae Allium Garlic Onion Leek Barssicales Barriscaceae
Amoracia Horseradish Caryophyllales Amaranthaceae Chenopodium
Quinoa Spinacia Spinach Magnoliales Annonaceae Annona Cherimoya
Atemoya Soursop Sweetsop Custard apple Guanabana Malpighiales
Euphorbiaceae Jatropha Barbados nut Malvales Malvaceae Hibiscus
Hibiscus Piperales Piperaceae Piper Black pepper Poales Poaceae
Eragrostis Teff Zea Corn Protealese Nelumbonaceae Nelumbo Sacred
Lotus Rosales Cannabaceae Cannabis Hemp Ziziphus Red date Lycium
Goji/wolf berry Sapindales Rutaceae Zanthoxylum Szechuan peppercorn
Solanales Convolvulaveae Ipomea Sweet potato Solanaceae Capsicum
Serrano pepper Thai Chili Piri piri pepper Solanum Tomato Potato
Zygophyllaceae Ophyllales Tribulus Goat thorn Puncture vine
[0104] By way of illustration, an extract containing
N-trans-caffeoyltyramine is obtained pulverizing the dried fruit of
by Tribulus grinding or terrestris, subjecting the pulverized
material to 80% ethanol at room temperature, filtering and
concentrating the 80% ethanol extract, resuspending the
concentrated extract in water, partitioning the aqueous solution
with hexane, adding chloroform to the aqueous layer, and subjecting
the chloroform layer to liquid chromatography with silica gel. See,
e.g., Ko, et al. (2015) Internatl. J. Mol. Med. 36(4):1042-8.
[0105] An extract containing a tyramine containing hydroxycinnamic
acid amide can be standardized using conventional techniques such
as high-performance liquid chromatography (HPLC) or
high-performance thin-layer chromatography (HPTLC). The term
"standardized extract" refers to an extract which is standardized
by identifying characteristic ingredient(s) or bioactive marker(s)
present in the extract. Characterization can be, for example, by
analysis of the spectral data such as mass spectrum (MS), infrared
(IR), ultraviolet (UV) and nuclear magnetic resonance (NMR)
spectroscopic data.
Biological Activity
[0106] Biological activity of compounds and/or extracts can be
determined using one or more of the well-known biological assays
and animal models described in more detail below. Each of these
assays would provide a measure of the activity of the compounds of
the present disclosure to provide beneficial effects on cellular
endpoints linked to digestive health and chronic intestinal
diseases or disorders including but not limited to IBD, irritable
bowel syndrome (IBS), UC, celiac disease and CD.
[0107] Model of Epithelial Barrier Integrity. To assess barrier
function, 3D spheroids are incubated basolaterally with the plasma
samples from subjects with IBS or healthy controls. Medium only and
2 mM ethylene glycol tetra-acetic acid (EGTA) ae used as negative
and positive controls, respectively. Spheroids are incubated with 2
mL containing 37.5% (v/v) plasma, 52.5% (v/v) medium and 10% (v/v)
fluorescein isothiocyanate-labelled dextran of 4 kDa (FD4) in the
presence or absence of a compound or extract of this disclosure.
The basal to luminal FD4 permeation is assessed by confocal
microscopy. See Ludidi, et al. (2015) PLoS One 10(5):e0123498.
[0108] Enteroid-Derived Polarized Monolayer (EDM)-Monocyte
Co-Culture Model. To assess the 3-way interactions between
microbes, gut epithelium, and the immune system, an EDM-monocyte
EDM-monocyte co-culture model may be used. See WO 2018/161077 A1.
In this assay, the EDMs are adapted for coculture in 2 chamber
slides with IBD-associated microbes on the apical side and
non-epithelial (immune and non-immune cells, e.g., monocytes,
T-cells, myofibroblasts, etc.) on the basolateral side to recreate
the 3-way system comprising microbes, gut epithelium, and the
immune system. The impact of microbes on the epithelium, and the
ability of the latter to release soluble factors on the basolateral
side (cytokines such as MCP-1 or Butyrophillins, which attract
y.delta. T-cells) can be assessed, alongside the measurement of how
such factors trigger the recruitment and activation of
non-epithelial cells. Using this approach, the effect of extracts
or compounds of the present disclosure on the complex interplay
between the gut microbes, the epithelium, and non-epithelial cells
can individually be assessed for gene expression by RNA sequencing
and cytokine expression by qPCR and ELISAs.
[0109] Animal Model of IBS. The Wrap Restrain Stress (WRS) model is
an established model for human IBS (Williams, et al. (1988)
Gastroenterology 94: 611-621). WRS model is commonly applied once
(acute test) and includes a forced immobilization of the animal
lasting at least for 2 hours. The efficacy of this test is
confirmed by the development of an immediate hyperalgesia,
quantifiable in colon-rectal distention (CRD) number, the
inhibition of small intestinal transit, the stimulation of large
intestinal activity and increased fecal excretion. In addition, it
has been demonstrated that rats in this assay presented a low-grade
mucosal inflammation with a significant increase in mast cells and
eosinophylic granulocytes (Traini, et al. (2016)
Neurogastroenterol. Motil. 28:1172-1185; Traini, et al. (2017) J.
Cell. Mol. Med. 21:735-745) that overlapped what is described in
colonic biopsies of IBS. Moreover, these animals showed important
changes in the glial cells, in inhibitory and excitatory
neurotransmitters and receptors that were interpreted as
responsible for the dysmotility and hypersensitivity present in IBS
patients. Such a model is useful for demonstrating in vivo response
for compounds of the present disclosure and exploring key concepts
such as dose-response.
[0110] Animal Model of Chronic Colitis. Chronic colitis is induced
by exposure to 1% to 5% (wt/vol) dextran sodium sulfate (molecular
weight 36,000-50,000 kDa) dissolved in drinking water (Okayasu, et
al. (1990) Gastroenterology 98:694-702). DSS is given ad libitum
for five to seven days, followed by several days of normal drinking
water. During DSS administration, mice develop an acute colitis
with ulcerations, body weight loss, and bloody diarrhea. Therefore,
beginning on the day after the third DSS cycle, mice are provided
with a compound or extract of this disclosure to demonstrate in
vivo response. Macroscopic and histological scores are assessed on
the whole colon, while biochemical assays may be performed on
colonic segments collected from an inflamed region adjacent and
distal to the gross necrotic damage.
[0111] Counter Screens. Counter screens are often used to select
among a library of compounds in order to avoid off target effects.
In the present disclosure, the activity of compounds as modulators
of HFN4.alpha. activity is the desired target even though other off
target effects may occur. Drugs that have been marketed for use in
humans based on target effects other than HFN4.alpha. have
subsequently been shown to have activity as HNF4.alpha. activators
(Alverine and Benfluorex; Lee, et al. (2013) ACS Chem. Biol. 8 (8):
1730-6). Alverine has been marketed as a smooth muscle relaxant for
gastrointestinal disorders, while Benfluorex was marketed as an
anorectic agent. Benfluorex was known to be metabolized by cleavage
of an ester moiety into fenfluramine, a potent agonist of serotonin
5-hydroxytryptamine 2 (5-HT.sub.2) receptors, an effect that was
thought to be related to its activity as an anorectic agent
(Porter, et al. (1999) Br. J. Pharmacol. 128 (1):13-20). However,
modulation of 5-HT.sub.2 receptors by Benfluorex was linked to
undesirable cardiopulmonary side effects. Accordingly, based on
these experiences with synthetic compounds, compounds and extracts
of the present disclosure will be tested for off target effects on
5-hydroxytryptamine receptor activation using, e.g. a fluorometric
imaging plate reader (FLIPR) assay, which allows rapid detection of
rises in intracellular calcium levels in cells expressing a human
5-HT.sub.2A, 5-HT.sub.2B or 5-HT.sub.2C receptor in CHO-Kl cells.
See, e.g., Porter, et al. (1999) Br. J. Pharma col. 128 (1): 13-20.
Other counter screens may be chosen based on initial studies where
toxic effects may be linked to other off target actions.
Formulations
[0112] A substantially pure compound or extract comprising a
compound of this disclosure can be combined with a carrier and
provided in any suitable form for consumption by or administration
to a subject. In this respect, the compound or extract is added as
an exogenous ingredient or additive to the consumable. Suitable
consumable forms include, but are not limited to, a dietary
supplement, food ingredient or additive, a medical food,
nutraceutical or pharmaceutical composition. In some embodiments,
the compound or extract is provided in either a liquid or powder
form.
[0113] A food ingredient or additive is an edible substance
intended to result, directly or indirectly, in its becoming a
component or otherwise affecting the characteristic of any food
(including any substance intended for use in producing,
manufacturing, packing, processing, preparing, treating, packaging,
transporting, or holding food). A food product, in particular a
functional food, is a food fortified or enriched during processing
to include additional complementary nutrients and/or beneficial
ingredients. A food product according to this disclosure can, e.g.,
be in the form of butter, margarine, sweet or savory spreads,
condiment, biscuits, health bar, bread, cake, cereal, candy,
confectionery, soup, milk, yogurt or a fermented milk product,
cheese, juice-based and vegetable-based beverages, fermented
beverages, shakes, flavored waters, tea, oil, or any other suitable
food. In some embodiments, the food product is a whole-food product
in which the concentration of the compound has been enriched
through particular post-harvest and food production processing
methods to levels that provide an efficacious amount of the
compound.
[0114] A dietary supplement is a product taken by mouth that
contains a compound or extract of the disclosure and is intended to
supplement the diet. A nutraceutical is a product derived from a
food source that provides extra health benefits, in addition to the
basic nutritional value found in the food. A pharmaceutical
composition is defined as any component of a drug product intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease,
or to affect the structure or any function of the body of humans or
other animals. Dietary supplements, nutraceuticals and
pharmaceutical compositions can be found in many capsules, forms
such as tablets, coated tablets, pills, capsules, pellets,
granules, softgels, gelcaps, liquids, powders, emulsions,
suspensions, elixirs, syrup, and any other form suitable for
use.
[0115] The pharmaceutical compositions disclosed herein may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tableting
processes. Additionally, the active ingredients are contained in an
amount effective to achieve its intended purpose. Many of the
compounds used in the pharmaceutical combinations disclosed herein
may be provided as salts with pharmaceutically compatible
counterions.
[0116] Multiple techniques of administering a compound, salt and/or
composition exist in the art including, but not limited to, oral,
rectal, pulmonary, topical, aerosol, injection, infusion and
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, intrathecal, direct
intraventricular, intraperitoneal, intranasal and intraocular
injections. In some embodiments, a compound described herein,
including a compound of Formula (I), (II), (III), or a
pharmaceutically acceptable salt thereof, can be administered
orally.
[0117] One may also administer the compound, salt and/or
composition in a local rather than systemic manner, for example,
via injection or implantation of the compound directly into the
affected area, often in a depot or sustained release formulation.
Furthermore, one may administer the compound in a targeted drug
delivery system, for example, in a liposome coated with a
tissue-specific antibody. The liposomes will be targeted to and
taken up selectively by the organ. For example, intranasal or
pulmonary delivery to target a respiratory disease or condition may
be desirable.
[0118] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions that can
include a compound and/or salt described herein formulated in a
compatible pharmaceutical excipient may also be prepared, placed in
an appropriate container, and labeled for treatment of an indicated
condition.
[0119] The compounds, salt and/or pharmaceutical composition can be
provided to an administering physician or other health care
professional in the form of a kit. The kit is a package which
houses a container which contains the compound(s) in a suitable
pharmaceutical composition, and instructions for administering the
pharmaceutical composition to a subject. The kit can optionally
also contain one or more additional therapeutic agents. The kit can
also contain separate doses of a compound(s) or pharmaceutical
composition for serial or sequential administration. The kit can
optionally contain one or more diagnostic tools and instructions
for use. The kit can contain suitable delivery devices, for
example, syringes, and the like, along with instructions for
administering the compound(s) and any other therapeutic agent. The
kit can optionally contain instructions for storage, reconstitution
(if applicable), and administration of any or all therapeutic
agents included. The kits can include a plurality of containers
reflecting the number of administrations to be given to a
subject.
[0120] In some embodiments, a compound of Formula (I), Formula
(II), or Formula (III) is administered at a dose in the range of
about 1-200 mg/kg body weight. In some embodiments, a compound of
Formula (I), Formula (II), or Formula (III) is administered at a
dose in the range of about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60,
1-70, 1-80, 1-90, 1-100, 1-200, 1-300, 1-400, 1-500, 1-600, 1-700,
1-800, 1-900, 1-1000, 1-11, 1-12, 1-13, 1-13, 1-14, 1-15, 1-16,
1-17, 1-18, 1-19, 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80,
10-90, 10-100, 10-200, 10-300, 10-400, 10-500, 10-600, 10-700,
10-800, 10-900, 10-1000, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80,
20-90, 20-100, 20-200, 20-300, 20-400, 20-500, 20-600, 20-700,
20-800, 20-900, 20-1000, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90,
30-100, 30-200, 30-300, 30-400, 30-500, 30-600, 30-700, 30-800,
30-900, 30-1000, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-200,
40-300, 40-400, 40-500, 40-600, 40-700, 40-800, 40-900, 40-1000,
50-60, 50-70, 50-80, 50-90, 50-100, 50-200, 50-300, 50-400, 50-500,
50-600, 50-700, 50-800, 50-900, 60-70, 60-80, 60-90, 60-100,
60-200, 60-300, 60-400, 60-500, 60-600, 60-700, 60-800, 60-900,
60-1000, 70-80, 70-90, 70-100, 70-200, 70-300, 70-400, 70-500,
70-600, 70-700, 70-800, 70-900, 70-1000, 80-90, 80-100, 80-200,
80-300, 80-400, 80-500, 80-600, 80-700, 80-800, 80-900, 80-100,
90-100, 90-200, 90-300, 90-400, 90-500, 90-600, 90-700, 90-800,
90-900, 90-1000, 100-150, 100-200, 100-300, 100-400, 100-500,
100-600, 100-700, 100-800, 100-900, or 100-1000 mg/kg of body
weight. In some embodiments, a compound of Formula (I), Formula
(II), or Formula (III) is administered at a dose of about 0.01,
0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,
3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11,
11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5,
18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24,
24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 55, 60, 65, 70, 80, 90, or 95 mg/kg of the body weight.
In some embodiments, a compound of Formula (I), Formula (II), or
Formula (III) is administered at a dose less than about 0.01, 0.02,
0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5,
12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18,
18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5,
25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40 mg/m.sup.2 of the body surface area.
In some embodiments, a compound of Formula (I), Formula (II), or
Formula (III) is administered at a dose greater than about 0.01,
0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,
3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11,
11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5,
18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24,
24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of a
subjects body weight.
[0121] In some embodiments, a compound of Formula (I), Formula
(II), or Formula (III) dose is about 0.1 mg-10 mg, 0.1 mg-25 mg,
0.1 mg-30 mg, 0.1 mg-50 mg, 0.1 mg-75 mg, 0.1 mg-100 mg, 0.5 mg-10
mg, 0.5 mg-25 mg, 0.5 mg-30 mg, 0.5 mg-50 mg, 0.5 mg-75 mg, 0.5
mg-100 mg, 1 mg-10 mg, 1 mg-25 mg, 1 mg-30 mg, 1 mg-50 mg, 1 mg-75
mg, 1 mg-100 mg, 2 mg-10 mg, 2 mg-25 mg, 2 mg-30 mg, 2 mg-50 mg, 2
mg-75 mg, 2 mg-100 mg, 3 mg-10 mg, 3 mg-25 mg, 3 mg-30 mg, 3 mg-50
mg, 3 mg-75 mg, 3 mg-100 mg, 4 mg-100 mg, 5 mg-10 mg, 5 mg-25 mg, 5
mg-30 mg, 5 mg-50 mg, 5 mg-75 mg, 5 mg-300 mg, 5 mg-200 mg, 7.5
mg-15 mg, 7.5 mg-25 mg, 7.5 mg-30 mg, 7.5 mg-50 mg, 7.5 mg-75 mg,
7.5 mg-100 mg, 7.5 mg-200 mg, 10 mg-20 mg, 10 mg-25 mg, 10 mg-50
mg, 10 mg-75 mg, 10 mg-100 mg, 15 mg-30 mg, 15 mg-50 mg, 15 mg-100
mg, 20 mg-20 mg, 20 mg-100 mg, 30 mg-100 mg, 40 mg-100 mg, 10 mg-80
mg, 15 mg-80 mg, 20 mg-80 mg, 30 mg-80 mg, 40 mg-80 mg, 10 mg-60
mg, 15 mg-60 mg, 20 mg-60 mg, 30 mg-60 mg, or about 40 mg-60 mg. In
some embodiments, a compound of Formula (I), Formula (II), or
Formula (III) administered is about 20 mg-60 mg, 27 mg-60 mg, 20
mg-45 mg, or 27 mg-45 mg. In some embodiments, a compound of
Formula (I), Formula (II), or Formula (III) administered is about 1
mg-5 mg, 1 mg-7.5 mg, 2.5 mg-5 mg, 2.5 mg-7.5 mg, 5 mg-7.5 mg, 5
mg-9 mg, 5 mg-10 mg, 5 mg-12 mg, 5 mg-14 mg, 5 mg-15 mg, 5 mg-16
mg, 5 mg-18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg-26 mg, 5
mg-28 mg, 5 mg-30 mg, 5 mg-32 mg, 5 mg-34 mg, 5 mg-36 mg, 5 mg-38
mg, 5 mg-40 mg, 5 mg-42 mg, 5 mg-44 mg, 5 mg-46 mg, 5 mg-48 mg, 5
mg-50 mg, 5 mg-52 mg, 5 mg-54 mg, 5 mg-56 mg, 5 mg-58 mg, 5 mg-60
mg, 7 mg-7.7 mg, 7 mg-9 mg, 7 mg-10 mg, 7 mg-12 mg, 7 mg-14 mg, 7
mg-15 mg, 7 mg-16 mg, 7 mg-18 mg, 7 mg-20 mg, 7 mg-22 mg, 7 mg-24
mg, 7 mg-26 mg, 7 mg-28 mg, 7 mg-30 mg, 7 mg-32 mg, 7 mg-34 mg, 7
mg-36 mg, 7 mg-38 mg, 7 mg-40 mg, 7 mg-42 mg, 7 mg-44 mg, 7 mg-46
mg, 7 mg-48 mg, 7 mg-50 mg, 7 mg-52 mg, 7 mg-54 mg, 7 mg-56 mg, 7
mg-58 mg, 7 mg-60 mg, 9 mg-10 mg, 9 mg-12 mg, 9 mg-14 mg, 9 mg-15
mg, 9 mg-16 mg, 9 mg-18 mg, 9 mg-20 mg, 9 mg-22 mg, 9 mg-24 mg, 9
mg-26 mg, 9 mg-28 mg, 9 mg-30 mg, 9 mg-32 mg, 9 mg-34 mg, 9 mg-36
mg, 9 mg-38 mg, 9 mg-40 mg, 9 mg-42 mg, 9 mg-44 mg, 9 mg-46 mg, 9
mg-48 mg, 9 mg-50 mg, 9 mg-52 mg, 9 mg-54 mg, 9 mg-56 mg, 9 mg-58
mg, 9 mg-60 mg, 10 mg-12 mg, 10 mg-14 mg, 10 mg-15 mg, 10 mg-16 mg,
10 mg-18 mg, 10 mg-20 mg, 10 mg-22 mg, 10 mg-24 mg, 10 mg-26 mg, 10
mg-28 mg, 10 mg-30 mg, 10 mg-32 mg, 10 mg-34 mg, 10 mg-36 mg, 10
mg-38 mg, 10 mg-40 mg, 10 mg-42 mg, 10 mg-44 mg, 10 mg-46 mg, 10
mg-48 mg, 10 mg-50 mg, 10 mg-52 mg, 10 mg-54 mg, 10 mg-56 mg, 10
mg-58 mg, 10 mg-60 mg, 12 mg-14 mg, 12 mg-15 mg, 12 mg-16 mg, 12
mg-18 mg, 12 mg-20 mg, 12 mg-22 mg, 12 mg-24 mg, 12 mg-26 mg, 12
mg-28 mg, 12 mg-30 mg, 12 mg-32 mg, 12 mg-34 mg, 12 mg-36 mg, 12
mg-38 mg, 12 mg-40 mg, 12 mg-42 mg, 12 mg-44 mg, 12 mg-46 mg, 12
mg-48 mg, 12 mg-50 mg, 12 mg-52 mg, 12 mg-54 mg, 12 mg-56 mg, 12
mg-58 mg, 12 mg-60 mg, 15 mg-16 mg, 15 mg-18 mg, 15 mg-20 mg, 15
mg-22 mg, 15 mg-24 mg, 15 mg-26 mg, 15 mg-28 mg, 15 mg-30 mg, 15
mg-32 mg, 15 mg-34 mg, 15 mg-36 mg, 15 mg-38 mg, 15 mg-40 mg, 15
mg-42 mg, 15 mg-44 mg, 15 mg-46 mg, 15 mg-48 mg, 15 mg-50 mg, 15
mg-52 mg, 15 mg-54 mg, 15 mg-56 mg, 15 mg-58 mg, 15 mg-60 mg, 17
mg-18 mg, 17 mg-20 mg, 17 mg-22 mg, 17 mg-24 mg, 17 mg-26 mg, 17
mg-28 mg, 17 mg-30 mg, 17 mg-32 mg, 17 mg-34 mg, 17 mg-36 mg, 17
mg-38 mg, 17 mg-40 mg, 17 mg-42 mg, 17 mg-44 mg, 17 mg-46 mg, 17
mg-48 mg, 17 mg-50 mg, 17 mg-52 mg, 17 mg-54 mg, 17 mg-56 mg, 17
mg-58 mg, 17 mg-60 mg, 20 mg-22 mg, 20 mg-24 mg, 20 mg-26 mg, 20
mg-28 mg, 20 mg-30 mg, 20 mg-32 mg, 20 mg-34 mg, 20 mg-36 mg, 20
mg-38 mg, 20 mg-40 mg, 20 mg-42 mg, 20 mg-44 mg, 20 mg-46 mg, 20
mg-48 mg, 20 mg-50 mg, 20 mg-52 mg, 20 mg-54 mg, 20 mg-56 mg, 20
mg-58 mg, 20 mg-60 mg, 22 mg-24 mg, 22 mg-26 mg, 22 mg-28 mg, 22
mg-30 mg, 22 mg-32 mg, 22 mg-34 mg, 22 mg-36 mg, 22 mg-38 mg, 22
mg-40 mg, 22 mg-42 mg, 22 mg-44 mg, 22 mg-46 mg, 22 mg-48 mg, 22
mg-50 mg, 22 mg-52 mg, 22 mg-54 mg, 22 mg-56 mg, 22 mg-58 mg, 22
mg-60 mg, 25 mg-26 mg, 25 mg-28 mg, 25 mg-30 mg, 25 mg-32 mg, 25
mg-34 mg, 25 mg-36 mg, 25 mg-38 mg, 25 mg-40 mg, 25 mg-42 mg, 25
mg-44 mg, 25 mg-46 mg, 25 mg-48 mg, 25 mg-50 mg, 25 mg-52 mg, 25
mg-54 mg, 25 mg-56 mg, 25 mg-58 mg, 25 mg-60 mg, 27 mg-28 mg, 27
mg-30 mg, 27 mg-32 mg, 27 mg-34 mg, 27 mg-36 mg, 27 mg-38 mg, 27
mg-40 mg, 27 mg-42 mg, 27 mg-44 mg, 27 mg-46 mg, 27 mg-48 mg, 27
mg-50 mg, 27 mg-52 mg, 27 mg-54 mg, 27 mg-56 mg, 27 mg-58 mg, 27
mg-60 mg, 30 mg-32 mg, 30 mg-34 mg, 30 mg-36 mg, 30 mg-38 mg, 30
mg-40 mg, 30 mg-42 mg, 30 mg-44 mg, 30 mg-46 mg, 30 mg-48 mg, 30
mg-50 mg, 30 mg-52 mg, 30 mg-54 mg, 30 mg-56 mg, 30 mg-58 mg, 30
mg-60 mg, 33 mg-34 mg, 33 mg-36 mg, 33 mg-38 mg, 33 mg-40 mg, 33
mg-42 mg, 33 mg-44 mg, 33 mg-46 mg, 33 mg-48 mg, 33 mg-50 mg, 33
mg-52 mg, 33 mg-54 mg, 33 mg-56 mg, 33 mg-58 mg, 33 mg-60 mg, 36
mg-38 mg, 36 mg-40 mg, 36 mg-42 mg, 36 mg-44 mg, 36 mg-46 mg, 36
mg-48 mg, 36 mg-50 mg, 36 mg-52 mg, 36 mg-54 mg, 36 mg-56 mg, 36
mg-58 mg, 36 mg-60 mg, 40 mg-42 mg, 40 mg-44 mg, 40 mg-46 mg, 40
mg-48 mg, 40 mg-50 mg, 40 mg-52 mg, 40 mg-54 mg, 40 mg-56 mg, 40
mg-58 mg, 40 mg-60 mg, 43 mg-46 mg, 43 mg-48 mg, 43 mg-50 mg, 43
mg-52 mg, 43 mg-54 mg, 43 mg-56 mg, 43 mg-58 mg, 42 mg-60 mg, 45
mg-48 mg, 45 mg-50 mg, 45 mg-52 mg, 45 mg-54 mg, 45 mg-56 mg, 45
mg-58 mg, 45 mg-60 mg, 48 mg-50 mg, 48 mg-52 mg, 48 mg-54 mg, 48
mg-56 mg, 48 mg-58 mg, 48 mg-60 mg, 50 mg-52 mg, 50 mg-54 mg, 50
mg-56 mg, 50 mg-58 mg, 50 mg-60 mg, 52 mg-54 mg, 52 mg-56 mg, 52
mg-58 mg, or 52 mg-60 mg. In some embodiments, a compound of
Formula (I), Formula (II), or Formula (III) dose is greater than,
equal to, or about 0.1 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg,
1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10
mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about
20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about
40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90
mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about
300 mg. about 400 mg, about 500 mg, about 600 mg, about 700 mg,
about 800 mg, about 900 mg, or about 1000 mg. In some embodiments,
a compound of Formula (I), Formula (II), or Formula (III) dose is
about less than about 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75
mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5
mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about
22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about
50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about
100 mg, about 125 mg, about 150 mg, or about 200 mg.
[0122] The term "carrier" as used herein means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, manufacturing aid (e.g., lubricant, talc magnesium,
calcium or zinc stearate, or steric acid), or solvent encapsulating
material, involved in carrying or transporting the subject compound
from one organ, or portion of the body, to another organ, or
portion of the body. Each carrier should be compatible with the
other ingredients of the formulation and not injurious to the
subject. Some examples of materials that can serve as carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2)
starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, cellulose acetate, and hydroxyl propyl methyl cellulose;
(4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters,
polycarbonates and/or polyanhydrides; and (22) other nontoxic
compatible substances employed in conventional formulations.
[0123] For preparing solid compositions such as tablets or
capsules, the compound or extract is mixed with a carrier (e.g.,
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums) and other diluents (e.g., water) to
form a solid composition. This solid composition is then subdivided
into unit dosage forms containing an effective amount of the
compound of the present disclosure. The tablets or pills containing
the compound or extract can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged
action.
[0124] In particular embodiments of this disclosure, a consumable
composition includes the compound or extract, a carrier and a
preservative to reduce or retard microbial growth. The preservative
is added in amounts up to about 5%, preferably from about 0.01% to
1% by weight of the film. Preferred preservatives include sodium
benzoate, methyl parabens, propyl parabens, sodium nitrite, sulphur
dioxide, sodium sorbate and potassium sorbate. Other suitable
preservatives include, but are not limited to, salts of edetate,
(also known as salts of ethylenediaminetetraacetic acid, or EDTA,
such a disodium EDTA).
[0125] The liquid forms in which the compound or extract of the
disclosure is incorporated for oral or parenteral administration
include aqueous solution, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils as well as
elixirs and similar vehicles. Suitable dispersing or suspending
agents for aqueous suspensions include synthetic natural gums, such
as tragacanth, acacia, alginate, dextran, sodium carboxymethyl
cellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Liquid
preparations for oral administration may take the form of, for
example, solutions, syrups or suspensions, or they may be presented
as a dry product for reconstitution with water or other suitable
vehicles before use. Such liquid preparations may be prepared by
conventional means with acceptable additives such as suspending
agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated
edible fats); emulsifying agents (e.g., lecithin or acacia);
non-aqueous vehicles (e.g., almond oil, oily esters or ethyl
alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoates
or sorbic acid); and artificial or natural colors and/or
sweeteners.
[0126] Methods of preparing formulations or compositions of this
disclosure include the step of bringing into association a compound
or extract of the present disclosure with the carrier and,
optionally, one or more accessory and/or active ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association a compound or extract of the present
disclosure with liquid carriers, or finely divided solid carriers,
or both, and then, if necessary, shaping the product. As such, the
disclosed formulation may consist of, or consist essentially of a
compound or extract described herein in combination with a suitable
carrier.
[0127] When a compound or extract of the present disclosure is
administered as pharmaceuticals, nutraceuticals, or dietary
supplements to humans and animals, they can be given per se or as a
composition containing, for example, 0.1 to 99% (more preferably,
10 to 30%) of active ingredient in combination with an acceptable
carrier.
[0128] A consumable product may be consumed by a subject to provide
less than 100 mg of a compound disclosed herein per day. In certain
embodiments, the consumable provides between 10 and 60 mg/day of a
tyramine containing hydroxycinnamic acid amide. The effective
amount can be established by methods known in the art and be
dependent upon bioavailability, toxicity, etc.
[0129] While it is contemplated that individual tyramine containing
hydroxycinnamic acid amides may be used in the consumables of this
disclosure, it is further contemplated that two or more of the
compounds or extracts could be combined in any relative amounts to
produce custom combinations of ingredients containing two or more
tyramine containing hydroxycinnamic acid amides in desired ratios
to enhance product efficacy, improve organoleptic properties or
some other measure of quality important to the ultimate use of the
product.
Molecular Target
[0130] HNF4.alpha. (hepatocyte nuclear factor 4a) is a global
nuclear transcription factor, regulating expression of many genes
involved in maintaining balanced metabolism (homeostasis). It is
expressed in a number of tissues including the liver, pancreas, and
kidney, as well as the intestine. HNF4.alpha. is known to have a
diverse role in epithelial biology, including the architecture of
epithelial cells, central regulation of epithelial morphogenesis,
and homeostasis and barrier functioning of the intestinal
epithelium (Cattin, et al. (2009) Mal. Cell. Biol.
29(23):6294-6308; Spath & Weiss (1998) J. Cell Biol. 140:
935-946). In addition, the HNF4.alpha. gene is highly expressed in
the small intestine and colon and the HNF4.alpha. protein is
abundant in the nucleus of mucosal epithelial cells (Jiang, et al.
(2003) Nucl. Recept. 1:5). Further, it has been suggested that
HNF4.alpha. has a protective role in IBD, and that HNF4.alpha.
agonists may be of use in the treatment of IBD (Chahar, et al.
(2014) Mol. Cell. Biol. 34:3291-3304).
[0131] Studies have shown that HNF4.alpha. is critical to the
expression and proper localization of tight and adherens junction
proteins (Chiba, et al. (2003) Exp. Cell Res. 286:288-297; Parviz,
et al. (2003) Nat. Genet. 34:292-296), and the formation of
microvilli within the intestine (Chiba, et al. (2006) J. Cell Biol.
175(6):971-980). Further, HNF4.alpha. has also been described as a
central regulator protecting the intestinal epithelium against
inflammation (Babeu & Boudreau (2014) World J. Gastroenterol.
20(1):22-30). Moreover, HNF4.alpha. expression has been shown to be
drastically reduced in intestinal tissues from patients with
Crohn's disease (CD) or Ulcerative colitis (UC) (Darsigny, et al.
(2009) PLoS One 4:e7609; Ahn, et al. (2008) Inflamm. Bowel Dis.
14:908-920).
[0132] Studies with intestine-specific HNF4.alpha. null mice have
shown that the null mice are prone to increased susceptibility to
dextran sulfate sodium (DSS) model of colitis, as well as showed
increased intestinal permeability than control mice (Ahn, et al.
(2008) Inflamm. Bowel Dis. 14:908-920). In another study, mice
lacking intestinal expression of both HNF4.alpha. P1 and P2
isoforms developed progressive, chronic gut inflammation similar to
human IBD, suggesting that long-term reduction of HNF4.alpha.
activity is likely to promote IBD (Darsigny, et al. (2009) PLoS One
4:e7609).
[0133] Alternatively, or in addition to, the underlying
pathophysiological mechanism for HNF4.alpha.'s role in regulating
gut permeability is that HNF4.alpha. may interact with gut
microbiota to prevent the development of chronic inflammation. In
particular, it has been suggested that HNF4.alpha. is a
microbial-suppressed transcription factor within the gut, and that
the genes governed by this regulation may include factors that
could provide new targets for IBD therapy (Davison, et al. (2017)
Genome Res. 27:1195-206). Further, it has been demonstrated that
HNF4.alpha. expression is influenced by diet and bacteria. In
particular, products of bacterial metabolism within the colon may
produce fatty acids that serve as ligands for HNF4.alpha. thereby
altering its expression (Qin, et al. (2018) Genome Biol. 19:7).
Moreover, bile acids (or their derivatives), which are also related
to intestinal permeability (Stenman, et al. (2012) World J.
Gastroenterol. 18(9):923-9), may act as HNF4.alpha. ligands.
[0134] Clinical evidence further indicates that HNF4.alpha.
agonists may be beneficial for treatment of digestive disorders and
disease. Specifically, the HNF4.alpha. agonist Alverine has been
approved for use in Europe for treatment of IBS.
Chronic Gastrointestinal Disorder
[0135] The terms "chronic gastrointestinal disorder,"
"gastrointestinal epithelial cell barrier function disorder,"
"chronic disease related to disruption of the intestinal epithelial
barrier," and the like refer to conditions in which individuals
have chronic or recurring immune response and inflammation of the
gastrointestinal (GI) tract. The most common diseases or disorders
are irritable bowel syndrome (IBS), inflammatory bowel disease
(IBD), Crohn's disease (CD), ulcerative colitis (UC), and celiac
disease. Other chronic gastrointestinal disorders include, but are
not limited to, necrotizing enterocolitis, indeterminate colitis,
chronic colitis, HIV enteropathy, Helicobacter gastritis,
NSAID-enteropathy/enteritis, pouchitis, discontinuous or patchy
disease, ileal inflammation, extracolonic inflammation,
granulomatous inflammation in response to ruptured crypts, aphthous
ulcers, transmural inflammation, microscopic colitis,
diverticulitis, diversion colitis, short bowel syndrome, GI
mucositis, chemotherapy induced mucositis, radiation induced
mucositis, and interstitial cystitis.
[0136] Ulcerative colitis (UC). UC is a disease that causes
inflammation and sores, called ulcers, in the lining of the large
intestine. The inflammation usually occurs in the rectum and lower
part of the colon, but it may affect the entire colon. UC may occur
in people of any age and is believed to be the result of the body's
immune system reacting to a virus or a bacterium by causing ongoing
inflammation in the intestinal wall. People with ulcerative colitis
have abnormalities of the immune system, but it has not been shown
that these abnormalities are the cause or the result of the
disease.
[0137] The most common symptoms of ulcerative colitis are abdominal
pain and bloody diarrhea. Patients also may experience fatigue,
weight loss, loss of appetite, rectal bleeding, and loss of body
fluids and nutrients. About half of patients have mild symptoms.
Others suffer frequent fever, bloody diarrhea, nausea, and severe
abdominal cramps.
[0138] Crohn's Disease (CD). Crohn's disease is characterized by
intestinal inflammation and the development of intestinal stenosis
and fistulas; neuropathy often accompanies these symptoms. In some
instances, it is believed that Crohn's disease results from a
failure of the intestinal mucosal barrier, possibly resulting from
genetic susceptibilities and environmental factors (e.g., smoking),
which exposes the immune system to antigens from the intestinal
lumen including bacterial and food antigens. Another hypothesis is
that persistent intestinal infection by pathogens such as
Mycobacterium paratuberculosis, Listeria monocytogenes, abnormal
Escherichia coli, or paramyxovirus, stimulates the immune response;
or alternatively, symptoms result from a dysregulated immune
response to ubiquitous antigens, such as normal intestinal
microflora and the metabolites and toxins they produce.
[0139] The presence of IgA and IgG anti-Saccharomyces cerevisiae
antibodies (ASCA) in the serum has been found to be highly
diagnostic of pediatric Crohn's disease. Further, in active cases
of Crohn's disease, elevated concentrations of TNF-.alpha. and IL-6
are secreted into the blood circulation, and TNF-.alpha., IL-I,
IL-6, and IL-8 are produced in excess locally by mucosal cells. In
this respect, it has been suggested that cytokine profiles in stool
samples could be a useful diagnostic tool for Crohn's disease.
[0140] Irritable Bowel Syndrome (IBS). IBS is a disorder that
affects mainly the bowel or large intestine. IBS causes cramping,
bloating, gas, diarrhea, and constipation. With IBS, the nerves and
muscles in the bowel are extra sensitive and may be activated
during or shortly after a meal or exercise thereby cramping and
diarrhea. Foods that tend to cause symptoms include milk products,
chocolate, alcohol, caffeine, carbonated drinks, and fatty foods.
In some cases, simply eating a large meal will trigger
symptoms.
[0141] Necrotizing Enterocolitis. Necrotizing enterocolitis is an
acquired disease, primarily in premature infants or sick newborns,
in which intestinal tissue dies. In necrotizing enterocolitis, the
lining of the intestinal wall dies and the tissue sloughs off. The
cause for this disorder is unknown, but it is thought that a
decreased blood flow to the bowel keeps the bowel from producing
the normal protective mucus. Bacteria in the intestine may also be
a cause. At risk are small, premature infants, infants who are fed
concentrated formulas, infants in a nursery where an outbreak has
occurred (suggesting an infectious cause), and infants who have
received blood exchange transfusions.
[0142] Symptoms include abdominal distention, vomiting, lethargy,
feeding intolerance, blood in the stool, temperature instability,
and diarrhea. Diagnosis usually involves abdominal x-ray, and
examination for occult stool blood, elevated white count,
thrombocytopenia, and lactic acidosis.
[0143] Celiac Disease. Celiac disease is a digestive disease that
damages the small intestine with absorption of nutrients from food.
People who have digestive interferes who have celiac disease cannot
tolerate gluten, a protein found in wheat, rye, and barley. When
people with celiac disease eat foods or use products containing
gluten, their immune system responds by damaging the small
intestine.
[0144] Celiac disease is a genetic disease, which may be triggered
or become active for the first time after surgery, pregnancy,
childbirth, viral infection, or severe emotional stress. A subject
with celiac disease may present with diarrhea and abdominal pain,
irritability, depression, gas, recurring abdominal bloating,
foul-smelling or fatty stool, weight loss/gain, fatigue,
unexplained anemia, bone or joint pain, osteoporosis, osteopenia,
behavioral changes, tingling numbness in the legs (from nerve
damage), muscle cramps, seizures, missed menstrual periods (often
because of excessive weight loss), infertility, recurrent
miscarriage, delayed growth, failure to thrive in infants, pale
sores inside the mouth (called aphthous ulcers), tooth
discoloration or loss of enamel, and itchy skin rash (dermatitis
herpetiformis). Celiac disease may be diagnosed using a test blood
for measuring levels of Immunoglobulin A (IgA), anti-tissue
transglutaminase (tTGA) and IgA antiendomysium antibodies
(AEA).
[0145] HIV Enteropathy. HIV enteropathy is a syndrome characterized
by chronic, well-established diarrhea (greater than one month in
duration) without an identified infectious cause after thorough
evaluation, in an HIV-positive individual. It is thought to be due
to direct or indirect effects of HIV on the enteric mucosa.
[0146] Helicobacter Gastritis. Helicobacter pylori can cause
infections of the stomach that may contribute to the development of
dyspepsia (heartburn, bloating and nausea), gastritis (inflammation
of the stomach), and ulcers in the stomach and duodenum. H. pylori
infection can be diagnosed by endoscopic biopsy followed by testing
of the removed tissue for the bacteria, a breath test, or a blood
test (measuring antibodies against these bacteria present in the
blood). Symptoms include discomfort, bloating, nausea and perhaps
vomiting, as well as ulcers.
[0147] NSAID-Enteropathy/Enteritis. The anti-inflammatory,
analgesic, and anti-pyretic properties of NSAIDs are well
established and can be used in a wide range of disorders. A major
limitation of NSAIDs' clinical utility is their gastroduodenal
epithelial toxicity. NSAID toxicity is not site-specific to the
gastroduodenum, and can induce toxicity in the more distal
intestine.
Digestive Health
[0148] This disclosure provides methods for improving, restoring,
or maintaining digestive health. In accordance with such methods,
an effective amount of a compound or extract of this disclosure is
provided to a subject in need thereof so that the subject's
digestive function is improved or maintained thereby addressing the
underlying pathogenesis of one or more chronic gastrointestinal
disorders and promoting the health, well-being, and quality of life
of the subject. The term "subject" as used herein refers to an
animal, preferably a mammal. In some embodiments, the subject is a
veterinary, companion, farm, laboratory or zoological animal. In
other embodiments, the subject is a human.
[0149] In some aspects, a composition comprising a compound of
Formula (I), Formula (II), or Formula (III), or a pharmaceutically
acceptable salt thereof, isomer, homodimer, heterodimer, or
conjugate, improves digestive health in a subject. In some
embodiments, a composition comprising a compound of Formula (I),
Formula (II), or Formula (III) treats or ameliorates a disease or
condition associated with digestive health in a subject. In some
embodiments, treating or ameliorating digestive health in a subject
is not treatment or improving of inflammation. In some embodiments,
a composition comprising a compound of Formula (I), Formula (II),
or Formula (III) treats or ameliorates a disease or condition
associated with digestive health in a subject by increasing
HNF4.alpha. expression. In some embodiments, a composition
comprising a compound of Formula (I), Formula (II), or Formula
(III) treats or ameliorates a disease or condition associated with
digestive health in a subject reverses the loss of Paneth cells
that occur from a high fat diet. In some embodiments, a composition
comprising a compound of Formula (I), Formula (II), or Formula
(III) treats or ameliorates a disease or condition associated with
digestive health in a subject increases intestinal villus. In some
embodiments, a composition comprising a compound of Formula (I),
Formula (II), or Formula (III) treats or ameliorates a disease or
condition associated with digestive health in a subject by
increasing Paneth cell formation. In some embodiments, a
composition comprising a compound of Formula (I), Formula (II), or
Formula (III) treats or ameliorates a disease or condition
associated with digestive health in a subject by decreasing a
condition associated with an allergic response.
[0150] In an embodiment, a composition comprising a compound of
Formula (I), Formula (II), or Formula (III), or a pharmaceutically
acceptable salt thereof, treats or improves at least one factor
associated with digestive health of a subject. In other aspects, a
composition comprising a compound of Formula (I), Formula (II), or
Formula (III), or a pharmaceutically acceptable salt thereof
disclosed herein improves digestive health of a subject by, e.g.,
at least 10%, at least 15%, at least 20%, at least 25%, at least
30%, at least 35%, at least 40%, at least 45%, at least 50%, at
least 55%, at least 60%, at least 65%, at least 70%, at least 75%,
at least 80%, at least 85%, at least 90% or at least 95%. In yet
other aspects, a composition comprising Formula (I), Formula (II),
or Formula (III), or a pharmaceutically acceptable salt thereof,
improves digestive health by of reducing a disease or condition
associated with digestive health from a range from, e.g., about 10%
to about 100%, about 20% to about 100%, about 30% to about 100%,
about 40% to about 100%, about 50% to about 100%, about 60% to
about 100%, about 70% to about 100%, about 80% to about 100%, about
10% to about 90%, about 20% to about 90%, about 30% to about 90%,
about 40% to about 90%, about 50% to about 90%, about 60% to about
90%, about 70% to about 90%, about 10% to about 80%, about 20% to
about 80%, about 30% to about 80%, about 40% to about 80%, about
50% to about 80%, or about 60% to about 80%, about 10% to about
70%, about 20% to about 70%, about 30% to about 70%, about 40% to
about 70%, or about 50% to about 70%. In some embodiments, disease
or condition associated with digestive health level of Paneth
cells, HNF4.alpha. level, allergic response, or intestinal villus
levels
[0151] In an embodiment, a composition comprising a compound of
Formula (I), Formula (II), or Formula (III), or a pharmaceutically
acceptable salt thereof, has an anti-inflammatory activity capable
of reducing the levels of an inflammation in the liver or
intestine. In other aspects, a composition comprising a compound of
Formula (I), Formula (II), or Formula (III), or a pharmaceutically
acceptable salt thereof disclosed herein has an anti-inflammatory
activity capable of reducing the levels of a inflammation by, e.g.,
at least 10%, at least 15%, at least 20%, at least 25%, at least
30%, at least 35%, at least 40%, at least 45%, at least 50%, at
least 55%, at least 60%, at least 65%, at least 70%, at least 75%,
at least 80%, at least 85%, at least 90% or at least 95%. In yet
other aspects, a composition comprising Formula (I), Formula (II),
or Formula (III), or a pharmaceutically acceptable salt thereof,
has an anti-inflammatory activity capable of reducing the levels of
an inflammation in the liver or intestines from a range from, e.g.,
about 10% to about 100%, about 20% to about 100%, about 30% to
about 100%, about 40% to about 100%, about 50% to about 100%, about
60% to about 100%, about 70% to about 100%, about 80% to about
100%, about 10% to about 90%, about 20% to about 90%, about 30% to
about 90%, about 40% to about 90%, about 50% to about 90%, about
60% to about 90%, about 70% to about 90%, about 10% to about 80%,
about 20% to about 80%, about 30% to about 80%, about 40% to about
80%, about 50% to about 80%, or about 60% to about 80%, about 10%
to about 70%, about 20% to about 70%, about 30% to about 70%, about
40% to about 70%, or about 50% to about 70%. In some embodiments,
the inflammation is chronic inflammation. In some embodiments, the
composition reduces a symptom associated with inflammation. In some
embodiments, the composition treats, reduces, or eliminates a
symptom associated with inflammation in a subject. In some
embodiments, the composition treats, reduces, or eliminates
inflammation in a subject.
[0152] In some embodiments, inflammation symptoms may include,
without limitation, edema, hyperemia, erythema, bruising,
tenderness, stiffness, swollenness, fever, chills, stuffy nose,
stuffy head, breathing problems, fluid retention, blood clots, loss
of appetite, increased heart rate, formation of granulomas,
fibrinous, pus, non-viscous serous fluid, or ulcer and pain.
[0153] In some embodiments, inflammation symptoms can be associated
with a large, unrelated group of disorders which underlay a variety
of diseases and disorders. In some embodiments, the immune system
is often involved with inflammation disorders, demonstrated in both
allergic reactions and some myopathies, with many immune system
disorders resulting in abnormal inflammation.
[0154] A subject in need of a composition of this disclosure
includes a subject with observable symptoms of a chronic
gastrointestinal disorder (e.g., a subject with abdominal pain,
blood in stool, pus in stool, fever, weight loss, frequent
diarrhea, fatigue, reduced appetite, tenesmus, and rectal
bleeding), as well as a subject who has no observable symptoms of a
chronic gastrointestinal disorder but has been determined to be
susceptible to developing the gastrointestinal disorder (i.e., a
subject at risk of developing the gastrointestinal disorder)
[0155] The term "effective amount" as used herein means an amount
of the compound, extract, or formulation containing the compound or
extract, which is sufficient to significantly improve a disorder.
As used herein, the term "improve" or "improved" should be taken
broadly to encompass improvement in an identified characteristic of
a disease state, said characteristic being regarded by one of skill
in the art to generally correlate, or be indicative of, the disease
in question, as compared to a control, or as compared to a known
average quantity associated with the characteristic in question.
For example, "improved" digestive health associated with
application of a compound or extract of the disclosure can be
demonstrated by comparing the digestive health (e.g., abdominal
symptoms, stool, fever, weight, appetite and/or epithelial barrier
integrity) of a human treated with the compound or extract, as
compared to the digestive health of a human not treated.
Alternatively, one could compare the digestive health of a human
treated with a compound or extract of the disclosure to the average
digestive health of a human, as represented in scientific or
medical publications known to those of skill in the art. In the
present disclosure, "improved" does not necessarily demand that the
data be statistically significant (i.e., p<0.05); rather, any
quantifiable difference demonstrating that one value (e.g., the
average treatment value) is different from another (e.g., the
average control value) can rise to the level of "improved."
[0156] Of concern when determining an effective amount to be used
in humans is balancing the desired effects (benefits) against risks
associated with use of a compound. At issue for such risk/benefit
assessments is the types of adverse effects observed and the
likelihood that they will occur. Also considered is the fact that
the effective amount may vary with the particular disorder being
treated, e.g., IBD, IBS, UC, or CD, the age and physical condition
of the end user, the severity of the condition, the duration of the
treatment, the particular carrier utilized, and like factors.
[0157] In general, a suitable daily dose of a compound or extract
of the disclosure will be that amount of a compound or extract
which is the lowest dose that is effective at producing a desired
benefit, in this case an effect that improves digestive health and
consequently overall health and well-being. Such an effective dose
will generally depend upon the factors described herein. For oral
administration, the dose may range from about 0.0001 mg to about 10
grams per kilogram of body weight per day, about 5 mg to about 5
grams per kilogram of body weight per day, about 10 to about 2
grams per kilogram of body weight per day, or any other suitable
dose. If desired, the effective daily dose of the compound or
extract may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. In some
embodiments, dosing is one administration per day.
[0158] The compound or extract of the disclosure can be used alone
or in combination with a particular diet or standard of care. By
way of illustration, a compound or extract of this disclosure may
be combined with a gluten-free diet, or used in combination with an
aminosalicylate, a corticosteroid, athiopurine, methotrexate, a JAK
inhibitor, a sphingosine 1-phosphate (SIP) receptor inhibitor, an
anti-integrin biologic, an anti-IL12/23R or anti-IL23 biologic,
and/or an anti-tumor necrosis factor agent or biologic.
[0159] Administration of a compound or extract of the disclosure
improves digestive function thereby addressing the underlying
pathogenesis of one or more gastrointestinal disorders and
promoting the health, well-being, and quality of life of the
subject. Ideally, an effective amount of a compound or extract
provides a measurable improvement in the levels or activity of
HNF4.alpha. activity and/or intestinal epithelial barrier and/or
digestive function compared to a subject not receiving treatment.
More particularly, use of a compound or extract of the disclosure
preferably prevents, slows the progression of, delays or treats an
intestinal disorder such as IBD, IBS, UC and/or CD.
[0160] The following non-limiting examples are provided to further
illustrate the present disclosure.
Example 1: Assessing Indicators of Metabolic Activity: Materials
and Methods
[0161] Expression of Insulin and HNF4.alpha.. RNA was purified
using a RNEASY.RTM. chromatographic separation and isolation kits
(Qiagen), and converted to cDNA using the qScript.TM. cDNA SuperMix
(Quanta Biosciences). Q-PCR was conducted with cDNA corresponding
to 2 .mu.g of RNA using an Optic on Real-Time System (MJ Research)
and QPCR SuperMix (BioPioneer). See All mRNA values were normalized
to 18S rRNA values and are expressed as fold changes over
vehicle-treated control.
[0162] Primary Antibodies. HNF4.alpha. antibodies were used
(#sc-6556, Santa Cruz Biotechnology; Santa Cruz, Calif. and #3113,
Cell Signaling Technology; Danvers, Mass.). For fluorescent
imaging, samples were incubated with ALEXA FLUOR.RTM. 488
green-fluorescent dye or Rhodamine labeled anti-mouse, rabbit or
goat and nuclei were counterstained with DAPI
(4',6-diamidino-2-phenylindole). antibodies alone were used
immunostaining. Fluorescently Controls to ensure labeled using
secondary specificity of sections were analyzed with a conventional
inverted microscope (Olympus, PlanFl 40.times./0.60) or with a
confocal microscope equipped with a krypton/argon laser.
[0163] Bioavailability Determinations. Male C57BL/6 mice were
administered N-trans-caffeoyl tyramine or N-transferuloyl tyramine
via IV, intraperitoneal or oral route (three mice for each route)
(Table 2).
TABLE-US-00002 TABLE 2 Route Formulation Dosage (mg/kg) IV 1 mg/mL
in 75% PEG 300/25% water, clear solution 2.0 Oral 3 mg/mL in 0.5%
methyl cellulose, homogenous opaque 30.0 suspension with fine
particles IP 3 mg/mL in 5% DMSO/5% Polysorbate 80/90% water, 30
clear solution
[0164] A blood sample from each mouse was drawn at 0.25, 0.5, 1, 2,
4, 6 and 24 hours after administration. An 8 .mu.L aliquot of blood
was used for analysis. After adding 200 L of an internal standard
comprising 100 ng/mL Labetalol, 100 ng/mL dexamethasone, 100 ng/mL
tolbutamide, 100 ng/mL Verapamil, 100 ng/mL Glyburide, and 100
ng/mL Celecoxib in ACN, the mixture was vortex-mixed and
centrifuged at 12000 rpm for 15 minutes at 4.degree. c. to pellet
precipitated protein. Four L of the supernatant was injected for
LC-MS/MS analysis. Bioavailability (%) was calculated using
AUC.sub.0-inf (% AUC.sub.Extra<20%) or AUC.sub.0-last (%
AUC.sub.Extra>20%) with nominal dose.
[0165] pH Stability Assessment. Individual stock solutions were
prepared in DMSO at concentrations of 10 mg/mL. Four different
buffer solutions were prepared to achieve solutions with a pH of 2,
7.4, 8.5 and 10. For each pH assay, 5 .mu.L of stock solution was
added to 245 .mu.L of buffered solution to a 2 mL tube, vortexed
and incubated in a 37.degree. C. water bath. At each timepoint, 50
.mu.L aliquots were taken, neutralized and analyzed via HPLC
analysis using a DAD detector at 280 nm. The fold change of the
peak area at 280 nm was analyzed for the initial and final
timepoint, 0.5 and 72 hours, respectively.
Example 2: Assessing Compounds for Activity as HNF4.alpha.
Agonists
[0166] Given the role of HNF4.alpha. in maintaining a healthy
metabolism in humans, test compounds were screened for activity as
HNF4.alpha. agonists (either direct or indirect effects). Using a
known insulin promoter-reporter assay, Kiselyuk and colleagues
(2010. J. Biomol. Screen 15(6):663-70), screened a library of
compounds for activity to promote insulin activation. They
identified compound 1 as an insulin activator (Kiselyuk, et al.
(2012) Chem. Biol. 19(7):806-18) and the compound was subsequently
shown to possess HNF4.alpha. agonistic activity in an ornithine
transcarbamoylase (OTC) promoter assay. The OTC promoter is known
to be responsive to HNF4.alpha. in transient transfection assays
(Inoue, et al. (2002) J. Biol. Chem. 277:25257-65).
[0167] To identify plant compounds that have similar bioactivity as
this synthetic agent (compound 1), a bioinformatics approach was
taken to predict, from the set of all known plant compounds, a
targeted sub-set with the desired HNF4.alpha. agonistic activity.
Using a number of algorithms in combination with training data
(i.e., positive data), models were built around important features
of the positive data, which were predictive of the desired
biological activity. More specifically, a set of 18 synthetic
compounds with known ability to affect HNF4.alpha. activity (e.g.,
compound 1) were included in the positive data set. These
structures were used to search a database of plant compounds for
chemical structures that had similar structural features. A number
of metrics were used to measure similarity based on concepts from
the fields of graph theory and information theory, either solely or
in combination.
[0168] Plant compounds in the top 10th percentile of similarity to
the 18 target structures were selected and compounds predicted to
be potential agonists of HNF4.alpha. activity given their chemical
structural features were screened in the HNF4.alpha. assay. The
results of the screening identified a class of plant tyramine
containing hydroxycinnamic acid amides (i.e.,
N-transcaffeoyltyramine, N-cis-caffeoyltyramine,
N-transferuloyltyramine and p-coumaroyltyramine) that are able to
act as HNF4.alpha. modulators. Notably, N-trans-caffeoyltyramine
was determined to be roughly an order-of-magnitude more potent than
Alverine in activating HNF4.alpha. (FIG. 1). Due to hydroxyl
derivatization of both phenyl rings, N-transcaffeoyltyramine is
less lipophilic and therefore expected to be more bioavailable.
Overall, the increased potency and expected enhanced
bioavailability indicated that N-transcaffeotyramine and other
tyramine containing hydroxycinnamic acid amides would be expected
to be more desirable compounds for use in the methods disclosed
herein.
[0169] Experiments were performed to demonstrate that these
compounds directly modulate HNF4.alpha. activity. In particular, it
was demonstrated that HNF4.alpha. gene expression was upregulated
(e.g., as determined by quantitative PCR analysis) in the presence
of N-trans-caffeoyl tyramine and N-trans-feruloyltyramine (FIG. 2).
In addition, it was found that p-coumaroyltyramine also upregulated
HNF4.alpha. gene expression; however, cis-feruloyltyramine,
N-coumaroyldopamine, N-trans-feruloyloctopamine and
pcoumaroyloctopamine were inactive.
Example 3: Evaluation of Compound-Related Toxicity
[0170] Given the need to balance benefits and risks of the
compounds of the present disclosure, in vivo toxicity studies in
laboratory animals (e.g., mice, rats, dogs) are typically
performed. Such studies are typically performed consistent with
Good Laboratory Practice (GLP) regulations to ensure reliability
and reproducibility for regulatory purposes. If compounds are to be
administered for periods of weeks to months to years in humans,
chronic toxicity studies typically are performed (studies of from
six months to one year in duration). For compounds to be used in
foods, oral toxicity studies are recommended.
[0171] The purpose of chronic toxicity testing is to determine the
toxicological profile of a test compound. In the initial phase of
testing, a study will be performed in rats. A total of 160 Sprague
Dawley rats (80 males and 80 females) approximately 5-7 weeks old
and weighing between 80-100 g each will be randomly selected and
allocated to treatment groups by weight; such that the mean body
weights of each group will not be significantly different. The test
compound or extract will be administered orally at dose levels of
0.5, 1 and 2 g/kg body weight per day to rats for a period of 90
consecutive days. The animals will be observed daily for any
clinical signs of toxicity (e.g., behavioral changes; skin and fur
appearance; eating and drinking; etc.). At the end of the
experiment, the animals will be subjected to hematological,
biochemical and histopathological evaluation consistent with
standard toxicological methods.
[0172] Initial safety/toxicity assays were also performed, the
collective results of which are presented in Table 3.
TABLE-US-00003 TABLE 3 N-trans-caffeoyl N-trans-feruloyl
p-coumaroyl Assay tyramine tyramine tyramine HNF.alpha. Activity +
+ + HNF.alpha. mRNA + + + Insulin mRNA + + + Estrogenic
Counter-Screen + + + pH Stability Acid Stable Stable Acid Stable
Bioavailability ~11% ~7% ND ND, not determined.
Example 4: Isolation of Tyramine Containing Hydroxycinnamic Acid
Amides from Plant Sources
[0173] Ethanolic extracts were prepared from various plant species
and plant tissues thereof. Individual compounds were identified in
the extracts by extracting dry plant powder material with 95%
aqueous ethanol. The ethanol extract was concentrated and adsorbed
onto celite and dryloaded onto a C18 solid phase extraction column.
The extract was desalted by washing with two column volumes of
water which were collected and discarded. Compounds were eluted
with two column volumes of methanol and the extract was
concentrated to dryness. The extract was resuspended in 1:1
Acetonitrile:water prior to analysis. Synthetic standards of known
concentrations were used to generate calibration curves prior to
analysis. The listing of sources used in the analysis are presented
below in Table 4. Plants are displayed for each compound in
descending order with the plants that produce the highest amount of
compound on the top of the list and the lowest producers at the
bottom of the list.
TABLE-US-00004 TABLE 4 Genus species Plant Tissues(s)
N-Trans-caffeoyltyramine Annona muricata Seed, pulp, skin Annona
spp. Seed, pulp, skin Tribulus terrestris Seed, fruit Cannabis sp.
Seed, hull, leaf Annona cherimola Seed, pulp, skin, leaf, wood
Annona montana Leaf Solanum lycopersicum Fruit Solanum tuberosum
Tuber, peel Lycium barbarum Fruit, stem N-Trans-feruloyltyramine
Annona spp. Seed, pulp, skin Annona cherimola Seed, pulp, skin,
leaf, wood Piper nigrum Fruit Tribulus terrestris Seed, fruit
Annona muricata Seed, pulp, skin Solanum lycopersicum Fruit
Cannabis Seed, hull, leaf Capsicum frutescens Fruit Allium
fistulosum Aerial plant Solanum tuberosum Tuber, peel Zea mays
Seed, stalk, leaf Allium sativum Bulb Annona montana Leaf Annona
squamosa Fruit Lycium barbarum Fruit, stem Capsicum annuum Fruit
Ipomoea batatas Peel Chenopodium quinoa Seed Armoracia rusticana
Root Capsicum annuum Fruit, leaf, stem Fagopyrum esculentum Hull
Eragrostis tef Seed p-Coumaroyltyramine Annona spp. Seed, pulp,
skin Tribulus terrestris Seed, fruit Solanum lycopersicum Fruit
Annona muricata Seed, pulp, skin Annona montana Leaf Annona
cherimola Seed, pulp, skin, leaf, wood Cannabis spp. Seed, hull,
leaf Solanum tuberosum Tuber, peel Allium fistulosum Aerial plant
Zea mays Seed, stalk, leaf Allium sativum Bulb Ipomoea batatas
Peel
[0174] The amounts of N-trans-caffeoyltyramine,
N-transferuloyltyramine and p-coumaroyltyramine present in certain
ethanol extracts (% of extract, w/w) was determined. Quantification
of the compounds was performed by normalizing the results by the
weight of the ethanol extracts (FIG. 3).
Example 5: N-Trans-Caffeoyltyramine Improves Tight Junctions
[0175] TNF-.alpha. is an inflammatory cytokine that increases
intestinal tight junction permeability. To analyze the effect of
N-trans-caffeoyltyramine on tight junctions, 200 ng or 300 ng
TNF-.alpha. was added to a monolayer of epithelial CaCo-2 cells to
induced tight junction damage. After TNF-.alpha. exposure,
N-trans-caffeoyltyramine was added and tight junction formation was
determined by antibody staining for zonula occludens (ZO) -1.
Nuclear stain (DAPI) was used to demonstrate cell viability. The
CaCo-2 cells was sorted for high TNF-.alpha. expression with
compromised integrity of tight junctions. Increasing concentration
of exogenous TNF-.alpha. from 200 ng to 300 ng reduced ZO-1
staining. However, N-transcaffeoyltyramine addition reversed the
effects of TNF-.alpha. on ZO-1 at both the 200 ng to 300 ng
amounts.
[0176] To confirm the in vivo caffeoyltyramine, C57BL/6 mice effect
intraperitoneal injection (IP) caffeoyltyramine twice a day for 14
were with days. of N-transdosed by N-transIntestinal samples were
harvested and stained to visualize HNF.alpha. expression, ZO-1 and
DAPI staining. HNF4.alpha. expression was observed in the stem
cells of the epithelial layer in all mice. Extension of HNF4.alpha.
expression along the villi of the epithelial was visible after 2
weeks of treatment with N-trans-caffeoyl tyramine demonstrating
that this compound induced HNF4.alpha. expression in the intestinal
lining of N-trans-caffeoyltyramine-treated mice.
Example 6: Effect of N-Trans-Caffeoyltyramine on the Intestine
[0177] Intestine from mice treated with DMSO or
N-trans-caffeoyltyramine were examined histologically. Gross
morphological appearance was unchanged. DIG mice did not exhibit
significant change in HNF4.alpha. expression. In both, HNF4.alpha.
was highly expressed in the crypt, with much less being detectable
in the villi (see FIG. 4). N-trans-caffeoyltyramine induced a large
increase in HNF4.alpha. expression throughout, with a large
increase in the villi and a smaller increase in the crypt, where
expression was already quite strong (see FIG. 5, quantified in
lower panel). Analysis of genes induced by N-trans-caffeoyltyramine
suggested that N-trans-caffeoyltyramine may be promoting Paneth
cell formation and/or function. Paneth cells are specialized
secretory cells that play a critical role in defenses against
intestinal microbes. To that end, they secrete a variety of
antimicrobial peptides. Of note, Paneth cells play an important
role in IBD pathogenesis. High fat diet has been reported to reduce
the number of Paneth cells, and our studies reproduced that finding
(see FIG. 4), but the mechanism by which that occurs has not been
understood. Remarkably, N-trans-caffeoyltyramine induced a complete
recovery in the number of Paneth cells in DIG mice (see FIG.
4).
[0178] The disclosure is generally described herein using
affirmative language to describe the numerous embodiments. The
disclosure also includes embodiments in which subject matter is
excluded, in full or in part, such as substances or materials,
method steps and conditions, protocols, or procedures. Various
other omissions, additions and modifications may be made to the
methods and structures described above without departing from the
scope of the claimed subject matter. All such modifications and
changes are intended to fall within the scope of the subject
matter, as defined by the appended claims.
[0179] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity.
[0180] It will be understood by those within the art that, in
general, terms used herein, and especially in the appended claims
(for example, bodies of the appended claims) are generally intended
as "open" terms (for example, the term "including" should be
interpreted as "including but not limited to," the term "having"
should be interpreted as "having at least," the term "includes"
should be interpreted as "includes but is not limited to," etc.).
It will be further understood by those within the art that if a
specific number of an introduced claim recitation is intended, such
an intent will be explicitly recited in the claim, and in the
absence of such recitation no such intent is present. For example,
as an aid to understanding, the following appended claims may
contain usage of the introductory phrases "at least one" and "one
or more" to introduce claim recitations. However, the use of such
phrases should not be construed to imply that the introduction of a
claim recitation by the indefinite articles "a" or "an" limits any
particular claim containing such introduced claim recitation to
embodiments containing only one such recitation, even when the same
claim includes the introductory phrases "one or more" or "at least
one" and indefinite articles such as "a" or "an" (for example, "a"
and/or "an" should be interpreted to mean "at least one" or "one or
more"); the same holds true for the use of definite articles used
to introduce claim recitations. In addition, even if a specific
number of an introduced claim recitation is explicitly recited,
those skilled in the art will recognize that such recitation should
be interpreted to mean at least the recited number (for example,
the bare recitation of "two recitations," without other modifiers,
means at least two recitations, or two or more recitations).
Furthermore, in those instances where a convention analogous to "at
least one of A, B, and C, etc." is used, in general such a
construction is intended in the sense one having skill in the art
would understand the convention (for example, "a system having at
least one of A, B, and C" would include but not be limited to
systems that have A alone, B alone, C alone, A and B together, A
and C together, B and C together, and/or A, B, and C together,
etc.). In those instances where a convention analogous to "at least
one of A, B, or C, etc." is used, in general such a construction is
intended in the sense one having skill in the art would understand
the convention (for example, "a system having at least one of A, B,
or C" would include but not be limited to systems that have A
alone, B alone, C alone, A and B together, A and C together, B and
C together, and/or A, B, and C together, etc.). It will be further
understood by those within the art that virtually any disjunctive
word and/or phrase presenting two or more alternative terms,
whether in the description, claims, or drawings, should be
understood to contemplate the possibilities of including one of the
terms, either of the terms, or both terms. For example, the phrase
"A or B" will be understood to include the possibilities of "A" or
"B" or "A and B."
[0181] In addition, where features or aspects of the disclosure are
described in terms of Markush groups, those skilled in the art will
recognize that the disclosure is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[0182] As will be understood by one skilled in the art, for any and
all purposes, such as in terms of providing a written description,
all ranges disclosed herein also encompass any and all possible
sub-ranges and combinations of sub-ranges thereof. Any listed range
can be easily recognized as sufficiently describing and enabling
the same range being broken down into at least equal halves,
thirds, quarters, fifths, tenths, etc. As a non-limiting example,
each range discussed herein can be readily broken down into a lower
third, middle third and upper third, etc. As will also be
understood by one skilled in the art all language such as "up to,"
"at least," "greater than," "less than," and the like include the
number recited and refer to ranges which can be subsequently broken
down into sub-ranges as discussed above. Finally, as will be
understood by one skilled in the art, a range includes each
individual member. Thus, for example, a group having 1-3 articles
refers to groups having 1, 2, or 3 articles. Similarly, a group
having 1-5 articles refers to groups having 1, 2, 3, 4, or 5
articles, and so forth.
[0183] While various aspects and embodiments have been disclosed
herein, other aspects and embodiments will be apparent to those
skilled in the art. The various aspects and embodiments disclosed
herein are for purposes of illustration and are not intended to be
limiting, with the true scope and spirit being indicated by the
following claims.
* * * * *