U.S. patent application number 10/202670 was filed with the patent office on 2003-04-17 for cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods.
Invention is credited to Bobzin, Steven, Boddupalli, Sekhar, Brown, Lesley, Chen, Jian, Del Balzo, Ughetta, Gilat, Sylvain, Miller, Guy, Song, Jiangao, Wang, Bing, Zhang, Wei, Zhang, Yong-Kang.
Application Number | 20030073712 10/202670 |
Document ID | / |
Family ID | 26975749 |
Filed Date | 2003-04-17 |
United States Patent
Application |
20030073712 |
Kind Code |
A1 |
Wang, Bing ; et al. |
April 17, 2003 |
Cytoprotective compounds, pharmaceutical and cosmetic formulations,
and methods
Abstract
Cytoprotective compounds, many of which are phenolic derivatives
characterized by a substituted phenol having certain conjugated
bonds, are useful in the treatment of certain ischemic or
inflammatory conditions, including but not limited to stroke,
myocardial infarction, congestive heart failure, and skin disorders
characterized by inflammation or oxidative damage. They are also
useful in the manufacture of pharmaceutical and cosmetic
formulations for the treatment of such conditions.
Inventors: |
Wang, Bing; (Cupertino,
CA) ; Zhang, Yong-Kang; (San Jose, CA) ; Chen,
Jian; (Sunnyvale, CA) ; Zhang, Wei; (Santa
Clara, CA) ; Song, Jiangao; (Cupertino, CA) ;
Del Balzo, Ughetta; (Morgan Hill, CA) ; Brown,
Lesley; (East Palo Alto, CA) ; Boddupalli,
Sekhar; (San Jose, CA) ; Bobzin, Steven; (San
Jose, CA) ; Gilat, Sylvain; (San Francisco, CA)
; Miller, Guy; (San Jose, CA) |
Correspondence
Address: |
David A. Lowin
P.O. Box 620535
Woodside
CA
94062-0535
US
|
Family ID: |
26975749 |
Appl. No.: |
10/202670 |
Filed: |
July 23, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60307439 |
Jul 23, 2001 |
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60353702 |
Jan 31, 2002 |
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Current U.S.
Class: |
514/277 ;
514/408; 514/520; 514/623; 514/645; 514/676; 514/680; 514/709;
514/718 |
Current CPC
Class: |
A61P 17/02 20180101;
A61P 17/16 20180101; C07C 235/42 20130101; A61P 25/02 20180101;
C07D 213/30 20130101; C07D 277/24 20130101; C07F 9/4021 20130101;
A61P 11/00 20180101; A61P 37/00 20180101; C07C 49/737 20130101;
C07C 205/35 20130101; C07D 311/72 20130101; A61P 3/10 20180101;
A61P 9/10 20180101; C07C 43/23 20130101; C07D 277/20 20130101; A61P
17/06 20180101; C07C 311/29 20130101; C07C 205/17 20130101; A61P
9/00 20180101; A61P 17/10 20180101; A61P 25/16 20180101; A61P 37/06
20180101; C07C 2603/24 20170501; C07C 45/71 20130101; A61P 25/00
20180101; A61P 21/00 20180101; A61P 5/24 20180101; C07C 45/71
20130101; A61P 17/00 20180101; C07C 45/30 20130101; C07C 205/20
20130101; C07C 47/575 20130101; C07C 205/57 20130101; C07C 47/575
20130101; A61P 11/06 20180101; A61P 25/18 20180101; C07D 295/26
20130101; A61P 25/28 20180101; A61P 19/02 20180101; A61P 1/04
20180101; C07C 69/94 20130101; A61P 15/00 20180101; A61P 27/02
20180101; A61P 43/00 20180101; C07C 45/30 20130101; C07C 205/22
20130101; C07D 213/53 20130101; C07D 231/26 20130101; A61P 13/12
20180101; A61P 9/04 20180101; C07C 255/36 20130101; A61P 29/00
20180101 |
Class at
Publication: |
514/277 ;
514/408; 514/520; 514/645; 514/676; 514/680; 514/718; 514/709;
514/623 |
International
Class: |
A61K 031/435; A61K
031/40; A61K 031/277; A61K 031/13; A61K 031/12; A61K 031/10; A61K
031/165 |
Claims
We claim:
1. A method of treatment for a mammal suffering from a condition
characterized by oxidative stress, comprising administering an
effective amount of a compound represented by the formula:
54wherein: R is: substituted alkenyl, optionally substituted aryl,
(optionally substituted aryl)carbonyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, or nitro; R' is:
hydrogen or (optionally substituted alkoxy)carbonyl; R.sup.1 to
R.sup.5 are independently selected from: optionally substituted
alkoxy, optionally substituted alkenyl, optionally substituted
alkyl, optionally substituted aryl, (optionally substituted
alkoxy)carbonyl, carboxy, cyano, halo, optionally substituted
heteroaryl, hydrogen, hydroxy, nitro, nitrone, sulfonate; or two
adjacent members of R.sup.1 to R are each O.sup.- and together are
complexed with carbon or a metal; provided that at least one of
R.sup.1 to R.sup.5 is methoxymethoxy, or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4, and further provided that when R.sup.1 to
R.sup.5 is methoxymethoxy, R is phenyl having cyano, nitro,
nitroso, hydroxylamino, aminocarbonyl, a lower alkyl ester or a
nitrogen-bearing heterocyclyl substituent at its para position, or
by the formula: 55wherein: R" is: optionally substituted
anthracenone, di-cyano, or optionally substituted heterocyclyl
selected from: 2,5-(optionally
substituted)-2,4-dihydro-pyrazol-3-one; 5-(optionally
substituted)-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione; R.sup.6 to R.sup.10 are independently
selected from: optionally substituted alkenyl, optionally
substituted alkoxy, optionally substituted alkyl, optionally
substituted aryl, (optionally substituted alkoxy)carbonyl,
hydrogen, hydroxy and nitrone; or two adjacent members of R.sup.6
to R.sup.10 are each O.sup.- and together are complexed with carbon
or a metal; provided that at least one of R.sup.6 to R.sup.10 is
not hydrogen, and further provided that where R.sup.10 and another
of R.sup.6 to R.sup.9 are hydrogen, at least one of R.sup.6 to
R.sup.9 is methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].- sub.n-- where n is an
integer from 1 to 4, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
2. The method of claim 1 comprising adminstering a compound of
Formula I where R' is hydrogen; and at least one of R.sup.1 to
R.sup.5 is methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 2.
3. The method of claim 2 where at least one of R.sup.1 to R.sup.5
is methoxymethoxy, and another of R.sup.1 to R.sup.5 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 2.
4. The method of claim 1 where R is para-nitro phenyl.
5. The method of claim 2, where R is para-nitro phenyl.
6. A compound represented by the formula: 56wherein: R is:
anthraquinone, optionally substituted heteroaryl, optionally
substituted heterocyclyl, nitro, or substituted phenyl having: a
substituent in the para position, selected from: cyano, nitro,
alkoxycarbonyl, (nitrogen-containing)-hetero- cyclyl and
(nitrogen-containing)-heteroaryl, and/or a substituent in the meta
position selected from: nitro and halo; R' is: hydrogen or
(optionally substituted alkoxy)-carbonyl; R.sup.1 to R.sup.5 are
independently selected from: optionally substituted alkoxy,
optionally substituted alkenyl, optionally substituted alkyl,
optionally substituted aryl, (optionally substituted
alkoxy)-carbonyl, carboxy, cyano, halo, optionally substituted
heteroaryl, hydrogen, hydroxy, nitro, nitrone, sulfonate; provided
that at least one of R.sup.1 to R.sup.5 is hydrogen, and at least
another of R.sup.1 to R.sup.5 is H--[CH.sub.2--(CH.sub.3)C.d-
bd.CH--CH.sub.2].sub.n-- or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].su- b.n--O-- where n is
an integer from 1 to 4, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
7. The compound of claim 6 where: R is: substituted phenyl; and R'
is: hydrogen.
8. The compound of claim 7 where at least one of R.sup.1 to R.sup.5
is hydroxy or lower alkoxy.
9. The compound of claim 8 where at least two of R.sup.1 to R.sup.5
is hydrogen.
10. The compound of claim 6 where n is 1 or 2.
11. The compound of claim 7 where n is 1 or 2.
12. The compound of claim 11 where R.sup.5 is hydrogen.
13. The compound of claim 6 where R.sup.1 to R.sup.5 are
independently selected from: optionally substituted alkoxy,
optionally substituted alkenyl, carboxy, cyano, halo, hydrogen,
hydroxy, and nitro.
14. The compound of claim 6 where: R.sup.5 and another of R.sup.1
to R.sup.4 are hydrogen, one of R.sup.1 to R.sup.4 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is 1,
2 or 3, and the others of R.sup.1 to R.sup.4 are selected from
hydrogen, hydroxy and lower alkoxy.
15. The compound of claim 7 where R is phenyl para-substituted with
cyano, nitro or alkoxycarbonyl.
16. The compound of claim 7 where R is phenyl meta-substituted with
bromo.
17. A pharmaceutical or cosmetic formulation comprising a compound
of claim 6 admixed with an acceptable excipient.
18. A compound represented by the formula: 57wherein: R is:
(substituted phenyl)-alkenyl; R' is: hydrogen; R.sup.1 to R.sup.5
are independently selected from: optionally substituted alkoxy,
optionally substituted alkenyl, optionally substituted alkyl,
optionally substituted aryl, (optionally substituted
alkoxy)-carbonyl, carboxy, cyano, halo, optionally substituted
heteroaryl, hydrogen, hydroxy, nitro, nitrone, and sulfonate;
provided that (a) at least one of R.sup.1 to R.sup.5 is
methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4, or (b) two adjacent members of R.sup.1 to
R.sup.5 are each O.sup.- and together are complexed with a metal,
including single stereoisomers, mixtures of stereoisomers, and the
pharmaceutically acceptable salts thereof.
19. The compound of claim 18 where R is substituted phenyl-vinyl,
having: a substituent in the para position, selected from: cyano,
nitro, alkoxycarbonyl, (nitrogen-containing)-heterocyclyl and
(nitrogen-containing)-heteroaryl, or a substituent in the meta
position selected from: nitro and halo.
20. The compound of claim 19 where R is
1-nitro-4-vinyl-benzene.
21. A compound represented by the formula: 58wherein: R is:
(optionally substituted heterocyclyl)-alkenyl R' is: hydrogen;
R.sup.1 to R.sup.5 are independently selected from: optionally
substituted alkoxy, optionally substituted alkenyl, optionally
substituted alkyl, optionally substituted aryl, (optionally
substituted alkoxy)-carbonyl, carboxy, cyano, halo, optionally
substituted heteroaryl, hydrogen, hydroxy, nitro, nitrone, and
sulfonate, with the proviso that at least one of R.sup.1 to R.sup.5
is hydroxy, methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].su- b.n--, where n is
an integer from 1 to 4; or two adjacent members of R.sup.1 to
R.sup.5 are each O.sup.- and together are complexed with a metal;
including single stereoisomers, mixtures of stereoisomers, and the
pharmaceutically acceptable salts thereof.
22. The compound of claim 21 where R is (optionally substituted
heterocyclyl)-methylene.
23. The compound of claim 22 where R is
5-methyl-4-methylene-2-phenyl-2,4-- dihydro-pyrazol-3-one or
5-methylene-thiazolidine-2,4-dione.
24. The compound of claim 22 or 23, where: R.sup.5 and another of
R.sup.1 to R.sup.4 are hydrogen, and the others of R.sup.1 to
R.sup.4 are selected from alkoxy, hydrogen, hydroxy,
methoxymethoxy, and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 2.
25. A pharmaceutical or cosmetic formulation comprising a compound
of any of claims 18 or 21 admixed with an acceptable excipient.
26. A compound represented by the formula: 59wherein: R is:
optionally substituted heteroaryl, selected from the group:
1-carboxymethyl-pyridini- um-4-yl bromide;
1-(2-carboxy-2-oxo-ethyl)-pyridinium-4-yl bromide; thiazol-2-yl;
6-nitro-benzo[1,3]dioxo-5-yl; and a [2,2']bipyridin-5-yl metal
complex; R' is: hydrogen; R.sup.1 to R.sup.5 are independently
selected from: optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkyl, optionally
substituted aryl, (optionally substituted alkoxy)carbonyl, carboxy,
cyano, halo, optionally substituted heteroaryl, hydrogen, hydroxy,
nitro, nitrone, sulfonate; or two adjacent members of R.sup.1 to
R.sup.5 are each O.sup.- and together are complexed with a metal;
provided that where R is a [2,2']bipyridin-5-yl Ru or Pd metal
complex, R.sup.3 and R.sup.4 are not both hydroxy, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
27. The compound of claim 26 where: R.sup.5 and another of R.sup.1
to R.sup.4 are hydrogen, the others of R.sup.1 to R.sup.4 are
selected from: alkoxy, (optionally substituted alkoxy)carbonyl,
hydrogen, hydroxy, and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 4.
28. The compound of claim 27 where R.sup.1 is hydrogen, R.sup.2 is
hydroxy, R.sup.3 is hydroxy and R.sup.4 is hydrogen.
29. The compound of claim 27 where R.sup.1 is hydrogen, R.sup.2 is
methoxymethoxy, R.sup.3 is methoxymethoxy, and R.sup.4 is
hydrogen.
30. The compound of claim 27 where R.sup.1 is hydrogen, R.sup.2 is
hydrogen, R.sup.3 is methoxycarbonyl and R.sup.4 is hydrogen.
31. The compound of claim 26 where R is [2,2']bipyridin-5-yl, the
nitrogen atoms of which are complexed to a metal having one or more
apical ligands.
32. The compound of claim 31 where the metal is selected from
Zn(II), Mn(III) and Cu(II).
33. The compound of claim 32 where the apical ligand is selected
from chloride and acetate.
34. The compound of claim 31 or 32 where R.sup.1 is hydrogen,
R.sup.2 is hydrogen, R.sup.3 is methoxymethoxy, R.sup.4 is
methoxymethoxy and R.sup.5 is hydrogen.
35. The compound of claim 26 selected from the group:
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethoxymethoxy-benzene,
zinc(II) chloride;
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethoxymethoxy-benzene- ,
copper(II) chloride; and
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethox- ymethoxy-benzene,
manganese(III) acetate.
36. A pharmaceutical or cosmetic formulation comprising a compound
of claim 26 admixed with an acceptable excipient.
37. A compound represented by the formula: 60wherein: R is:
substituted alkenyl, optionally substituted aryl, (optionally
substituted aryl)-carbonyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, or nitro; R' is: hydrogen or
(optionally substituted alkoxy)-carbonyl; three members of R.sup.1
to R.sup.5 are independently selected from: optionally substituted
alkoxy, optionally substituted alkenyl, optionally substituted
alkyl, optionally substituted aryl, (optionally substituted
alkoxy)-carbonyl, carboxy, cyano, halo, optionally substituted
heteroaryl, hydrogen, hydroxy, nitro, nitrone, and sulfonate; and
two adjacent members of R.sup.1 to R.sup.5 are each O.sup.- and
together are complexed with a metal having one or more apical
ligands, said metal optionally being further complexed with a
second compound of Formula I, including single stereoisomers,
mixtures of stereoisomers, and the pharmaceutically acceptable
salts thereof.
38. The compound of claim 37 where R' is hydrogen.
39. The compound of claim 38 where R.sup.3 and R.sup.4 are O.sup.-
and together are complexed with a metal.
40. The compound of claim 39 where R.sup.1, R.sup.2 and R.sup.5 are
hydrogen.
41. The compound of claim 37 or 39, where the metal is selected
from Zn(II), Mn(III) and Cu(II).
42. The compound of claim 41 where the apical ligand is selected
from chloride and acetate.
43. The compound of claim 38 where R is substituted phenyl having:
a substituent in the para position, selected from: cyano, nitro,
alkoxycarbonyl, (nitrogen-containing)-heterocyclyl and
(nitrogen-containing)-heteroaryl, or a substituent in the meta
position selected from: nitro and halo.
44. The compound of claim 43 where R is
para-alkoxycarbonyl-phenyl.
45. The compound of claim 43 selected from the group:
4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester, zinc(II)
chloride; 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
copper(II) chloride; 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid
ethyl ester, manganese(III) acetate; and
bis-{4-[2-(4-methoxycarbonyl-phenyl)-v- inyl]-benzene-1,2-diol},
zinc(II) chloride.
46. The compound of claim 37 selected from Formula III, IV and V:
61where: M is: a metal; L is: a ligand associated with a remaining
free valence on M; n is: an integer from 1 to 3, corresponding to
the remaining free valences on M and the number of associated
ligands; R and R* are independently selected from: optionally
substituted anthraquinone, substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, or nitro; and
R.sup.2, R.sup.4 and R.sup.4* are independently selected from:
optionally substituted alkoxy, hydrogen, or hydroxy.
47. A pharmaceutical or cosmetic formulation comprising a compound
of claim 37 admixed with an acceptable excipient.
48. A compound represented by the formula: 62wherein: R" is:
optionally substituted anthracenone, di-cyano, or optionally
substituted heterocyclyl selected from: 2,5-(optionally
substituted)-2,4-dihydro-pyra- zol-3-one; 5-(optionally
substituted)-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione; R.sup.6 to R.sup.10 are independently
selected from: optionally substituted alkenyl, optionally
substituted alkoxy, optionally substituted alkyl, optionally
substituted aryl, (optionally substituted alkoxy)carbonyl,
hydrogen, hydroxy and nitrone; or two adjacent members of R.sup.6
to R.sup.9 are each O.sup.- and together are complexed with a
metal; provided that at least one of R.sup.6 to R.sup.10 is not
hydrogen, and further provided that where R.sup.10 and another of
R.sup.6 to R.sup.9 are hydrogen, at least one of R.sup.6 to R.sup.9
is methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
49. The compound of claim 48 where R.sup.10 and another of R.sup.6
to R.sup.9 are hydrogen.
50. The compound of claim 48 where R" is selected from:
anthracenone, dihydroxyanthracenone, di-cyano,
5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-- one; 3H-benzofuran-2-one;
5-hydroxy-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione.
51. The compound of claim 49 where R" is selected from:
anthracenone, dihydroxyanthracenone, di-cyano,
5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-- one; 3H-benzofuran-2-one;
5-hydroxy-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione.
52. The compound of claim 49 where R.sup.6 to R.sup.9 are selected
from: hydrogen, hydroxy, methoxymethoxy, t-butyl and
H--[CH.sub.2--(CH.sub.3)C.- dbd.CH--CH.sub.2].sub.n--, where n is 1
or 2.
53. The compound of claim 51 where R.sup.6 to R.sup.9 are selected
from: hydrogen, hydroxy, methoxymethoxy, t-butyl and
H--[CH.sub.2--(CH.sub.3)C.- dbd.CH--CH.sub.2].sub.n--, where n is 1
or 2.
54. The compound of claim 53 where R.sup.6 is hydrogen and: R.sup.7
is hydrogen, R.sup.8 is methoxymethoxy, and R.sup.9 is
methoxymethoxy; or R.sup.7 is methoxymethoxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH- .sub.2--, and R.sup.9 is
hydroxy; or R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--, and R.sup.9 is
methoxymethoxy; or R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)- C.dbd.CH--CH.sub.2--, and R.sup.9 is
hydroxy; or R.sup.7 is H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--,
R.sup.3 is methoxymethoxy, and R.sup.9 is hydrogen; or R.sup.7 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--C- H.sub.2--, R.sup.8 is hydroxy,
and R.sup.9 is hydrogen; or R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
methoxymethoxy, and R.sup.9 is hydrogen; or R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
hydroxy, and R.sup.9 is hydrogen; or R.sup.7 is
3-methoxy-4-methoxymethoxy-1-(thia-
zolidine-2,4-dionyl)-benzylidene-5-yl, R.sup.8 is methoxymethoxy,
and R.sup.9 is methoxy.
55. A pharmaceutical or cosmetic formulation comprising a compound
of claim 48 admixed with an acceptable excipient.
56. A compound selected from the group:
4-[2-(3,4-dihydroxy-phenyl)-vinyl]- -benzoic acid methyl ester;
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitr-
o-phenyl)-vinyl]-phenol;
2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5--
[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-met-
hyl-but-2-enyl-phenyl)-vinyl]-phenol;
2-methoxy-4-[4-(4-nitro-phenyl)-buta- -1,3-dienyl]-phenol;
2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-v-
inyl]-benzene-1,2-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phe-
nyl)-vinyl]-benzene-1,3-diol;
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl-
}-2-phenyl-2,4-dihydro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but--
2-enyl)-phenyl]-vinyl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-
-methyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-
-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-{2-[4-(5-hydroxy-1H-pyrazo-
l-3-yl)-phenyl]-vinyl}-benzene-1,2-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-v- inyl}-benzene-1,2-diol;
3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-benzo-
nitrile;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)--
vinyl]-phenol;
2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vinyl}-
-benzonitrile; and
2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
57. A compound of claim 56 selected from the group:
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5,-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-d-
iol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,3-diol;
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihy-
dro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vin-
yl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-
-phenyl]-vinyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene-1,3-diol;
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vin-
yl}-benzene-1,2-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-d- iol;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-b-
enzonitrile;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phen-
yl)-vinyl]-phenol; and
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5--
methoxy-phenyl]-vinyl}-benzonitrile, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
58. A compound selected from the group:
3-(3-methyl-but-2-enyl)-4-[2-(4-ni-
tro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-- 1,2,3-triol;
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl--
2,4-dihydro-pyrazol-3-one;
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-b-
enzylidene]-thiazolidine-2,4-dione;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro--
phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-en-
yl-phenyl)-vinyl]-phenol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phen-
yl)-vinyl]-phenol;
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}--
phenyl)-vinyl]-benzoic acid ethyl ester;
2-methoxy-6-(3-methyl-but-2-enyl)-
-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-[3-(3-methoxy-4-methoxymethoxy-phe-
nyl)-allylidene]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzamide;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-ben-
zamide;
{4-[2-(3,4-dihydroxy-phenyl}-vinyl]-phenyl-morpholin-4-yl-methanon-
e; 4-[2-(2,5-dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester; 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
methyl ester;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-die- nyl ester;
4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid methyl
ester; 4-[2-(4-hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
4-bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic acid
diisopropyl ester; and
(4-methoxyphenyl)-(benzo-1,3-dioxol-5-yl)-ethyne, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
59. A compound selected from the group:
5-{2-[4-hydroxy-3-(3-methyl-but-2--
enyl)-phenyl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene-1,3-diol;
4-(3,4-dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one-
;
4-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydr-
o-pyrazol-3-one;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H--
benzofuran-2-one;
5-{4-[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-trid-
ecyl)-chroman-5-ylmethoxy]-benzylidene}-thiazolidine-2,4-dione;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzamide;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-ben-
zamide;
{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-morpholin-4-yl-methano-
ne; 4-[2-(2,5-dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester; 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
methyl ester;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-die- nyl ester;
4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid methyl
ester; 4-[2-(4-hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
4-bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester; and
{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic acid
diisopropyl ester, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
60. A pharmaceutical or cosmetic formulation comprising a compound
of any of claims 56, 57, 58 and 59 and 60 admixed with an
acceptable excipient.
61. A compound is selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-be- nzene-1,2-diol;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylide-
ne]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5--
hydroxy-3H-benzofuran-2-one;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-di-
hydroxy-phenyl]-vinyl}-benzonitrile;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-
-phenyl)-vinyl]-benzene-1,3-diol;
4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-b- enzene-1,2-diol;
5-di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine-2,4-d- ione;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-b-
enzene-1,2-diol;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,3-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl-
)-vinyl]-phenol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vi-
nyl]-benzene-1,3-diol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-
-vinyl-benzonitrile; and
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-pheny-
l)-vinyl]-phenol, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
62. The compound of claim 61 selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-
-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5--
[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-met-
hyl-but-2-enyl-phenyl)-vinyl]-phenol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[-
2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-{2-[3,5-dihydroxy-4-(3-methy-
l-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-[2-(4-
-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vi- nyl}-benzene-1,2-diol; and
4-2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihyd-
roxy-phenyl]-vinyl}-benzonitrile.
63. A pharmaceutical or cosmetic formulation for topical
application comprising a one or more dermatologically acceptable
excipients and a compound of claim 61 or 62.
64. A method of treatment for a mammal suffering from a condition
characterized by oxidative stress, comprising administering a
therapeutically effective amount of a compound of any of claims 6,
18, 21, 26, 37, 48, 56, 58, 59 and 60.
65. The method of claim 63 comprising treating a cardiovascular,
cerebrovascular or neurologic, inflammatory and/or autoimmune, or
dermatologic condition.
66. The method of claim 64 wherein the condition is dermatologic,
further comprising a method of promoting a product by directing a
user to apply to the skin a pharmaceutical or cosmetic composition
incorporating said compound for regulating skin condition,
regulating the signs of skin aging, or for treating contact
dermatitis, acne, psoriasis, age-related damage or damage resulting
from harmful (UV) radiation, stress or fatigue.
67. A method of treatment for a mammal suffering from a
cardiovascular condition characterized by oxidative stress,
comprising administering a therapeutically effective amount of a
compound represented by Formula I: 63wherein: R is: nitro,
nitrogen-containing heteroaryl, or phenyl substituted in the para
position with alkoxycarbonyl or a nitrogen-bearing moiety; R' is:
hydrogen; R.sup.1 to R.sup.5 are independently selected from:
hydrogen, hydroxy, alkoxy, alkenyl or halo, or two adjacent members
of R.sup.1 to R.sup.5 are each O.sup.- and together are complexed
with a metal; or by Formula II: 64wherein: R" is: a
thiazolidine-2,4-dione or a 2-thioxo-thiazolidin-4-one; R.sup.6 to
R.sup.10 are independently selected from: hydrogen, hydroxy or
alkoxy; or two adjacent members of R.sup.6 to R.sup.10 are each
O.sup.- and together are complexed with a metal; including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
68. The method of claim 67 where: R is phenyl substituted in the
para position with nitro or cyano, or unsubstituted thiazole;
R.sup.1 and R.sup.5 are hydrogen; R.sup.2 to R.sup.4 are selected
from hydrogen, hydroxy, methoxy, methoxymethoxy, prenyl, geranyl
and bromo, provided that at least two of R.sup.2 to R.sup.4 are not
hydrogen; R" is thiazolidine-2,4-dione-5-yl; R.sup.6 and R.sup.10
are hydrogen; and at least two of R.sup.7 to R.sup.9 are
methoxymethoxy, with the third being hydrogen or
methoxymethoxy.
69. The method of claim 68 comprising administering a compound of
Formula I.
70. The method of claim 69 where at least two of R.sup.2 to R.sup.4
are methoxymethoxy.
71. The method of claim 69 where one of R.sup.2 to R.sup.4 is
methoxy, another of R.sup.2 to R.sup.4 is methoxymethoxy and the
third of R.sup.2 to R.sup.4 is prenyl, geranyl or bromo.
72. The method of claim 67 where the compound is selected from the
group: 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-[2-(4-hydroxy-3,5-dimeth- yl-phenyl)-vinyl]-benzoic acid methyl
ester; 4-[2-(4-hydroxy-3-methoxy-phe- nyl)-vinyl]-benzonitrile;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
4-(2-nitro-vinyl)-benzene-1,2-diol;
4-[2-(3,4-bis-methoxymethoxy-phenyl)--
vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzamide;
4-[2-(3,4-bis-methoxymethoxy-p- henyl)-vinyl]-phthalic acid
dimethyl ester; 1-methoxy-2-methoxymethoxy-3-(-
3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-viny-
l]-benzene;
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vinyl}-
-benzonitrile;
2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole;
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione; and
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vinyl}-
-benzoic acid methyl ester.
73. The method of claim 67 where the compound is selected from the
group: 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-[2-(4-hydroxy-3-methoxy-- phenyl)-vinyl]-benzonitrile;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-ben-
zamide; 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester;
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-p-
henyl)-vinyl]-benzene;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-
-(4-nitro-phenyl)-vinyl]-benzene;
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phe- nyl)-vinyl]-benzene;
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phen-
yl)-vinyl]-benzene;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-met-
hoxy-phenyl]-vinyl}-benzonitrile;
2-[2-(3,4-bis-methoxymethoxy-phenyl)-vin- yl]-thiazole;
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dion- e;
and
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester.
74. The method of claim 67 where the compound is selected from the
group: 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-[2-(4-hydroxy-3-methoxy-- phenyl)-vinyl]-benzonitrile;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)--
vinyl]-benzene;
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzen- e;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-viny-
l}-benzonitrile;
2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole; and
4-{2-[3-(3,7-dimethyl
octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vinyl}- -benzoic acid
methyl ester.
75. A method of treatment for a mammal suffering from a
cerebrovascular or neurologic condition characterized by oxidative
stress, comprising administering a therapeutically effective amount
of a compound represented by Formula I: 65wherein: R is: phenyl
substituted with an alkoxy, alkoxycarbonyl, hydroxy, a
nitrogen-bearing moiety, or nitrogen-bearing heteroaryl; R' is:
hydrogen; one or more of R.sup.1 to R.sup.5 is other than hydrogen,
selected from hydroxy, alkoxy, alkenyl or halo; or two adjacent
members of R.sup.1 to R.sup.5 are each O.sup.- and together are
complexed with a metal; or by Formula II: 66wherein: R" is: a
thiazolidine-2,4-dione or a 2-thioxo-thiazolidin-4-one; and one or
more of R.sup.6 to R.sup.10 are not hydrogen, selected from
hydroxy, alkoxy and alkenyl; or two adjacent members of R.sup.6 to
R.sup.10 are each O.sup.- and together are complexed with a metal;
including single stereoisomers, mixtures of stereoisomers, and the
pharmaceutically acceptable salts thereof.
76. The method of claim 75 where: R is selected from: optionally
substituted pyridinium bromide,
vinyl-5-methyl-2-phenyl-2,4-dihydro-pyrax- ol-3-one, phenyl
substituted in the para position with nitro or a methyl-, ethyl-,
or tetradecyl-ester, and tri-substituted phenyl having a nitro and
a methoxy substituent at the two meta positions and methoxymethoxy
or hydroxy at the para position; R.sup.1 and R.sup.5 are hydrogen;
R.sup.2 to R.sup.4 are selected from hydrogen, hydroxy,
methoxymethoxy, and prenyl or geranyl, provided that at least two
of R.sup.2 to R.sup.4 are not hydrogen; R" is
thiazolidine-2,4-dione-5-yl; R.sup.6 and R.sup.10 are hydrogen; and
two or more of R.sup.7 to R.sup.9 are not hydrogen, selected from
hydroxy, methoxymethoxy, prenyl and geranyl.
77. The method of claim 76 comprising administering a compound of
Formula I.
78. The method of claim 77 where at least one of R.sup.2 to R.sup.4
is prenyl or geranyl.
79. The method of claim 78 where R is tri-substituted phenyl having
a nitro and a methoxy substituent at the two meta positions and
methoxymethoxy or hydroxy at the para position.
80. The method of claim 75 where the compound is selected from the
group: 2,6-di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide-4-{2-[4-amino-sulfo-
nyl)-phenyl]-vinyl}-benzene-1,2-diol;
3,4-bis-[2-(3,4-dihydroxy-phenyl)-vi- nyl]-benzoic acid methyl
ester; 4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-- vinyl]-benzoic
acid methyl ester; 4-[2-(2,3,4-trihydroxy-phenyl)-vinyl]-be-
nzonitrile;
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2-
,4-dihydro-pyrazol-3-one;
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-viny- l]-pyridinium;
bromide; 1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[-
2-(4-nitro-phenyl)-vinyl]-benzene;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vi- nyl]-benzoic acid
tetradecyl ester; 4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-
-ethoxy]-ethoxy}-phenyl)-vinyl]-benzoic acid ethyl ester;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-phenyl]-vin-
yl}-benzoic acid methyl ester;
2-methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-
-phenyl)-vinyl]-benzene;
1,2-bis-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-
-1,3-dienyl]-benzene;
2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoi- c acid
methoxymethyl ester;
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-
-3-[2-(4-nitro-phenyl)-vinyl]-benzene;
1,3-bis-methoxymethoxy-2-(3-methyl--
but-2-enyl)-5-[2-(3-nitro-4-methoxymethoxy-5-methoxy-phenyl)-vinyl]-benzen-
e;
1-iodo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-benzylid-
ene]-thiazolidine-2,4-dione;
5-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-b-
enzyldene]-thiazolidine-2,4-dione;
5-[4-hydroxy-3-(3-methyl-but-2-enyl)-be-
nzylidene]-thiazolidine-2,4-dione;
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-h-
ydroxy-benzylidene]-thiazolidine-2,4-dione; 5-[3-(3,7-dim
ethyl-octa-2,6-dienyl)-4-methoxymethoxy-benzylidene]-thiazolidine-2,4-dio-
ne;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester;
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4--
nitro-phenyl)-vinyl]-phenol;
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-vin-
yl]-2-(3-methyl-but-2-enyl)-benzene-1,3-diol; and
4-{2-[4-(3,7-dimethyl-oc-
ta-2,6-dienyl)-3,5-bis-methoxymethoxy-phenyl]-vinyl}-benzonitrile.
81. The method of claim 75 where the compound is selected from the
group: 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl ester;
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one;
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridini- um;
bromide;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro--
phenyl)-vinyl]-benzene;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoi- c acid
tetradecyl ester;
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-et-
hoxy}-phenyl)-vinyl]-benzoic acid ethyl ester;
2-methoxymethoxy-1,3-dimeth-
yl-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
5-[3-(3,7-dimethyl-octa-2,6-dieny-
l)-4-hydroxy-benzylidene]-thiazolidine-2,4-dione;
2-methoxymethoxy-5-[2-(4- -nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl)-viny-
l]-benzene;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-
-methoxymethoxy-5-methoxy-phenyl)-vinyl]-benzene;
1-iodo-3-methoxy-2-metho-
xymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
1-bromo-3-methoxy-2-methox-
ymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
4-[3-(3-methoxy-4-methoxyme-
thoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}--
benzoic acid methyl ester;
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-
-phenyl)-vinyl]-phenol; and
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-viny-
l]-2-(3-methyl-but-2-enyl)-benzene-1,3-diol.
82. The method of claim 75 where the compound is selected from the
group: 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl ester;
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitr-
o-phenyl)-vinyl]-benzene;
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benz- oic acid
tetradecyl ester; 4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]--
ethoxy}-phenyl)-vinyl]-benzoic acid ethyl ester;
5-[3-(3,7-dimethyl-octa-2-
,6-dienyl)-4-hydroxy-benzylidene-thiazolidine-2,4-dione;
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-methoxymet-
hoxy-5-methoxy-phenyl)-vinyl]-benzene;
1-bromo-3-methoxy-2-methoxymethoxy--
5-[2-(4-nitro-phenyl)-vinyl]-benzene;
4-[3-(3-methoxy-4-methoxymethoxy-phe-
nyl)-allylidene]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}--
benzoic acid methyl ester;
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-
-phenyl)-vinyl]-phenol; and
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-viny-
l]-2-(3-methyl-but-2-enyl)-benzene-1,3-diol.
83. The method of claim 75 where the condition is selected from:
stroke, cerebral ischemia, retinal ischemia, post-surgical
cognitive dysfunctions, peripheral neuropathy spinal chord injury,
head injury, surgical trauma, Alzheimer's, dementia and Parkinson's
disease.
84. The method of claim 75 comprising administering said compound
about 5 or more hours following an ischemic or oxidative
insult.
85. The method of claim 75 or 84 where the compound is:
4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2-diol; or
4-[2-(3,4-Dihydroxy-phe- nyl)-vinyl]-benzoic acid methyl ester.
86. A method of treatment for a mammal suffering from a disease
characterized by oxidative stress and involving inflammatory and/or
autoimmune components, comprising administering a therapeutically
effective amount of a compound represented by Formula I: 67wherein:
R is: phenyl substituted in the para position with alkoxycarbonyl
or a nitrogen-bearing moiety, vinyl-nitrogen-containing heteroaryl,
or vinyl-nitrogen-containing heterocyclyl; R' is: hydrogen; one or
more of R.sup.1 to R.sup.5 is other than hydrogen, selected from
hydroxy, alkoxy, alkoxycarbonyl and alkenyl; or two adjacent
members of R.sup.1 to R.sup.5 are each O.sup.- and together are
complexed with a metal; including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
87. The method of claim 86 where: R is selected from:
vinyl-thiazolidine-2,4-dione phenyl substituted in the para
position with nitro or cyano, and
vinyl-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one; R.sup.1 is
hydrogen; R.sup.2 to R.sup.5 are selected from hydrogen, hydroxy,
methoxy, methoxymethoxy, methoxymethoxycarbonyl, prenyl or geranyl,
provided that at least two of R.sup.2 to R.sup.5 are not
hydrogen.
88. The method of claim 87 where one of R.sup.2 to R.sup.5 is
prenyl or geranyl, and two others are selected from hydroxy,
methoxy and methoxymethoxy.
89. The method of claim 88 where R is phenyl substituted in the
para position with nitro or cyano.
90. A method of treatment for a mammal suffering from a disease
characterized by oxidative stress and involving inflammatory and/or
autoimmune components, comprising administering a therapeutically
effective amount of a compound is selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl- )-vinyl]-benzoic acid methyl ester;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1- ,2,3-triol;
5-methyl-2-(4-styryl-phenyl)-2,4-dihydro-pyrazol-3-one;
2-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-pyrazo-
l-3-one;
4-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one;
4-[3-(4-hydroxy-3-methoxy-phenyl)-allylidene]-5-me-
thyl-2-phenyl-2,4-dihydro-pyrazol-3-one;
4-{2-[3-methoxy-4-methoxymethoxy--
5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic acid methyl ester;
4-[2-(3-iodo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester; 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic
acid methoxymethyl ester;
4-[2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-vinyl]-b- enzoic acid
methyl ester; 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-be-
nzoic acid methoxymethyl ester;
N-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vi- nyl]-phenyl}-benzamide;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allyidene-
]-5-methyl-2-phenyl-2,4-dhydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymet-
hoxy-phenyl)-allylidene]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hy-
droxy-benzylidene)-5-hydroxy-3H-benzofuran-2-one;
5-[3,5-bis-methoxymethox-
y-4-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4-dione;
5-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4-
-dione;
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazol-
idine-2,4-dione;
5-[3-methoxy-4-methoxymethoxy-5-(3-methoxy-4-methoxymetho-
xy-1-(thiazolidine-2,4-dionyl)-benzylidene-5-yl)-benzylidene]-thiazolidine-
-2,4-dione;
4-{2-[3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-pheny-
l]-vinyl}-benzoic acid methyl ester;
4-{2-[3,4-dihydroxy-2-(3-methyl-but-2-
-enyl)-phenyl]-vinyl}-benzoic acid methyl ester;
4-{2-[3,4-dihydroxy-5-(3--
methyl-but-2-enyl)-phenyl]-vinyl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
4-{2-[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl-
]-vinyl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2--
enyl)-phenyl]-vinyl}-benzoic acid methyl ester;
3-(3-methyl-but-2-enyl)-4--
[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
3-(3-methyl-but-2-enyl)-5-[2--
(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4--
nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nit-
ro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2--
(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4--
nitro-phenyl)-vinyl]-benzene-1,3-diol;
4-{2-[4-(3,7-dimethyl-octa-2,6-dien-
yl)-3,5-dihydroxy-phenyl]-vinyl}-benzonitrile;
4-{2-[3,5-dihydroxy-4-(3-me-
thyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
2-bromo-4-[4-hydroxy-3-(3-me-
thyl-but-2-enyl-phenyl)-vinyl]-phenol;
5-{2-[4-hydroxy-3-(3-methyl-but-2-e-
nyl)-phenyl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene-1,3-diol; and
5-{3-[3-methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-allylidene}-thiazolidi-
ne-2,4-dione, including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
91. The method of claim 90 where the compound is selected from the
group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-[3-(3-methoxy-4-metho-
xymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2,4-dio-
ne;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-2--
one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-b-
enzene-1,2-diol;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,-
3-diol;
4-2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl--
benzonitrile;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-b-
enzonitrile; and
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl-
]-phenol.
92. The method of claim 91 where the compound is selected from the
group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
3-(3-methyl-but-2-enyl)-
-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol; and
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol.
93. A method of treatment for a mammal suffering from a
dermatologic condition characterized by oxidative stress,
comprising administering a therapeutically effective amount of a
compound represented by Formula I: 68wherein: R is: phenyl
substituted in the para position with a nitrogen-bearing moiety or
a lower alkoxycarbonyl, or is phenyl substituted in the meta
position with bromo and in the para position with hydroxy; R' is:
hydrogen; one or more of R.sup.1 to R.sup.5 is other than hydrogen,
selected from hydroxy, alkoxy, alkenyl and halo or two adjacent
members of R.sup.1 to R.sup.5 are each O.sup.- and together are
complexed with a metal; including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts
thereof.
94. The method of claim 93 where: R is phenyl substituted in the
para position with nitro or cyano; and R.sup.1 is hydrogen.
95. The method of claim 93 where one or two of R.sup.2 to R.sup.4
is hydroxy, one of R.sup.1 to R.sup.4 is prenyl or geranyl, and the
remaining substituents of R.sup.1 to R.sup.5 are hydrogen.
96. The method of claim 95 where R is phenyl substituted in the
para position with nitro or cyano.
97. A method of treatment for a mammal suffering from a
dermatologic condition characterized by oxidative stress,
comprising administering a therapeutically effective amount of a
compound selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl- )-vinyl]-benzoic acid methyl ester;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1- ,2,3-triol
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]--
phenol; 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2,6-di-tert-butyl-4-[2-(4-- nitro-phenyl)-vinyl]-phenol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-
-vinyl]-benzene-1,3-diol;
2-bromo-4-(4-hydroxy-3-(3-methyl-but-2-enyl-phen-
yl)-vinyl]-phenol; 4-(2-nitro-vinyl)-benzene-1,2-diol;
2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-d-
iol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,3-diol;
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihy-
dro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vin-
yl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-
-phenyl]-vinyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene-1,3-diol;
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vin-
yl}-benzene-1,2-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-d- iol;
3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylide-
ne]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5--
hydroxy-3H-benzofuran-2-one;
2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]- -phenol;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-viny-
l}-benzonitrile;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro--
phenyl)-vinyl]-phenol;
2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phen- ol;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vin-
yl}-benzonitrile; 2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
acetic acid 4-(1-acetoxy-allyl)-phenyl ester;
2-(4-methoxy-phenyl)-1-(3,4,5-trim- ethoxy-phenyl)-ethanol; acetic
acid 4-[2-(4-acetoxy-3-methoxy-phenyl)-viny- l]-2-methoxy-phenyl
ester; 3,4,5-trio; 4-(3-ethoxy-propenyl)-phenol;
2,3-bis-(4-acetoxy-3-methoxy-phenyl)-acrylic acid; cis-gnetin;
5-[2-(4-methoxy-phenyl)-vinyl]-benzo[1,3]dioxole; and
(4-methoxyphenyl)-(benzo-1,3-dioxol-5-yl)-ethyne, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
98. The method of claim 97 where the compound is selected from the
group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl- )-vinyl]-benzoic acid methyl ester;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1- ,2,3-triol;
2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-
-diol;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-be-
nzene-1,3-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol; and
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-benzo-
nitrile.
99. The method of claim 98 where the compound is selected from the
group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-
-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5--
[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol; 2-bromo-4-[4
-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-
-diol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-dio-
l; 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol; and
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-benzo-
nitrile.
100. The method of claim 97 comprising topically administering a
compound is selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol- ;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylide-
ne]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5--
hydroxy-3H-benzofuran-2-one;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-di-
hydroxy-phenyl]-vinyl}-benzonitrile;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-
-phenyl)-vinyl]-benzene-1,3-diol;
4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-b- enzene-1,2-diol;
5-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine--
2,4-dione;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benz-
oic acid methyl ester;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl-
]-benzene-1,2-diol;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-b-
enzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene-1,3-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phe-
nyl)-vinyl]-phenol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-
-vinyl]-benzene-1,3-diol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phen-
yl]-vinyl}-benzonitrile; and
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-p-
henyl)-vinyl]-phenol.
101. The method of claim 100 comprising topically administering a
compound is selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol- ;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylide-
ne]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5--
hydroxy-3H-benzofuran-2-one;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-di-
hydroxy-phenyl]-vinyl}-benzonitrile; and
2-(3-methyl-but-2-enyl)-5-[2-(4-n-
itro-phenyl)-vinyl]-benzene-1,3-diol.
102. The method of claim 101 comprising topically administering a
compound is selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol- ;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonitrile;
and
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-b-
enzonitrile.
103. The method of any of claims 93 or 97 where the dermatologic
condition is selected from: regulating skin condition, regulating
the signs of skin aging, contact dermatitis, acne, psoriasis,
age-related damage, and damage resulting from harmful (UV)
radiation, stress and fatigue.
104. The method of any of claims 93 or 97 further comprising a
method of promoting a product by directing a user to apply to the
skin a pharmaceutical or cosmetic composition incorporating said
compound for regulating skin condition, regulating the signs of
skin aging, or for treating contact dermatitis, acne, psoriasis,
age-related damage or damage resulting from harmful (UV) radiation,
stress or fatigue.
105. A product comprising instructions directing the user to apply
a composition to the skin for regulating skin condition, regulating
the signs of skin aging, or for treating contact dermatitis, acne,
psoriasis, age-related damage or damage resulting from harmful (UV)
radiation, stress or fatigue, said composition comprising a
compound of any of claims 6, 18, 21, 26, 37, 48, 56, 58, 59 and 60;
or a compound of the formula: 69wherein: R is: phenyl substituted
in the para position with a nitrogen-bearing moiety or a lower
alkoxycarbonyl, or is phenyl substituted in the meta position with
bromo and in the para position with hydroxy; R' is: hydrogen; one
or more of R.sup.1 to R.sup.5 is other than hydrogen, selected from
hydroxy, alkoxy, alkenyl and halo; or two adjacent members of
R.sup.1 to R.sup.5 are each O.sup.- and together are complexed with
a metal, or a compound selected from the group:
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl- )-vinyl]-benzoic acid methyl ester;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1- ,2,3-triol
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]--
phenol; 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2,6-di-tert-butyl-4-[2-(4-- nitro-phenyl)-vinyl]-phenol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-
-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phen-
yl)-vinyl]-phenol; 4-(2-nitro-vinyl)-benzene-1,2-diol;
2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-d-
iol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,3-diol;
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihy-
dro-pyrazol-3-one;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vin-
yl}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-
-phenyl]-vinyl}-benzonitrile;
4-(3-methyl-but-enyl)-5-[2-(4-nitro-phenyl)--
vinyl]-benzene-1,3-diol;
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl-
}-benzene-1,2-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-dio- l;
3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,-
4-dihydro-pyrazol-3-one;
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylide-
ne]-thiazolidine-2,4-dione;
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5--
hydroxy-3H-benzofuran-2-one;
2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]- -phenol;
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-viny-
l}-benzonitrile;
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro--
phenyl)-vinyl]-phenol;
2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phen- ol;
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]-vin-
yl}-benzonitrile; 2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
acetic acid 4-(1-acetoxy-allyl)-phenyl ester;
2-(4-methoxy-phenyl)-1-(3,4,5-trim- ethoxy-phenyl)-ethanol; acetic
acid 4-[2-(4-acetoxy-3-methoxy-phenyl)-viny- l]-2-methoxy-phenyl
ester; 2-{3-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-
-phenoxy}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-trio;
4-(3-ethoxy-propenyl)-phenol;
2,3-bis-(4-acetoxy-3-methoxy-phenyl)-acryli- c acid; cis-gnetin;
5-[2-(4-methoxy-phenyl)-vinyl]-benzo[1,3]dioxole; and
(4-methoxyphenyl)-(benzo-1,3-dioxol-5-yl)-ethyne, including single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
106. The product of claim 105 where: R is phenyl substituted in the
para position with nitro or cyano; and R.sup.1 is hydrogen.
107. The product of claim 105 where one or two of R.sup.2 to
R.sup.4 is hydroxy, one of R.sup.1 to R.sup.4 is prenyl or geranyl,
and the remaining substituents of R.sup.1 to R.sup.5 are
hydrogen.
108. The product of claim 107 where R is phenyl substituted in the
para position with nitro or cyano.
109. The product of claim 105 wherein said compound is selected
from the group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl ester;
4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
2-hydroxy-5-[2-(4-nitro- -phenyl)-vinyl]-benzoic acid;
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl-
)-vinyl]-benzene-1,2-diol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-v-
inyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-viny-
l]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-v-
inyl]-phenol;
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-
-1,2-diol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-b-
enzene-1,3-diol;
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl-
}-benzoic acid methyl ester;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-p-
henyl]-vinyl}-benzonitrile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)--
vinyl]-benzene-1,3-diol;
4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,- 2-diol;
3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol; and
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-benzo-
nitrile.
110. The product of claim 105 wherein said compound is selected
from the group: 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-
-diol;
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-dio-
l; 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol; and
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-benzo-
nitrile.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of co-pending provisional
applications U.S. Serial No. 60/307,439, filed Jul. 23, 2001, and
U.S. Serial No. 60/353,702, filed Jan. 31, 2002, incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to certain compounds having
cytoprotective activity, and particularly to a series of phenolic
derivatives. The invention is also directed to formulations and
methods for treating stroke, myocardial infarction and chronic
heart failure, as well as other oxidative stress-related conditions
that are typically responsive to cellular enzyme modulation.
BACKGROUND INFORMATION
[0003] The present invention is concerned with cytoprotective
compounds, many of which are phenolic derivatives characterized by
a substituted phenol having certain conjugated bonds, also referred
to herein as a "conjugated phenol."
[0004] Compositions of the invention are active in certain
experimental models that predict efficacy in, for example, certain
ischemic or inflammatory conditions, including but not limited to
stroke, myocardial infarction, congestive heart failure, and skin
disorders characterized by inflammation or oxidative damage. The
invention is therefore related to the use of the cytoprotective
derivatives in such conditions.
[0005] Various agents have heretofore been provided for such
conditions. In one group of compounds, the substituted stilbenes
(e.g., including resveratrol and its derivatives), many if not all
of the possible positions have been disclosed as substituted with
various moieties for use as cosmetics, antioxidants, fungicides and
as pharmaceutical active agents for the treatment of dermatological
conditions, inflammation, menopause, diabetes, cell growth
inhibition, protection against UV damage, antimicrobial agents and
the like (see, e.g., U.S. Pat. Nos. 4,992,468; 5,547,983;
5,565,191; and 6,147,121). It has, however, remained desired to
provide new, improved and more specifically targeted therapies for
conditions characterized by oxidative stress, and particularly, for
providing protection in the event of cerebral ischemia or
ultraviolet exposure; especially desired are agents that are
effective even if first administered after a significant period of
time (e.g., about 5 or more hours) following an ischemic or
oxidative insult.
SUMMARY OF THE INVENTION
[0006] The present invention is concerned with certain novel and
related cytoprotective compounds that are particularly active in
restoring or preserving metabolic integrity in oxidatively
competent cells that have been subjected to oxygen deprivation.
Such compounds, predominantly conjugated phenols (both synthetic
and naturally occurring), are useful in the manufacture of
pharmaceutical and cosmetic compositions for treating a number of
conditions characterized by oxidative stress, and particularly, in
providing protection in the event of cerebral ischemia or
ultraviolet exposure, even when administered a significant time
interval after an ischemic or oxidative insult. In particular, the
compositions of the present invention are useful in the treatment
of stroke, as demonstrated by providing neuroprotection in a
standard experimental model of focal cerebral ischemia. They are
also useful in the treatment of myocardial ischemia (myocardial
infarction), as well as other indications characterized by
oxidative stress and/or inflammation, including, but not limited
to, neurodegenerative disorders such as Alzheimer's, dementia, and
Parkinson's disease; diabetes, renal disease, pre-menstrual
syndrome, asthma, cardiopulmonary inflammatory disorders, chronic
heart failure, rheumatoid arthritis, inflammatory bowel syndrome,
muscle fatigue, intermittent claudication and for the preservation
of allograft tissue for transplantation. Particularly with regard
to dermatological conditions, the compounds, formulations and
methods of the present invention are useful in regulating skin
condition, regulating the signs of skin aging and in treating a
number of conditions, including, but not limited to contact
dermatitis, acne, psoriasis, and in the prevention and protection
of skin tissue against age-related damage or damage resulting from
insults such as harmful (UV) radiation, stress and fatigue.
[0007] The present invention concerns the compounds represented by
Formulae I to V, particularly compounds embodying certain preferred
combinations and permutations of substituent groups, including
single stereoisomers, mixtures of stereoisomers, and the
pharmaceutically acceptable salts thereof. For example, the
substituent group methoxymethoxy has been identified as conferring
activity in various methods of treatment of the invention, in
addition to serving as a protecting group in the synthesis of
hydroxyl-substituted compounds. Another preferred substituent group
is alkenyl, represented by the formula
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 4 (most preferably n is 1 or 2, i.e., prenyl and
geranyl). The invention further concerns the use of these compounds
as active agents in practice of methods of treatment for a mammal
suffering from a condition characterized by oxidative stress, their
use in the manufacture of the pharmaceutical and/or cosmetic
formulations of the invention, and their use as intermediates in
the synthesis of active agents.
[0008] With regard to Formula I: 1
[0009] R is selected from: substituted alkenyl, optionally
substituted aryl, (optionally substituted aryl)carbonyl, optionally
substituted heteroaryl (including bipyridinyl metal complexes),
optionally substituted heterocyclyl, or nitro;
[0010] R' is selected from: hydrogen or (optionally substituted
alkoxy)carbonyl;
[0011] R.sup.1 to R.sup.5 are independently selected from:
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)carbonyl, carboxy, cyano, halo,
optionally substituted heteroaryl, hydrogen, hydroxy, nitro,
nitrone, sulfonate; or
[0012] two adjacent members of R.sup.1 to R.sup.5 are each O.sup.-
and together are complexed with carbon or a metal;
[0013] provided that at least one of R.sup.1 to R.sup.5 is not
hydrogen.
[0014] With regard to Formula II: 2
[0015] R" is selected from: optionally substituted anthracenone,
substituted alkenyl, di-cyano, optionally substituted heteroaryl,
or optionally substituted heterocyclyl;
[0016] R.sup.6 to R.sup.10 are independently selected from:
optionally substituted alkenyl, optionally substituted alkoxy,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)carbonyl, hydrogen, hydroxy and
nitrone; or
[0017] two adjacent members of R.sup.6 to R are each O.sup.- and
together are complexed with carbon or a metal;
[0018] provided that at least one of R.sup.6 to R.sup.10 is not
hydrogen. Those skilled in the art will appreciate that many
compounds analogous to those of Formula II, bearing a single bond
to R", can be employed in the methods of treatment of the present
invention.
[0019] Formula III, IV and V represent compounds of Formula I where
two adjacent members of R.sup.1 to R.sup.5 (preferably R.sup.3 with
R.sup.2 or R.sup.4) are each O.sup.- and together are complexed
with a metal having one or more apical ligands, where the metal can
optionally be further complexed with a second compound of Formula I
forming dimers of such complexes: 3 4
[0020] where:
[0021] M is: a metal;
[0022] L is: a ligand associated with a remaining free valence on
M;
[0023] n is: an integer from 1 to 3, corresponding to the remaining
free valences on M and the number of associated ligands;
[0024] R and R* are independently selected from: optionally
substituted anthraquinone, substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, or nitro; and
[0025] R.sup.2, R.sup.4 and R.sup.4* are independently selected
from: optionally substituted alkoxy, hydrogen, or hydroxy.
[0026] Certain naturally occurring conjugated phenols and the like
are also useful in the methods and compositions of the invention
including: acetoxychavicol acetate, arachidin I, arachadin II,
arachidin III, astringin, cis-gnetin,
1-(3,4,5-trimethoxyphenyl)-2-(4-methoxyphenyl)-eth- anol,
trans-(4,4'-diacetoxy-3,3'-dimethoxy)carboxystilbene, and
trans-(4,4'-diacetoxy-3,3'-dimethoxy)stilbene, including single
isomers, mixtures of isomers, and the pharmaceutically acceptable
salts thereof. Other compounds of interest include
(4-methoxyphenyl)-(benzo-1,3-dioxol-5- -yl)-ethyne.
[0027] As further described below, certain embodiments of the
invention provide novel and preferred combinations of the
substituents groups pendant from Formulae I to V. Also provided are
methods of treatment for cardiovascular, cerebrovascular and
neurologic, inflammatiory and/or autoimmune, and dermatologic
conditions characterized as involving oxidative stress, and certain
preferred combinations of the substituent groups pendant from
Formulae I to V for their respective treatment.
[0028] In another aspect, the invention relates to a pharmaceutical
and/or cosmetic compositions containing a therapeutically effective
amount of a compound of any of Formulae I to V, an above-described
naturally occurring conjugated phenol, or a pharmaceutically
acceptable salt thereof admixed with at least one pharmaceutically
acceptable excipient. Particularly preferred are those
pharmaceutical or cosmetic compositions wherein a compound of
Formulae I to V is selected from the Preferred Compounds.
[0029] In still another aspect, the invention relates to a method
of treating stroke and other oxidative stress-related conditions
that are responsive to cellular enzyme modulation such as cerebral
ischemia, myocardial infarction, chronic heart failure and exposure
to UV radiation in a mammal by administering to a mammal in need of
such treatment (even a significant period of time following an
ischemic or oxidative insult, such as about 5 or more hours) a
therapeutically effective amount of a compound of any of Formulae I
to V, an above-described naturally occurring conjugated phenol, or
a pharmaceutically acceptable salt thereof. In a method for
regulating skin condition, regulating the signs of skin aging, or
for treating contact dermatitis, acne, psoriasis, age-related
damage or damage resulting from harmful (UV) radiation, stress or
fatigue, the invention entails topically administering to a mammal
in need of such treatment a therapeutically effective amount of a
compound of any of Formulae I to V, an above-described naturally
occurring conjugated phenol, or a pharmaceutically acceptable salt
thereof. Particularly preferred are those methods of treatment and
uses in the manufacture of pharmaceutical and/or cosmetic
compositions therefor, wherein a compound of Formulae I to V is
selected from the Preferred Compounds.
[0030] In yet another aspect, the invention relates to a method of
promoting a product by directing a user to apply to the skin a
pharmaceutical or cosmetic composition incorporating a compound of
any of Formulae I to V, an above-described naturally occurring
conjugated phenol, or a pharmaceutically acceptable salt thereof,
for regulating skin condition, regulating the signs of skin aging,
or for treating contact dermatitis, acne, psoriasis, age-related
damage or damage resulting from harmful (UV) radiation, stress or
fatigue. The invention also entails a-product including
instructions directing the user to apply a composition of the
invention to the skin for regulating skin condition, regulating the
signs of skin aging, or for treating contact dermatitis, acne,
psoriasis, age-related damage or damage resulting from harmful (UV)
radiation, stress or fatigue, where the composition incorporates a
compound of any of Formulae I to V, an above-described naturally
occurring conjugated phenol, or a pharmaceutically acceptable salt
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Definitions
[0032] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0033] The term "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. For
example, "optionally substituted alkyl" means either "alkyl" or
"substituted alkyl," as defined below. It will be understood by
those skilled in the art with respect to any group containing one
or more substituents that such groups are not intended to introduce
any substitution or substitution patterns that are sterically
impractical and/or synthetically non-feasible.
[0034] Certain compound, reactant, or reaction parameter
abbreviations are defined as follows:
[0035] "DCM" refers to dichloromethane or methylene chloride
[0036] "t-Bu" refers to t-butyl
[0037] "DIC" refers to N,N-diisopropylcarbodiimide
[0038] "DIPEA" refers to diisopropyl ethylamine
[0039] "DMAP" refers to 4-N,N-dimethylamino pyridine
[0040] "DMF" refers to N,N-dimethyl formamide
[0041] "Eq." refers to equivalent
[0042] "MeOH" refers to methanol
[0043] "MOM" refers to methoxymethyl
[0044] "OMOM" refers to methoxymethoxy
[0045] "EtOH" refers to ethanol
[0046] "PCC" refers to pyridinium chlorochromate
[0047] "TBDMS" refers to t-butyl di-methyl silyl
[0048] "THF" refers to tetrahydrofuran
[0049] "TBAF" refers to tetrabutyl ammonium fluoride
[0050] "TMEDA" refers to N,N,N',N'-tetramethylethylenediamine
[0051] "CSA" refers to camphorsulfonic acid, and
[0052] "EtOAc" refers to ethyl acetate.
[0053] The term "acyl" refers to the groups --C(O)--H,
--C(O)-(optionally substituted alkyl), --C(O)-(optionally
substituted cycloalkyl), --C(O)-(optionally substituted alkenyl),
--C(O)-(optionally substituted cycloalkenyl), --C(O)-(optionally
substituted aryl), --C(O)-(optionally substituted heteroaryl) and
--C(O)-(optionally substituted heterocyclyl).
[0054] The term "alkenyl" refers to a monoradical branched or
unbranched, unsaturated or polyunsaturated hydrocarbon chain,
having from about 2 to 20 carbon atoms, more preferably about 2 to
10 carbon atoms. This term is exemplified by groups such as
ethenyl, but-2-enyl, 3-methyl-but-2-enyl (also referred to as
"prenyl"), octa-2,6-dienyl, 3,7-dimethyl-octa-2,6-di- enyl (also
referred to as "geranyl"), and the like.
[0055] The term "substituted alkenyl" refers to an alkenyl group in
which 1 or more (up to about 5, preferably up to about 3) hydrogen
atoms is replaced by a substituent independently selected from the
group: optionally substituted anthraquinone, optionally substituted
aryl, (optionally substituted aryl)carbonyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, or nitro.
Preferred optional substituents for alkenyl are substituted aryl
and substituted heteroaryl, exemplified by groups, such as
p-nitrobenzyl, 5-methyl-2-phenyl-2,4-dihyd- ro-pyrazol-3-one, and
thiazolidine-2,4-dione.
[0056] The term "alkoxy" refers to the groups --O-alkyl,
--O-alkenyl, --O-cycloalkyl, --O-cycloalkenyl, and --O-alkynyl.
Preferred alkoxy groups are --O-alkyl and --O-alkenyl and include,
by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy, 3,7-dimethyl-octa-2,6-dienyloxy and the
like.
[0057] The term "substituted alkoxy" refers to the groups
--O-(substituted alkyl), --O-(substituted alkenyl),
--O-(substituted cycloalkyl), --O-(substituted cycloalkenyl),
--O-(substituted alkynyl) and --O-(optionally substituted
alkylene)-alkoxy. One preferred substituted alkoxy group is
"polyalkoxy" or --O-(substituted alkylene)-alkoxy, and includes
groups such as --OCH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.-
3, and (or PEG) groups such as --O(CH.sub.2CH.sub.2O).sub.xCH.sub.3
and --O(CH.sub.2CH.sub.2O).sub.x H where x is an integer of about
2-20, preferably about 2-10, and more preferably about 2-5.
[0058] The term "alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain preferably having from about
1 to 20 carbon atoms, more preferably about 1 to 10 carbon atoms,
and even more preferably about 1 to 6 carbon atoms. This term is
exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
[0059] The term "substituted alkyl" refers to an alkyl group in
which 1 or more (up to about 5, preferably up to about 3) hydrogen
atoms is replaced by a substituent independently selected from the
group: .dbd.O, .dbd.S, acyl, acyloxy, optionally substituted
alkoxy, optionally substituted amino, azido, carboxyl, (optionally
substituted alkoxy)carbonyl, (optionally substituted
amino)carbonyl, cyano, optionally substituted cycloalkyl,
optionally substituted cycloalkenyl, halogen, hydroxyl, nitro,
sulfanyl, sulfinyl, and sulfonyl. One of the preferred optional
substituents for alkyl is hydroxy, exemplified by hydroxyalkyl
groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl,
4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such
as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and
the like; mixed hydroxy and carboxy substituted alkyl groups, such
as pyruvates; and those compounds known as polyethylene glycols,
polypropylene glycols and polybutylene glycols, and the like.
[0060] The term "alkylene" refers to a diradical derived from the
above-defined monoradical, alkyl. This term is exemplified by
groups such as methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), the propylene isomers [e.g.,
--CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2--] and the
like.
[0061] The term "substituted alkylene" refers to a diradical
derived from the above-defined monoradical, substituted alkyl.
Examples of substituted alkylenes are chloromethylene (--CH(Cl)--),
aminoethylene (--CH(NH.sub.2)CH.sub.2--), methylaminoethylene
(--CH(NHMe)CH.sub.2--), 2-carboxypropylene isomers
(--CH.sub.2CH(CO.sub.2H)CH.sub.2--), ethoxyethylene
(--CH.sub.2CH.sub.2O--CH.sub.2CH.sub.2--),
ethyl(N-methyl)aminoethylene
(--CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub- .2--),
1-ethoxy-2-(2-ethoxy-ethoxy)ethylene
(--CH.sub.2CH.sub.2O--CH.sub.2-
CH.sub.2--OCH.sub.2CH.sub.2--OCH.sub.2CH.sub.2--), and the
like.
[0062] The term "amino" refers to the group --NH.sub.2.
[0063] The term "substituted amino" refers to the group --NHR or
--NRR where each R is independently selected from the group:
optionally substituted alkyl, optionally substituted cycloalkyl,
optionally substituted alkenyl, optionally substituted
cycloalkenyl, optionally substituted alkynyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, acyl, optionally substituted alkoxy,
carboxy and alkoxycarbonyl.
[0064] The term "aromatic" refers to a cyclic or polycyclic moiety
having a conjugated unsaturated (4n+2) .pi. electron system (where
n is a positive integer), sometimes referred to as a delocalized 7
electron system.
[0065] The term "aryl" refers to an aromatic cyclic hydrocarbon
group of from 6 to 20 carbon atoms having a single ring (e.g.,
phenyl) or multiple condensed (fused) rings (e.g., naphthyl or
anthryl). Preferred aryls include phenyl, naphthyl and the
like.
[0066] The term "substituted aryl" refers to an aryl group as
defined above, which unless otherwise constrained by the definition
for the aryl substituent, is substituted with from 1 to 5
substituents, and preferably 1 to 3 substituents, independently
selected from the group consisting of: .dbd.O, .dbd.S, acyl,
acyloxy, optionally substituted alkenyl, optionally substituted
alkoxy, optionally substituted alkyl (such as tri-halomethyl),
optionally substituted alkynyl, optionally substituted amino,
optionally substituted aryl, optionally substituted aryloxy, azido,
carboxyl, (optionally substituted alkoxy)carbonyl, (optionally
substituted amino)carbonyl, cyano, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl, halogen,
optionally substituted heteroaryl, optionally substituted
heteroaryloxy, optionally substituted heterocyclyl, optionally
substituted heterocyclooxy, hydroxyl, hydroxylamino, nitro,
nitroso, phosphoryl, sulfanyl, sulfinyl, and sulfonyl. Preferred
aryl substituents include: .dbd.O (e.g., anthracenone and
anthraquinone), optionally substituted alkenyl, optionally
substituted alkyl, alkoxy, substituted amino, halo, hydroxyl,
alkoxycarbonyl, carboxy, cyano, nitro, phosphoryl,
2,4-dihydro-pyrazol-3-one, thiazolidine-2,4-dione, trihalomethyl,
sulfinyl, sulfonamide, methyl-sulfonamide.
[0067] The term "carbonyl" refers to the di-radical
"--C(.dbd.O)--", which is also illustrated as "--C(O)--".
[0068] The term "(optionally substituted alkoxy)carbonyl" refers to
the groups: --C(O)O-(optionally substituted alkyl),
--C(O)O-(optionally substituted cycloalkyl), --C(O)O-(optionally
substituted alkenyl), --C(O)O-(optionally substituted alkynyl),
--C(O)O-(optionally substituted aryl), --C(O)O-(optionally
substituted heteroaryl), and --C(O)O-(optionally substituted
heterocyclyl). These moieties are also referred to as esters.
[0069] The term "(optionally substituted amino)carbonyl" refers to
the group --C(O)-(optionally substituted amino). This moiety is
also referred to as a primary, secondary or tertiary
carboxamide.
[0070] The term "carboxy" or "carboxyl" refers to the moiety
"--C(O)OH", which is also illustrated as "--COOH".
[0071] The term "compound of Formula" is intended to encompass the
derivatives of the invention as disclosed, and/or the
pharmaceutically acceptable salts of such compounds. In addition,
the compounds employed in this invention include the individual
stereochemical isomers (arising from the selection of substituent
groups) and mixtures of isomers. For the sake of brevity,
particularly in the dependent claims, except where specifically
indicated to the contrary (e.g., by designation of a single salt,
isomer or mixture) the term should be understood to include single
stereoisomers, mixtures of stereoisomers, and the pharmaceutically
acceptable salts thereof.
[0072] The term "cycloalkyl" refers to non-aromatic cyclic
hydrocarbon groups of having 3 to about 20 (preferably about 4 to
10) carbon atoms having a single ring or multiple condensed rings.
Such cycloalkyl groups include, by way of example, single ring
structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclooctyl, and the like, or multiple ring structures such as
adamantanyl, and the like.
[0073] The term "cosmetics" includes make-up, foundation, and skin
care products. "Cosmetic formulation" entails an active component
and the excipients (typically dermatologically-acceptable) employed
in cosmetics. The term "make-up" refers to products that leave
color on the face, including foundations, blacks and browns, i.e.,
mascara, concealers, eye liners, brow colors, eye shadows,
blushers, lip colors, and so forth. The term "foundation" refers to
liquid, creme, mousse, pancake, compact, concealer or like products
that even out the overall coloring of the skin. Foundation is
typically manufactured to work better over moisturized and/or oiled
skin. The term "skin care products" refers to products used to
treat or otherwise care for, moisturize, improve, or clean the
skin. Products contemplated by the phrase "skin care products"
include, but are not limited to, adhesives, bandages, toothpaste,
moisturizers, lotions, antiperspirants, deodorants, occlusive drug
delivery patches, nail polish, powders, tissues, wipes, solid
emulsion compact, hair conditioners, medicated shampoos, scalp
treatments and the like. The term "personal care products" refer to
health and cosmetic beauty aid products generally recognized as
being formulated for beautifying and grooming the skin and hair.
For example, personal care products include sunscreen products
(e.g., lotions, skin creams, etc.), cosmetics, toiletries, and
over-the-counter pharmaceutical products intended for topical
usage. The term "dermatologically-acceptable," as used herein,
means that the compositions or excipient components thereof are
suitable for use in contact with human skin without undue toxicity,
incompatibility, instability, allergic response, or the like.
[0074] The term "excipient" refers to a cosmetic excipient or a
pharmaceutically acceptable excipient.
[0075] The term "halo" or "halogen" refers to fluoro, chloro, bromo
and iodo.
[0076] The term "heteroaryl" refers to an aromatic cyclic
hydrocarbon group having about 1 to 40 (preferably from about 3 to
15) carbon atoms and about 1 to 10 hetero atoms (preferably about 1
to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,
and/or oxygen) within at least one ring. Such heteroaryl groups can
have a single ring (e.g., pyridyl or furyl) or multiple condensed
rings (e.g., indolizinyl, benzothienyl, and benzo[1,3]dioxo-5-yl).
Preferred heteroaryls include pyridyl, [2,2']bipyridinyl, pyrrolyl
and furyl.
[0077] The term "substituted heteroaryl" refers to a heteroaryl
group as defined above, which unless otherwise constrained by the
definition for the heteroaryl substituent, is substituted with from
1 to 5 substituents, and preferably 1 to 3 substituents,
independently selected from the group consisting of: .dbd.O,
.dbd.S, acyl, acyloxy, optionally substituted alkenyl, optionally
substituted alkoxy, optionally substituted alkyl (such as
tri-halomethyl), optionally substituted alkynyl, optionally
substituted amino, optionally substituted aryl, optionally
substituted aryloxy, azido, carboxyl, (optionally substituted
alkoxy)carbonyl, (optionally substituted amino)carbonyl, cyano,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, halogen, optionally substituted heteroaryl,
optionally substituted heteroaryloxy, optionally substituted
heterocyclyl, optionally substituted heterocyclooxy, hydroxyl,
nitro, sulfanyl, sulfinyl, and sulfonyl. Preferred substituted
heteroaryls include [2,2']bipyridinyl metal complexes, especially
with Zn(II), Cu(II), Mn(III), Ru(II), Fe, Fe(II) or Fe(III).
[0078] The term "heteroaralkyl" refers to the moiety
"-alkylene-heteroaryl" each having the meaning as defined
herein.
[0079] The term "substituted heteroaralkyl" refers to the moiety
"-(optionally substituted aklylene)-(optionally substituted
heteroaryl)", each having the meaning as defined herein.
[0080] The term "heteroarylene" refers to the diradical group
derived from heteroaryl (including substituted heteroaryl), as
defined above, and is exemplified by the groups 2,6-pyridylene,
2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene,
1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the
like.
[0081] The terms "heterocycle", "heterocyclic" and "heterocyclyl"
refer to a monoradical, saturated or unsaturated, non-aromatic
cyclic hydrocarbon group having about 1 to 40 (preferably from
about 3 to 15) carbon atoms and about 1 to 10 hetero atoms
(preferably about 1 to 4 heteroatoms, selected from nitrogen,
sulfur, phosphorus, and/or oxygen) within the ring. Such
heterocyclic groups can have a single ring or multiple condensed
rings. Preferred heterocyclics include morpholino, piperidinyl, and
the like.
[0082] The terms "substituted heterocycle", "substituted
heterocyclic" and "substituted heterocyclyl" refer to a
heterocyclyl group as defined above, which unless otherwise
constrained by the definition for the heterocycle, is substituted
with from 1 to 5 substituents, and preferably 1 to 3 substituents,
independently selected from the group consisting of: .dbd.O,
.dbd.S, acyl, acyloxy, optionally substituted alkenyl, optionally
substituted alkoxy, optionally substituted alkyl (such as
tri-halomethyl), optionally substituted alkynyl, optionally
substituted amino, optionally substituted aryl, optionally
substituted aryloxy, azido, carboxyl, (optionally substituted
alkoxy)carbonyl, (optionally substituted amino)carbonyl, cyano,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, halogen, optionally substituted heteroaryl,
optionally substituted heteroaryloxy, optionally substituted
heterocyclyl, optionally substituted heterocyclooxy, hydroxyl,
nitro, sulfanyl, sulfinyl, and sulfonyl. Preferred substituted
heterocycles include 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione.
[0083] The term "heterocycloalkyl" refers to the moiety
"-alkylene-heterocycle" each having the meaning as defined
herein.
[0084] The term "substituted heterocycloalkyl" refers to the moiety
"-(optionally substituted aklylene)-(optionally substituted
heterocycle)", each having the meaning as defined herein.
[0085] As used herein, "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0086] The term "pharmaceutically acceptable salt" refers to salts
which retain the biological effectiveness and properties of the
compounds of this invention and which are not biologically or
otherwise undesirable. In many cases, the compounds of this
invention are capable of forming acid and/or base salts by virtue
of the presence of amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable base addition salts can be
prepared from inorganic and organic bases. Salts derived from
inorganic bases, include by way of example only, sodium, potassium,
lithium, ammonium, calcium and magnesium salts. Salts derived from
organic bases include, but are not limited to, salts of primary,
secondary and tertiary amines, such as alkyl amines, dialkyl
amines, trialkyl amines, substituted alkyl amines, di(substituted
alkyl) amines, tri(substituted alkyl) amines, alkenyl amines,
dialkenyl amines, trialkenyl amines, substituted alkenyl amines,
di(substituted alkenyl) amines, tri(substituted alkenyl) amines,
cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine,
trisubstituted cycloalkyl amines, cycloalkenyl amines,
di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted
cycloalkenyl amines, disubstituted cycloalkenyl amine,
trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,
triaryl amines, heteroaryl amines, diheteroaryl amines,
triheteroaryl amines, heterocyclic amines, diheterocyclic amines,
triheterocyclic amines, mixed di- and tri-amines where at least two
of the substituents on the amine are different and are selected
from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,
heterocyclic, and the like. Also included are amines where the two
or three substituents, together with the amino nitrogen, form a
heterocyclic or heteroaryl group.
[0087] Specific examples of suitable amines include, by way of
example only, isopropylamine, trimethyl amine, diethyl amine,
tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,
2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine,
piperidine, morpholine, N-ethylpiperidine, and the like.
[0088] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propidnic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
[0089] The term "phosphoryl" refers to the group --P(O)(OR").sub.2,
where R" is independently selected from hydrogen or alkyl and aryl,
which group is sometimes also referred to as "phosphono" or as a
"phosphate" or "phosphonic acid."
[0090] "Regulating skin condition" includes prophylactically
regulating and/or therapeutically regulating skin condition,
including visible and/or tactile discontinuities in skin such as,
but not limited to, regulating visible and/or tactile
discontinuities in the texture of skin, reducing post-inflammatory
hyperpigmentation, regulating non-melanin discoloration of skin,
regulating moisturization and barrier properties of skin,
regulating epidermal differentiation of skin, regulating
exfoliation of skin, thickening of skin to reduce skin atrophy,
regulating the elasticity of skin, reducing oily skin, regulating
cellulite in skin, regulating pruritus in skin, and promoting wound
healing in skin. As used herein, prophylactically regulating skin
condition includes delaying, minimizing and/or preventing visible
and/or tactile discontinuities in skin. As used herein,
therapeutically regulating skin condition includes ameliorating,
e.g., diminishing, minimizing and/or effacing, discontinuities in
skin. Regulating skin condition involves improving skin appearance
and/or feel.
[0091] "Regulating the signs of skin aging" includes
prophylactically regulating and/or therapeutically regulating one
or more of such signs (similarly, regulating a given sign of skin
aging, e.g., lines, wrinkles or pores, includes prophylactically
regulating and/or therapeutically regulating that sign). As used
herein, prophylactically regulating such signs includes delaying,
minimizing and/or preventing signs of skin aging. As used herein,
therapeutically regulating such signs includes ameliorating, e.g.,
diminishing, minimizing and/or effacing signs of skin aging.
[0092] "Signs of skin aging" include, but are not limited to, all
outward visibly and tactilely perceptible manifestations as well as
any other macro or micro effects due to skin aging. Such signs may
be induced or caused by intrinsic factors or extrinsic factors,
e.g., chronological aging and/or environmental damage (e.g.,
sunlight, UV, smoke, ozone, pollutants, stress, etc.). These signs
may result from processes which include, but are not limited to,
the development of textural discontinuities such as wrinkles,
including both fine superficial wrinkles and coarse deep wrinkles,
skin lines, facial frown lines, expression lines, rhytides,
dermatoheliosis, photodamage, premature skin aging, crevices,
bumps, pits, large pores (e.g., associated with adnexal structures
such as sweat gland ducts, sebaceous glands, or hair follicles),
"orange-peel" skin appearance, dryness, scaliness, flakiness and/or
other forms of skin unevenness or roughness; blemishes such as
acne, pimples, breakouts; excess skin oil problems such as over
production of sebum, oiliness, facial shine, foundation
breakthrough; abnormal desquamation (or exfoliation) or abnormal
epidermal differentiation (e.g., abnormal skin turnover) such as
scaliness, flakiness, keratoses, hyperkeratinization; inadequate
skin moisturization (or hydration) such as caused by skin barrier
damage, environmental dryness; loss of skin elasticity (loss and/or
inactivation of functional skin elastin) such as elastosis, sagging
(including puffiness in the eye area and jowls), loss of skin
firmness, loss of skin tightness, loss of skin recoil from
deformation; non-melanin skin discoloration such as undereye
circles, blotching (e.g., uneven red coloration due to, e.g.,
rosacea), sallowness (pale color), discoloration caused by
telangiectasia or spider vessels; melanin-related hyperpigmented
(or unevenly pigmented) skin regions such as age spots (liver
spots, brown spots) and freckles; post-inflammatory
hyperpigmentation such as that which occurs following an
inflammatory event (e.g., as an acne lesion, in-grown hair,
insect/spider bite or sting, scratch, cut, wound, abrasion, and the
like); atrophy such as, but not limited to, that associated with
aging or steroid use; other histological or microscopic alterations
in skin components such as ground substance (e.g., hyaluronic acid,
glycosaminoglycans, etc.), collagen breakdown and structural
alterations or abnormalities (e.g., changes in the stratum corneum,
dermis, epidermis, the skin vascular system such as telangiectasia
or spider vessels); tissue responses to insult such as itch or
pruritus; and alterations to underlying tissues (e.g., subcutaneous
fat, cellulite, muscles, trabeculae, septae, and the like),
especially those proximate to the skin.
[0093] The term "sulfonyl" refers to the groups:
--S(O.sub.2)-(optionally substituted alkyl),
--S(O.sub.2)-(optionally substituted amino),
--S(O.sub.2)-optionally substituted aryl), --S(O.sub.2)-(optionally
substituted heteroaryl), --S(O.sub.2)-(optionally substituted
heterocyclyl). Preferred sulfonyl groups include, by way of
example, methylsulfonyl, ethylsulfonyl, aminosulfonyl,
piperidin-1-sulfonyl and morpholine-4-sulfonyl.
[0094] The term "therapeutically effective amount" or "effective
amount" refers to that amount of a compound of any of Formulae I to
V that is sufficient to effect treatment, as defined below, when
administered to a mammal in need of such treatment. The
therapeutically effective amount will vary depending upon the
subject and disease condition being treated, the weight and age of
the subject, the severity of the disease condition, the particular
compound chosen, the dosing regimen to be followed, timing of
administration, the manner of administration and the like, all of
which can readily be determined by one of ordinary skill in the
art.
[0095] The term "treatment" or "treating" means any treatment of a
disease or disorder in a mammal, including:
[0096] preventing or protecting against the disease or disorder,
that is, causing the clinical symptoms not to develop;
[0097] inhibiting the disease or disorder, that is, arresting or
suppressing the development of clinical symptoms; and/or
[0098] relieving the disease or disorder, that is, causing the
regression of clinical symptoms. It will be understood by those
skilled in the art that in human medicine, it is not always
possible to distinguish between "preventing" and "suppressing"
since the ultimate inductive event or events may be unknown,
latent, or the patient is not ascertained until well after the
occurrence of the event or events. Therefore, as used herein the
term "prophylaxis" is intended as an element of "treatment" to
encompass both "preventing" and "suppressing" as defined herein.
The term "protection," as used herein, is meant to include
"prophylaxis."
[0099] The term "topical application," as used herein, means to
apply or spread the compositions of the present invention onto the
surface of the skin.
[0100] Nomenclature
[0101] The compounds employed in the present invention are named
and numbered herein as described below. 5
[0102] Formula Ia represents the compound according to Formula I
where R.sup.1, R.sup.4 and R.sup.5 are H, R.sup.2 and R.sup.3 are
OH, and R is p-bromo-phenyl, and can be named
4-[2-(4-bromo-phenyl)-vinyl]-benzene-1,2- -diol. 6
[0103] Formula Ib represents the compound according to Formula I
where R.sup.1, R.sup.4 and R.sup.5 are H, R.sup.2 and R.sup.3 are
OMOM (i.e., the group --O--CH.sub.2--O--CH.sub.3, which can also be
named "methoxymethoxy"), and R is
N,N-bis-(2-hydroxy-ethyl)-benzamide, and can be named
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-e-
thyl)-benzamide. 7
[0104] Formula Ic represents the compound according to Formula I
where R.sup.1, R.sup.4 and R.sup.5 are H, R.sup.2 and R.sup.3 are
OH, and R is p-phenyl-vinyl benzoic acid methyl ester, and can be
named
4-(2-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-vinyl)-benzoic
acid methyl ester. 8
[0105] Formula Id represents the compound according to Formula I
where R.sup.1, R.sup.2 and R.sup.5 are H, R.sup.3 and R.sup.4 are
OH, and R is a [2,2']bipyridinyl-5-yl Zn(II) chloride complex, and
can be named 4-(2-[2,2']bipyridinyl-5-yl-vinyl)benzene-1,2-diol,
Zn(II) chloride. 9
[0106] Formula Ie represents the compound according to Formula I
where R.sup.1and R.sup.5 are H, R.sup.2 is methoxy, R.sup.3 is
methoxymethoxy, R.sup.4 is geranyl (i.e.,
3,7-dimethyl-octa-2,6-dienyl), and R is nitro-benzene, and can be
named 4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-5--
methoxy-4-methoxymethoxy-phenyl]-vinyl}-1-nitro-benzene. 10
[0107] Formula IIa represents the compound according to Formula II
where R.sup.6, R.sup.7 and R.sup.10 are H, R.sup.3 and R.sup.9 are
OH, and R" is 10H-anthracen-9-one, and can be named
10-(3,4-dihydroxy-benzylidene)-1- 0H-anthracen-9-one. 11
[0108] Formula IIIa represents the compound according to Formula
III where R.sup.2 and R.sup.3 are each O.sup.- and together are
complexed to a metal M.sup.n (in which M is zinc and n is two), L
is chloro, R.sup.4 is H, and R is p-benzoic acid ethyl ester, and
can be named 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl
ester, zinc(II) chloride. 12
[0109] Formula Va represents the compound according to Formula V
where M is Mn, R.sup.4 and R.sup.4* are H, and R and R* are
p-nitro-phenyl, and can be named
bis-{4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol},
manganese(III).
Synthesis of the Compounds of the Invention
[0110] The compounds of Formulae I to V can be prepared by solution
phase synthesis, as described in greater detail below with
reference to the Reaction Schemes. In general, the compounds of
Formula I can be prepared using Wittig reaction between a
benzaldehyde and a substituted phosphonium salt at room temperature
in the presence of a base, preferably lithium ethoxide. An
MOM-masking step is performed for OH-masking in those compounds
where one or more, but not all of R.sup.1 to R.sup.5 are OH.
Alternatively, the Wittig reaction can also be carried out using
reverse intermediates, such as hydroxyl-masked phenyl phosphonium
salt and a substituted benzaldehyde. Compounds of Formula II are
made by condensation of the R' group with a benzaldehyde. Compounds
of Formulae III, IV and V are made by treating a compound of
Formula I with the desired metal to be complexed. A compound of
Formula I to V is contacted with a pharmaceutically acceptable acid
to form the corresponding acid addition salt. A pharmaceutically
acceptable acid addition salt of Formula I to V is contacted with a
base to form the corresponding free base of Formula I.
Representative specific reaction schemes are shown in the
Examples.
[0111] Synthetic Reaction Parameters
[0112] The terms "solvent", "inert organic solvent" or "inert
solvent" mean a solvent inert under the conditions of the reaction
being described in conjunction therewith. Solvents employed in
synthesis of the compounds of the invention include, for example,
methanol, acetone, water, acetonitrile, 1,4-dioxane,
dimethylformamide ("DMF"), benzene, toluene, tetrahydrofuran
("THF"), chloroform, methylene chloride (or dichloromethane),
diethyl ether, pyridine and the like, as well as mixtures thereof.
Unless specified to the contrary, the solvents used in the
reactions of the present invention are inert organic solvents.
[0113] The term "q.s." means adding a quantity sufficient to
achieve a stated function, e.g., to bring a solution to the desired
volume (i.e., 100%).
[0114] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure within a temperature
range from -10.degree. C. to 110.degree. C. (preferably from
0.degree. C. to 40.degree. C.; most preferably at "room" or
"ambient" temperature, e.g., 20.degree. C.). Further, unless
otherwise specified, the reaction times and conditions are intended
to be approximate, e.g., taking place at about atmospheric pressure
within a temperature range of about -10.degree. C. to about
110.degree. C. (preferably from about 0.degree. C. to about
40.degree. C.; most preferably at about "room" or "ambient"
temperature, e.g., approximately 20.degree. C.) over a period of
about 1 to about 10 hours (preferably about 5 hours). Parameters
given in the Examples are intended to be specific, not
approximate.
[0115] Isolation and purification of the compounds and
intermediates described herein can be effected, if desired, by any
suitable separation or purification procedure such as, for example,
filtration, extraction, crystallization, column chromatography,
thin-layer chromatography or thick-layer chromatography, or a
combination of these procedures. Specific illustrations of suitable
separation and isolation procedures can be had by reference to the
examples hereinbelow. However, other equivalent separation or
isolation procedures can, of course, also be used. Starting
Materials
[0116] The compounds methyl 4-(bromomethyl)-benzoate,
3,4-dihydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, and
chloromethylmethyl ether are commercially available, e.g., from
Aldrich Chemical Company, Milwaukee, Wis. Other reactants, such as
concentrated HCl and triphenylphosphine are likewise commercially
available or may be readily prepared by those skilled in the art
using commonly employed methodology. 13
[0117] Referring to Reaction Scheme 1, Step 1, a
bromomethyl-anthraquinone- , -substituted aryl, -optionally
substituted heteroaryl or -optionally substituted heterocyclyl
compound of Formula 101 is refluxed for 2 hours in an inert organic
solvent (such as toluene) with one molar equivalent of
triphenylphosphine, to give the corresponding phosphonium salt of
Formula 102.
[0118] In Step 2, a Wittig reaction is performed with the
intermediate of Formula 102 and a benzaldehyde of Formula 103,
which are mixed in an inert organic solvent (e.g., methanol) at
0.degree. C. to which a strong base (such as lithium ethoxide) is
slowly added, with stirring. The reaction mixture is allowed to
warm to room temperature and stirring continued for 2 hours to give
the corresponding vinyl conjugate compound of Formula I (where R'
is H).
[0119] Phenolic conjugates and further derivatized compounds of
Formula I (e.g., amidation of compounds where R is a benzoic acid)
can be synthesized, for example, as illustrated with reference to a
representative di-phenolic derivative in Reaction Scheme 1A. 14
[0120] Referring to Reaction Scheme 1A, Step 1, a
bromomethyl-anthraquinon- e, -substituted aryl, -optionally
substituted heteroaryl or -optionally substituted heterocyclyl
compound of Formula 101 is refluxed for 2 hours in an inert organic
solvent (such as toluene) with one molar equivalent of
triphenylphosphine, to give the corresponding phosphonium salt of
Formula 102.
[0121] In Step 2, a hydroxyl benzaldehyde of Formula 103 is
dissolved in an inert organic solvent (e.g,. DMF) with a 2.2 molar
excess of sodium hydride, and then slowly contacted with 4 molar
equivalents of a hydroxyl protecting (or masking) reactant, such as
chloromethyl methylether, which is added with stirring at a reduced
temperature such as 0.degree. C. (e.g., in an ice bath). The
reaction mixture is warmed to 50-55.degree. C. for 3 hours, and
cooled to give the corresponding MOM-ether masked benzaldehyde of
Formula 104.
[0122] In Step 3, a Wittig reaction is performed with the
intermediates of Formulae 102 and 104, which are mixed in an inert
organic solvent (e.g., methanol) at 0.degree. C. to which a strong
base (such as lithium ethoxide) is slowly added, with stirring. The
reaction mixture is allowed to warm to room temperature and
stirring continued for 2 hours to give the corresponding vinyl
conjugate compound of Formula 105 (which can be a compound of
Formula I where R.sup.2 and R.sup.3 are OMOM).
[0123] In Step 4, a MOM-ether masked compound of Formula 105
dissolved in an inert organic solvent (e.g., methanol) is converted
to the corresponding phenol of Formula I by acid catalyzed
hydrolysis (e.g., dropwise addition of concentrated HCl) followed
by stirring at room temperature for 12 hours.
[0124] Alternatively, as illustrated in Step 4a (particularly for
the compounds where R is a substituted phenyl group), the MOM-ether
masked compound of Formula 105 can be further derivatized (e.g., a
benzoic acid can be amidated by the addition of carbonyldiimidazole
and diethanolamine) to give the corresponding compound of Formula
106 (which can also be a compound of Formula I where R.sup.2 and
R.sup.3 are OMOM). As illustrated in Step 5, a further derivatized
compound of Formula 106 can be converted to the corresponding
phenol of Formula I (e.g., as described with reference to Step 4).
15
[0125] As illustrated in Reaction Scheme 2, a benzaldehyde compound
of Formula 201 is condensed with malonitrile or an optionally
substituted-anthraquinone, -heteroaryl or -heterocyclyl compound of
Formula 202 (i.e. a precursor to the R" substituenqt) to give the
corresponding compound of Formula II. The reaction conditions will
depend on the nature of Formula 202. For example, where Formula 202
is malonitrile the reaction takes place in an inert organic solvent
(e.g., methanol) under basic conditions (e.g., by addition of NaOH)
with stirring at room temperature. Where Formula 202 is anthrone or
dianthrol, the reaction takes place in an inert organic solvent
(e.g., toluene) under acidic conditions (e.g., by addition of
camphorsulfonic acid) at reflux. Where Formula 202 is
thiazolidine-2,4-dione or 2,4-dihydro-pyrazol-3-one, the reaction
takes place in an inert organic solvent (e.g., toluene) in the
presence of benzoic acid at reflux.
[0126] Similarly, by substituting the compound of Formula 202 with
a compound of the formula R--CH.sub.2--R' (where R' is
alkoxycarbonyl or cyano, and where R is, for example, optionally
substituted heteroaryl or cyano) in the condensation reaction
described with reference to Reaction Scheme II, the compounds of
Formula I where R' is alkoxycarbonyl and the compounds where R' is
H and R' is di-cyano can be obtained. 16
[0127] As illustrated in Reaction Scheme 3, a compound of Formula
I, dissolved in an inert organic solvent (e.g., methanol) is
treated with a metal compound of Formula 301, followed by stirring
at room temperature for 2 hours. When using a slight molar excess
of Fomula I, a compound of Formula III results. Alternatively, if a
significant molar excess of Formula 301 is employed, the
corresponding compound of Formulae IV or V will result (also
depending on the starting compound(s) of Formula I).
Compounds of the Present Invention
[0128] In one aspect, the present invention provides certain new
and useful compounds (including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts thereof)
represented by Formula I: 17
[0129] where:
[0130] R is: anthraquinone, optionally substituted heteroaryl,
optionally substituted heterocyclyl, nitro, or substituted phenyl
having:
[0131] a substituent in the para position, selected from: cyano,
nitro, alkoxycarbonyl, (nitrogen-containing)-heterocyclyl and
(nitrogen-containing)-heteroaryl, and/or
[0132] a substituent in the meta position selected from: nitro and
halo;
[0133] R' is: hydrogen or (optionally substituted alkoxy)-carbonyl;
and
[0134] R.sup.1 to R.sup.5 are independently selected from:
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)-carbonyl, carboxy, cyano, halo,
optionally substituted heteroaryl, hydrogen, hydroxy, nitro,
nitrone, sulfonate;
[0135] provided that at least one of R.sup.1 to R.sup.5 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--O-- where n is
an integer from 1 to 4, and at least another of R.sup.1 to R.sup.5
is hydrogen.
[0136] In another aspect, the present invention provides certain
new and useful compounds (including single stereoisomers, mixtures
of stereoisomers, and the pharmaceutically acceptable salts
thereof) represented by Formula I, where:
[0137] R is: (substituted phenyl)-alkenyl;
[0138] R' is: hydrogen; and
[0139] R.sup.1 to R.sup.5 are independently selected from:
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)-carbonyl, carboxy, cyano, halo,
optionally substituted heteroaryl, hydrogen, hydroxy, nitro,
nitrone, and sulfonate,
[0140] provided that (a) at least one of R.sup.1 to R.sup.5 is
methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4, or (b) two adjacent members of R.sup.1 to
R.sup.5 are each O.sup.- and together are complexed with a
metal,
[0141] In still another aspect, the present invention provides
certain new and useful compounds (including single stereoisomers,
mixtures of stereoisomers, and the pharmaceutically acceptable
salts thereof) represented by Formula I, where:
[0142] R is: (optionally substituted heterocyclyl)-alkenyl;
[0143] R' is: hydrogen; and
[0144] R.sup.1 to R.sup.5 are independently selected from:
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)-carbonyl, carboxy, cyano, halo,
optionally substituted heteroaryl, hydrogen, hydroxy, nitro,
nitrone, and sulfonate, with the proviso that at least one of
R.sup.1 to R.sup.5 is hydroxy, methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 4; or
[0145] two adjacent members of R.sup.1 to R.sup.5 are each O.sup.-
and together are complexed with a metal.
[0146] In yet another aspect, the present invention provides
certain new and useful compounds (including single stereoisomers,
mixtures of stereoisomers, and the pharmaceutically acceptable
salts thereof) represented by Formula I, where:
[0147] R is: optionally substituted heteroaryl, selected from the
group: 1-carboxymethyl-pyridinium-4-yl bromide;
1-(2-carboxy-2-oxo-ethyl)-pyridi- nium-4-yl bromide; thiazol-2-yl;
6-nitro-benzo[1,3]dioxo-5-yl; and a [2,2']bipyridin-5-yl metal
complex;
[0148] R' is: hydrogen; and
[0149] R.sup.1 to R.sup.5 are independently selected from:
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)carbonyl, carboxy, cyano, halo,
optionally substituted heteroaryl, hydrogen, hydroxy, nitro,
nitrone, sulfonate; or
[0150] two adjacent members of R.sup.1 to R.sup.5 are each O.sup.-
and together are complexed with a metal;
[0151] provided that where R is a [2,2']bipyridin-5-yl Ru or Pd
metal complex, R.sup.3 and R.sup.4 are not both hydroxy.
[0152] Another aspect of the present invention provides certain new
and useful compounds (including single stereoisomers, mixtures of
stereoisomers, and the pharmaceutically acceptable salts thereof)
represented by Formula I, where:
[0153] R is: substituted alkenyl, optionally substituted aryl,
(optionally substituted aryl)-carbonyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, or nitro;
[0154] R' is: hydrogen or (optionally substituted
alkoxy)-carbonyl;
[0155] three members of R.sup.1 to R.sup.5 are independently
selected from: optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkyl, optionally
substituted aryl, (optionally substituted alkoxy)-carbonyl,
carboxy, cyano, halo, optionally substituted heteroaryl, hydrogen,
hydroxy, nitro, nitrone, and sulfonate; and
[0156] two adjacent members of R.sup.1 to R.sup.5 are each O.sup.-
and together are complexed with a metal having one or more apical
ligands, said metal optionally being further complexed with a
second compound of Formula I.
[0157] Still another aspect of the present invention provides
certain new and useful compounds (including single stereoisomers,
mixtures of stereoisomers, and the pharmaceutically acceptable
salts thereof) represented by Formula II: 18
[0158] where:
[0159] R" is: optionally substituted anthracenone, di-cyano, or
optionally substituted heterocyclyl selected from: 2,5-(optionally
substituted)-2,4-dihydro-pyrazol-3-one; 5-(optionally
substituted)-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione;
[0160] R.sup.6 to R.sup.10 are independently selected from:
optionally substituted alkenyl, optionally substituted alkoxy,
optionally substituted alkyl, optionally substituted aryl,
(optionally substituted alkoxy)carbonyl, hydrogen, hydroxy and
nitrone; or
[0161] two adjacent members of R.sup.6 to R.sup.10 are each O.sup.-
and together are complexed with a metal; provided that at least one
of R.sup.6 to R.sup.10 is not hydrogen,
[0162] and further provided that where R.sup.10 and another of
R.sup.6 to R.sup.9 are hydrogen, at least one of R.sup.6 to R.sup.9
is methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 4.
Preferred Compounds
[0163] In the presently preferred embodiments of the invention, the
following combinations and permutations of substituent groups
(sub-grouped, respectively, in increasing order of preference, each
sub-grouping being intended as combinable with other sub-groupings)
define compounds (including single stereoisomers, mixtures of
stereoisomers, and pharmaceutically acceptable salts) that are
preferred as compositions of matter and/or compounds for use in its
methods, and pharmaceutical and cosmetic compositions.
[0164] The compounds of Formula I where R' is hydrogen.
[0165] Especially where R is anthraquinone, optionally substituted
heteroaryl, optionally substituted heterocyclyl, nitro, or
substituted phenyl having (a) a substituent in the para position
selected from: cyano, nitro, alkoxycarbonyl,
(nitrogen-containing)-heterocyclyl and
(nitrogen-containing)-heteroaryl, and/or (b) a substituent in the
meta position selected from: nitro and halo.
[0166] Particularly where R is substituted phenyl.
[0167] Particularly where at least one of R.sup.1 to R.sup.5 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--O-- where n is
an integer from 1 to 4, and at least another of R.sup.1 to R.sup.5
is hydrogen.
[0168] Preferably where n is 1 or 2.
[0169] More preferably where R is substituted phenyl.
[0170] Most preferably where R is phenyl (a) para-substituted with
cyano, nitro or alkoxycarbonyl, and/or (b) meta-substituted with
bromo.
[0171] Preferably where R.sup.1 to R.sup.5 are independently
selected from: optionally substituted alkoxy, optionally
substituted alkenyl, carboxy, cyano, halo, hydrogen, hydroxy, and
nitro.
[0172] More preferably where R.sup.5 and another of R.sup.1 to
R.sup.4 are hydrogen, one of R.sup.1 to R.sup.4 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--- CH.sub.2].sub.n-- (where n is
1, 2 or 3, especially 1 or 2), and the others of R.sup.1 to R.sup.4
are selected from hydrogen, hydroxy and lower alkoxy.
[0173] Even more preferably where R is substituted phenyl.
[0174] Most preferably where R is phenyl (a) para-substituted with
cyano, nitro or alkoxycarbonyl, and/or (b) meta-substituted with
bromo.
[0175] More preferably where R is substituted phenyl.
[0176] Most preferably where R is phenyl (a) para-substituted with
cyano, nitro or alkoxycarbonyl, and/or (b) meta-substituted with
bromo.
[0177] Preferably where at least two of R.sup.1 to R.sup.5 are
hydrogen.
[0178] Especially where R is (substituted phenyl)-alkenyl.
[0179] Particularly where at least one of R.sup.1 to R.sup.5 is
methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4.
[0180] Preferably where R is (substituted phenyl)-vinyl (a)
para-substituted with cyano, nitro, alkoxycarbonyl,
(nitrogen-containing)-heterocyclyl or
(nitrogen-containing)-heteroaryl, and/or (b) meta-substituted with
nitro or halo.
[0181] More preferably where R is 1-nitro-4-vinyl-benzene.
[0182] Especially where R is (optionally substituted
heterocyclyl)-alkenyl.
[0183] Particularly where R is (optionally substituted
heterocyclyl)-methene.
[0184] Preferably where at least one of R.sup.1 to R.sup.5 is
hydroxy, methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- where n is an
integer from 1 to 4.
[0185] More preferably where R is
5-methyl-4-methylene-2-phenyl-2,4-dihydr- o-pyrazol-3-one or
5-methylene-thiazolidine-2,4-dione.
[0186] Even more preferably where R.sup.5 and another of R.sup.1 to
R.sup.4 are hydrogen, and the others of R.sup.1 to R.sup.4 are
selected from alkoxy, hydrogen, hydroxy, methoxymethoxy, and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n-- (where n is an
integer from 1 to 2).
[0187] Preferably where R.sup.5 and another of R.sup.1 to R.sup.4
are hydrogen, and the others of R.sup.1 to R.sup.4 are selected
from alkoxy, hydrogen, hydroxy, methoxymethoxy, and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--- CH.sub.2].sub.n-- where n is an
integer from 1 to 2.
[0188] Particularly where at least one of R.sup.1 to R.sup.5 is
hydroxy, methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is an
integer from 1 to 4.
[0189] Preferably where R.sup.5 and another of R.sup.1 to R.sup.4
are hydrogen, and the others of R.sup.1 to R.sup.4 are selected
from alkoxy, hydrogen, hydroxy, methoxymethoxy, and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--- CH.sub.2].sub.n--, where n is
an integer from 1 to 2.
[0190] Especially where R is optionally substituted heteroaryl,
selected from the group: 1-carboxymethyl-pyridinium-4-yl bromide;
1-(2-carboxy-2-oxo-ethyl)-pyridinium-4-yl bromide; thiazol-2-yl;
6-nitro-benzo[1,3]dioxo-5-yl; and a [2,2']bipyridin-5-yl metal
complex (provided that where R is a [2,2']bipyridin-5-yl Ru or Pd
metal complex, R.sup.3 and R.sup.4 are not both hydroxy).
[0191] Particularly where R.sup.5 and another of R.sup.1 to R.sup.4
are hydrogen, and the others of R.sup.1 to R.sup.4 are selected
from: alkoxy, (optionally substituted alkoxy)carbonyl, hydrogen,
hydroxy, and H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--,
where n is an integer from 1 to 4.
[0192] Preferably where R.sup.1 is hydrogen, R.sup.2 is hydroxy,
R.sup.3 is hydroxy and R.sup.4 is hydrogen.
[0193] Preferably where R.sup.1 is hydrogen, R.sup.2 is
methoxymethoxy, R.sup.3 is methoxymethoxy, and R.sup.4 is
hydrogen.
[0194] Preferably where R.sup.1 is hydrogen, R.sup.2 is hydrogen,
R.sup.3 is methoxycarbonyl and R.sup.4 is hydrogen.
[0195] Preferably where R.sup.1 is hydrogen, R.sup.2 is hydrogen,
R.sup.3 is methoxymethoxy and R.sup.4 is methoxymethoxy.
[0196] More preferably where R is [2,2']bipyridin-5-yl, the
nitrogen atoms of which are complexed to a metal having one or more
apical ligands.
[0197] Even more preferably where the metal is selected from
Zn(II), Mn(III) and Cu(II) Most preferably where the apical ligand
is selected from chloride and acetate.
[0198] Particularly where R is [2,2']bipyridin-5-yl, the nitrogen
atoms of which are complexed to a metal having one or more apical
ligands.
[0199] Preferably where the metal is selected from Zn(II), Mn(III)
and Cu(II)
[0200] More preferably where the apical ligand is selected from
chloride and acetate.
[0201] Most preferably, a compound selected from the group:
[0202]
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethoxymethoxy-benzene,
zinc(II) chloride;
[0203]
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethoxymethoxy-benzene,
copper(II) chloride; and
[0204]
4-(2-[2,2']bipyridinyl-5-yl-vinyl)-1,2-dimethoxymethoxy-benzene,
manganese(III) acetate.
[0205] Especially where two adjacent members of R.sup.1 to R.sup.5
are each O.sup.- and together are complexed with a metal having one
or more apical ligands and optionally being further complexed with
a second compound of Formula I,
[0206] Particularly where R is substituted alkenyl, optionally
substituted aryl, (optionally substituted aryl)-carbonyl,
optionally substituted heteroaryl, optionally substituted
heterocyclyl, or nitro.
[0207] Preferably where R is substituted phenyl having (a) a
substituent in the para position selected from: cyano, nitro,
alkoxycarbonyl, (nitrogen-containing)-heterocyclyl and
(nitrogen-containing)-heteroaryl, and/or (b) a substituent in the
meta position selected from: nitro and halo.
[0208] More preferably where R is para-alkoxycarbonyl-phenyl.
[0209] Most preferably, a compound selected from the group:
[0210] 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
zinc(II) chloride;
[0211] 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
copper(II) chloride;
[0212] 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
manganese(III) acetate; and
[0213]
bis-{4-[2-(4-methoxycarbonyl-phenyl)-vinyl]-benzene-1,2-diol},
zinc(II) chloride.
[0214] More preferably where R.sup.3 and R.sup.4 are complexed with
a metal.
[0215] Even more preferably where R.sup.1, R.sup.2 and R.sup.5 are
hydrogen.
[0216] Still more preferably where the metal is selected from
Zn(II), Mn(III) and Cu(II).
[0217] Most preferably where the apical ligand is chloride or
acetate.
[0218] Most preferably where R is para-alkoxycarbonyl-phenyl.
[0219] Even more preferably where the metal is selected from
Zn(II), Mn(III) and Cu(II).
[0220] Still more preferably where the apical ligand is chloride or
acetate.
[0221] Most preferably where R is para-alkoxycarbonyl-phenyl.
[0222] Preferably where R.sup.3 and R.sup.4 are complexed with a
metal.
[0223] More preferably where R.sup.1, R.sup.2 and R.sup.5 are
hydrogen.
[0224] Even more preferably where the metal is selected from
Zn(II), Mn(III) and Cu(II).
[0225] Most preferably where the apical ligand is chloride or
acetate.
[0226] More preferably where the metal is selected from Zn(II),
Mn(III) and Cu(II).
[0227] Even more preferably where the apical ligand is chloride or
acetate.
[0228] Particularly where R.sup.3 and R.sup.4 are complexed with a
metal.
[0229] Preferably where R.sup.1, R.sup.2 and R.sup.5 are
hydrogen.
[0230] More preferably the metal is selected from Zn(II), Mn(III)
and Cu(II).
[0231] Even more preferably where the apical ligand is chloride or
acetate.
[0232] Preferably where the metal is selected from Zn(II), Mn(III)
and Cu(II).
[0233] More preferably where the apical ligand is chloride or
acetate.
[0234] Particularly where the compound is selected from Formulae
III, IV and V
[0235] Preferably where R and R* are independently selected from:
optionally substituted anthraquinone, substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocyclyl, or
nitro.
[0236] More preferably where R.sup.2, R.sup.4 and R.sup.4* are
independently selected from: optionally substituted alkoxy,
hydrogen, or hydroxy.
[0237] Preferably where R.sup.2, R.sup.4 and R.sup.4* are
independently selected from: optionally substituted alkoxy,
hydrogen, or hydroxy.
[0238] The compounds of Formula II where at least one of R.sup.6 to
R.sup.9 is methoxymethoxy or
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].- sub.n-- (where n is
an integer from 1 to 4).
[0239] Especially where R.sup.10 and another of R.sup.6 to R.sup.9
are hydrogen.
[0240] Particularly where the rest of R.sup.6 to R.sup.9 are
independently selected from: optionally substituted alkenyl,
optionally substituted alkoxy, optionally substituted alkyl,
optionally substituted aryl, (optionally substituted
alkoxy)carbonyl, hydrogen, hydroxy and nitrone.
[0241] Especially where R" is optionally substituted anthracenone,
di-cyano, or optionally substituted heterocyclyl selected from:
2,5-(optionally substituted)-2,4-dihydro-pyrazol-3-one;
5-(optionally substituted)-3H-benzofuran-2-one;
2-thioxo-thiazolidin-4-one and thiazolidine-2,4-dione.
[0242] Particularly where R.sup.10 and another of R.sup.6 to
R.sup.9 are hydrogen.
[0243] Preferably where the rest of R.sup.6 to R.sup.9 are
independently selected from: optionally substituted alkenyl,
optionally substituted alkoxy, optionally substituted alkyl,
optionally substituted aryl, (optionally substituted
alkoxy)carbonyl, hydrogen, hydroxy and nitrone.
[0244] More preferably where the rest of R.sup.6 to R.sup.9 are
selected from: hydrogen, hydroxy, methoxymethoxy, t-butyl and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is 1
or 2.
[0245] Most preferably where R.sup.6 is hydrogen and:
[0246] R.sup.7 is hydrogen, R.sup.8 is methoxymethoxy, and R.sup.9
is methoxymethoxy; or
[0247] R.sup.7 is methoxymethoxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd- .CH--CH.sub.2--, and R.sup.9 is
hydroxy; or
[0248] R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH- .sub.2--, and R.sup.9 is
methoxymethoxy; or
[0249] R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH- .sub.2--, and R.sup.9 is
hydroxy; or
[0250] R.sup.7 is H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--,
R.sup.8 is methoxymethoxy, and R.sup.9 is hydrogen; or
[0251] R.sup.7 is H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--,
R.sup.8 is hydroxy, and R.sup.9 is hydrogen; or
[0252] R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
methoxymethoxy, and R.sup.9 is hydrogen; or
[0253] R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
hydroxy, and R.sup.9 is hydrogen; or
[0254] R.sup.7 is
3-methoxy-4-methoxymethoxy-1-(thiazolidine-2,4-dionyl)--
benzylidene-5-yl, R.sup.8 is methoxymethoxy, and R.sup.9 is
methoxy.
[0255] Particularly where R" is selected from: anthracenone,
dihydroxyanthracenone, di-cyano,
5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-- one; 3H-benzofuran-2-one;
5-hydroxy-3H-benzofuran-2-one; 2-thioxo-thiazolidin-4-one and
thiazolidine-2,4-dione.
[0256] Preferably where R.sup.10 and another of R.sup.6 to R.sup.9
are hydrogen.
[0257] More preferably where the rest of R.sup.6 to R.sup.9 are
independently selected from: optionally substituted alkenyl,
optionally substituted alkoxy, optionally substituted alkyl,
optionally substituted aryl, (optionally substituted
alkoxy)carbonyl, hydrogen, hydroxy and nitrone.
[0258] Even more preferably where the rest of R.sup.6 to R.sup.9
are selected from: hydrogen, hydroxy, methoxymethoxy, t-butyl and
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.n--, where n is 1
or 2.
[0259] Most preferably where R.sup.6 is hydrogen and:
[0260] R.sup.7 is hydrogen, R.sup.8 is methoxymethoxy, and R.sup.9
is methoxymethoxy; or
[0261] R.sup.7 is methoxymethoxy, R.sup.3 is
H--CH.sub.2--(CH.sub.3)C.dbd.- CH--CH.sub.2--, and R.sup.9 is
hydroxy; or
[0262] R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.- sub.2--, and R.sup.9 is
methoxymethoxy; or
[0263] R.sup.7 is hydroxy, R.sup.8 is
H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.- sub.2--, and R.sup.9 is
hydroxy; or
[0264] R.sup.7 is H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--,
R.sup.8 is methoxymethoxy, and R.sup.9 is hydrogen; or
[0265] R.sup.7 is H--CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2--,
R.sup.8 is hydroxy, and R.sup.9 is hydrogen; or
[0266] R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
methoxymethoxy, and R.sup.9 is hydrogen; or
[0267] R.sup.7 is
H--[CH.sub.2--(CH.sub.3)C.dbd.CH--CH.sub.2].sub.2--, R.sup.8 is
hydroxy, and R.sup.9 is hydrogen; or
[0268] R.sup.7 is
3-methoxy-4-methoxymethoxy-1-(thiazolidine-2,4-dionyl)-b-
enzylidene-5-yl, R.sup.8 is methoxymethoxy, and R.sup.9 is
methoxy.
[0269] Compounds (including single stereoisomers, mixtures of
stereoisomers, and pharmaceutically acceptable salts) employed as
compositions of matter and/or compounds for use in its the methods,
and pharmaceutical and cosmetic compositions of the present
invention include:
[0270] 4-(2-Pentafluorophenyl-vinyl)-benzene-1,2-diol
[0271] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzonitrile
[0272] 1-Benzyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide
[0273] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl ester
[0274] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
3-hydroxy-3-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]p-
henanthren-17-yl ester
[0275]
4-[4-(3-Methoxy-4-methoxymethoxy-phenyl)-buta-1,3-dienyl]-benzoic
acid methyl ester
[0276]
4-[4-(3-Methoxy-4-methoxymethoxy-phenyl)-buta-1,3-dienyl]-benzoic
acid methyl ester
[0277] 4-[4-(3,4-Dihydroxy-phenyl)-buta-1,3-dienyl]-benzoic acid
methyl ester
[0278]
4-[4-(3,4-Bis-methoxymethoxy-phenyl)-buta-1,3-dienyl]-benzoic acid
methyl ester
[0279] 3,4-Bis-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0280]
3-4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl-3-oxo-propioni-
c acid ethyl ester
[0281]
4-{2-[4-(5-Hydroxy-1-phenyl-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-
-1,2-diol
[0282] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenylamine
[0283]
N-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-acetamide
[0284] N-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-acetamide
[0285]
N-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-di-methanesu-
lfonamide
[0286]
N-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-methanesulfo-
namide
[0287]
{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-ethyl-amine
[0288]
4-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzenesulfonyl}-morpholine
[0289]
4-(3,4-Bis-methoxymethoxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydr-
o-pyrazol-3-one
[0290]
3,4-Bis-[2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0291]
3-(3,4-Bis-methoxymethoxy-phenyl)-1-[2-hydroxy-3,4-dimethyl-5-(tetr-
ahydro-pyran-2-yloxy)-phenyl]-propenone
[0292] 5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-2-hydroxy-benzoic acid
ethyl ester
[0293] 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzenesulfonamide
[0294]
3-(3,5-Bis-methoxymethoxy-benzylidene)-3H-benzofuran-2-one
[0295] 3-(3,5-Dihydroxy-benzylidene)-3H-benzofuran-2-one
[0296] 5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-2-methoxymethoxy-benzoic
acid ethyl ester
[0297]
4-{2-[3,4-Bis-(3,7-dimethyl-octa-2,6-dienyloxy)-phenyl]-vinyl}-benz-
oic acid methyl ester
[0298]
4-{2-[3,4-Bis-(3,7-dimethyl-octa-2,6-dienyloxy)-phenyl]-vinyl}-benz-
oic acid methyl ester
[0299] 5-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,3-diol
[0300]
2-[2-(3,4-Dimethoxy-phenyl)-vinyl]-5-(4-nitro-phenyl)-furan
[0301] 4-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0302]
3,3'-Dimethoxy-2,2'-bis-methoxymethoxy-5,5'-bis-[2-(4-nitro-phenyl)-
-vinyl]-biphenyl
[0303] 4-[2-(2-Bromo-4,5-dimethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0304] 4-[2-(5-Bromo-2,4-dimethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0305]
1-Bromo-2,4-dimethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0306]
4-[2-(3-Bromo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0307] 4-[2-(3-Bromo-4-hydroxy-5-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0308]
5-[6-Hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman--
5-ylmethylene]-thiazolidine-2,4-dione
[0309]
1-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzenesulfonyl}-piperidine
[0310]
1-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzenesulfonyl}-pyrrolidine
[0311]
4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-N-dimethylaminomethylen-
e-benzenesulfonamide
[0312] 4-(2-[2,2']Bipyridinyl-5-yl-vinyl)-benzene-1,2-diol
[0313] 4-(2-[2,2']Bipyridinyl-5-yl-vinyl)-benzene-1,2-diol,
Zn(II)chloride
[0314] 4-(2-[2,2']Bipyridinyl-5-yl-vinyl)-benzene-1,2-diol,
Cu(II)chloride
[0315] 4-(2-[2,2']Bipyridinyl-5-yl-vinyl)-benzene-1,2-diol,
Mn(II)acetate
[0316] 4-(2-[2,2']Bipyridinyl-5-yl-vinyl)-benzene-1,2-diol, Ru(II)
di-[2,2']bipyridine chloride
[0317]
4(N-t-butiylamino-methyl)benzilidene]thiazolidine-2,4-dione-N-oxide
[0318]
1-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzenesulfonyl-pipe-
ridine
[0319] 4-[2-(3,5-Dimethoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0320] 4-[2-(4-Hydroxy-3,5-dimethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0321]
1,3-Dimethoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0322] 4-[2-(2,3,4-Tris-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0323]
2-Chloro-1-methoxymethoxy-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0324]
4-[2-(3,5-Dimethoxy-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0325]
4-[2-(4-Hydroxy-3,5-dimethoxy-phenyl)-vinyl]-benzonitrile
[0326] 2,6-Dimethoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0327]
1-Methoxymethoxy-2-nitro-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0328] 2-Bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0329]
1-Bromo-2-methoxy-4-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene
[0330]
1-Bromo-2-methoxy-4-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene
[0331]
4-[2-(5-Bromo-4-methoxy-2-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0332] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
[0333]
1,2,3-Tris-methoxymethoxy-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0334] 4-[2-(3-Bromo-4-hydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0335] 4-[2-(3,5-Dibromo-4-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0336]
1,3-Dibromo-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0337]
4-[2-(3,5-Dibromo-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0338] 4-[2-(3,5-Dibromo-4-hydroxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0339]
2-3-[2-(3,4-Dihydroxy-phenyl)-vinyl]-5-hydroxy-phenoxy}-6-hydroxyme-
thyl-tetrahydro-pyran-3,4,5-triol
[0340] Astringin
[0341] 2,3-Bis-(4-acetoxy-3-methoxy-phenyl)-acrylic acid
[0342] Acetic acid
4-[2-(4-acetoxy-3-methoxy-phenyl)-vinyl]-2-methoxy-phen- yl
ester
[0343] 3,3-'dimethoxy-4,4'-dihydroxy-stilbene
[0344] 5-[2-(4-Methoxy-phenyl)-vinyl]-benzo[1,3]dioxole
[0345] Gnelin
[0346] 4-(3-Ethoxy-propenyl)-phenol
[0347] 2-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-ethanol
[0348] 5-[2-(4-Hydroxy-phenyl)-vinyl]-benzene-1,3-diol
[0349]
1,2-Bis-methoxymethoxy-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0350] 1,2,3-Trimethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0351] 4-[2-(3,4,5-Trimethoxy-phenyl)-vinyl]-phenylamine
[0352] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
[0353] 4-(2-Pyridin-4-yl-vinyl)-benzene-1,2-diol
[0354] 4-[2-(4-Bromo-phenyl)-vinyl]-benzene-1,2-diol
[0355] 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0356] 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzoic acid
[0357] 4-[2-(4-tert-Butyl-phenyl)-vinyl]-benzene-1,2-diol
[0358] 4-[2-(4-Trifluoromethyl-phenyl)-vinyl]-benzene-1,2-diol
[0359] 4-[2-(4-Fluoro-phenyl)-vinyl]-1,2-dimethoxy-benzene
[0360] 3-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-phenyl}-acrylic acid
ethyl ester
[0361]
4-(2-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-phenyl}-vinyl)-benzoic
acid ethyl ester
[0362] 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzaldehyde
[0363] 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-benzaldehyde
[0364] 4-[2-(4-Fluoro-phenyl)-vinyl]-benzene-1,2-diol
[0365] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid decyl
ester
[0366] 2-(3,4-Bis-methoxymethoxy-benzylidene)-malononitrile
[0367] 2-(3,4-Dihydroxy-benzylidene)-malononitrile
[0368]
4-[2-(4-tert-Butyl-phenyl)-vinyl]-1,2-bis-methoxymethoxy-benzene
[0369]
1,2-Bis-methoxymethoxy-4-[2-(4-trifluoromethyl-phenyl)-vinyl]-benze-
ne
[0370] 10-(3,4-Dihydroxy-benzylidene)-10 H-anthracen-9-one
[0371] 2-Methoxy-4-(2-pentafluorophenyl-vinyl)-phenol
[0372]
2-Methoxy-1-methoxymethoxy-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0373]
4-{2-[6-Methoxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chrom-
an-5-yl]-vinyl}-benzoic acid ethyl ester
[0374]
4-[2-(3-Methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0375] 4-[2-(3,5-Bis-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0376]
2-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-anthraquinone
[0377] 4-[2-(3,5-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0378] 3-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0379]
1-[2-(3,4-Dimethoxy-phenyl)-vinyl]-4,5-dimethoxy-2-nitro-benzene
[0380]
4-{2-[3-Iodo-5-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-vinyl}-benzo-
ic acid methyl ester
[0381]
4-{2-[3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-vinyl}-benzoic acid
methyl ester
[0382]
Bis-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-diazene
N,N'-dioxide
[0383] Bis-{4-[2-(3,4-bis-hydroxy-phenyl)-vinyl]-phenyl}-diazene
N,N'-dioxide
[0384]
N-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-benzamide
[0385]
2-Bromo-4-methoxy-3-methoxymethoxy-1-[2-(4-nitro-phenyl)-vinyl]-ben-
zene
[0386]
4-[2-(2-Bromo-4-methoxy-3-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0387]
1-Bromo-4,5-dimethoxy-2-[2-(4-nitro-phenyl)-vinyl]-benzene
[0388]
1-Bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene
[0389] 2-Nitro-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0390]
4-[2-(5-Bromo-4-methoxy-2-methoxymethoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0391] 4-[2-(3-Bromo-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0392] Acetic acid 4-(1-acetoxy-allyl)-phenyl ester
[0393] Acetoxychavicol.
[0394] The compounds (including single stereoisomers, mixtures of
stereoisomers, and pharmaceutically acceptable salts) preferred as
compositions of matter and/or compounds for use in its the methods,
and pharmaceutical and cosmetic compositions of the present
invention include:
[0395] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0396] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
[0397]
5-(3,4-Bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione
[0398] 5-(3,4-Dihydroxy-benzylidene)-thiazolidine-2,4-dione
[0399] 4-(2-Nitro-vinyl)-benzene-1,2-diol
[0400]
4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-N-methyl-N-(2,3,4,5,6-pentahydro-
xy-hexyl)-benzamide
[0401] 3-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-acrylic acid
ethyl ester
[0402]
4-(2-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-vinyl)-benzoic
acid methyl ester
[0403] 4-[2-(3,4 Dihydroxy-phenyl)-vinyl]-benzoic acid decyl
ester
[0404] (E)-4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid hexyl
ester
[0405] (Z)-4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid hexyl
ester
[0406] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-dienyl ester
[0407] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid hex-3-enyl
ester
[0408] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
hex-3-enyl ester
[0409] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
heptadec-12-enyl ester
[0410]
4-[2-(3-Hydroxy-4-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}phenyl)-v-
inyl]-benzoic acid ethyl ester
[0411] 4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0412] 2-Methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0413] 4-[2-(3,5-Dihydroxy-phenyl)-vinyl]-benzonitrile
[0414]
4-[2-(4-Methanesulfonyl-phenyl)-vinyl]-1,2-dimethoxy-benzene
[0415] 4-[2-(3,5-Dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0416]
5-[2-(4-Methoxycarbonyl-phenyl)-vinyl]-2-methoxymethoxy-benzoic
acid methoxymethyl ester
[0417] 2-Hydroxy-5-[2-(4-methoxycarbonyl-phenyl)-vinyl]-benzoic
acid
[0418]
4-[4-(3,4-Dimethoxy-phenyl)-buta-1,3-dienyl]-2-methoxy-phenol
[0419]
2-Methoxy-1-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-b-
enzene
[0420]
1-[2-(3,4-Dimethoxy-phenyl)-vinyl]-5-methoxymethoxy-2-nitro-benzene
[0421] 4-[2-(4-Methoxymethoxy-3,5-dimethyl-phenyl)-vinyl]-benzoic
acid methyl ester
[0422]
4-(3,4-Bis-methoxymethoxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydr-
o-pyrazol-3-one
[0423]
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-6-nitro-benzo[1,3]dioxole
[0424]
1-Iodo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene
[0425] 5-[2-(4-Dimethylamino-phenyl)-vinyl]-2-methoxy-phenol
[0426]
4-{2-[4-(5-Hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol
[0427]
{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-dimethyl-amine
[0428]
{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-methyl-amine
[0429]
N,N-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-dimethanesulfonyl-a-
mide
[0430]
N-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-methanesulfonamide
[0431]
4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-4'-methyl-[2,2']bipyrid-
inyl
[0432]
N-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-benzamide
[0433]
4-[2-(4'-Methyl-[2,2']bipyridinyl-4-yl)-vinyl]-benzene-1,2-diol
[0434]
4-{2-[3,5-Bis-methoxymethoxy-2,6-bis-(3-methyl-but-2-enyl)-phenyl]--
vinyl}-benzoic acid methyl ester
[0435]
1,5-Bis-methoxymethoxy-2,4-bis-(3-methyl-but-2-enyl)-3-[2-(4-nitro--
phenyl)-vinyl]-benzene
[0436]
5-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-thiazolidine-2,4-dion-
e
[0437]
3-(3,4-Bis-methoxymethoxy-benzylidene)-3H-benzofuran-2-one
[0438] 3-(3,4-Dihydroxy-benzylidene)-3H-benzofuran-2-one
[0439] 5-[2-(4-Nitro-phenyl)-vinyl]-1H-benzoimidazole
[0440] 3-(3,4-Dihydroxy-phenyl)-2-(2,5-dihydroxy-phenyl)-acrylic
acid methyl ester
[0441]
3-(3,4-Dihydroxy-benzylidene)-5-hydroxy-3H-benzofuran-2-one
[0442]
5-Hydroxy-3-(4-hydroxy-3-methoxy-benzylidene)-3H-benzofuran-2-one
[0443]
1,2-Bis-(3,7-dimethyl-octa-2,6-dienyloxy)-4-[2-(4-nitro-phenyl)-vin-
yl]-benzene
[0444]
1,3-Bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0445]
3,3'-Dimethoxy-2,2'-bis-methoxymethoxy-5,5'-bis-[2-(4-carbomethoxy--
phenyl)-vinyl]-biphenyl
[0446]
5-[3-Methoxy-4-methoxymethoxy-5-(3-methoxy-4-methoxymethoxy-1-(thia-
zolidine-2,4-dionyl)-benzylidene-5-yl)-benzylidene]-thiazolidine-2,4-dione
[0447] 4-[2-(2-Bromo-3-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0448]
4-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-5-methyl-2-phenyl-2,4-d-
ihydro-pyrazol-3-one
[0449]
3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one
[0450]
2-{4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one
[0451]
4-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzenesulfonyl}-mor-
pholine
[0452]
4-{2-[4-(Morpholine-4-sulfonyl)-phenyl]-vinyl}-benzene-1,2-diol
[0453]
4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzenesulfonamide
[0454]
4-{2-[4-(Piperidine-1-sulfonyl)-phenyl]-vinyl}-benzene-1,2-diol
[0455]
5-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl,
Cu(III)chloride
[0456]
5-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl,
Mn(II)acetate
[0457]
1-Bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene
[0458] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester
[0459] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phthalic acid dimethyl
ester
[0460]
1,2,3-Tris-methoxymethoxy-4-[2-(4-nitro-phenyl)-vinyl]-benzene
[0461]
4-[2-(2,3,4-Tris-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0462] 4-[2-(2,3,4-Trihydroxy-phenyl)-vinyl]-benzonitrile
[0463] 4-[2-(3-Chloro-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0464] 4-[2-(3-Chloro-4-hydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0465] 4-[2-(3-Chloro-4-hydroxy-phenyl)-vinyl]-benzonitrile
[0466]
4-[2-(3,4-Bis-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid methyl ester
[0467]
2-[2-(2-{2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-5-[2-(4-nitro-p-
henyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethanol
[0468]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester
[0469]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid tetradecyl ester
[0470]
4-[2-(3,4-Bis-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid tetradecyl ester
[0471]
4-[2-(3,4-Bis-12-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy)-phenyl)-viny-
l]-benzoic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester
[0472] Phosphoric acid
2-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenyl ester dimethyl
ester
[0473] Phosphoric acid
2-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenyl ester dimethyl ester,
sodium salt
[0474]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-N-(2-hydroxy-1, -bis-hydroxymethyl-ethyl)-benzamide
[0475] Phosphoric acid
mono-{4-[2-(4-cyano-phenyl)-vinyl]-2-methoxy-phenyl- }ester
[0476] Phosphoric acid
mono-{3-[2-(4-nitro-phenyl)-vinyl]-5-phosphonooxy-p-
henyl}ester
[0477]
4-(4-Methoxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-o-
ne.
[0478] The compounds (including single stereoisomers, mixtures of
stereoisomers, and pharmaceutically acceptable salts) most
preferred as compositions of matter and/or compounds for use in the
methods, and pharmaceutical and cosmetic compositions of the
present invention include:
[0479] 4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2-diol
[0480] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0481]
4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzam-
ide
[0482]
4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide
[0483]
{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-morpholin-4-yl-methanon-
e
[0484] 4-[2-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester
[0485] 4-{2-[4-(2-Nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol
[0486]
1-Carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide
[0487]
1-(2-Carboxy-2-oxo-ethyl)-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridi-
nium; bromide
[0488] {4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic acid
diisopropyl ester
[0489] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl ester
[0490] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-dienyl ester
[0491] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester
[0492]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester
[0493] 4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile
[0494] 4-[2-(5-Methyl-thiophen-2-yl)-vinyl]-benzoic acid methyl
ester
[0495] 4-[2-(phenyl-1,2-diol)vinyl]-benzoic acid methyl ester,
zinc(II) chloride
[0496] 4-[2-(phenyl-1,2-diol)vinyl]-benzoic acid methyl ester,
manganese(III) acetate
[0497] 4-[2-(phenyl-1,2-diol)vinyl]-benzoic acid methyl ester,
Copper(II) chloride
[0498]
bis-{4-[2-(4-methoxycarbonyl-phenyl)-vinyl]-benzene-1,2-diol},
zinc(II) chloride
[0499]
4-{2-[3-Methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester
[0500]
4-{2-[4-Hydroxy-3-methoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-be-
nzoic acid methyl ester
[0501]
1-Methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-ph-
enyl)-vinyl]-benzene
[0502]
2-Methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol
[0503] 2-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-thiazole
[0504] 2-[2-(3,4-Dihydroxy-phenyl)-vinyl]-anthraquinone
[0505] 2-Methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol
[0506] 3-[2-(3,4-Dimethoxy-phenyl)-vinyl]-4-nitro-phenol
[0507]
2-Methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-phenyl)-vinyl]-benzene
[0508] 4-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester
[0509] 2,6-Dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0510] 2-Hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
[0511]
1,2-Bis-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benze-
ne
[0512] 4-[2-(6-Nitro-benzo[1,3]dioxol-5-yl)-vinyl]-benzoic acid
methyl ester
[0513] 2-Methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester
[0514] 4-[4-(4-Nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol
[0515]
4-[2-(3-Iodo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0516] 3,4-Bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[0517]
4-[3-(3-Methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one
[0518]
4-{2-[3,4-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester
[0519]
4-{2-[3,4-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester
[0520]
4-{2-[3,4-Bis-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester
[0521]
1,2-Bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene
[0522]
4-{2-[3,4-Dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester
[0523]
4-{2-[4,5-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester
[0524]
3-(3-Methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol
[0525]
3-(3-Methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol
[0526]
5-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-
-dihydro-pyrazol-3-one
[0527]
5-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro--
pyrazol-3-one
[0528] 2-Iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0529]
3-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-4H-isoxazol-5-one
[0530]
4-{2-[3,5-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester
[0531]
4-{2-[3,5-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester
[0532]
1,5-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl-
)-vinyl]-benzene
[0533]
4-(3-Methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol
[0534]
4-(3-Methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol
[0535] 4-[2-(4-Hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[0536]
4-(3,4-Dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
-3-one
[0537]
4-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one
[0538]
4-[3-(3-Methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one
[0539]
5-[3-(3-Methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione
[0540]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzoic acid methyl ester
[0541]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzoic acid methyl ester
[0542]
2-(3,7-Dimethyl-octa-2,6-dienyl)-1,3-bis-methoxymethoxy-5-[2-(4-nit-
ro-phenyl)-vinyl]-benzene
[0543]
2-(3,7-Dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol
[0544]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzonitrile
[0545]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile
[0546] 2,6-Di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0547]
2-(3,7-Dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol
[0548]
5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine-2,4-dione
[0549] 2-Bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0550]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester
[0551]
4-{2-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester
[0552]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzonitrile
[0553]
4-{2-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile
[0554]
1,3-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene
[0555]
2-(3-Methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol
[0556]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzoic acid methyl ester
[0557]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester
[0558]
1-(3,7-Dimethyl-octa-2,6-dienyl)-3-methoxy-2-methoxymethoxy-5-[2-(4-
-nitro-phenyl)-vinyl]-benzene
[0559]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzonitrile
[0560]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile
[0561] 5-Methyl-2-(4-styryl-phenyl)-2,4-dihydro-pyrazol-3-one
[0562]
2-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one
[0563]
2-{4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-di-
hydro-pyrazol-3-one
[0564] 2-bromo-4[4
-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol
[0565]
5-{4-[6-Hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chrom-
an-5-ylmethoxy]-benzylidene}-thiazolidine-2,4-dione
[0566] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzenesulfonamide
[0567] 4-{2-[4-amino-sulfonyl)-phenyl]-vinyl}-benzene-1,2-diol
[0568]
5-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl
[0569]
5-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl,
Zn(II)chloride
[0570]
1,3-Bis-methoxymethoxy-5-{2-[4-methoxymethoxy-3-(3-methyl-but-2-eny-
l)-phenyl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene
[0571]
5-{2-[4-Hydroxy-3-(3-methyl-but-2-enyl)-phenyl]-vinyl}-2-(3-methyl--
but-2-enyl)-benzene-1,3-diol
[0572]
5-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzylidene]-thia-
zolidine-2,4-dione
[0573]
5-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine--
2,4-dione,
[0574]
5-[4-Methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidi-
ne-2,4-dione
[0575]
5-[4-Hydroxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4--
dione
[0576]
5-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione
[0577]
5-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-methoxymethoxy-benzylidene]-t-
hiazolidine-2,4-dione
[0578]
5-[2-(3,5-dimethoxy-4-methoxymethoxy-phenyl)-vinyl]-2-(3-methyl-but-
-2-enyl)-,3-(bis-methoxymethoxy)-benzene
[0579]
5-[2-(4-Hydroxy-3,5-dimethoxy-phenyl)-vinyl]-2-(3-methyl-but-2-enyl-
)-benzene-1,3-diol
[0580]
5-[2-(3-Methoxy-4-methoxymethoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-
-but-2-enyl)-1,3-(bis-methoxymethoxy)-benzene
[0581]
5-[2-(4-Hydroxy-3-methoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-but-2--
enyl)-benzene-1,3-diol
[0582]
1,3-Bis-methoxymethoxy-5-[2-(4-methoxymethoxy-3-nitro-phenyl)-vinyl-
]-2-(3-methyl-but-2-enyl)-benzene
[0583]
5-[2-(4-Hydroxy-3-nitro-phenyl)-vinyl]-2-(3-methyl-but-2-enyl)-benz-
ene-1,3-diol
[0584] 2-Chloro-4-[2-(4-nitro-phenyl)-vinyl]-phenol
[0585]
4-[2-(3-Chloro-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile
[0586] 4-Bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol
[0587] 4-[2-(5-Bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester
[0588] (E).sub.4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2,3-triol
[0589] (Z).sub.4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2,3-triol
[0590]
5-{3-[3-Methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-allylidene}-thia-
zolidine-2,4-dione.
[0591] One preferred sub-group of compounds (including single
stereoisomers, mixtures of stereoisomers, and pharmaceutically
acceptable salts) employed as compositions of matter and/or
compounds for use in its the methods, and pharmaceutical and
cosmetic compositions of the present invention is:
[0592] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0593]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl-pheno-
l;
[0594] 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
[0595]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0596]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0597] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[0598]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0599]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0600] 2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
[0601] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0602]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0603]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0604]
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro--
pyrazol-3-one;
[0605]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0606]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0607]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0608]
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol-
;
[0609] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0610] 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
[0611] 4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
[0612] 2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0613]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0614]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol;
[0615] 2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0616]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile; and
[0617] 2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol.
[0618] Another preferred sub-group of compounds (including single
stereoisomers, mixtures of stereoisomers, and pharmaceutically
acceptable salts) employed as compositions of matter and/or
compounds for use in its the methods, and pharmaceutical and
cosmetic compositions of the present invention is:
[0619]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[0620]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0621]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0622]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0623]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0624] 2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
[0625] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0626]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0627]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0628]
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro--
pyrazol-3-one;
[0629]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0630]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0631]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0632]
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol-
;
[0633] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0634]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0635]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol; and
[0636]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile.
[0637] Still another preferred sub-group of compounds (including
single stereoisomers, mixtures of stereoisomers, and
pharmaceutically acceptable salts) employed as compositions of
matter and/or compounds for use in its the methods, and
pharmaceutical and cosmetic compositions of the present invention
is:
[0638]
3-(3-methyl-but-2-enyl)-4-(2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0639] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0640]
2-(4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl)-5-methyl-2,4-di-
hydro-pyrazol-3-one;
[0641]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[0642]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0643]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0644]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0645]
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[0646]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[0647]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0648]
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzam-
ide;
[0649]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[0650]
{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-morpholin-4-yl-methanon-
e;
[0651] 4-[2-(2,5-dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[0652] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0653] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide;
[0654] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-dienyl ester;
[0655] 4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[0656] 4-[2-(4-hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
[0657] 4-bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0658] 4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester; and
[0659] {4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic acid
diisopropyl ester.
[0660] Another preferred sub-group of compounds (including single
stereoisomers, mixtures of stereoisomers, and pharmaceutically
acceptable salts) employed as compositions of matter and/or
compounds for use in its the methods, and pharmaceutical and
cosmetic compositions of the present invention is:
[0661]
5-{2-[4-hydroxy-3-(3-methyl-but-2-enyl)-phenyl]-vinyl}-2-(3-methyl--
but-2-enyl)-benzene-1,3-diol;
[0662]
4-(3,4-dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
-3-one;
[0663]
4-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-methyl-2-phenyl-2,4-d-
ihydro-pyrazol-3one;
[0664]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[0665]
5-{4-[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chrom-
an-5-ylmethoxy]-benzylidene}-thiazolidine-2,4-dione;
[0666]
4-[2-(3,4-dihydroxy-phenyl)-vinyl]N,N-bis-(2-hydroxy-ethyl)-benzami-
de;
[0667]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[0668]
{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl)}-morpholin-4-yl-methano-
ne;
[0669] 4-[2-(2,5-dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[0670] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0671] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide;
[0672] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-dienyl ester;
[0673] 4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[0674] 4-[2-(4-hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
[0675] 4-bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0676] 4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester; and
[0677] {4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic acid
diisopropyl ester.
Utility, Testing and Administration
[0678] General Utility
[0679] Compounds, compositions/formulations and methods of the
present invention are useful in treating a number of disorders,
particularly those characterized by oxidative stress, e.g., in the
treatment of cerebral ischemia ("stroke"), neurodegenerative
disorders, myocardial ischemia (myocardial infarction and other
forms of heart disease), diabetes, renal disease, pre-menstrual
syndrome, asthma, cardiopulmonary inflammatory disorders, chronic
heart failure, rheumatoid arthritis, muscle fatigue, irritable
bowel syndrome, inflammatory bowel disease, intermittent
claudication and for the preservation of allograft tissue for
transplantation.
[0680] The compounds, formulations and methods of the present
invention are useful in treating a number of dermatological
conditions, including, but not limited to prevention and protecting
skin tissue against age-related damage or damage resulting from
insults such as harmful ultraviolet (UV) radiation, stress and
fatigue. Such compounds, formulations and methods are likewise
useful, e.g., in treating contact dermatitis, acne and psoriasis
(including scalp psoriasis), and are amenable to topical
application for hair care and treatments of the scalp, for example
by incorporation in medicated shampoos, anhydrous hair conditioners
and the like.
[0681] Compounds Preferred for Certain Groups of Indications
[0682] Certain of the conditions characterized by oxidative stress
fall within the cardiovascular group, including: myocardial
ischemia, myocardial infarction, cardiopulmonary inflammatory
disorders; and heart failure (including chronic and congestive
heart failure). Preferred for the treatment of such disorders are
the compounds of Formula I where R' is hydrogen and R is phenyl
substituted in the para position with alkoxycarbonyl or a
nitrogen-bearing moiety, such as nitro or cyano, or where R is a
nitrogen-containing heteroaryl, particularly a thiazole. Also
preferred are the compounds of Formula I where one or more of
R.sup.1 to R.sup.5 is hydroxy, alkoxy (especially methoxy and
methoxymethoxy), alkenyl (especially prenyl and geranyl) or halo
(especially bromo), especially where R and R' are as defined above.
Also preferred are the compounds of Formula II where R" is
2-thioxo-thiazolidin-4-one thiazolidine-2,4-dione (preferably
thiazolidine-2,4-dione) and one or more of R.sup.6 to R.sup.10 is
hydroxy or alkoxy (especially methoxymethoxy). Particularly
preferred for the treatment of such disorders are the following
compounds:
[0683] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[0684] 4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[0685] 4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile;
[0686] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
[0687] 5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
[0688] 4-(2-nitro-vinyl)-benzene-1,2-diol;
[0689]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[0690] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester;
[0691]
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-ph-
enyl)-vinyl]-benzene;
[0692]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0693]
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[0694]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[0695]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[0696] 2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole;
[0697]
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione;
and
[0698]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester,
[0699] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0700] Of the foregoing group, especially preferred for the
treatment of cardiovascular conditions are the following
compounds:
[0701] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[0702] 4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile;
[0703] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
[0704] 5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
[0705]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[0706] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester;
[0707]
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-ph-
enyl)-vinyl]-benzene;
[0708]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0709]
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[0710]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[0711]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[0712] 2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole;
[0713]
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione;
and
[0714]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester,
[0715] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0716] Of the foregoing group, most preferred for the treatment of
cardiovascular conditions are the following compounds:
[0717] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[0718] 4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile;
[0719] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
[0720] 5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
[0721]
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-ph-
enyl)-vinyl]-benzene;
[0722]
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[0723]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[0724] 2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole;
and
[0725]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester,
[0726] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0727] Another group of conditions characterized by oxidative
stress fall within the cerebrovascular and neurologic group,
including: stroke, cerebral ischemia, retinal ischemia,
post-surgical cognitive dysfunctions (e.g., following bypass
surgery), peripheral neuropathy spinal chord injury, head injury
and surgical trauma, and neurodegenerative disorders including
Alzheimer's, dementia and Parkinson's disease. Preferred for the
treatment of such disorders are the compounds of Formula I where R'
is hydrogen and R is phenyl substituted with an alkoxy,
alkoxycarbonyl, hydroxy, or a nitrogen-bearing moiety, such as
nitro or nitrogen-bearing heterocyclyl (e.g.,
2,4-dihydro-pyrazol-3-one); particularly preferred are the
compounds where R is phenyl substituted in the para position with
nitro or an alkyl ester (especially methyl-, ethyl-, or
tetradecyl-ester). Also preferred are the compounds of Formula I
where R is a nitrogen-containing heteroaryl (particularly a
optionally substituted pyridinium bromide) or
vinyl-nitrogen-containing heterocyclyl (particularly
vinyl-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one). Similarly
preferred are the compounds of Formula I where R is tri-substituted
phenyl having a nitro and a methoxy substituent at the two meta
positions and methoxymethoxy or hydroxy at the para position. Also
preferred are the compounds of Formula I where one or more of
R.sup.1 to R.sup.5 is other than hydrogen, selected from hydroxy,
alkoxy (especially methoxy and methoxymethoxy), alkenyl (especially
prenyl and geranyl) or halo (especially bromo), especially where R
and R' are as defined above; particularly where R.sup.1and R.sup.5
are hydrogen and two or three of R.sup.2, R.sup.3 and R.sup.4 are
selected from hydroxy, methoxymethoxy, and prenyl or geranyl. Also
preferred are the compounds of Formula II where R" is
2-thioxo-thiazolidin-4-one or thiazolidine-2,4-dione (preferably
thiazolidine-2,4-dione) and one or more of R.sup.6 to R.sup.10 are
not hydrogen, selected from hydroxy, alkoxy (especially
methoxymethoxy) and alkenyl (especially prenyl and geranyl).
Particularly preferred for the treatment of such disorders are the
following compounds:
[0728] 2,6-di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0729] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0730]
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide-4-{2-[4-amino-
-sulfonyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0731] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0732] 4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester;
[0733] 4-[2-(2,3,4-trihydroxy-phenyl)-vinyl]-benzonitrile;
[0734]
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-di-
hydro-pyrazol-3-one;
[0735]
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide;
[0736]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0737] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[0738]
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[0739]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzoic acid methyl ester;
[0740]
2-methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[0741]
1,2-bis-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benze-
ne;
[0742] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0743]
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0744]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-meth-
oxymethoxy-5-methoxy-phenyl)-vinyl]-benzene;
[0745]
1-iodo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene;
[0746]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[0747]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0748]
5-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine--
2,4-dione;
[0749]
5-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidi-
ne-2,4-dione;
[0750]
5-[4-hydroxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4--
dione;
[0751]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[0752]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-methoxymethoxy-benzylidene]-t-
hiazolidine-2,4-dione;
[0753]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0754]
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0755]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[0756]
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-but-2--
enyl)-benzene-1,3-diol; and
[0757]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzonitrile
[0758] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0759] Of the foregoing group, especially preferred for the
treatment of cerebrovascular/neurologic conditions are the
following compounds:
[0760] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0761] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0762]
2-(4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl)-5-methyl-2,4-di-
hydro-pyrazol-3-one;
[0763]
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide;
[0764]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0765] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[0766]
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[0767]
2-methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[0768]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[0769] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0770]
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0771]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-meth-
oxymethoxy-5-methoxy-phenyl)-vinyl]-benzene;
[0772]
1-iodo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene;
[0773]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[0774]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0775]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0776]
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0777]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol; and
[0778]
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-viny]-2-(3-methyl-but-2-e-
nyl)-benzene-1,3-diol,
[0779] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0780] Of the foregoing group, most preferred for the treatment of
cerebrovascular/neurologic conditions are the following
compounds:
[0781] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0782] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0783]
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-di-
hydro-pyrazol-3-one;
[0784]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[0785] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[0786]
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[0787]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[0788]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-meth-
oxymethoxy-5-methoxy-phenyl)-vinyl]-benzene;
[0789]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[0790]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0791]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0792]
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0793]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol; and
[0794]
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-but-2--
enyl)-benzene-1,3-diol,
[0795] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0796] Another group of diseases characterized by oxidative stress
and involving inflammatory and/or autoimmune components includes:
diabetes; renal disease; pre-menstrual syndrome; asthma; rheumatoid
arthritis; osteoarthritis, muscle fatigue; irritable bowel
syndrome, inflammatory bowel disease and intermittent claudication.
Preferred for the treatment of such disorders are the compounds of
Formula I where R' is hydrogen and R is phenyl substituted in the
para position with alkoxycarbonyl or a nitrogen-bearing moiety,
such as nitro or cyano, or where R is vinyl-nitrogen-containing
heteroaryl, particularly vinyl-thiazolidine-2,4-dione or
vinyl-nitrogen-containing heterocyclyl, particularly
vinyl-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one. Also preferred
are the compounds of Formula I where one or more of R.sup.1 to
R.sup.5 is hydroxy, alkoxy (especially methoxy and methoxymethoxy),
alkoxycarbonyl (especially methoxymethoxycarbonyl) or alkenyl
(especially prenyl and geranyl), especially where R and R' are as
defined above. Particularly preferred for the treatment of such
disorders are the following compounds:
[0797] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0798] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0799] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0800] 5-methyl-2-(4-styryl-phenyl)-2,4-dihydro-pyrazol-3-one;
[0801]
2-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one;
[0802]
4-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-methyl-2-phenyl-2,4-d-
ihydro-pyrazol-3-one;
[0803]
4-[3-(4-hydroxy-3-methoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one;
[0804]
4-{2-[3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester;
[0805]
4-[2-(3-iodo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
[0806] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0807] 4-[2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-vinyl]-benzoic
acid methyl ester;
[0808] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0809]
N-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-benzamide;
[0810]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0811]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[0812]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[0813]
5-[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzylidene]-thia-
zolidine-2,4-dione;
[0814]
5-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidi-
ne-2,4-dione;
[0815]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[0816]
5-[3-meth-oxy-4-methoxymethoxy-5-(3-methoxy-4-methoxymethoxy-1-(thi-
azolidine-2,4-dionyl)-benzylidene-5-yl)-benzylidene]-thiazolidine-2,4-dion-
e;
[0817]
4-{2-[3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester;
[0818]
4-{2-[3,4-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0819]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0820]
4-{2-[3,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0821]
4-{2-[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester;
[0822]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0823]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0824]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0825]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0826]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0827]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0828]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0829]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0830]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0831]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0832]
5-{2-[4-hydroxy-3-(3-methyl-but-2-enyl)-phenyl]-vinyl}-2-(3-methyl--
but-2-enyl)-benzene-1,3-diol; and
[0833]
5-{3-[3-methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-allylidene}-thia-
zolidine-2,4-dione,
[0834] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0835] Of the foregoing group, especially preferred for the
treatment of inflammatory/autoimmune conditions are the following
compounds:
[0836] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0837]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0838]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[0839]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[0840]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0841]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0842]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0843]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0844]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0845]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0846]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile; and
[0847]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol,
[0848] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0849] Of the foregoing group, most preferred for the treatment of
inflammatory/autoimmune conditions are the following compounds:
[0850] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0851]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol; and
[0852]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol,
[0853] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0854] Another group of diseases characterized by oxidative stress
fall within the group dermatologic conditions, including, but not
limited to prevention and protecting skin tissue against
age-related damage or damage resulting from insults such as harmful
ultraviolet (UV) radiation, stress and fatigue. Preferred for the
treatment of such disorders are the compounds of Formula I where R'
is hydrogen and R is phenyl substituted in the para position with a
nitrogen-bearing moiety, such as nitro or cyano. Also preferred are
the compounds of Formula I where one or more of R.sup.1 to R.sup.5
is hydroxy, alkoxy (especially methoxy) or alkenyl (especially
prenyl and geranyl), especially where R and R' are as defined
above. Particularly preferred are the compounds of Formula I where
one or two of R.sup.2 to R.sup.4 is hydroxy, one of R.sup.1 to
R.sup.4 is prenyl or geranyl, and the remaining substituents of
R.sup.1 to R.sup.5 are hydrogen; especially where R and R' are as
defined above. Particularly preferred for the treatment of such
disorders are the following compounds:
[0855] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0856] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0857] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol
[0858]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[0859] 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
[0860]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0861]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0862] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[0863] 2,6-di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0864]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0865]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0866] 4-(2-nitro-vinyl)-benzene-1,2-diol;
[0867] 2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
[0868] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[0869]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0870]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0871]
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro--
pyrazol-3-one;
[0872]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0873]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0874]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0875]
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol-
;
[0876] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0877] 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
[0878] 4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
[0879]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene-]-5-methyl-2-ph-
enyl-2,4-dihydro-pyrazol-3-one;
[0880]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[0881] 2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0882]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0883]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol;
[0884] 2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0885]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[0886] 2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[0887] acetic acid 4-(1-acetoxy-allyl)-phenyl ester;
[0888]
2-(4-methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-ethanol;
[0889] acetic acid
4-[2-(4-acetoxy-3-methoxy-phenyl)-vinyl]-2-methoxy-phen- yl
ester;
[0890]
2-{3-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-phenoxy}-6-hydroxym-
ethyl-tetrahydro-pyran-3,4,5-trio;
[0891] 4-(3-ethoxy-propenyl)-phenol;
[0892] 2,3-bis-(4-acetoxy-3-methoxy-phenyl)-acrylic acid;
[0893] cis-gnetin;
[0894] 5-[2-(4-methoxy-phenyl)-vinyl]-benzo[1,3]dioxole; and
[0895] (4-methoxyphenyl)-(benzo-1,3-dioxol-5-yl)-ethyne,
[0896] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0897] Of the foregoing group, especially preferred for the
treatment of dermatologic conditions are the following
compounds:
[0898] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0899] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[0900] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0901] 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
[0902]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0903]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0904]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0905]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0906]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0907]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0908]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0909]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0910]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0911] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[0912] 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol; and
[0913]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile,
[0914] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0915] Of the foregoing group, most preferred for the treatment of
dermatologic conditions are the following compounds:
[0916] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0917]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0918]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0919]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0920]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0921]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0922]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0923] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
and
[0924]
4-2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl-b-
enzonitrile,
[0925] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0926] With respect to treatment by topical application, e.g., in
the treatment of contact dermatitis, psoriasis, acne, signs of skin
aging or exposure to harmful levels of UV radiation, particularly
preferred are the following compounds:
[0927] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0928] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0929]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0930]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0931]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0932]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0933]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[0934]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[0935]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[0936]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0937] 4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
[0938]
5-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine-2,4-dione;
[0939]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[0940]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0941]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[0942]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0943]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol;
[0944]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[0945]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile; and
[0946]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol.
[0947] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0948] More preferred for treatment by topical application are the
following compounds:
[0949] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0950] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0951]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0952]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0953]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[0954]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[0955]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[0956]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[0957]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile; and
[0958]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol,
[0959] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0960] Most preferred for treatment by topical application are the
following compounds:
[0961] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[0962] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[0963]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[0964]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[0965]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile; and
[0966] 4-{2-[4-(3,7-dim
ethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl-
}-benzonitrile,
[0967] including single stereoisomers, mixtures of stereoisomers,
and the pharmaceutically acceptable salts thereof.
[0968] For example, exposure to sunlight can pose a number of
hazards to the skin. The major short-term hazard of prolonged
exposure to sunlight is erythema, i.e., sunburn, which primarily
results from UVB radiation having a wavelength of from about 290 nm
to about 320 nm. Over the long term, however, such prolonged
exposure can often cause malignant changes in the skin surface to
occur. Epidemiologic studies demonstrate a strong relationship
between sunlight exposure and human skin cancer. Another long-term
hazard of ultraviolet radiation is premature aging of the skin,
which is primarily caused by UVA radiation having a wavelength of
from about 320 nm to about 400 nm. This condition is characterized
by wrinkling and pigment changes of the skin, along with other
physical changes such as cracking, telangiectasis, solar
dermatoses, ecchymoses, and loss of elasticity. Individuals,
particularly those having light-skin who burn easily and tan
poorly, who have had a great deal sun exposure in childhood can
show the following gross cutaneous alterations in later adult life:
wrinkling, leatheriness, yellowing, looseness, roughness, dryness,
mottling (hyperpigmentation) and various premalignant growths
(often subclinical). These cumulative effects of sunlight are often
referred to as "photoaging". Although the anatomical degradation of
the skin is most advanced in the elderly, the destructive effects
of excessive sun exposure are already evident by the second decade.
Serious microscopic alterations of the epidermis and dermis occur
decades before these become clinically visible. Wrinkling,
yellowing, leatheriness and loss of elasticity are very late
changes.
[0969] Other skin conditions that may benefit from the methods of
the present invention include, but are not limited to, diaper rash,
a common form of contact dermatitis and irritation occurring in
infants, as well as adults, who wear diapers. U.S. Pat. No.
6,211,186, incorporated herein by reference, describes possible
etiologies and methods of treating this condition. It is generally
thought that one or more fecal and lipolytic enzymes, as well as
ammonia, bacteria, urine pH, overhydration and Candida albicans may
be involved in the onset of skin irritation and inflammation
associated with diaper rash. It is also likely that physiological
responses of the skin to the irritants, such as production of
cytokines by keratinocytes, contribute to the ensuing appearance of
erythema, papules, scaling and ulceration characteristic of the
condition. In addition, compositions and methods of the present
invention may be useful in treating acne, a skin condition
characterized by a profound inflammatory component.
[0970] The compositions of the present invention are also useful
for regulating skin condition, including visible and/or tactile
discontinuities in skin (especially the skin surface; such
discontinuities are generally undesired). Such discontinuities may
be induced or caused by internal and/or external factors, and
include the signs of skin aging described herein.
[0971] The compositions of the present invention are useful for
regulating signs of skin aging, especially visible and/or tactile
discontinuities in skin texture associated with aging. It is to be
understood that the present invention is not to be limited to
regulation of the "signs of skin aging" that arise due to the
above-mentioned mechanisms associated with skin aging, but is
intended to include regulation of such signs irrespective of their
mechanism of origin.
[0972] Testing
[0973] This section describes how compositions incorporating
compositions of the present invention are selected, using in vitro
and/or in vivo models, and used as therapeutic interventions in
exemplary indications, e.g., stroke, chronic heart failure and
myocardial infarction. Those skilled in the art will appreciate
that safety and efficacy for use as human therapeutics must
typically be demonstrated in randomized, double-blind, placebo- (or
active-) controlled, human clinical trials.
[0974] Insults to the brain that disrupt its blood supply, as in
ischemia, or its oxygen supply, as in hypoxia (low oxygen) or
anoxia (no oxygen), rapidly cause neuronal imbalance leading to
cell death (Flynn, C. J., et al., 1989, in G. Siegel et al., (Eds),
Basic Neurochemistry, Raven Press, NY). Investigations into the
cellular and molecular mechanisms that lead to neuronal damage and
inflammation associated with various types of brain ischemia can be
carried out using in vitro model systems, such as primary cell
cultures, that retain the metabolic characteristics of neurons in
vivo. The use of such cell-based models has led to advances in
identification of biochemical mechanisms leading to neuronal death
in conditions such as anoxia, hypoglycemia, excitotoxicity, and
exposure to reactive oxygen species. Neuronal cell lines such as
the pheochromocytoma cell line, PC12, are also useful models for
studying the effects of oxidative stress on the structure and
function of neuron-specific proteins that are expressed in the cell
lines. As many neuronal cell lines do not express all the
properties of genuine neurons, primary neuronal cultures are now
widely used as in vitro models in which to discern the processes
that occur in intact brain.
[0975] In vitro models of ischemia approximate oxygen and glucose
deprivation that mimic in vivo conditions, for example, by placing
neuronal cultures into large anaerobic or hypoxic chambers and
exchanging culture medium with de-oxygenated and defined ionic
composition media. The toxic overstimulation of neuronal glutamate
receptors, especially N-methyl-D-aspartate (NMDA) receptors,
contributes to hypoxic-ischemic neuronal injury (Choi, D. M., 1988,
Neuron 1: 623-634), ischemic induction of reactive oxygen species
(ROS) (Watson, B. D., et al., 1988, Ann NY Acad. Sci., 59:
269-281), excessive calcium influx (Grotta, J. C., 1988, Stroke 19:
447-454), arachidonic acid increase (Siesjo, B. K., 1981, J. Cereb.
Blood Flow Metab. 1: 155-186) and DNA damage (MacManus, J. P., et
al., 1993, Neurosci. Lett., 164: 89-92), each causing a cascade of
neurodegeneration.
[0976] Primary embryonic hippocampal neuronal cells are widely
recognized as useful in models of neuronal function. The
hippocampus is a source of a relatively homogenous population of
neurons with well-characterized properties typical of central
nervous system (CNS) neurons in general. Pyramidal neurons, the
principal cell type in the hippocampus, have been estimated to
account for 85% to 90% of the total neuronal population (Banker and
Goslin, 1998, Culturing Nerve Cells, 2.sup.nd edition. The MIT
Press, Cambridge, Mass.). The hippocampus also exhibits a
remarkable capacity for activity-dependent changes in synaptic
function, such as long-term potentiation (Hawkins R D, Kandel E R,
Siegelbaum S A. (1993) Learning to modulate transmitter release:
themes and variations in synaptic plasticity [review], Ann. Rev
Neurosci. 16:625-665.).
[0977] In experiments carried out in support of the present
invention according to methods detailed in the Examples,
anoxia/ischemia was induced in primary cultures of hippocampal
neuronal cells, and compounds were tested for their ability to
prevent cell death. Compounds found to have activity in such in
vitro assays are then further tested in one or more animal models
of cerebral ischemia ("stroke"), such as the middle cerebral artery
occlusion (MCAO) model in rats.
[0978] Briefly, primary cultures of hippocampal neurons are used to
test compounds for activity in neuronal protection. Hippocampal
cultures are typically prepared from 18- to 19-day fetal rats. At
this age, the generation of pyramidal neurons, which begins in the
rat at about E15, is essentially complete. The brain tissue at this
stage is relatively easy to dissociate, the meninges are removed
readily, and the number of glial cells still is relatively modest
(Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. (2000)
Metabolic impairment elicits brain cell type-selective changes in
oxidative stress and cell death in culture. J Neurochem
74(1):114-124).
[0979] In order to evaluate the activity of compounds of the
present invention, a test compound is assessed for its ability to
protect cells against one or more standard stressors, including
hypoxia, as detailed in the Examples. In general, desirable
therapeutic compound candidates are effective in this model at
concentrations less than about 10 mM, more preferably at
concentrations, less than about 1 mM and even more preferably, less
than about 100 .mu.M. By effective, it is meant that such compounds
protect at least 20%, preferably 30%, more preferably 40% and even
more preferably 50% or more of the cells tested from
stressor-induced death. By way of example, compounds that are
effective in providing protection over a concentration a range of
about 1 to 1000 .mu.M would be expected to provide neuroprotection
in vivo. Since precise values may vary depending upon the specific
conditions under which the neuroprotective cell assay is carried
out, it is the intent of the present disclosure to provide the
foregoing criteria as guidance in the form of a benchmark against
which to compare subsequently tested compounds, rather than to
provide absolute concentrations at which the compounds of the
present invention are considered to be effective. Typically,
compounds that are found to be neuroprotective in such in vitro
cell systems are then further tested in an in vivo animal model of
neuroprotection, such as the rat middle cerebral artery occlusion
model described below, or other appropriate models such as are well
known in the art.
[0980] Cerebral ischemic insults are modeled in animals by
occluding vessels to, or within, the cranium (Molinari, G. F.,
1986, in H. J. M. Barnett, et al., (Eds) Stroke: Pathophysiology,
Diagnosis and Management, Vol. 1, Churchill Livingstone, NY). The
rat middle cerebral artery occlusion (MCAO) model is one of the
most widely used techniques to induce transient focal cerebral
ischemia approximating cerebral ischemic damage in humans, e.g.,
those who suffer from a stroke (duration of occlusion and time to
treatment in rats can correspond with up to 2 to 5 fold longer
periods in humans). The middle cerebral artery used as the ischemic
trigger in this model is the most affected vessel in human stroke.
The model also entails a period of reperfusion, which typically
occurs in human stroke victims. MCAO involving a two-hour occlusion
has been found to produce the maximum size of cortical infarction
obtainable without increased mortality at twenty-four hours.
[0981] Briefly, a nylon filament is implanted into the right
carotid artery of the rat. To effect occlusion, the rat is
anesthetized, and the filament is advanced into the internal
carotid artery 18-20 mm from the point of bifurcation of internal
and external arteries and a suture is tightly ligated around the
filament for a period of two hours. Two hours post occlusion,
animals are re-anesthetized, and the filament is removed, to allow
reperfusion for the remainder of the experiment. Test drugs can be
administered any time during this process-before, during or after
occlusion, and can be administered by one or more of a variety of
means, including but not limited to intracerebroventriculhr (ICV)
infusion, intravenous (IV) infusion, intraperitoneal (IP)
administration, as well as enteral administration (e.g., gavage).
Animals are maintained normothermic during the experiment, as
described in the Examples. At a pre-determined time following
occlusion and reperfusion, animals are sacrificed and their brains
are removed and processed for assessment of damage as measured by
infarct volume. In general, compounds are considered to have
activity in this model, if they provide a significant reduction in
total infarct volume at a dose that is less than about 10 mg/kg,
preferably less than 1 mg/kg, more preferably less than 100
.mu.g/kg and even more preferably less than about 1 .mu.g/kg, when
administered ICV or IV. By significant reduction of total infarct
volume is meant a reduction of at least 20%, preferably at least
30%, more preferably at least 40%, and even more preferably about
50%, compared to control values.
[0982] Further validation of efficacy in neuroprotection can be
assessed in long term cerebral ischemia (MCAO-7 to 14 days) with
the additional sensory motor outcome relief, functional tests, such
as the grip strength test or the rotorod test. Animals treated with
compounds that show neuroprotection, show a reduction in infarct
size and maintain their pre-MCAO grip strength values after MCAO,
as compared to untreated animals, who showed a significant
reduction in grip strength, indicating loss of sensorimotor
function. Likewise, animals treated with compounds that show
neuroprotection also maintained their pre-MCAO rotorod activity
scores after MCAO, as compared to untreated animals, who showed a
significant reduction in rotorod scores, indicating loss of
sensorimotor function at higher brain levels.
[0983] Similarly, primary cultures of myocytes can be used to test
compounds in vitro for ability to provide protection against heart
damage, resulting for example from myocardial ischemia or
congestive heart failure. Preparation of myocardiocytes from
neonatal rats is described in the Examples. Such cells are
typically used to study molecular models of myocardial ischemia
(Webster, K A, Discher, D J & Bishopric, NH. 1995. J. Mol. Cell
Cardiol. 27:453-458; Camilleri, L, Moins, N, Papon, J, Maublant, J,
Bailly, P, de Riberolles, C & Veyre, A. 1997. Cell Biol. &
Toxicol. 13:435-444; Bielawska, A E, Shapiro, J P, Jiang, L,
Melkonyan, H S, Piot, C, Wolfe, C L, Tomei, L D, Hannun, Y A &
Umansky, SR. 1997. Am. J. Pathol. 151:1257-1263) and are therefore
accepted as indicative of myoprotective activity. Exemplary
stressor assays for this purpose are provided in the Examples. For
example, cardiomyocytes in culture exhibit contractile ("beating")
activity; each cardiomyocyte contraction is associated with a rise
in intracellular calcium termed a "calcium transient". These
calcium transients can be measured using Fluo-4, a fluorescent dye
which exhibits large fluorescence intensity increases upon the
binding of calcium. This assay is cell-based and tests the ability
of potential cytoprotectant molecules to guard against ischemic
damage and allow the cells to maintain their contractile function.
In vivo testing of therapeutic activity can be demonstrated in the
Left Coronary Artery Ligation model of myocardial ischemia Left
Coronary Artery Occlusion model of congestive heart failure (Hill,
M. et al., Circulation, 2414-2420, 1997), respectively, involving
complete blockage over a period of about 30 minutes followed by
reperfusion or partial blockage over a period of several weeks. As
in the MCAO model, duration of occlusion and time to treatment in
rats can correspond with up to 2 to 5 fold longer periods in
humans.
[0984] In vivo evaluation of anti-inflammatory activity can be
determined by well characterized assays measuring
Carrageenan-Induced Paw Edema and by Mouse Ear Inflammatory
Response to Topical Arachidonic Acid. (Gabor, M., Mouse Ear
Inflammation Models and their Pharmacological Applications, 2000.)
Carrageenan-Induced Paw Edema is a model of inflammation, which
causes time-dependent edema formation following carrageenan
administration into the intraplantar surface of a rat paw. The
application of arachidonic acid (AA) to the ears of mice produces
immediate vasodilatation and erythema, followed by the abrupt
development of edema, which is maximal at 40 to 60 min. The onset
of edema coincides with the extravasations of protein and
leukocytes. After one hour the edema wanes rapidly and the
inflammatory cells leave the tissue so that at 6 hours the ears
have returned to near normal. These assays, respectively, measure a
test compounds ability to treat these inflammatory processes via
systemic and topical routes of administration.
[0985] Further validation of compounds can be carried out in a
whole organ assay, such as the isolated heart (Langendorff) model
of cardiac function. Similarly, compounds can be further validated
in additional animal models of disease (e.g., diabetes, renal
failure, asthma, muscle fatigue, inflammation, arthritis), such as
are well known in the art.
[0986] Cytoprotective activity for skin can be evaluated in cell
culture using the Epiderm Skin Model (EPI-100) from the Mattek
Corporation of Ashland, Mass. Cell cultures of neonatal foreskin
are cultured in accordance with the manufacturer's directions, and
are assayed for percent cellular viability by measuring the amount
of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) dye taken up by the cells.
[0987] Administration
[0988] The compounds of Formula I to V and naturally occurring
conjugated phenols are administered at a therapeutically effective
dosage, e.g., a dosage sufficient to provide treatment for the
disease states previously described. Administration of the
compounds of the invention or the pharmaceutically acceptable salts
thereof can be via any of the accepted modes of administration for
agents that serve similar utilities.
[0989] While human dosage levels have yet to be optimized for the
compounds of the invention, generally, a daily dose is from about
0.01 to 15.0 mg/kg of body weight, preferably about 0.1 to 7.5
mg/kg of body weight, and most preferably about 0.3 to 1.5 mg/kg of
body weight. Thus, for administration to a 70 kg person, the dosage
range would be about 0.7 to 1',000 mg per day, preferably about 7.0
to 500 mg per day, and most preferably about 21 to 100 mg per day.
The amount of active compound administered will, of course, be
dependent on the subject and disease state being treated, the
severity of the affliction, the manner and schedule of
administration and the judgment of the prescribing physician.
[0990] The compositions of the present invention are suitable for
providing protection against the harmful effects of ultraviolet
radiation, preferably in personal care products. More preferably,
the compositions of the present invention are suitable for use as
sunscreens to provide protection to human skin from the harmful
effects of UV radiation, which include, but are not limited to,
sunburn and premature aging of the skin. The present invention
therefore also further relates to methods of protecting human skin
from the harmful effects of UV radiation. Such methods generally
involve attenuating or reducing the amount of UV radiation that
reaches the skin's surface. In the case of the present invention,
the methods of treatment for the harmful effects of ultraviolet
radiation also include administration of a composition of the
invention after the exposure to UV radiation has already taken
place. To protect the skin from UV radiation, a safe and effective
(photoprotective) amount of the composition is topically applied to
the skin. "Topical application" refers to application of the
present compositions by spreading, spraying, etc. onto the surface
of the skin. The exact amount applied may vary depending on the
level of UV protection desired. From about 0.5 mg of composition
per square centimeter of skin to about 25 mg of composition per
square centimeter of skin are typically applied.
[0991] Compounds and methods of the invention may be employed in
any skin care application where decreased inflammatory response is
desirable. For example, compounds and compositions of the invention
may be incorporated into leave-on and rinse-off acne preparations,
facial milks and conditioners, shower gels, foaming and non-foaming
facial cleansers, cosmetics, hand and body lotions, leave-on
moisturizers, cosmetic and cleaning wipes, salves for poison ivy,
chicken pox, or pruritis, or the like. Generally, for dermal
applications, topical administration is preferred; however,
systemic administration, as described elsewhere herein, is also
possible.
[0992] Compositions of the present invention may also be used in
cosmetic compositions. Cosmetic compositions of the present
invention are ideally suited for use in treating the skin and lips,
especially in the form of a lipstick or lip balm for applying to
the lips a permanent or semi-permanent color, ideally with a gloss
or luster finish. The cosmetic compositions can also be used in
treating the skin and/or lips with a skin care agent for protection
against exposure to adverse weather, including the wind and rain,
dry and/or hot environments, environmental pollutants (e.g., ozone,
smoke, and the like), or exposure to excessive doses of sunlight.
The compositions are also useful in providing sun protection,
moisturizing and/or conditioning for the hair and skin, improved
skin feel, regulating skin texture, reducing fine lines and
wrinkles, reducing oily shine on hair or skin, skin lightening and
reducing skin or hair odor.
[0993] The cosmetic compositions can accordingly be applied to the
skin and/or lips in the traditional manner with or without a
conventional holder or applicator to provide a decorative and/or
protective film thereto.
[0994] In employing the compounds of this invention for treatment
of the above conditions, any pharmaceutically acceptable mode of
administration can be used. The compounds of Formula I can be
administered either alone or in combination with other
pharmaceutically acceptable excipients, including solid,
semi-solid, liquid or aerosol dosage forms, such as, for example,
tablets, capsules, powders, liquids, suspensions, suppositories,
aerosols or the like. The compounds of Formula I can also be
administered in sustained or controlled release dosage forms,
including depot injections, osmotic pumps, pills, transdermal
(including electrotransport) patches, and the like, for the
prolonged administration of the compound at a predetermined rate,
preferably in unit dosage forms suitable for single administration
of precise dosages. The compositions will typically include a
conventional pharmaceutical carrier or excipient and a compound of
Formula I or a pharmaceutically acceptable salt thereof. In
addition, these compositions may include other medicinal agents,
pharmaceutical agents, carriers, adjuvants, and the like,
including, but not limited to anticoagulants, blood clot
dissolvers, permeability enhancers and slow release
formulations.
[0995] Generally, depending on the intended mode of administration,
the pharmaceutically acceptable composition will contain about 0.1%
to 90%, preferably about 0.5% to 50%, by weight of a compound or
salt of Formula I, the remainder being suitable pharmaceutical
excipients, carriers, etc.
[0996] One preferred manner of administration for the conditions
detailed above is oral, using a convenient daily dosage regimen
which can be adjusted according to the degree of affliction. For
such oral administration, a pharmaceutically acceptable, non-toxic
composition is formed by the incorporation of any of the normally
employed excipients, such as, for example, mannitol, lactose,
starch, magnesium stearate, sodium saccharine, talcum, cellulose,
sodium crosscarmellose, glucose, gelatin, sucrose, magnesium
carbonate, and the like. Such compositions take the form of
solutions, suspensions, tablets, dispersible tablets, pills,
capsules, powders, sustained release formulations and the like.
[0997] Preferably the compositions will take the form of a pill or
tablet and thus the composition will contain, along with the active
ingredient, a diluent such as lactose, sucrose, dicalcium
phosphate, or the like; a lubricant such as magnesium stearate or
the like; and a binder such as starch, gum acacia,
polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof,
and the like.
[0998] Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, etc. an active
compound as defined above and optional pharmaceutical adjuvants in
a carrier, such as, for example, water, saline, aqueous dextrose,
glycerol, glycols, ethanol, and the like, to thereby form a
solution or suspension. If desired, the pharmaceutical composition
to be administered may also contain minor amounts of nontoxic
auxiliary substances such as wetting agents, emulsifying agents, or
solubilizing agents, pH buffering agents and the like, for example,
sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan
monolaurate, triethanolamine acetate, triethanolamine oleate, etc.
Actual methods of preparing such dosage forms are known, or will be
apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 15th Edition, 1975. The composition or formulation to
be administered will, in any event, contain a quantity of the
active compound in an amount effective to alleviate the symptoms of
the subject being treated.
[0999] Dosage forms or compositions containing active ingredient in
the range of 0.005% to 95% with the balance made up from non-toxic
carrier may be prepared.
[1000] For oral administration, a pharmaceutically acceptable
non-toxic composition is formed by the incorporation of any of the
normally employed excipients, such as, for example pharmaceutical
grades of mannitol, lactose, starch, magnesium stearate, talcum,
cellulose derivatives, sodium crosscarmellose, glucose, sucrose,
magnesium carbonate, sodium saccharin, talcum and the like. Such
compositions take the form of solutions, suspensions, tablets,
capsules, powders, sustained release formulations and the like.
Such compositions may contain 0.01%-95% active ingredient,
preferably 0.1-50%.
[1001] For a solid dosage form, the solution or suspension, in for
example propylene carbonate, vegetable oils or triglycerides, is
preferably encapsulated in a gelatin capsule. Such diester
solutions, and the preparation and encapsulation thereof, are
disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
For a liquid dosage form, the solution, e.g. in a polyethylene
glycol, may be diluted with a sufficient quantity of a
pharmaceutically acceptable liquid carrier, e.g. water, to be
easily measured for administration.
[1002] Alternatively, liquid or semi-solid oral formulations may be
prepared by dissolving or dispersing the active compound or salt in
vegetable oils, glycols, triglycerides, propylene glycol esters
(e.g. propylene carbonate) and the like, and encapsulating these
solutions or suspensions in hard or soft gelatin capsule
shells.
[1003] Other useful formulations include those set forth in U.S.
Patents Nos. Re. 28,819 and 4,358,603.
[1004] The formulation can be administered in a single unit dosage
form for continuous treatment or in a single unit dosage form ad
libitum when relief of symptoms is specifically required. For
example, the formulation may be administered as a bolus or as a
continuous intravenous infusion after onset of symptoms of stroke,
myocardial infarction or chronic heart failure.
[1005] Parenteral administration is generally characterized by
injection, either subcutaneously, intramuscularly or intravenously.
Injectables can be prepared in conventional forms, either as liquid
solutions or suspensions, solid forms suitable for solution or
suspension in liquid prior to injection, or as emulsions. Suitable
excipients are, for example, water, saline, dextrose, glycerol,
ethanol or the like. In addition, if desired, the pharmaceutical
compositions to be administered may also contain minor amounts of
non-toxic auxiliary substances such as wetting or emulsifying
agents, pH buffering agents, solubility enhancers, and the like,
such as for example, sodium acetate, sorbitan monolaurate,
triethanolamine oleate, cyclodextrins, etc.
[1006] A more recently devised approach for parenteral
administration employs the implantation of a slow-release or
sustained-release system, such that a constant level of dosage is
maintained. See, e.g., U.S. Pat. No. 3,710,795. The percentage of
active compound contained in such parenteral compositions is highly
dependent on the specific nature thereof, as well as the activity
of the compound and the needs of the subject. However, percentages
of active ingredient of 0.01% to 10% in solution are employable,
and will be higher if the composition is a solid which will be
subsequently diluted to the above percentages. Preferably the
composition will comprise 0.2-2% of the active agent in solution.
Nasal solutions of the active compound alone or in combination with
other pharmaceutically acceptable excipients can also be
administered.
[1007] Formulations of the active compound or a salt may also be
administered to the respiratory tract as an aerosol or solution for
a nebulizer, or as a microfine powder for insufflation, alone or in
combination with an inert carrier such as lactose. In such a case,
the particles of the formulation have diameters of less than 50
microns, preferably less than 10 microns.
[1008] Dermatologic formulations of the present invention typically
comprise a cytoprotective derivative of any of Formulae I to V and
optionally, a polar solvent. Solvents suitable for use in the
formulations of the present invention include any polar solvent
capable of dissolving the cytoprotective derivative. Suitable polar
solvents include: water; alcohols (such as ethanol, propyl alcohol,
isopropyl alcohol, hexanol, and benzyl alcohol); polyols (such as
propylene glycol, polypropylene glycol, butylene glycol, hexylene
glycol, maltitol, sorbitol, and glycerine); and panthenol dissolved
in glycerine, flavor oils and mixtures thereof. Mixtures of these
solvents can also be used. Exemplary polar solvents are polyhydric
alcohols and water. Examples of preferred solvents include
glycerine, panthenol in glycerine, glycols such as propylene glycol
and butylene glycol, polyethylene glycols, water and mixtures
thereof. Additional preferred polar solvents for use are alcohols,
glycerine, panthenol, propylene glycol, butylene glycol, hexylene
glycol and mixtures thereof.
[1009] Typically, the formulations of the present invention will
comprise from about 0.1% to about 80%, preferably from about 0.5%
to about 60%, more preferably from about 1% to about 30% and most
preferably from about 3% to about 18% polar solvent.
[1010] An emollient may also be added to the
cosmetic/dermatological compositions of the present invention. The
emollient component can comprise fats, oils, fatty alcohols, fatty
acids and esters which aid application and adhesion, yield gloss
and most importantly provide occlusive moisturization. Suitable
emollients for use are isostearic acid derivatives, isopropyl
palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil,
octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl
ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl
acetate, phenyl trimethicone, glyceryl oleate, tocopheryl
linoleate, wheat germ glycerides, arachidyl propionate, myristyl
lactate, decyl oleate, propylene glycol ricinoleate, isopropyl
lanolate, pentaerythrityl tetrastearate, neopentylglycol
dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl
isononanoate, isotridecyl isononanoate, myristal myristate,
triisocetyl citrate, cetyl alcohol, octyl dodecanol, oleyl alcohol,
panthenol, lanolin alcohol, linoleic acid, linolenic acid, sucrose
esters of fatty acids, octyl hydroxystearate and mixtures thereof.
Examples of other suitable emollients can be found in the Cosmetic
Bench Reference, pp. 1.19-1.22 (1996), incorporated herein by
reference. Suitable emollients include polar emollient emulsifiers
(such as linear or branched chained polyglycerol esters) and
non-polar emollients. The emollient component typically comprises
from about 1% to about 90%, preferably from about 10% to about 80%,
more preferably from about 20% to about 70%, and most preferably
from about 40% to about 60%, of the cosmetic composition.
[1011] By "polar emollient," as used herein, is meant any emollient
emulsifier having at least one polar moiety and wherein the
solubility (at 30 degrees C.) of the cytoprotective derivative
compound in the polar emollient is greater than about 1.5%,
preferably greater than about 2%, more preferably greater than
about 3%. Suitable polar emollients include, but are not limited
to, polyol ester and polyol ethers such as linear or branched
chained polyglycerol esters and polyglycerol ethers. Nonlimiting
examples of such emollients include PG3 diisosterate,
polyglyceryl-2-sesquiisostearate, polyglyceryl-5-distearate,
polyglyceryl-10-distearate, polyglyceryl-10-diisostearate,
acetylated monoglycerides, glycerol esters, glycerol
tricaprylate/caprate, glyceryl ricinoleate, glyceryl isostearate,
glyceryl myristate, glyceryl linoleate, polyalkylene glycols such
as PEG 600, monoglycerides, 2-monolaurin, sorbitan esters and
mixtures thereof.
[1012] By "non-polar emollient," as used herein, means any
emollient emulsifier possessing no permanent electric moments.
Suitable non-polar emollients include, but are not limited to,
esters and linear or branched chained hydrocarbons. Non-limiting
examples of such emollients isononyl isononanoate, isopropyl
isostearate, octyl hydroxystearate, diisopropyl dimerate, lanolin
oil, octyl palmitate, isopropyl palmitate, pariffins, isoparrifins,
acetylated lanolin, sucrose fatty acid esters, isopropyl myristate,
isopropyl stearate, mineral oil, silicone oils, dimethicone,
allantoin, isohexadecane, isododecane, petrolatum, and mixtures
thereof. The solubility of the conjugated phenol compound in polar
or non-polar emollients is determined according to methods known in
the art.
[1013] Suitable oils include esters, triglycerides, hydrocarbons
and silicones. These can be a single material or a mixture of one
or more materials. They will normally comprise from 0% to about
100%, preferably from about 5% to about 90%, and most preferably
from about 70% to about 90% of the emollient component.
[1014] Oils that act as emollients also impart viscosity,
tackiness, and drag properties to cosmetic compositions such as
lipstick. Examples of suitable oils include caprylic triglycerides;
capric triglyceride; isostearic triglyceride; adipic triglyceride;
propylene glycol myristyl acetate; lanolin; lanolin oil;
polybutene; isopropyl palmitate; isopropyl myristate; isopropyl
isostearate; diethyl sebacate; diisopropyl adipate; tocopheryl
acetate; tocopheryl linoleate; hexadecyl stearate; ethyl lactate;
cetyl oleate; cetyl ricinoleate; oleyl alcohol; hexadecyl alcohol;
octyl hyroxystearate; octyl dodecanol; wheat germ oil; hydrogenated
vegetable oils; castor oil; petrolatum; modified lanolins;
branched-chain hydrocarbons; alcohols and esters; corn oil;
cottonseed oil; olive oil; palm kernel oil; rapeseed oil; safflower
oil; jojoba oil; evening primrose oil; avocado oil mineral oil,
sheabutter, octylpalmitate, maleated soybean oil, glycerol
trioctanoate, diisopropyl dimerate, and volatile and non-volatile
silicone oils including phenyl trimethicone.
[1015] Suitable oils for use herein are acetylglycerides,
octanoates, and decanoates of alcohols and polyalcohols, such as
those of glycol and glycerol, the ricinoleates of alcohols and
polyalcohols such as cetyl ricinoleate, PG-3 diisostearate,
polyglycerol ethers, polyglyerol esters, caprylic triglycerides,
capric triglycerides, isostearic triglyceride, adipic triglyceride,
phenyl trimethicone, lanolin oil, polybutene, isopropyl palmitate,
isopropyl isostearate, cetyl ricinoleate, octyl dodecanol, oleyl
alcohol, hydrogenated vegetable oils, castor oil, modified
lanolins, octyl palmitate, lanolin oil, maleated soybean oil, cetyl
ricinoleate, glyceryl trioctanoate, diisopropyl dimerate, synthetic
lanolin derivatives and branched chain alcohols, sucrose esters of
fatty acids, octyl hydroxystearate and mixtures thereof.
[1016] Preferably, the oils used are selected such that the
majority (at least about 75%, preferably at least about 80% and
most preferably at least about 99%) of the types of oils used have
solubility parameters that do not differ by more than from about 1
to about 0.1, preferably from about 0.8 to about 0.1.
[1017] A surfactant may also be added to compositions of the
invention, in order to confer beneficial cosmetic or application
properties. Surfactants suitable for use are those which can form
emulsions and/or association structures. Surfactant emulsifier can
be from 0% to about 20% of the formulation, preferably from 0% to
about 15% and most preferably from about 1% to about 10%. Examples
of suitable emulsifiers can be found in U.S. Pat. No. 5,085,856 to
Dunphy et al.; and U.S. Pat. No. 5,688,831 to El-Nokaly et al.
Examples of other suitable emulsifiers can be found in Cosmetic
Bench Reference, pp. 1.22, 1.24-1.26 (1996), all of which are
incorporated herein by reference.
[1018] Also useful herein are surfactants that form association
structures, preferably lamellar or hexagonal liquid crystals, at
ambient temperature when mixed with a polar solvent. Ambient
temperature/room temperature as used herein typically means about
20.degree. C. Generally ambient temperature can range from about
18.degree. C. to about 27.degree. C., preferably from about
20.degree. C. to about 25.degree. C., depending on such variables
as geographical location, i.e. sub-tropical vs. temperature
regions. One of ordinary skill in art is readily able to determine
if association structures form at ambient temperatures. The
surfactants suitable for use generally have a Krafft point at or
below about ambient temperature about 20.degree. C. or generally at
or below about 18.degree. C. to about 27.degree. C., preferably at
or below from about 20.degree. C. to about 25.degree. C.
[1019] The definition of Krafft point is well known in the art and
one of ordinary skill in the art can readily determine a
surfactant's Krafft point. In general terms, Krafft point is the
melting point of the hydrocarbon chains of the surfactants. It can
also be expressed as the temperature at which the solubility of an
association colloid in water suddenly increases because critical
micelle concentration is exceeded and micelles form.
[1020] In preparing a sample combination of surfactant and polar
solvent to demonstrate the ability to form association structures,
the surfactant needs to be sufficiently soluble in the polar
solvent such that an association structure can form at ambient
temperature. One of ordinary skill in the art is capable of
determining compatible interactions.
[1021] Any surfactant which forms association structures at ambient
temperature and is suitable for use in cosmetics is suitable for
use herein. Surfactants suitable for use in cosmetics do not
present dermatological or toxicological problems. Anionic
surfactants, nonionic surfactants, cationic surfactants, amphoteric
surfactants and mixtures thereof are suitable for use. Preferably
anionic surfactants, nonionic surfactants, cationic surfactants,
amphoteric surfactants and mixtures thereof having a Krafft point
at or below about ambient temperature are used. More preferably,
nonionic surfactants, cationic surfactants, amphoteric surfactants
and mixtures thereof having a Krafft point at or below about
ambient temperature are used.
[1022] The surfactants can be used at levels from about 4% to about
97%, preferably from about 5% to about 95%, more preferably from
about 20% to about 90% and most preferably from about 30% to about
70% of the association structure.
[1023] The cosmetic compositions of this invention can contain one
or more materials, herein singly or collectively referred to as a
"solidifying agent", that are effective to solidify the particular
liquid base materials to be used in a cosmetic composition. (As
used herein, the term "solidify" refers to the physical and/or
chemical alteration of the liquid base material so as to form a
solid or semi-solid at ambient conditions, i.e., to form a final
composition that has a stable physical structure and can be
deposited on the skin under normal use conditions.) As is
appreciated by those skilled in the art, the selection of the
particular solidifying agent for use in the cosmetic compositions
will depend upon the particular type of composition desired, i.e.,
gel or wax-based, the desired rheology, the liquid base material
used and the other materials to be used in the composition. The
solidifying agent is preferably present at a concentration of from
about 0 to about 90%, more preferably from about 1 to about 50%,
even more preferably from about 5% to about 40%, most preferably
from about 3% to about 20%.
[1024] The wax cosmetic stick embodiments of this invention
preferably contain from about 5% to about 50% (by weight) of a waxy
solidifying agent. By the term "waxy solidifying agent," as used
herein, is meant a solidifying material having wax-like
characteristics. Such waxy materials may also serve as emollients.
Among the waxy materials useful herein are the high melting point
waxes, i.e., having a melting point of from about 65.degree. C. to
about 125.degree. C., such as beeswax, spermaceti, carnauba,
baysberry, candelilla, montan, ozokerite, ceresin, paraffin,
synthetic waxes such as Fisher-Tropsch waxes, microcrystalline wax,
and mixtures thereof. Ceresin, ozokerite, white beeswax, synthetic
waxes, and mixtures thereof, are among those useful herein are
disclosed in U.S. Pat. No. 4,049,792, Elsnau, issued Sep. 20, 1977,
herein incorporated by reference in its entirety). Low melting
waxes, having a melting point of from about 37.degree. C. to about
75.degree. C., are preferred for use in the wax stick embodiments
of this invention. Wax stick embodiments of this invention, which
contain volatile silicone oils as a liquid base material,
preferably contain from about 10% to about 35%, more preferably
from about 10% to about 20% (by weight), of a low-melting wax. Such
materials include fatty acids, fatty alcohols, fatty acid esters
and fatty acid amides, having fatty chains of from about 8 to about
30 carbon atoms, and mixtures thereof. Preferred wax-like materials
include cetyl alcohol, palmitic acid, stearyl alcohol, behenamide,
sucrose esters of tallow fatty acids, mono and di-fatty acid esters
of polyethylene glycol, and mixtures thereof. Stearyl alcohol,
cetyl alcohol, and mixtures thereof, are particularly preferred.
Additional fatty acids, fatty alcohols, and other wax-like
materials useful in this invention are also well known in the
art.
EXAMPLES
[1025] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
[1026] General Characterization Methods
[1027] Nuclear Magnetic Resonance (NMR) spectra were recorded on a
Bruker DTX 300 spectrometer using, in most cases, tetramethyl
silane (TMS) as the internal reference. Mass spectra were obtained
on an Agilent 1100 LC/MSD instrument using either electrospray
ionization (positive or negative mode) (ESI) or atmospheric
pressure chemical ionization (positive or negative mode)
(APCI).
Example 1
Preparation of 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic
Acid Ethyl Ester
[1028] 19
[1029] 1A. (4-Methoxycarbonyl-benzyl)-triphenyl-phosphonium
bromide. A solution of, methyl 4-(bromomethyl)-benzoate (2.29 g, 10
mmol) and triphenylphosphine (2.62 g, 10 mmol) in toluene (40 mL)
was refluxed for 2 hours and then cooled down to room temperature.
The precipitate was filtered and dried under vacuum, giving 4.71 g
(95%) of white solid. 20
[1030] 1B. 3,4-Bis-methoxymethoxy-benzaldehyde. To a solution of
3,4-dihydroxbenzaldehyde (2.76 g, 20 mmol, Adrich) in anhydrous
N,N-dimethylformamide (DMF, 50 mL, Adrich) was added sodium hydride
(1.76 g, 44 mmol, 2.2 eq, 60% in mineral oil, Adrich) portionwise
under nitrogen at 0.degree. C. The reaction mixture was stirred at
room temperature for 30 min. To the dark blue mixture was added
chloromethyl methylether (6.1 mL, 6.44 g, 80 mmol, 4.0 eq, tech,
Adrich) dropwise with an ice-water bath and anhydrous potassium
carbonate (8.29 g, 60 mmol, 3.0 eq). The brown mixture was heated
at 50-55.degree. C. for 3 hours. After the reaction mixture was
cooled down, water was added and extracted with ethyl acetate. The
organic phase was washed with water, separated, dried over
anhydrous magnesium sulfate and chromatographed (silica gel,
hexane-methylene chloride 1:1). This gave a pal-yellow liquid as
the MOM-ether masked benzaldehyde:
3,4-Bis-methoxymethoxy-benzaldehyde (100% yield).
[1031] 1C. 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
ethyl ester. To a mixture of 3,4-bis-methoxymethoxy-benzaldehyde
(100 mmol) and (4-methoxycarbonyl-benzyl)-triphenyl-phosphonium
bromide (100 mmol) in of EtOH (300 mL) at 0.degree. C. was added
slowly of a lithium ethoxide solution (101 mL, 1 M in EtOH). Upon
the completion of the addition, the cold bath was removed and the
reaction was allowed to warm to room temperature. The stirring was
continued for additional 2 h. The solvent was then removed by
rotary evaporation and residue was taken up to 500 mL of EtOAc and
washed with ammonium chloride solution (2.times.100 mL) and water.
The organic layer was dried over Na.sub.2SO.sub.4 and the crude
product was purified on silica (hexane:EtOAc=2:1) to afford a clear
sticky solid (yield 99%). NMR indicated the purified product is a
mixture of cis/trans isomers containing ethyl and methyl esters.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.02 (d, J=0.84, 1.5H),
7.93 (d, J=0.84, 0.5H), 7.91 (s, 0.3H), 7.55 (s, 0.75H), 7.52 (s,
0.75H), 7.38-7.33 (m, 1.25H), 7.17-7.12 (m, 2.25H), 7.03-6.98 (m,
1.25H), 6.84 (m, 0.25H), 6.61-6.52 (m, 0.5H), 5.29-5.05 (m, 4H),
4.41-4.25 (m, 1H), 3.90 (s, 1.5H), 3.56-3.39 (m, 6H), 1.40 (q, J=6
Hz, 1.5H).
[1032] 1D. 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester. By following the procedures of Example 1 C and
substituting the ethanol there used with methanol, the title
compound is obtained without the presence of the corresponding
ethyl ester.
[1033] 1E. Other Compounds of Formula I Similarly, by following the
procedures of Example 1A, 1B and 1C and substituting
4-(bromomethyl)-benzoate and 3,4-dihydroxbenzaldehyde accordingly,
there are obtained:
[1034] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester
[1035] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester
[1036] 4-[(2-Pentafluorophenyl-vinyl)-benzene-1,2-diol
[1037] 4-[2-(4-Trifluoromethyl-phenyl)-vinyl]-benzene-1,2-diol
[1038] 4-[2-(4-Fluoro-phenyl)-vinyl]-benzene-1,2-diol
[1039]
4-(2-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-vinyl)-be-
nzoic acid ethyl ester
[1040] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid decyl
ester
[1041] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid hexyl
ester
[1042] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,7-dienyl ester
[1043] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid
3,7-dimethyl-octa-2,6-dienyl ester
[1044] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester
[1045] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
heptadec-12-enyl ester
[1046] 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid hex-3-enyl
ester
[1047] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
hex-3-enyl ester
[1048]
4-[2-(3-Hydroxy-4-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)--
vinyl]-benzoic acid ethyl ester
[1049] 4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile
[1050] 4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-benzoic acid methyl
ester
[1051] 5-[2-(3,4-Dihydroxy-phenyl)-vinyl]-2-hydroxy-benzoic acid
ethyl ester
[1052] 3-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic acid ethyl ester,
and
[1053] 4-[2-(3,5-Dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[1054] and, the following compounds of Formula I have been
obtained:
[1055] 2-[2-(3,4-Dihydroxy-phenyl)-vinyl]-anthraquinone, .sup.1HNMR
(300 MHz, DMSO) .delta. (ppm) 8.28-7.92 (m, 6H), 7.90-6.47 (m, 5H),
5.74 (s, H). ESI(+)/MS: 343 (M+H).sup.+, 365 (M+Na).sup.+;
[1056] 4-[2-(1H-Benzoimidazol-5-yl)-vinyl]-benzoic acid methyl
ester, .sup.1HMNR (300 MHz, CDCL.sub.3) .delta. (ppm) 8.04-7.98 (m,
2H), 7.87-7.84 (d, J=8.43, H), 7.64-7.34 (m, 3H), 7.33-7.12 (m,
2H), 6.86-6.82 (q, H), 3.93-3.82 (m, 3H);
[1057] 4-[2-(6-Nitro-benzo[1,3]dioxol-5-yl)-vinyl]-benzoic acid
methyl ester, .sup.1HMNR (300 MHz, CDCL.sub.3) .delta. (ppm)
8.06-7.86 (dd, J=8.4, 2H), 7.78-7.59 (m, 2H), 7.16-7.12 (m, H),
6.99-6.71 (dd, J=12, H), 6.51-6.07 (m, 2H), 3.93-3.89 (d, J=12.6,
2H), 1.56 (s, 3H);
[1058]
4-[2-(3-Iodo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester, .sup.1H NMR (300 MHz CDCl.sub.3) .delta. (ppm)
7.90-8.02 (dd, J=8.52H), 7.50-7.55 (m, H), 7.26-7.34 (m, 2H),
7.0-7.02 (m, H), 6.53-6.68 (m, 2H), 5.13-5.18 (d, 2H), 3.50-3.90
(m, 9H). ESI(+)/MS: 477 (M+Na).sup.+;
[1059] 4-[2-(4-Hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester, .sup.1H NMR (300 MHz CDCl.sub.3) .delta. (ppm)
7.91-8.03 (dd, J=8.42H), 7.47-7.53 (m, 2H), 7.32-7.35 (m, H),
6.98-7.02 (m, 2H), 6.53-6.64 (d, H), 3.49-3.94 (m, 6H), ESI(+)/MS:
411 (M+H).sup.+, 433 (M+Na).sup.+;
[1060] 3,4-Bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester, .sup.1H NMR (300 MHz CD.sub.3OD) .delta. (ppm) 6.49-8.26 (m,
13H), 4.26-4.46 (m, H), 3.80-3.90 (m, 3H), ESI(+)/MS: 405
(M+H).sup.+; and
[1061] 4-[2-(5-Bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester, .sup.1H NMR (300 MHz CDCl3) .delta. (ppm),
7.99-7.87 (dd, J=8.5, 2H), 7.31-7.28 (d, J=8.4, 2H), 6.88-6.83 (m,
2H), 6.80 (s, 2H), 5.8 (s, H), 3.90-3.85 (m, 6H). ESI(+)/MS: 364
(M+H).sup.+, 386 (M+Na).sup.+.
Example 2
Preparation of 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic Acid
Ethyl Ester
[1062] 21
[1063] 2A. To a solution of
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-be- nzoic acid ethyl
ester (1.0 mmol) of 3 in MeOH (100 mL) at room temperature was
added slowly 15 drops of a concentrated HCl solution. The resulting
solution was stirred for 12 h. The solvent was then evaporated
under reduced pressure and the residue was chromatographed (hexane:
EtOAc=1:1) to afford the product as a yellow solid (yield 90%). NMR
indicated the purified product contains cis/trans isomers and both
ethyl and methyl esters. .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.
7.98 (d, J=8.4 Hz, 1.82H), 7.87(d, J=8.4 Hz, 0.18H), 7.54 (d, J=8.4
Hz, 1.82H), 7.37 (d, J=8.4 Hz, 0.18H), 7.16-6.92 (m, 4H), 6.81 (m,
1H), 4.41-4.35 (m, 1.9H), 3.92 (m, 0.5H), 1.41 (m, 2.8H).
[1064] 2B. Other Compounds of Formula I Similarly, by following the
procedures of Example 2A, there are obtained:
[1065]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester, .sup.1HMNR (300 MHz, CDCL.sub.3)
.delta. (ppm) 8.03-7.88 (dd, J=8.5, 2H), 7.55-7.31 (d, J=8.3, 2H),
7.14-6.92 (m, 2H), 6.77 (s, 2H), 6.62-6.53 (q, 1H), 4.22-4.14 (m,
3H), 3.92-3.87 (m, 8H), 3.75-3.68 (m, 4H), 3.66-3.64 (m, 10),
3.56-3.54 (m, 4H), 3.37 (s, 6H);
[1066]
2-[2-(2-{2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-5-[2-(4-nitro-p-
henyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethanol, .sup.1HMNR (300
MHz, CDCL.sub.3) .delta. (ppm) 8.14-8.00 (dd, J=8.9, 2H) 7.55-7.33
(dd, J=8.9, 2H) 7.18-6.86 (m, 1H), 6.86-6.44 (m, 4H), 4.24-4.10 (m,
3H) 3.89-3.72 (m, 4H), 3.68-3.54 (m, 20H). ESI(+)/MS: 522
(M+H).sup.+, 545 (M+Na).sup.+;
[1067]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid tetradecyl ester, .sup.1HMNR (300 MHz, CD.sub.3OH)
.delta. (ppm) 7.97-7.95 (d, J=6.0, 2H) 7.62-7.60 (d, J=5.1, 2H)
7.35-6.96 (m, 5H) 4.29-4.34 (m, 6H) 3.99-3.88 (m, 4H), 3.88-3.74
(m, 4H), 3.67-3.45 (m, 8), 3.45-3.32 (m, 4H), 1.19-1.76 (m, 2H),
1.52-1.27 (m, 23H), 0.88-0.86 (m, 3H). ESI(+)/MS: 717 (M+H).sup.+,
739 (M+Na).sup.+;
[1068]
4-[2-(3,4-Bis-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester,
.sup.1HMNR (300 MHz, CD.sub.3OH) .delta. (ppm) 8.00-7.97 (dd, 2H)
7.62-7.60 (d, 2H) 7.26-6.97 (m, 5H) 4.35-4.32 (m, 4H) 4.27-4.15 (m,
4H), 3.87-3.76 (m, 6H), 3.75-3.67 (m, 21), 3.08-3.07 (m, 2H).
ESI(+)/MS: 653 (M+H).sup.+; and
[1069]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-benzamide, .sup.1HMNR
(300 MHz, CDCL.sub.3) .delta. (ppm) 7.99-7.96 (d, J=7.6, 2H),
7.51-7.49 (d, J=7.9, 2H), 7.12-7.02 (m, 3H), 6.95-6.86 (m, 2H),
4.42-4.37 (s, 2H), 4.22-4.18 (m, 4H), 3.88-3.77 (m, 4H), 3.76-3.75
(m, 4H), 3.70-3.67 (m, 12H), 3.57-3.55 (m, 5H), 3.39-3.37 (m, 7H),
3.18 (bs, 6H). ESI(+)/MS: 651 (M+H).sup.+, 674 (M+Na).sup.+.
Example 3
Preparation of
4-[2-(3,4-Dimethoxymethoxy-phenyl)-vinyl]-nitrobenzene
[1070] 22
[1071] 3A. To a solution of (4-nitrobenzyl)-triphenyl-phosphonium
bromide (725 mg, 1.51 mmol, prepared in 97% yield in a similar way
as described in Example 1) and 3,4-bis-methoxymethoxy-benzaldehyde
(299 mg, 1.38 mmol) in ethanol (20 mL) was added lithium ethoxide
(1.45 mL, 1.45 mmol, 1 M in tetrahydrofuran) at room temperature
over 4 hours. The resulting solution was stirred at room
temperature overnight. The solvent was removed under reduced
pressure and the residues were chromatographed (silica gel,
methylene chloride), affording an orange-red product (214 mg, 41%).
.sup.1H-NMR (300 Hz, D.sub.3CCl) .delta. (ppm) 8.25-8.05 (m, 2H),
7.65-6.95 (m, 5H), 6.85-6.50 (m, 2H), 5.31 (s, CH.sub.2, 40%), 5.28
(s, CH.sub.2, 40%), 5.23 (s, CH.sub.2, 60%), 5.05 (s, CH2, 60%),
3.56 (s, CH.sub.3, 40%), 3.53 (s, CH.sub.3, 40%), 3.51 (s,
CH.sub.3, 60%), 3.38 (s, CH.sub.3, 60%).
[1072] B. Other Compounds of Formula I Similarly, by following the
procedures of Example 3A, there are obtained:
[1073]
2-Methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-phenyl)-vinyl]-benzene,
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.21-8.18 (d,
J=8.8 Hz, 1H), 8.09-8.06 (d, J=8.9 Hz, 1H), 7.61-7.58 (d, J=8.8 Hz,
1H), 7.42-7.39 (d, J=8.8 Hz, 1H), 7.26-7.05 (m, 2H), 6.87 (s, 1H),
6.71-6.67 (d, J=12.2 Hz, 0.5H) 6.53-6.49 (d, J=12.2 Hz, 0.5H);
4.99-4.96 (d, J=8.1, 2H), 3.62-3.61 (d, J=4.2, 3H), 2.33, 2.20 (2
s, combined 6H), MS(ESI) m/z: 314 (M+H.sup.+, 80), 336 (M+Na.sup.+,
100);
[1074] 2-Methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester, .sup.1HMNR (300 MHz, CDCL.sub.3) .delta. (ppm)
8.26-8.11 (dd, J=8.7, 2H), 7.72-7.40 (m, 3H), 7.31-7.07 (m, 3H),
6.73-6.61 (q, H), 5.53-5.27 (m, 4H), 3.96-3.31 (m, 6H), ESI(+)/MS:
386 (M+Na).sup.+;
[1075]
1,2-Bis-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benze-
ne, .sup.1HMNR (300 MHz, CD.sub.3OH) .delta. (ppm) 8.24-8.16 (m,
2H), 7.54-7.50 (m, 2H), 7.26-7.17 (m, 4H), 6.98-6.48 (m, 3H),
5.30-5.23 (m, 4H), 3.55-3.50 (m, 6H), ESI(+)/MS: 394
(M+Na).sup.+;
[1076] 2-Iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol,
.sup.1H NMR (300 MHz CDCl.sub.3) .delta. 7.43-7.61 (m, 4H),
6.95-7.14 (m, 3H), 6.52-6.63 (m, H), 3.64-3.97 (m, 3H);
[1077] 2,6-Di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol,
.sup.1HMNR (300 MHz, CDCL.sub.3) .delta. (ppm) 8.24-8.17 (d, J=8.7,
2H), 7.65-7.62 (d, J=8.6, 2H), 7.41 (s, 2H), 7.28-6.93 (dd, 2H),
1.57-1.51 (m, 18H), ESI(+)/MS: 354 (M+H).sup.+;
[1078] 2-Bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol,
.sup.1H NMR (300 MHz CD.sub.3OD) .delta. (ppm) 8.04-8.00 (d, J=9.3,
2H), 7.30-7.27 (d, J=9.4, 2H), 6.80-6.77 (d, J=12.0, H), 6.67-6.59
(m, 3H), 6.06 (s, H), 3.88 (s, 3H), ESI(+)/MS: 351 (M+H).sup.+, 431
(M+Na).sup.+;
[1079] 4-Bromo-5-methoxy-2-[2-(4-nitro-phenyl)-vinyl]-phenol,
.sup.1H NMR (300 MHz CD.sub.3OD) .delta. (ppm) 8.10-8.07 (d, J=8.8,
2H), 7.40-7.36 (d, J=8.8, 2H), 6.93-6.66 (m, 3H), 5.80 (s, H), 3.92
(s, 3H), ESI(+)/MS: 351 (M+H), 373 (M+Na).sup.+;
[1080] 3-(3,4-Bis-methoxymethoxy-benzylidene)-3H-benzofuran-2-onel
ESI(+)/MS: 465 (M+Na).sup.+;
[1081] 3-(3,4-Dihydroxy-benzylidene)-5-hydroxy-3H-benzofuran-2-one,
.sup.1H NMR (300 MHz CDCl.sub.3) d 8.56-7.79 (m, H), 7.58-7.22 (m,
4H), 7.04-6.70 (m, 2H), 5.33 (s, 2H), 5.21-5.20 (s, H), 4.01-3.55
(m, 6H), 1.83-1.60 (m, 8H), ESI(+)/MS: 413 (M+H).sup.+, 435
(M+Na).sup.+; and
[1082] 3-(3,5-Bis-methoxymethoxy-benzylidene)-3H-benzofuran-2-one.
.sup.1H NMR (300 MHz CDCl.sub.3) .delta. 7.83-7.76 (m, H),
7.59-7.51 (m, H), 7.43-6.95 (m, 5H), 6.83-6.82 (m, H), 5.19 (d,
4H), 3.50 (s, 6H), ESI(+)/MS: 343 (M+H).sup.+, 365
(M+Na).sup.+.
Example 4
Preparation of 4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2-diol
[1083] 4A. A solution of
4-[2-(3,4-Dimethoxymethoxy-phenyl)-vinyl]-nitrobe- nzene (100 mg)
in ethanol (20 mL) was added 5 drops of concentrated hydrochloric
acid water solution. The resulting solution was stirred at room
temperature for two days. Solvents were removed under reduced
pressure. The residue was dissolved in methylene chloride and
washed with water. The water phase was adjusted to pH 6-7. Organic
phase was separated and dried over magnesium sulfate. Evaporation
off solvents gave the title compound (which can also be named
4-[2-(3,4-Dihydroxy-phenyl)-v- inyl]-nitrobenezene) a dark-brown
solid (60 mg, 81%). .sup.1H-NMR (300 Hz, D.sub.3CCl) .delta. ppm)
8.10-7.90 (m, 2H), 7.50-7.25 (m, 2H), 7.10-6.25 (m, 5H).
[1084] 4B. Other Compounds of Formula I Similarly, by following the
procedures of Example 4A and substituting
4-[2-(3,4-dimethoxymethoxy-phen- yl)-vinyl]-nitrobenzene
accordingly, there are obtained:
[1085] 4-[2-(3,4,5-Trimethoxy-phenyl)-vinyl]-nitrobenezene
[1086] 2-Methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol, and
[1087] 5[2-(4-Nitro-phenyl)-vinyl]benzene-1,3-diol;
[1088] and, the following compounds of Formula I have been
obtained:
[1089] 1-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-ethanone
oxime, .sup.1H NMR (MeOD, 300 MHz) .delta. (ppm): 7.72 (m, 3H),
7.18 (m, 6H). MS (ESI) m/z: 295 (M+H.sup.+);
[1090]
5-{2-[4-Hydroxy-3-(3-methyl-but-2-enyl)-phenyl]-vinyl}-2-(3-methyl--
but-2-enyl)-benzene-1,3-diol, .sup.1H NMR (CDCl3, 300 MHz) .delta.
(ppm): 7.23 (s, 2H), 6.96 (d, J=16.3, 1H), 6.80 (m, 2H), 6.55 (d,
2H), 5.32 (t, 1H), 5.27 (t, 1H), 5.19 (s, 1H), 5.12 (s, 2H), 3.43
(d, J=7.1, 2H), 3.38 (d, J=7.3, 2H), 1.77 (m, 12H) ppm, MS (ESI)
m/z: 364 (M+H.sup.+);
[1091]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-2,6-dimethoxy-phenol, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm): 6.93 (d, J=16.2, 1H), 6.80 (d, J=16.1, 1H), 6.71 (s, 2H),
6.54 (s, 2H), 5.60 (s, 1H), 5.30 (s, 2H), 5.28 (t, 1H), 3.93 (s,
6H), 3.44 (d, J=6.98, 2H), 1.83 (s, 3H), 1.76 (m, 3H), MS (ESI)
m/z: 357 (M+H), 379 (M+Na);
[1092]
5-[2-(4-Hydroxy-3-methoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-but-2--
enyl)-benzene-1,3-diol, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm): 7.58 (d, J=1.65, 2H), 7.04 (d, J=1.83, 2H), 6.54 (d, J=16.1,
1H), 6.44 (d, J=16.2, 1H), 6.46 (s, 2H), 5.27 (t, 1H), 3.66 (s,
3H), 3.40 (d, J=3.5, 2H), 1.81 (s, 3H), 1.76 (s, 3H), MS (ESI) m/z:
372 (M+H), 394 (M+Na);
[1093]
5-[2-(4-Hydroxy-3-nitro-phenyl)-vinyl]-2-(3-methyl-but-2-enyl)-benz-
ene-1,3-diol, .sup.1H N MR (CDCl.sub.3, 300 MHz) .delta. (ppm):
8.20 (d, J=2.18, 1H), 8.04 (d, J=2.0, 1H), 7.80 (m, 1H), 7.54 (m,
1H), 7.22 (d, J=8.74, 1H), 7.05 (d, J=8.72, 1H), 6.95 (s, 2H), 6.61
(s, 2H), 6.59 (d, J=12.25, 1H), 6.50 (d, J=12.12, 1H), 6.31 (s,
2H), 5.27 (t, 2H), 5.25 (s, 2H), 5.14 (s, 2H), 3.646 (s, 4H),
1.87(m, 12H), MS (ESI) m/z: 342 (M+H);
[1094] 2-Chloro-4-[2-(4-nitro-phenyl)-vinyl]-phenol, .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm): 8.26 (d, J=8.87, 2H), 7.64 (d,
J=8.78, 2H), 7.57 (d, J=2.07, 1H), 7.31 (d, J=8.30, 1H), 7.15 (d,
J=12.20, 1H), 7.06 (t, 2H), 5.69 (s, 1H), MS (ESI) m/z: 276
(M+H);
[1095] Z-4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2,3-triol, .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.13 (d, J=8.82, 2H), 7.54
(d, J=8.7, 2H), 6.86 (d, J=12.2, 1H), 6.74 (d, J=12.2, 1H), 6.64
(d, J=8.5, 1H), 6.48 (d, J=8.4, 1H), 5.29 (m, 3H), MS (ESI) m/z:
275 (M+H);
[1096] E-4-[2-(4-Nitro-phenyl)-vinyl]-benzene-1,2,3-triol, .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.35 (d, J=8.82, 2H), 7.64
(d, J=8.7, 2H), 7.49 (d, J=16.2, 1H), 7.17 (d, J=16.2, 1H), 7.04
(d, J=12.09, 1H), 6.50 (d, J=8.6, 2H), 5.72 (s, 1H), 5.30 (s, 1H),
5.22 (s, 1H);
[1097] 2-Methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol,
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.20-8.18 (d,
J=8.9, 2H), 7.55-7.52 (d, J=8.9, 2H), 7.10-6.63 (m, 7H), 5.73 (s,
1H), 3.95 (s, 3H), MS(ESI) m/z: 298 (M+H.sup.+, 100);
[1098] 3-[2-(3,4-Dimethoxy-phenyl)-vinyl]-4-nitro-phenol,
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.12-8.15 (d,
J=9.0 Hz, 0.4H), 8.05-8.02 (d, J=9.0 Hz, 0.6H), 7.61-7.56 (d,
J=16.0 Hz, 0.6H), 7.12-6.55 (m, 6.3H), 3.98-3.59 (4 s, combined
6H), MS(ESI) m/z: 302 (M+H.sup.+, 25), 319 (M-H.sub.2O, 20), 346
(MOM-M+H.sup.+);
[1099] 4-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester, .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm):
8.03-8.00 (d, J=8.0 Hz, 2H), 7.53-7.50 (d, J=8.0 Hz, 2H), 7.18-6.93
(m, 4H), 5.15 (s, 1H), 3.93 (s, 3H), 2.29, 2.16 (2 s, combined 6H),
very small amounts of cis isomer, MS(ESI) m/z: 283 (M+H.sup.+,
100);
[1100] 2,6-Dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol,
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 8.21-8.18 (d,
J=8.8 Hz, 2H), 7.59-7.56 (d, J=8.8 Hz, 2H), 7.26-6.95 (m, 4H), 4.84
(s, 1H), 2.29 (s, 6H), very small amounts of cis isomer, MS(ESI)
m/z: 270 (M+H.sup.+, 100);
[1101] 2-Hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid,
.sup.1HMNR (300 MHz, CD.sub.3OH) .delta. (ppm) 8.19-8.04 (m, 2H),
7.79-7.59 (m, 2H), 7.51-7.30 (m, 2H), 7.17-7.09 (m, H), 6.76-6.52
(m, 2H), ESI(+)/MS: 286 (M+H).sup.+;
[1102] 4-[4-(4-Nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol,
.sup.1HMNR (300 MHz, CDCL.sub.3) .delta. (ppm) 8.27-8.08 (m, 2H),
7.71-7.49 (m, 2H), 6.94-6.57 (m, 7H), ESI(+)/MS: 284 (M+H).sup.+,
306 (M+Na).sup.+;
[1103] 3-(3,4-Dihydroxy-benzylidene)-3H-benzofuran-2-one, .sup.1H
NMR (300 MHz CD3OD) d 8.12-7.40 (m, H), 7.21-6.98 (m, 2H),
6.95-6.75 (m, 3H), ESI(+)/MS: 271 (M+H).sup.+, 293
(M+Na).sup.+;
[1104]
5-Hydroxy-3-(4-hydroxy-3-methoxy-benzylidene)-3H-benzofuran-2-one,
.sup.1H NMR (300 MHz CD3OD) d 8.51-7.70 (m, H), 7.58-7.26 (m, 3H),
7.01-6.74 (m, 3H), 3.95-3.91 (s, 3H), ESI(+)/MS: 285 (M+H)+, 307
(M+Na).sup.+; and
[1105] 3-(3,5-Dihydroxy-benzylidene)-3H-benzofuran-2-one, .sup.1H
NMR (300 MHz CD3OD) d 7.91-7.87 (d, H), 7.70 (s, H), 7.43-7.3 (m,
H), 7.25-7.12 (m, 2H), 6.64 (s, 2H), 6.41-6.39 (m, H), ESI(+)/MS:
255 (M+H)+, 277 (M+Na).sup.+.
Example 5
Preparation of
10-(3,4-Dihydroxy-benzylidene)-10H-anthracen-9-one
[1106] 23
[1107] A solution of anthrone (194 mg, 1.0 mmol),
3,4-dihydroxybenzadehyde (138 mg, 1.0 mmol) and camphorsulfonic
acid (232 mg, 1.0 mmol) in toluene (5 mL) was refluxed overnight.
The solvents were removed under reduced pressure and the residues
were chromatographed (silica gel, hexane-ethyl acetate 90:10 to
80:20), resulted in 50 mg of product. .sup.1H-NMR (300 Hz,
D.sub.3COD) .delta. (ppm) 4.30-4.20 (m, 2H), 3.51 (br. s, 2H), 1.30
(t, J=7.1 Hz, 3H). .sup.13C-NMR (75 Hz, Cl.sub.3CD) .delta. (ppm)
184.7, 146.7, 146.1,141.7,137.5, 135.3,133.7, 133.2,131.8,131.4,
130.2,129.7,129.6, 129.1, 128.3, 127.4, 127.2, 124.3, 122.8, 117.1,
116.4. MS (ESI) m/z 315 (M+1, 100).
Example 6
Preparation of
10-(3,4-Dihydroxy-benzylidene)-1,8-dihydroxy-10H-anthracen--
9-one
[1108] 24
[1109] A solution of dithranol (452 mg, 2.0 mmol),
3,4-dihydroxybenzadehyd- e (276 mg, 2.0 mmol), and camphorsulfonic
acid (464 mg, 2.0 mmol) in 10 mL toluene was refluxed overnight The
solvents were removed under reduced pressure and the residues were
chromatographed (silica gel, methylene chloride-methanol 1:0 to
100:1 to 100:2), yielded 190 mg of product (28%). .sup.1H-NMR (300
Hz, D.sub.3CCl) .delta. ppm) 7.47 (t, J=8.0 Hz, 1H), 7.40-7.30 (m,
2H), 7.27-7.10 (m, 2H), 6.95-6.75 (m, 2H), 6.75-6.60 (m, 3H).
.sup.13C-NMR (75 Hz, Cl.sub.3CD) .delta. (ppm) 192.8, 162.0, 161.5,
145.1, 144.5, 142.7, 137.8, 136.8,136.8, 136.0, 134.4,129.2,128.7,
121.9, 121.0,116.3,115.8,115.7,115.3, 114.6,114.0. MS (APCI) m/z
347 (M+1, 100).
Example 7
Preparation of 4-(2-Nitro-vinyl)-benzene-1,2-diol
[1110] 25
[1111] A mixture of aldehyde (500 mg) and ammonium acetate (180 mg)
in nitromethane (11 mL) was stirred at 110.degree. C. for 1 h.
After cooling to room temperature, the mixture was poured into
water and extracted with EtOAc. The EtOAc phase was washed with
water and brine and then dried over MgSO.sub.4. Removal of solvents
under reduced pressure gave an orange solid (530 mg). Further
purification by silica gel column eluting with dichloromethane:
EtOAc: MeOH (70:30:2) afforded 520 mg of orange solid. .sup.1H-NMR
(300 MHz, acetone-d with D.sub.2O) .delta. (ppm) 7.93 (d, J=13.5
Hz, 1H), 7.74 (d, J=13.5 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.15 (dd,
J=8.1, 2.0 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H). .sup.13C-NMR (75 MHz,
acetone-d) .delta. (ppm) 150.06,146.14, 139.88, 135.39, 124.20,
122.88, 116.25, 115.98.
Example 8
Preparation of
4-{2-[4-(2-Nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol
[1112] 26
[1113] To a solution of
(3,4-bis-methoxymethoxy-benzyl)-triphenyl-phosphon- ium bromide
(720 mg) and 4-diethoxymethyl-benzaldehyd (308 mg) in EtOH (20 mL)
was added EtOLi (1M in EtOH solution, 2 mL) slowly over a period of
1 h. After stirring overnight, the solution was diluted with ethyl
acetate and washed with water and brine, dried over MgSO.sub.4 and
then concentrated. The residue was dissolved in MeOH (20 mL) and
conc. HCl (10 drops) was added. The solution was stirred at room
temperature overnight. The low boiling point materials were
stripped off and the residue was purified by silica gel column
eluting with 40% EtOAc in hexane to give 190 mg of yellow solid
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzaldehyde which was a mixture
of cis and trans isomers. This intermediate (180 mg) and
NH.sub.4OAc (100 mg) were dissolve in nitromethane (10 mL). Then
the mixture was stirred at 110.degree. C. for 1 h. The solution was
diluted with ethyl acetate and washed with water and brine, dried
over MgSO.sub.4, and then concentrated. The residue was purified
using silica gel column eluting with 5% MeOH in dichloromethane to
give a product as a red solid (126 mg). .sup.1H-NMR (300 MHz,
MeOD-d.sub.4) .delta. (ppm) 8.03 (d, J=13.6 Hz, 1H), 7.86 (d,
J=13.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H),
7.15 (d, J=16.3 Hz, 1H), 7.04 (d, J=1.9 Hz, 1H), 6.94-6.87 (m, 2H),
6.77 (d, J=8.2 Hz, 1H). .sup.13C-NMR (75 MHz, methonal-d.sub.4)
.delta. (ppm) 145.51, 144.80, 141.50, 138.02, 135.92, 130.81,
129.18, 128.70, 128.23, 126.05, 123.60, 119.14, 114.68, 112.34.
Example 9
Preparation of
1-Carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridini- um
Bromide
[1114] 27
[1115] 9A. A mixture of MOM-conjugated pyridine (150 mg) and
tert-butyl bromoacetate (250 microliter) in 1,4-dioxane (10 mL) was
stirred 90-110.degree. C. overnight. The initial colorless solution
was turned into brown. And an orange solid was precipitated out.
The dioxane was stripped off and the solid was washed with ether
extensively. This orange solid was directly used in next step. To a
solution of the orange solid and in MeOH-water (18:2 mL) a conc.
HBr (48% aqueous solution, 10 drops) was added and the solution was
stirred at room temperature overnight. The MeOH was stripped off
and the remaining solid was washed with ether, ethyl acetate, and
dichloromethane and dried under vacuum to give a brown solid (108
mg). .sup.1H-NMR (300 MHz, acetone-d.sub.6 with D2O) .delta. (ppm)
8.70-8.50 (m, 2H), 8.05-7.80 (m, 2H), 7.75-7.50 (m, 1H), 7.20-6.50
(m, 3H), 5.52 and 5.46 (2s, combined 2H). .sup.13CNMR (75 MHz,
acetone-d.sub.6 with D.sub.2O) .delta. (ppm) 165.63, 165.14,
151.82, 144.70, 141.69, 141.53, 139.20, 126.03, 124.49, 120.00,
119.88, 116.80, 112.99, 111.53, 56.52, 50.59.
[1116] 9B. Other Compounds of Formula I Similarly, by following the
procedures of Example 9A and substituting MOM-conjugated pyridine
accordingly, there are obtained:
[1117] 1-Benzyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide, and
[1118]
1-(2-Carboxy-2-oxo-ethyl)-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridi-
nium; bromide.
Example 10
Preparation of
{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-phosphonic Acid
Diisopropyl Ester
[1119] 28
[1120] To a solution of 3,4-dimethoxymethoxy-benzaldehyde (500 mg)
and phosphonate (1.10 g) in THF (50 mL) was added NaH (60% oil
suspension, 170 mg) and the mixture was stirred at 70.degree. C.
for 2 h. To this mixture was then added a small amount of MeOH and
50 mL of EtOAc. Washed with water and brine, dried over MgSO.sub.4,
the EtOAc phase was concentrated. The residue was purified using a
SiO2 column, eluting with 2-5% MeOH in CH.sub.2Cl.sub.2, leading to
the MOMO-phosphonate compound as a clear oil. The intermediate (500
mg) was dissolved in MeOH (30 mL) and conc. HCl (10 drops) was
added. The solution was stirred at room temperature overnight, then
MeOH was evaporated. The residue was dissolved in EtOAc and washed
with water and brine, dried over MgSO.sub.4. After the EtOAc layer
was concentrated, the residue was purified using SiO.sub.2 column,
eluting with 2-5% MeOH in CH.sub.2Cl.sub.2. A glass solid product
(about 340 mg) was obtained. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. (ppm) 7.80 (m, 2H), 7.48(m, 2H), 7.16-6.70(m, 5H), 4.70(m,
2H), 1.38, 1.26(2d, J=6.2 Hz, 12H). .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta. (ppm) 145.39, 144.25, 141.83, 141.79, 131.65,
131.51, 128.63, 127.30, 125.86, 125.65, 124.73, 123.89, 119.73,
114.53, 112.44, 71.33, 71.25, 23.62, 23.56, 23.43, 23.37 ppm.
.sup.3PNMR (121 MHz, CDCl.sub.3) .delta. (ppm) 17.18(s).
Example 11
Preparation of
5-(3,4-Dihydroxy-benzylidene)-thiazolidine-2,4-dione
[1121] 29
[1122] 11A. A mixture of 3,4-Bis-methoxymethoxy-benzaldehyde (5
mmol), thiazolidine-2,4-dione (5 mmol), benzoic acid (0.5 mmol),
and piperidine (0.5 mmol) in toluene (150 mL) was heated to reflux
for 15 h. Upon cooling, to the reaction mixture was added hexane
(50 mL). The resulting suspension was gently stirred for 2 min and
then allowed to settle. It was then filtrated and the solid was
washed with cold benzene.
5-(3,4-Bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione was
obtained as a yellow solid (yield 92%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. (ppm) 7.81 (s, 1H), 7.38 (d, J=2.0 Hz, 1H),
7.28-7.25(m, 1H), 7.18-7.15 (m, 1H), 5.32 (s, 2H), 5.63 (s, 2H),
3.57 (s, 3H), 3.54 (s, 3H). .sup.13C-NMR (75 MHz) .delta. (ppm)
168.1, 167.6, 149.8, 147.9, 134.6, 127.7, 126.1, 121.0, 118.8,
116.8, 96.0, 95.5, 56.9, 56.8.
[1123] 5-(3,4-Dihydroxy-benzylidene)-thiazolidine-2,4-dione was
prepared from
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione after
treatment with HCl as described for synthesis of Example 2.
.sup.1H-NMR (300 MHz, CD.sub.3OD) .delta. (ppm) 7.65 (s, 1H),
7.01-6.93 (m, 2H), 6.88-6.85 (m, 1H).
[1124] 11 B. Other Compounds of Formula II Similarly, by following
the procedures of Example 11A, there are obtained:
[1125]
5-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzylidene]-thia-
zolidine-2,4-dione, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm): 8.43 (s, 1H), 7.79 (s, 1H), 6.97 (s, 2H), 5.23 (s, 4H), 5.14
(t, 1H), 3.50 (s, 6H), 3.42 (d, J=7.1, 2H), 1.79 (s, 3H), 1.66 (s,
3H), MS (ESI) m/z: 394 (M+H.sup.+), 416 (M+Na).sup.+;
[1126]
5-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine--
2,4-dione, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 7.48
(s, 1H), 6.45 (s, 3H), 5.13 (t, 1H), 3.24 (d, J=7.1, 2H), 1.79 (s,
3H), 1.66 (s, 3H), MS (ESI) m/z: 306 (M+H).sup.+;
[1127]
5-[4-Methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidi-
ne-2,4-dione, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 7.82
(s, 1H), 7.33 (s, 2H), 7.23 (s, 1H), 5.33 (t, 1H), 5.27 (s, 2H),
3.48 (s, 3H), 3.36 (d, J=7.4, 2H), 1.79 (s, 3H), 1.66 (s, 3H), MS
(ESI) m/z: 334 (M+H.sup.+), 356 (M+Na).sup.+;
[1128]
5-[4-Hydroxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4--
dione, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 7.77 (s,
1H), 7.29 (m, 3H), 6.95 (d, J=8.3, 1H), 5.33 (t, 1H), 3.37 (d,
J=7.1, 2H), 1.79 (s, 3H), 1.66 (s, 3H), MS (ESI) m/z: 290
(M+H).sup.+, 312 (M+Na).sup.+;
[1129]
5-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm):
7.77 (s, 1H), 7.27 (s, 3H), 6.95 (d, J=8.2, 1H), 5.36 (t, 1H), 5.11
(t, 1H), 3.42 (d, J=7.4, 2H), 2.15 (m, 2H), 1.75 (s, 3H), 1.68 (s,
3H), 1.60 (s, 3H). MS (ESIO m/z: 358 (M+H).sup.+, 380
(M+Na).sup.+;
[1130]
5-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-methoxymethoxy-benzylidene]-t-
hiazolidine-2,4-dione, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm): 7.77 (s, 1H), 7.27 (s, 3H),6.95 (d, J=8.2, 1H), 5.36 (t,
1H), 5.11 (t, 1H), 5.27 (s, 2H), 3.50 (s, 3H), 3.38 (d, J=7.4, 2H),
2.15 (m, 2H), 1.75 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H), MS (ESI)
m/z: 358 (M+H).sup.+, 380 (M+Na).sup.+;
[1131]
5-{3-[3-Methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-allylidene}-thia-
zolidine-2,4-dione, The compound obtained as a yellow solid
(>45% yield), .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm):
7.55 (d, J=11.5, 1H), 7.00 (m, 4H), 6.54 (m, 1H), 5.51 (t, 1H),
5.30 (s, 1H), 4.64 (d, J=6.39, 2H), 3.93 (s, 3H), 1.78 (s, 3H),
1.75 (s, 3H), MS (ESI) m/z: 346 (M+H), 368 (M+Na);
[1132]
4-(3,4-Dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
-3-one, .sup.1H NMR (300 MHz CDCl.sub.3) .delta. (ppm) 8.46 (s, H),
7.81-7.88 (m, 3H), 7.36-7.44 (m, 3H), 7.14-7.20 (t, H), 6.84-6.87
(d, J=8.3, H), 2.27 (s, 3H);
[1133]
4-[3-(4-Hydroxy-3-methoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one, .sup.1H NMR (300 MHz CDCl.sub.3) .delta.
(ppm) 8.36-8.40 (q, H), 7.94-7.97 (d, J=9.8, 2H), 7.38-7.43 (m,
3H), 7.11-7.19 (m, 5H), 6.90-6.94 (d, 2H), 3.92 (s, 3H), 2.26 (s,
3H), ESI(+)/MS: 335 (M+H).sup.+, 357 (M+Na).sup.+;
[1134]
5-[3-(3-Methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione, .sup.1H NMR (300 MHz CDCl.sub.3) .delta. (ppm) 8.21-7.46
(m, H), 6.54-7.15 (m, 5H), 5.25-5.28 (d, 2H), 3.90-3.97 (s, 3H),
3.50-3.51 (s, 3H), ESI(+)/MS: 322 (M+H).sup.+, 344 (M+Na).sup.+;
and
[1135]
5-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine-2,4-dione,
.sup.1HMNR (300 MHz, CDCL.sub.3 & CDCL.sub.3) .delta. (ppm)
7.82 (s, H), 7.36 (s, 2H), 5.71 (s, H) 1.47 (s, 18H), ESI(+)/MS:
334 (M+H).sup.+, 356 (M+Na).sup.+.
Example 12
Preparation of 2-(3,4-Dihydroxy-benzylidene)-malononitrile
[1136] 30
[1137] A mixture of 3,4-Bis-methoxymethoxy-benzaldehyde (1.0 mmol),
malononitrile (1.0 mmol), and NaOH (2 mg) in 5 mL of MeOH was
stirred for 24 at room temperature. After solvent removal, the
residue was dissolved in EtOAc and filtered through a silica pad.
Solvent was evaporated to afford condensation product,
2-(3,4-bis-methoxymethoxy-benzylidene)-malon- onitrile, as a yellow
solid (yield 94%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm)
7.86 (s, 1H), 7.68 (s, 1H), 7.53 (d, J=9 Hz, 1H), 7.29 (d, J=9 Hz,
1H), 5.35 (s, 2H), 5.28 (s, 2H), 3.54 (s, 3H), 3.53 (s, 3H).
13C-NMR (75 MHz) .delta. (ppm) 168.1,167.6, 149.8,147.9,
134.6,127.7, 126.1,121.0, 118.8, 116.8, 96.0, 95.5, 56.9, 56.8.
[1138] Treatment of
2-(3,4-bis-methoxymethoxy-benzylidene)-malononitrile with HCl as
described in Example 2 to remove MOM protecting group and
chromatography afforded the product as a light brown solid (yield
85%). .sup.1H-NMR (300 MHz, aceton-d.sub.6) .delta. (ppm) 9.79 (bs,
0.3H), 8.01 (s, 1H), 7.75 (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.04 (d,
J=8.2 Hz, 1H); .sup.13C-NMR (75 MHz) .delta. (ppm) 159.5, 151.8,
145.1, 126.9, 123.6, 115.5, 115.3, 114.4, 113.4, 75.9.
Example 13
Preparation of 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic
Acid
[1139] To a solution of
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoi- c acid ethyl
ester (1.0 mmol) in MeOH (20 mL) was added 10% NaOH solution (3
eq). The resulting suspension was vigorously stirred for 8 h at
room temperature. The mixture was then quenched by adding saturated
NaH.sub.2PO.sub.4 (50 mL). The mixture was extracted with EtOAc
(3.times.50 mL) and the combined organic layers were dried over
Na.sub.2SO.sub.4. The crude product was purified on a short silica
gel column.
Example 14
Preparation of
4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl-
)-benzamide
[1140] 31
[1141] 14A. A mixture of
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzo- ic acid (1.0
mmol) and carbonyldiimidazole (1.0 mmol) in dry THF (20 mL) was
stirred at room temperature for 3 h. Diethanolamine (1.0 mmol) was
added dropwise and the mixture was stirred for additional 3 days at
room temperature. Solvent was then removed under reduced pressure
and the residue was chromatographed on a silica gel column
(EtOAc/hexanes) to afford MOMO-phenyl-vinyl-benzamide-as a clear
oil. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 7.97 (m,
2.5H), 7.45 (m, 2H), 7.30-6.96 (m, 4H), 6.50 (m, 0.5H), 5.27-5.03
(m, 4H), 3.89 (s, 2H), 3.66 (s, 4H), 3.54-3.37 (m, 8H).
[1142] To a solution of the obtained compound (0.5 mmol) in MeOH
(50 mL) was added 10 drops of concentrated HCl. The solution was
stirred at room temperature for 24 h followed by solvent
evaporation. The residue was chromatographed on a silica gel column
(DCM/hexanes) to afford the product as a pale yellow solid (50%
overall yield). .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta. 7.96-7.33
(m, 4H), 7.05-6.40 (m, 5H), 3.88 (s, 2H), 3.66 (m, 4H), 3.52 (s,
2H).
[1143] 14B. Other Compounds of Formula I Similarly, by following
the procedures of Example 14A, there is obtained:
[1144]
{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-morpholin-4-yl-methanon-
e, .sup.1HNMR (300 MHz, DMSO) .delta. 7.61-7.58 (d, J=8.3 Hz, 2H),
7.39-7.36 (d, J=8.1 Hz, 2H), 7.17-7.12 (d, J=16.3 Hz, H), 6.98 (s,
H), 6.93-6.88 (d, J=15.1 Hz, H), 6.92-6.89 (m, H), 6.75-6.72 (d,
J=8 Hz, H), 5.74 (s, H) 3.45-3.65 (m, 8H).
Example 15
Preparation of 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic Acid
3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-yl methyl Ester
[1145] 32
[1146] A mixture of
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid (1.0
mmol), a protected glucose (1.5 mmol), DCC (1.2 mmol), DMAP (1.0
mmol), and 10 mL dichloromethane was stirred for 24 h at room
temperature. The reaction was then quenched by adding 50 mL of
EtOAc and pouring into a saturated NH4Cl solution (aq). The organic
layer was washed with 0.5 N HCl (3.times.20 mL) and dried over
Na.sub.2SO.sub.4. Solvent removal followed by chromatography on a
silica gel column afforded the conjugate illustrated as an
intermediate as a pale yellow oil. To the solution of the obtained
compound in MeOH (50 mL) was added 5 mL of 6 N HCl. The resulting
suspension was stirred for 72 h at room temperature. The solvent
was then evaporated under reduced pressure and residue was
chromatographed (silica gel, DCM/MeOH) to afford product as a
yellow solid (overall yield 68%). .sup.1H-NMR (300 MHz, CD.sub.3OD)
.delta. (ppm) 8.02-7.94 (m, 2H), 7.56 (m, 2H), 7.20-6.78 (m, 5H),
5.25 (m, 0.5H), 4.56-4.38 (m, 2.5H), 4.15-3.80 (m, 3H), 3.62-3.51
(m, 1H).
Example 16
Preparation of
4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-N-methyl-N-(2,3,4,5,6-pe-
ntahydroxy-hexyl)-benzamide
[1147] 33
[1148] To a solution of
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoi- c acid (1.0
mmol) and N-hydroxysuccinamide (1.1 mmol) in MeOH (10 mL) was added
dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.2 mmol) in
small portions. The mixture was stirred for 1 h followed by
addition of amine (1.2 mmol). The resulting mixture was stirred for
10 h at room temperature. The solvent was removed under reduced
pressure and the residue was chromatographed on a silica gel column
(DCM/MeOH) to afford a yellow solid compound illustrated as an
intermediate. To this compound in 50 mL MeOH was added 12 drops of
concentrated HCl and stirred was continued for 24 h. After solvent
evaporation, the residue was again chromatographed (silica gel,
DCM/MeOH) to afford final product as a yellow solid. .sup.1H-NMR
(300 MHz, CD.sub.3OD) .delta. (ppm) 7.72-7.62 (m, 2H), 7.46-7.22
(m, 4H), 6.94-6.63 (m, 2H), 6.50-6.28 (m, 1H), 3.95-3.20 (m, 8H),
2.99-2.89 (m, 3H).
Example 17
Preparation of 4-{2-[6-Methoxy-2,
7,8-trimethyl-2-(4,8,12-trimethyl-tridec-
yl)-chroman-5-yl]-vinyl}-benzoic Acid Methyl Ester
[1149] 34
[1150]
6-Methoxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-c-
arbaldehyde. To a solution of
6-methoxy-2,7,8-trimethyl-2-(4,8,12-trimethy- l-tridecyl)-chroman
(1.0 g, 2.32 mmol) in methylene chloride (4 mL) at 0.degree. C. was
added titanium tetrachloride (0.528 mL, 308 mg, 2.78 mmol). The
solution turned into black. To this solution was added
.alpha.,.alpha.-dichloromethyl methyl ether tetrachloride (0.252
mL, 320 mg, 2.78 mmol). After 5 min the ice-water bath was removed.
The solution was stirred at 20.degree. C. for 1 hour, then poured
into ice-water. The mixture was extracted with methylene chloride,
dried over magnesium sulfate. Evaporation off solvents and
chromatography of the obtained residues (silica gel, hexane-ethyl
acetate 95:5) gave 1.0 g (94%) of aldehyde. .sup.1H-NMR (300 Hz,
D.sub.3CCl) .delta. ppm) 10.5 (s, 1H), 3.77 (s, 3H), 3.08 (t, J=7.2
Hz, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 1.78-1.00 (m, 23H), 0.88-0.80
(m, 15H).
[1151]
4-{2-[6-Methoxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chrom-
an-5-yl]-vinyl}-benzoic acid methyl ester. To a solution of the
intermediate aldehyde (100 mg, 0.218 mmol) and
(4-methoxycarbonyl-benzyl)- -triphenyl-phosphonium bromide (128 mg,
0.262 mmol) in ethanol (4 mL) was added lithium ethoxide (1 M in
ethanol, 0.262 mL, 0.262 mmol) dropwise. The resulted solution was
stirred at 20.degree. C. overnight. Ethanol was removed under
reduced pressure, and the residue was chromatographed (silica gel,
hexane-ethyl acetate 95:5), affording 95 mg of products, which was
a mixture of 50%-50% of cis-, trans-isomers. .sup.1H-NMR (300 Hz,
D.sub.3CCl) .delta. ppm) 8.05-8.00 (m, 1H), 7.90-7.80 (m, 1H),
7.60-7.50 (m, 1H), 7.35-7.10 (m, 2H), 6.80-6.60 (m, 1H), 4.38 (s,
CH.sub.3, 50%), 4.32 (s, CH.sub.3, 50%), 3.61 (s, CH.sub.3, 50%),
3.60 (s, CH.sub.3, 50%), 2.81 (t, J=6.6 Hz, 2H), 2.30-2.10 (m, 6H),
1.78-1.00 (m, 23H), 0.88-0.80 (m, 15H). MS (APCI) m/z 591 (M+1,
46).
Example 18
Preparation of
2-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-thiazole
[1152] 35
[1153] 18A. To a solution of the
(3,4-bis-methoxymethoxy-benzyl)-triphenyl- -phosphonium bromide
(0.731 g, 1.32 mmoles) and 2-thiazolecarbox-aldehyde (0.134 g, 1.2
mmoles) in ethanol was added lithium ethoxide (1.32 ml, 1.32 mmol).
The solution turned into a brown color. It was allowed to stir for
about two hours at room temperature. The reaction mixture was then
added to 100 ml of concentrated NaH.sub.2PO.sub.4 and was extracted
with ethyl acetate. The organic layer was dried over sodium sulfate
and concentrated. The crude product was purified using a silica gel
column (hexanes:EtOAc 3:1), resulting 26 mg of product. NMR
spectrum indicated that it is a mixture of cis/trans isomers.
.sup.1H-NMR (300 Hz, D.sub.3CCl) .delta. ppm) 7.76 (dd, 1H), 7.40
(m, 1.4H), 7.09-7.24 (m, 3.2H), 6.8 (dd, 1.3H), 5.2-5.28 (ss, 4H),
3.4-3.5 (ss, 6H). MS (ESI) m/z: 308 (M+H, 100).
[1154] 18B. Other Compounds of Formula I Similarly, by following
the procedures of Example 18A and substituting
2-thiazolecarbox-aldehyde accordingly, there are obtained:
[1155] 2-[2-(3,4-Dihydroxy-phenyl)-vinyl]-3-methyl-thiazol-3-ium
iodide, and
[1156] 4-[2-(5-Methyl-thiophen-2-yl)-vinyl]-benzene-1,2-diol.
Example 19
Preparation of 4-[2-(3,4-Dimethoxy-phenyl)-vinyl]-
methanesulfonyl-benzene
[1157] 36
[1158] To a solution of the 4-methanesulfonyl-benzaldehyde (0.53 g,
2.71 mmoles) and (3,4-dimethoxy-benzyl)-triphenyl-phosphonium
bromide (1.47 g, 2.99 mmoles) in ethanol was added lithium ethoxide
(2.99 ml, 2.99 mmoles) dropwise to give a brown colored solution.
The reaction was complete within two hours. The reaction was
quenched by adding 100 ml of concentrated NaH.sub.2PO.sub.4,
followed by the extraction with ethyl acetate. The organic layer
was dried over sodium sulfate and concentrated. The crude product
was purified using a silica gel column (hexanes:EtOAc 3:1),
resulting 26 mg of product. NMR spectrum indicated that it is a
mixture of cis/trans isomers. .sup.1H-NMR (300 Hz, D.sub.3CCl)
.delta. (ppm) 7.92-7.79 (m, 2H), 7.48-7.45 (m, 2.2H), 7.27-6.68 (m,
4.6H), 6.55 (d, 0.4H), 3.96-3.92 (d, 2.6H), 3.87-3.66 (d, 2.6H),
3.07-3.04 (d, 3H). MS (ESI) m/z: 319 (M+H, 100), 341 (M+Na,
30).
Example 20
Preparation of 4-(2-Thiazol-2-yl-vinyl)-benzoic Acid Methyl
Ester
[1159] 37
[1160] 20A. To a solution of
(4-methoxycarbonyl-benzyl)-triphenyl-phosphon- ium bromide and
2-thiazolcarbox-aldehyde (0.50 g, 4.42 mmoles) in ethanol (10 mL)
was added lithium ethoxide (4.86 mL, 4.86 mmol) drop-wise and the
solution became orange in color quickly. The reaction was allowed
to stir for about one hour. The volume was reduced and a
concentrated NaH.sub.2PO.sub.4 aqueous solution (100 mL) was added
and followed by EtOAc extraction. The organic layer was dried over
sodium sulfate and concentrated. The crude product was purified
using a silica gel column (DCM as the eluent), affording 1.0 g of
product. NMR spectrum indicated that it is a mixture of methyl and
ethyl esters. .sup.1H-NMR (300 Hz, D.sub.3CCl) .delta. ppm) 8.05
(d, J=6 Hz, 2H), 7.75 (d, J=3.26 Hz, 1H), 7.52 (d, J=6.5 Hz, 2H),
7.16 (d, J=3.26 Hz, 1H), 6.92 (s, 2H), 4.40 (q, J=7.12 Hz, 1.32H),
3.92 (s, 1.5H), 1.40 (t, J=7.12 Hz, 2H).
[1161] 20B. Other Compounds of Formula I Similarly, by following
the procedures of Example 20A and substituting
(4-methoxycarbonyl-benzyl)-tri- phenyl-phosphonium bromide and
2-thiazolcarbox-aldehyde accordingly, there are obtained:
[1162] 4-[2-(1H-Benzoimidazol-5-yl)-vinyl]-benzoic acid ethyl
ester, and
[1163] 4-(5-Methyl-thiophen-2-yl-vinyl)-benzoic acid ethyl
ester
Example 21
Preparation of
4-[2-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic Acid Ethyl
Ester
[1164] 38
[1165] The compound was prepared in a similar way described in
Example 1. The crude product was purified on a silica gel column
(hexane:EtOAc=3:1) to afford a clear oil (yield 99%). NMR spectrum
indicated the purified product is a mixture of cis/trans isomers
containing ethyl and methyl esters. .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. (ppm) 7.95-7.88 (m, 2H), 7.38-7.23 (m, 2H),
7.00-6.60 (m, 3H), 4.75-4.63 (m, 1.4H), 3.94-3.64 (m, 6.9H),
2.22-2.12 (m, 6H), 1.27-1.24 (m, 2.1H).
Example 22
Preparation of 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic Acid
Ethyl Ester, Zinc (II) Chloride
[1166] 39
[1167] To a solution of 4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-benzoic
acid ethyl ester (0.023 g, 0.08 mmol) in methanol (5 mL) was added
zinc (II) chloride (0.011 g, 0.080 mmol) portion-wise. The reaction
was allowed to stir for two hours before it was evaporated to
dryness. This afforded 0.030 g of product as a brownish solid.
.sup.1H-NMR (300 Hz, D.sub.3COD) .delta. (ppm) 7.97 (d, J=8.4 Hz,
2H), 7.60 (d, J=8.37 Hz, 2H), 7.15 (d, J=16.2 Hz, 1H), 7.05 (s,
1H), 6.99 (d, J=16.4 Hz, 1H), 6.94 (d, 2H), 6.77 (d, J=8.1 Hz, 1H),
4.37(q, J=7.12 Hz, 2H), 1.39 (t, J=7.12 Hz, 3H). MS (ESI) m/z: 419
(M+H, 100), 441 (M+Na, 80).
[1168] 22B. Other Compounds of Formula III Similarly, by following
the procedures of Example 22A and substituting zinc (II) chloride
accordingly, there are obtained:
[1169] 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
manganese(III) acetate, and
[1170] 4-[2-(phenyl-1,2-diol)-vinyl]-benzoic acid ethyl ester,
copper(II) chloride.
Example 23
Preparation of Prenylated and Geranylated, MOM-Vanillin
Intermediates
[1171] 40
[1172] 23A. A mixture of vanillin (12 g) and prenyl bromide was
stirred in 1N NaOH aqueous solution (1 eq.) at 0.degree. C. with
the aid of an ice-water bath. With vigorously stirring, prenyl
bromide was added dropwise in 45 min. The solution was stirred at
this temperature for 3 h. After acidfied with aqueous HCl, the
solution was extracted with DCM. The DCM phase was washed with
brine and then dried over anhydrous sodium sulfate. A crude product
was obtained as a clear oil (1.5 g) after evaporation. Column
chromatography purification (silica gel, 20-30% EtOAc in hexane the
eluents) gave the prenylated vanillin
4-hydroxy-3-methoxy-5-(3-methyl-but-2-enyl)-benzaldehyde.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 9.79 (s, 1H), 7.27
(m, 2H), 6.43(br., s, 1H), 5.31 (m, 1H), 3.90 (s, 3H), 3.37 (d,
J=7.3 Hz, 2H), 1.74, 1.71 (2s, 6H). .sup.13C-NMR (CDCl.sub.3, 75
MHz) .delta. (ppm) 191.76, 149.81, 147.26, 134.13, 129.32, 128.11,
128.05, 121.57, 107.15, 56.62, 28.16, 26.23, 18.24.
[1173] Similarly, a geranyled vanillin was made using the described
procedure. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 9.80 (s,
H, CHO), 7.30 (s, 2H, ArH), 6.26 (s, H, OH), 5.42 (t, H, vinylH),
5.10 (t, H, vinylH), 3.96 (s, 3H, OCH.sub.3), 3.42 (d, J=7.26, 2H,
allylicH), 2.05 (s, 3H, CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS (ESI)
m/z: 289 (M+H).sup.+, 311 (M+Na).sup.+.
[1174] 23B. A solution of prenylated vanillin (220 mg), MOM-Cl
(0.12 mL) and DIPEA (0.2 mL) in DCM (20 mL) was stirred for 2 h.
The reaction was quenched by adding water and saturated aqueous
K.sub.2CO.sub.3 solution. DCM extraction followed by evaporation to
dryness gave a crude product. The title compound
3-methoxy-4-methoxymetnoxy-5-(3-methyl-but-2-enyl)-ben- zaldehyde
was obtained as an oil (250 mg) after column chromatography
purification. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 9.87
(s, 1H), 7.31 (m, 2H), 5.31 (m, 1H), 5.20 (s, 2H), 3.89 (s, 3H),
3.58 (s, 3H), 3.46 (d, J=7.3 Hz, 2H), 1.76, 1.73 (2s, 6H) ppm.
.sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta. (ppm) 191.92, 152.99,
149.95, 136.70, 134.07, 132.85, 126.66, 122.08, 108.91, 99.26,
58.08, 56.32, 28.74, 26.22, 18.30.
[1175] Similarly, a geranyled MOM-vanillin intermediate was made
using the described procedure with the exception of using NaH and
DMF in lieu of DIPEA and DCM, respectively. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 9.86 (s, H, CHO), 7.31 (s, 2H,
ArH), 5.42 (t, H, vinylH), 5.20 (s, 2H, OCH.sub.2O), 5.10 (t, H,
vinylH), 3.90 (s, 3H, OCH.sub.3), 3.59 (s, 3H, OCH.sub.3), 3.49 (d,
J=7.26, 2H, allylicH), 2.05 (s, 3H, CH.sub.3), 1.60 (s, 2H,
CH.sub.2). MS (ESI) m/z: 333 (M+H).sup.+, 355 (M+Na).sup.+.
Example 24
Preparation of Prenyl-substituted, MOM-3,4-dihydroxylbenzaldehyde
Intermediates
[1176] 41
[1177] 24A. By following a procedure corresponding to the one
described in Example 23A, the prenyl-substituted
3,4-dihydroxylbenzaldehydes were prepared. For
2-prenyl-3,4-dihydroxylbenzaldehyde: .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. (ppm) 10.00 (s, 1H, CHO), 7.37 (d, J=8.3 Hz, 1H), 6.69
(d, J=8.3 Hz, 1H), 5.8 (br., 2H, OH), 5.20 (m, 1H), 3.89 (d, J=6.7
Hz, 2H), 1.83, 1.76 (2s, 6H). For 5-prenyl-3,4-dihydroxylbenzal-
dehyde: .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 9.77(s, 1H,
CHO), 7.35(d, J=3.1 Hz, 1H), 7.26 (d, J=3.1 Hz, 1H), 5.8 (br., 2H,
OH), 5.30 (m, 1H), 3.42 (d, J=7.3 Hz, 2H), 1.78, 1.73 (2s, 6H).
[1178] 24B. The corresponding MOM-prenyl-substitituted
benzaldehydes were prepared following a procedure corresponding to
the one described in Example 23B. For
2-prenyl-3,4-bis-methoxymethoxy-benzaldehyde: .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 10.12(s, 1H, CHO), 7.64(d,
J=8.7 Hz, 1H), 7.12(d, J=8.3 Hz, 1H), 5.28 (s, 2H), 5.15 (m, 1H),
5.11 (s, 2H), 3.84(d, J=6.5 Hz, 2H), 3.61 (s, 3H), 3.51 (s, 3H),
1.79, 1.54 (2s, 6H). For
5-prenyl-3,4-bis-methoxymethoxy-benzaldehyde: .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 9.86 (s, 1H, CHO), 7.52(d,
J=1.9 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 5.25 (m, 5H), 3.60 (s, 3H),
3.51 (s, 3H), 3.46 (d, J=7.3 Hz, 2H), 1.77,1.73 (2s, 6H).
.sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta. (ppm) 191.67, 150.57,
150.41, 137.08, 134.06, 132.87, 126.25, 122.00, 114.22, 99.38,
95.41, 58.02, 56.78, 28.84, 26.17, 18.26. For
6-prenyl-3,4-bi-methoxymethoxy-benzaldehy- de): .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 10.14 (s, 1H, CHO), 7.63(s,
1H), 7.03(s, 1H), 5.24 (m, 5H), 3.66 (d, J=6.9 Hz, 2H), 3.50 (s,
6H), 1.71, 1.70 (2s, 6H).
Example 25
Preparation of Prenyl-substituted, MOM-3,5-dihydroxylbenzaldehyde
Intermediates
[1179] 42
[1180] 25A. To a solution of methyl 3,5-hydroxybenzoate (500 mg,
2.97 mmol) in deionized water (2.97 mL) placed in an ice-bath, NaOH
(118.8 mg, 2.97 mmol) pellets were added and allowed to dissolve.
Bromo-3-methyl-2-butene (prenyl bromide) (590 mg, 1.3 mmol) was
added dropwise. This solution was stirred at 0.degree. C. and after
30 minutes white solid started to appear. After an hour of
stirring, workup was carried out with water and the pH of the
aqueous layer was tested to be acidic, indicating the completion of
reaction. Extraction with EtOAc followed by column chromatography
purification (silica gel, 30% EtOAc in hexane as the eluents) gave
two major fractions. Fraction 1: methyl
2-(3-methyl-2-butene)-3,5-hydroxybenzoate (26% yield). .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 6.85 (d, J=2.6, H, ArH), 6.51,
(d, J=2.6, H, ArH), 6.13 (s, H, OH), 5.81 (s, H, OH), 5.18 (t,
J=6.7, H, vinyl H), 3.57 (d, J=6.7, 2H, allylic H), 1.78 (s, 3H,
CH.sub.3), 1.71 (s, 3H, CH.sub.3). .sup.13C-NMR (CDCl.sub.3, 75
MHz) .delta. (ppm) 169.43, 156.68, 154.84, 134.95, 132.34, 122.73,
120.68, 109.87, 107.40, 52.82, 26.17, 18.32. MS (ESI) m/z: 237
(MH.sup.+). Fraction 2: methyl
2,6-di-(3-methyl-2-butene)-3,5-hydroxybenzoate (23% yield).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 6.35 (s, H, ArH),
5.19 (t, 6.8, 2H, vinyl H), 3.87 (s, 3H, OCH.sub.3), 3.20 (d,
J=6.8, 2H, allylic H), 1.70 (s, 3H, CH.sub.3), 1.64 (s, 3H,
CH.sub.3). .sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta. (ppm) 174.66,
157.85, 139.20, 138.20, 126.18, 120.29, 109.21, 64.83, 56.35,
31.00, 29.82, 21.93, 18.24. MS (ESI) m/z: 305 (MH.sup.+).
[1181] 25B. MOM-addition to methyl
2-(3-methyl-2-butene)-3,5-hydroxybenzoa- te and methyl
2,6-di-(3-methyl-2-butene)-3,5-hydroxybenzoate were carried out
following a procedure corresponding to the one described in Example
23B. For methyl
2-(3-methyl-2-butene)-3,5-bis-methoxymethoxybenzoate: .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 7.10 (d, J=3.0, H, ArH), 6.93
(d, J=3.0, H, ArH), 5.18 (s, 2H, OCH.sub.2O), 5.16 (s, 2H,
OCH.sub.2O), 5.15 (t, H, vinylH), 3.87 (d, J=6.9, 2H, allylicH),
3.86 (s, 3H, OCH.sub.3), 3.47 (s, 6H, OCH.sub.3), 1.75 (s, 3H,
CH.sub.3), 1.66 (s, 3H, CH.sub.3). For methyl
2,6-di-(3-methyl-2-butene)-3,5-bis-methoxymetho- xybenzoate:
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 7.27 (s, 2H, ArH),
6.93 (d, J=3.0, H, ArH), 5.18 (s, 2H, OCH.sub.2O), 5.16 (s, 2H,
OCH.sub.2O), 5.15 (t, H, vinylH), 3.87 (d, J=6.9, 2H, allylicH),
3.86 (s, 3H, OCH.sub.3), 3.47 (s, 6H, OCH.sub.3), 1.75 (s, 3H,
CH.sub.3), 1.66 (s, 3H, CH.sub.3). 43
[1182] 25C. To a solution of methyl
2-(3-methyl-2-butene)-3,5-bis-methoxym- ethoxybenzoate (1.62 g, 5.0
mmol) in THF was added LAH (227 mg, 6.0 mmol) slowly with stirring.
Stirred at room temperature for an hour, the reaction mixture was
then heated up to reflux (60.degree. C.) for an additional hour. It
was worked up by quenching with aqueous HCl solution, extracting
with EtOAc and drying over anhydrous MgSO.sub.4. Upon filtration
and evaporation to dryness, it afforded the alcohol intermediate.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 6.80 (d, J=2.4, 2H,
ArH), 6.77 (d, J=1.2, 2H, ArH), 5.18 (s, 2H, OCH.sub.2O), 5.16 (s,
2H, OCH.sub.2O), 5.15 (t, H, vinylH), 4.65 (s, 2H, CH.sub.2OH),
3.87 (d, J 6.9, 2H, allylicH), 3.48 (s, 6H, OCH.sub.3), 1.78 (s,
3H, CH.sub.3), 1.70 (s, 3H, CH.sub.3). MS (ESI) m/z: 297
(MH.sup.+), 319 (M+Na).sup.+.
[1183] 25D. A solution of this alcohol intermediate (200 mg, 0.68
mmol) was dissolved in dry CH.sub.2Cl.sub.2, while stirring added
molecular sieves. After 2 minutes, PCC (218 mg, 1.03 mmol) was
added slowly. The reaction mixture was stirred for 2 hours and its
color turned from a bright orange to dark brown. A dry silica gel
was used to filter out the impurities leaving the desired product
3,5-bis-methoxymethoxy-2-(3-methyl- -but-2-enyl)-benzaldehyde.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 10.26 (s, H, CHO),
7.20 (d, J=2.7, 2H, ArH), 7.03 (d, J=1.2, 2H, ArH), 5.21 (s, 2H,
OCH.sub.2O), 5.16 (s, 2H, OCH.sub.2O), 5.15 (t, H, vinylH), 3.71
(d, J=6.9, 2H, allylicH), 3.48 (s, 6H, OCH.sub.3), 1.78 (s, 3H,
CH.sub.3), 1.66 (s, 3H, CH.sub.3). MS (ESI) m/z: 295 (M+H).sup.+,
317 (M+Na).sup.+.
[1184] 25E. By following a synthetic sequence corresponding to the
one described in Example 25C and 25D,
3,5-bis-methoxymethoxy-2,6-di-(3-methyl- -but-2-enyl)-benzaldehyde
was prepared, starting from
2,6-di-(3-methyl-2-butene)-3,5-bis-methoxymethoxybenzoate. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 10.44 (s, H, CHO), 7.13 (s,
H, ArH), 5.26 (s, 4H, OCH.sub.2O), 5.18 (t, 2H, vinylH), 3.59 (d,
J=6.9, 4H, allylicH), 3.48 (s, 12H, OCH.sub.3), 1.78 (s, 6H,
CH.sub.3), 1.66 (s, 6H, CH.sub.3). MS (ESI) m/z: 363 (M+H).sup.+,
385 (M+Na).sup.+.
Example 26
Preparation of 4-prenyl- and 4-geranyl-substituted,
MOM-3,5-bis-methoxymethoxybenzaldehyde
[1185] 26A. MOM-Addition to Methyl-3,5-dihydroxybenzonate 44
[1186] To a solution of methyl-3,5-dihydroxybenzonate (5.0 g, 29.7
mmol), DIPEA (16.63 ml, 95.2 mmol), and a catalytic amount of DMAP
in CH.sub.2Cl.sub.2 was added MOM-Cl (6.78 ml, 89.9 mmol) dropwise
over 30 minutes with stirring. The reaction mixture was allowed to
stir at room temperature overnight. It was worked up by adding
dilute aqueous HCl solution and followed by extraction with DCM.
Removal of most mono-protected side product was achieved by washing
with aqueous NaOH solution. This solution was then evaporated to
dryness and afforded the product as yellow oil. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 7.36 (d, J=2.31, 2H, ArH), 6.92
(d, J=2.31, H, ArH), 5.19 (s, 4H, OCH.sub.2), 3.90 (s, 3H,
OCH.sub.3), 3.49 (s, 6H, OCH.sub.3). MS (ESI) m/z: 257
(M+H).sup.+.
[1187] 26B. Reduction of Methyl-3,5-dihydroxybenzonate to the
Alcohol Intermediate 45
[1188] The alcohol intermediate was prepared from
methyl-3,5-dihydroxybenz- onate by employing a reduction procedure
corresponding to the one described in Example 25. The product
obtained was a yellow oil. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 6.69 (d, J=4.29, 2H, ArH), 6.64 (d, J=1.87, H, ArH),
5.14 (s, 4H, OCH.sub.2), 4.60 (s, 2H, CH.sub.2OH), 3.49 (s, 6H,
OCH.sub.3). MS (ESI) m/z: 229 (M+H).sup.+, 251 (M+Na).sup.+.
[1189] 26C. TBDMS Protection of
(3,4-bis-methoxymethoxy-phenyl)-methanol
[1190] A solution of (3,4-bis-methoxymethoxy-phenyl)-methanol (4.2
g, 18.4 mmol), imidazole, and TBDMS-Cl (3.33 g, 22.1 mmol) in a
minimum amount of DMF (5 ml) was stirred at room temperature for 2
hours. It was worked up by adding water to the mixture and followed
with extraction with EtOAc. Column chromatography purification on
silica gel using 30%EtOAc in hexanes as the eluents afforded the
product (3,5-bis-methoxymethoxy-benzy-
loxy)-tert-butyl-dimethyl-silane as a clear oil. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 6.69 (d, J=4.29, 2H, ArH), 6.62
(d, J=1.87, H, ArH), 5.14 (s, 4H, OCH.sub.2), 4.68 (s, 2H,
CH.sub.2OTBDMS), 4.13 (s, 6H, OCH.sub.3), 0.95 (s, 9H, t-butyl
CH.sub.3), 0.099 (s, 6H, Si--CH.sub.3). MS (ESI) m/z: 343
(M+H).sup.+, 365 (M+Na).sup.+.
[1191] 26D. Prenylation and Geranylation of
(3.5-bis-methoxymethoxy-benzyl- oxy)-tert-butyl-dimethyl-silane
[1192] To cold solution (-20.degree. C.) of
(3,5-bis-methoxymethoxy-benzyl- oxy)-tert-butyl-dimethyl-silane
(1.80 g, 5.26 mmol) and TMEDA (1.27 g, 10.89 mmol) in THF was added
n-BuLi (2.31 ml, 5.79 mmol) dropwise under nitrogen atmosphere. It
was allowed to stir at this temperature for 50 minutes and followed
by addition of CuCN (480 mg, 5.37 mmol). After stirring for
additional 50 minutes at -20.degree. C., the mixture was then
transferred via a cannula to a solution of prenyl bromide in THF
and allowed to stir for 2 hours at -78.degree. C. under nitrogen.
The reaction mixture was warmed up to room temperature ant then
quenched with water. After extraction with EtOAc, the organic
solution was evaporated to dryness, yielding a yellow oil. This
crude product was purified using column chromatography (silica gel,
20% EtOAc in hexanes as the eluents). This gave a
3-prenyl-substituted product as a clear oil. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm) 6.75 (s, 2H, ArH), 5.18 (s, 4H,
OCH.sub.2), 4.67 (s, 2H, CH.sub.2OTBDMS), 3.46 (s, 6H, OCH.sub.3),
3.35 (d, 2H, allylicH) 1.78 (s, 3H, CH.sub.3), 1.65 (s, 3H,
CH.sub.3), 0.95 (s, 9H, t-butyl CH.sub.3), 0.099 (s, 6H,
S.sub.1--CH.sub.3). MS (ESI) m/z: 411 (M+H).sup.+, 433
(M+Na).sup.+.
[1193] Similarly, the corresponding 3-geranyl-substituted
derivative was made using the same starting material along with
geranyl bromide. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
6.79 (d, J=4.29, 2H, ArH), 5.22 (t, H, vinylH), 5.15 (s, 4H,
OCH.sub.2), 5.08 (t, H, vinylH), 4.68 (s, 2H, CH.sub.2OTBDMS), 3.46
(s, 6H, OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2), 2.00 (q, 2H,
geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77 (s, 3H,
geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s, 3H,
geranylCH.sub.3), 0.95 (s, 9H, t-butyl CH.sub.3), 0.099 (s, 6H,
S.sub.1--CH.sub.3). MS (ESI) m/z: 479 (M+H).sup.+, 501
(M+Na).sup.+.
[1194] 26E. Hydrolysis of
[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)--
benzyloxy]-tert-butyl-dimethyl-silane and
tert-butyl-[4-(3,7-dimethyl-octa-
-2,6-dienyl)-3,5-bis-methoxymethoxy-benzyloxy]-dimethyl-silane
[1195] To a solution of
[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-be-
nzyloxy]-tert-butyl-dimethyl-silane (1.6 g, 3.9 mmol) in THF was
added TBAF solution in THF (4.68 ml, 4.68 mmol) dropwise with
stirring. It was stirred for 2 hours at room temperature until TLC
indicated the completion of reaction. The mixture was partitioned
between water and EtOAc. The solvent removal of organic layer gave
a clean product as a clear oil that was characterized without
further purification. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm) 6.78 (s, 2H, ArH), 5.20 (s, 4H, OCH.sub.2), 5.16 (t, H,
vinylH), 4.63 (s, 2H, CH.sub.2OH), 3.48 (s, 6H, OCH.sub.3), 3.39
(d, 2H, allylicH) 1.78 (s, 3H, CH.sub.3), 1.65 (s, 3H, CH.sub.3).
MS (ESI) m/z: 297 (M+H).sup.+, 319 (M+Na).sup.+.
[1196] Similarly,
tert-butyl-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-met-
hoxymethoxy-benzyloxy]-dimethyl-silane was made using the same
procedure starting from the corresponding TBDMS-protected
precursor. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 6.79 (d,
J=4.29, 2H, ArH), 5.22 (t, H, vinylH), 5.15 (s, 4H, OCH.sub.2),
5.08 (t, H, vinylH), 4.63 (s, 2H, CH.sub.2OH), 3.46 (s, 6H,
OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2), 2.00 (q, 2H,
geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77 (s, 3H,
geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s, 3H,
geranylCH.sub.3). MS (ESI) m/z: 365 (M+H).sup.+, 387
(M+Na).sup.+.
[1197] 26F. Preparation of
3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-- benzaldehyde and
4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-b-
enzaldehyde
[1198]
[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-methanol
(1.3 g, 4.39 mmol) was prepared by employing the an oxidation
procedure corresponding to the one described in Example 25.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 9.88 (s, H, CHO),
7.28 (s, 2H, ArH), 5.30 (s, 4H, OCH.sub.2), 5.17 (t, H, vinylH),
3.49 (s, 6H, OCH.sub.3), 3.43 (d, 2H, allylicH), 1.79 (s, 3H,
CH.sub.3), 1.67 (s, 3H, CH.sub.3). MS (ESI) m/z: 295 (M+H).sup.+,
317 (M+Na).sup.+.
[1199]
4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-benzaldehyd-
e was also prepared in the same way. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. (ppm) 9.88 (s, H, CHO), 7.31 (d, J=6.69, 2H, ArH),
5.26 (s, 4H, OCH.sub.2), 5.16 (t, H, vinylH), 5.08 (t, H, vinylH),
3.46 (s, 6H, OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2), 2.00 (q,
2H, geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77 (s, 3H,
geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s, 3H,
geranylCH.sub.3). MS (ESI) m/z: 363 (M+H).sup.+, 385
(M+Na).sup.+.
Example 27
Preparation of prenyl-/aeranyl-substituted, MOM-compounds of
Formula I
[1200] A mixture of the aldehyde (1.0 eq.), phosphonium salt (1.2
eq.), and EtOLi (1.2 eq.) was stirred at room temperature for 1.5
h. Workup and purification was carried out following a procedure
corresponding to the one described in Example 3. As such, the
following compounds were made:
[1201]
4-{2-[3-Methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester. The compound was obtained as an oil
(>95% yield). .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
8.00 (m, 2H), 7.56-7.34 (m, 2H), 7.20-6.94 (m, 2H), 6.60 (m, 2H),
5.16-5.07(m, 1H), 5,08, 5.07 (2s, 2H), 3.91, 3.90 (2s, 3H), 3.60,
3.58 (2s, 3H), 3.40 (m, 2H), 1.62, 1.60, 1.56, 1.50 (4s, 3H).
.sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta. (ppm) 167.32, 152.75,
152.10, 142.87, 142.37, 136.49, 136.03, 133.24, 133.07, 132.70,
132.42, 131.62, 130.43, 129.88, 129.34128.82, 127.01, 126.59,
123.15, 122.77, 121.48, 110.88, 108.10, 99.07, 99.29, 57.97, 57.90,
56.12, 55.93, 52.48, 28.93, 28.64, 26.24, 26.07, 18.34, 18.14. MS
(ESI) m/z: 397 (M+H).sup.+.
[1202]
4-[2-(3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl)-vi-
ny]l-nitrobenzene. The compound was obtained as a yellow thick oil
(yield 69%). .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.20,
8.08 (2d, J=8.8 Hz, 2H), 7.63, 7.43 (2d, J=8.8 Hz, 2H), 6.96-6.52
(m, 4H), 5.20, 5.13, 5.08(m+2s, 3H), 3.91, 3.60 (m, 6H), 3.44, 3.30
(2d, J=7.3 Hz, 2H), 1.77-1.57 (m, 6H). .sup.13C-NMR (CDCl.sub.3, 75
MHz): 152.82, 152.33, 144.98, 144.44, 144.20, 136.65, 136.30,
134.15, 133.74, 133.25, 132.64, 132.13, 130.17, 127.57, 127.10,
125.70, 124.57, 123.87, 123.05, 122.59, 121.85, 110.88, 108.27,
99.37, 99.30, 58.00, 57.92, 56.24, 56.02, 28.92, 28.61, 26.25,
26.07, 18.34, 18.11. MS (ESI) m/z: 384 (M+H).sup.+, 406
(M+Na).sup.+.
[1203]
4-{2-[3,4-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester. Yield 91%. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. (ppm) 8.02, 7.91 (2d, J=8.4 Hz, 2H), 7.53, 7.36(2d,
J=8.4 Hz, 2H), 7.17-6.93(m, 2H), 6.80-6.60(m, 2H), 5.22-5.11 (m,
5H), 3.92, 3.88 (2s, 3H, COOMe), 3.60-3.45 (m, 8H), 1.75,1.67,
1.63, 1.56 (4s, 6H). .sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta.
(ppm) 167.35, 149.76, 142.82, 142.21, 135.08, 132.22, 132.08,
131.58, 130.44, 129.76, 129.54, 129.33, 128.65, 126.59, 125.72,
122.85, 114.19, 99.66, 99.61, 95.44, 58.05, 57.98, 56.70, 52.50,
27.23, 26.12, 26.07, 18.61, 18.53. MS (ESI) m/z: 449
(M+Na).sup.+.
[1204]
4-{2-[3,4-Bis-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester. Yield 96%. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. (ppm) 8.02, 7.91 (2d, J=8.4 Hz, 2H), 7.53, 7.36(2d,
J=8.4 Hz, 2H), 7.17-6.93 (m, 2H), 6.80-6.60(m, 2H), 5.24-4.99 (m,
5H), 3.90 (s, 3H, COOMe), 3.60-3.29 (m, 8H), 1.75, 1.67, 1.63, 1.56
(4s, 6H). .sup.13C-NMR (CDCl.sub.3, 75 MHz) .delta. (ppm) 167.31,
150.46, 149.82, 144.61, 142.73, 136.18, 132.86, 132.22, 130.41,
129.89, 129.29, 129.08, 129.01, 128.80, 126.62, 124.82, 122.66,
115.19, 99.53, 99.46, 95.44, 57.88, 56.47, 52.44, 29.01, 28.68,
26.24, 26.04, 18.34, 18.11. MS (ESI) m/z: 449 (M+Na).sup.+.
[1205]
4-[2-(3,4-Dimethoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl)-vinyl]-n-
itrobenzene. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.10,
8.08 (2d, J=8.4 Hz, 2H), 7.53, 7.36(2d, J=8.4 Hz, 2H), 7.17-6.93(m,
2H), 6.80-6.60(m, 2H), 5.25-5.10 (m, 5H), 3.60-3.29 (m, 6H), 1.75,
1.67, 1.63, 1.56 (4s, 6H). .sup.13C-NMR (CDCl.sub.3, 75 MHz)
.delta. (ppm) 150.53, 149.97, 144.91, 136.44, 133.92, 133.51,
132.79, 132.22, 130.12, 127.70, 127.13, 124.55, 124.26, 123.90,
122.49, 115.06, 99.53, 99.47, 95.38, 57.92, 56.73, 56.51, 28.99,
28.66, 26.25, 26.07, 18.35, 18.11. MS (ESI) m/z: 436
(M+Na).sup.+.
[1206]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzoic acid methyl ester. .sup.1H-NMR (CDCl.sub.3,
300 MHz) .delta. (ppm) 8.02 (d, J=8.46, H, ArH), 7.92 (d, J=8.37,
H, ArH), 7.56 (d, J=8.28, H, ArH), 7.36 (d, J=8.25, 2H, ArH), 6.95
(m, J=2H, ArH), 6.62 (m, H, ArH), 5.25 (t, H, vinylH), 5.20 (s, 2H,
OCH.sub.2O), 5.10 (t, H, vinylH), 3.90 (s, 3H, OCH.sub.3), 3.59 (s,
3H, OCH.sub.3), 3.49 (d, J=7.26, 2H, allylicH), 2.05 (s, 3H,
CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS (ESI) m/z: 465 (M+H).sup.+,
487 (M+Na).sup.+.
[1207]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-nitrobenzene. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.22 (d, J=8.85 Hz, 2H, ArH), 8.10 (d, J=8.82 Hz, H,
ArH), 7.62 (d, J=8.82 Hz, H, ArH), 7.17 (m, 2H, ArH), 7.04 (m,
ArH), 6.62 (m, H, ArH), 5.15 (t, H, vinylH), 5.08 (s, 2H,
OCH.sub.2O), 5.10 (t, H, vinylH), 3.90 (s, 3H, OCH.sub.3), 3.59 (s,
3H, OCH.sub.3), 3.49 (d, J=7.26 Hz, 2H, allylicH), 2.05 (s, 3H,
CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS (ESI) m/z: 452 (M+H).sup.+,
474 (M+Na).sup.+.
[1208]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzonitrile. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 7.56 (m, 3H, ArH), 7.55 (d, J=8.82, H, ArH), 7.28 (m,
3H, ArH), 6.64 (m, 2H, ArH), 5.15 (t, H, vinylH), 5.08 (s, 2H,
OCH.sub.2O), 5.10 (t, H, vinylH), 3.90 (s, 3H, OCH.sub.3), 3.59 (s,
3H, OCH.sub.3), 3.49 (d, J=7.26, 2H, allylicH), 2.05 (s, 3H,
CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS: 432 (M+H).sup.+, 454
(M+Na).sup.+.
[1209]
1-(3,7-Dimethyl-octa-2,6-dienyl)-3-methoxy-2-methoxymethoxy-5-[2-(4-
-nitro-phenyl)-vinyl]-benzene. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm): 8.22.(d, J=8.8, 2H), 8.10 (d, J=8.8, 1H), 7.62 (d,
J=8.8, 1H), 7.17 (m, 2H), 7.04 (m, 2H), 6.62 (m, 1H), 5.15 (t, 1H),
5.08 (s, 2H), 5.10 (t, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.49 (d,
J=7.26, 2H), 2.05 (s, 3H), 1.60 (s, 2H). MS(ESI) m/z: 452
(M+H.sup.+), 474 (M+Na).sup.+.
[1210]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzonitrile. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm):
7.54 (m, 3H), 7.38 (d, J=8.9, 2H), 7.36 (m, 1H), 6.64 (m, 2H), 5.25
(s, 4H), 5.22 (t, 1H), 3.51 (s, 6H), 3.42 (d, 2H), 1.77 (s, 3H),
1.71 (s, 3H). MS (ESI) m/z: 394 (M+H.sup.+), 416 (M+Na).sup.+.
[1211] 4-[2-(3-Chloro-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 7.57 (m, 5.2H),
7.33 (t, 2.6H), 7.02 (m, 5.6H), 6.64 (d, J=12.18, 1H), 6.56 (d,
J=12.20, 1H), 5.28 (s, 1.3H), 5.24 (s, 2H), 3.54 (s, 1.7H), 3.52
(s, 3.5H). MS (ESI) m/z: 300 (M+H), 322 (M+Na).
Example 28
Preparation of Prenyl-/qeranyl-substituted, Phenolic Compounds of
Formula I
[1212] MOM-hydrolysisreaction was carried out by following a
procedure corresponding to the one described in Example 4. As such
the following compounds were made:
[1213]
4-{2-[4-Hydroxy-3-methoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-be-
nzoic acid methyl ester. Yield 90%. .sup.1H NMR (CDCl.sub.3, 300
MHz): 8.01, 7.91 (2d, J=8.4 Hz, 2H), 7.53, 7.36(2d, J=8.4 Hz, 2H),
7.17-6.93(m, 2H), 6.60-6.45(m, 2H), 5.80, 5.69(2s, 1H, OH), 5.34,
5.15 (2m, 1H), 3.95, 3.92 (2s, 6H, OMe), 3.37, 3.25 (2d, J=7.1 Hz,
2H), 1.75, 1.67,1.63, 1.56 (4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3,
75 MHz): 167.40, 167.37, 147.03,147.34,144.38,
132.77,130.43,129.88,129.34, 128.68, 128.10, 128.06, 127.59,
126.38, 122.10, 109.32, 106.44, 56.44, 56.22, 28.28, 26.28, 26.14,
18.28, 18.11 ppm. MS (ESI) m/z: 353 (M+H).sup.+.
[1214]
4-{2-[4-Hydroxy-3-methoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-ni-
trobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.20, 8.08 (2d,
J=8.8 Hz, 2H), 7.63, 7.43 (2d, J=8.8 Hz, 2H), 6.96-6.52 (m, 4H),
5.87, 5.74 (2s, 1H, OH), 5.20-5.13, 5.08(m, 1H), 3.95, 3.68 (2s,
3H), 3.44, 3.30 (2d, J=7.3 Hz, 2H), 1.77-1.57 (m, 6H) ppm. .sup.13C
NMR (CDCl.sub.3, 75 MHz): 147.04, 144.87, 144.79, 13415, 133.58,
130.13, 128.12, 126.41, 124.59, 124.06, 123.87, 122.52, 122.24,
109.22, 106.54, 56.51, 28.48, 28.18, 26.28, 26.13, 18.29, 18.09
ppm. MS (ESI) m/z: 340 (M+H).sup.+, 362 (M+Na).sup.+.
[1215]
4-{2-[4,5-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.01, 7.98
(2d, J=8.4 Hz, 2H), 7.53, 7.36(2d, J=8.4 Hz, 2H), 7.17-6.93(m, 2H),
6.80-6.60(m, 2H), 5.80 (br., 2H, OH), 5.20 (m, 1H), 3.92, 3.86 (2s,
3H, COOMe), 3.35, 3.19 (2d, J=7.14 Hz, 2H), 1.75, 1.67, 1.63, 1.56
(4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz): 168.02, 167.97,
144.12, 143.15, 142.63, 142.44, 133.47, 132.87, 132.72, 131.96,
130.48, 129.84, 129.34, 129.17, 128.25, 126.57, 123.17, 116.41,
52.69, 31.97, 26.17, 18.38, 18.28 ppm. MS (ESI) m/z: 339
(M+H).sup.+, 361 (M+Na).sup.+.
[1216]
4-{2-[3,4-Dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.01, 7.88
(2d, J=8.4 Hz, 2H), 7.53, 7.36(2d, J=8.4 Hz, 2H), 7.17-6.93(m, 2H),
6.80-6.60(m, 2H), 5.80 (br., 2H, OH), 5.34-5.15 (m, 1H), 3.89, 3.88
(2s, 3H, COOMe), 3.40, 3.25 (2d, J=6.36 Hz, 2H), 1.75, 1.67,1.63,
1.56 (4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz): 167.67,
143.77, 443.16, 142.24, 132.35, 130.48, 129.79, 129.58, 129.54,
129.41, 126.55, 122.35, 121.89, 121.83, 113.60, 113.47, 52.65,
52.61, 27.25, 26.21, 26.17, 26.08, 18.36, 18.23 ppm. MS (ESI) m/z:
339 (M+H).sup.+, 361 (M+Na).sup.+.
[1217]
4-{2-[3,4-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.02, 7.91
(2d, J=8.4 Hz, 2H), 7.53, 7.36(2d, J=8.4 Hz, 2H), 7.17-6.93(m, 2H),
6.80-6.60(m, 2H), 5.80 (br., 2H, OH), 5.22-5.11 (m, 1H), 3.92, 3.88
(2s, 3H, COOMe), 3.53, 3.38 (2d, J=6.36 Hz, 2H), 1.75, 1.67, 1.63,
1.56 (4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz): 167.76,
144.43, 443.94, 142.60, 132.35, 130.48, 129.79, 129.58, 129.54,
129.41, 126.55, 122.35, 121.89, 121.83, 113.60, 113.47, 52.65,
52.61, 27.25, 26.21, 26.17, 26.08, 18.51, 18.40 ppm. MS (ESI) m/z:
339 (M+H).sup.+, 361 (M+Na).sup.+.
[1218]
4-{2-[3,4-Dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-nitroben-
zene. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.16, 8.06 (2d, J=8.8 Hz,
2H), 7.70, 7.58(2d, J=8.8 Hz, 2H), 7.17-6.93(m, 2H), 6.80-6.60(m,
2H), 5.50 (br., 2H, OH), 5.34 (m, 1H), 3.33 (2d, J=6.74 Hz, 2H),
1.75, 1.67, 1.63, 1.56 (4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75
MHz): 146.69, 144.75, 144.60, 142.59, 131.55, 130.07, 128.94,
128.85, 127.04, 124.60, 123.83, 122.10, 121.82, 119.26, 113.74,
113.67, 27.29, 26.21, 26.12, 18.53, 18.23 ppm. MS (ESI) m/z: 326
(M+H).sup.+.
[1219]
4-{2-[3,4-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-nitroben-
zene. .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.33, 8.14 (2d, J=8.8 Hz,
2H), 7.70, 7.58(2d, J=8.8 Hz, 2H), 7.17-6.93(m, 2H), 6.80-6.60(m,
2H), 5.50 (br., 2H, OH), 5.34 (m, 1H), 3.67, 3.52 (2d, J=6.74 Hz,
2H), 1.75, 1.67,1.63, 1.56 (4s, 6H) ppm. .sup.13C NMR (CDCl.sub.3,
75 MHz): 146.81, 144.83, 144.20, 142.59, 131.55, 130.07, 128.94,
128.85, 127.04, 124.60, 123.83, 122.10, 121.82, 119.26, 113.74,
113.67, 27.29, 26.21, 26.12, 18.53, 18.42 ppm. MS (ESI) m/z: 326
(M+H).sup.+.
[1220]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 7.56 (m, 3H, ArH),
7.55 (d, J=8.82, H, ArH), 7.28 (m, 3H, ArH), 6.64 (m, 2H, ArH),
5.15 (t, H, vinylH), 5.10 (t, H, vinylH), 3.90 (s, 3H, OCH.sub.3),
3.49 (d, J=7.26, 2H, allylicH), 2.05 (s, 3H, CH.sub.3), 1.60 (s,
2H, CH.sub.2). MS (ESI) m/z: 388 (M+H).sup.+, 442 (M+Na).sup.+.
[1221]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.02 (d, J=8.46, H, ArH), 7.92 (d, J=8.37, H, ArH),
7.56 (d, J=8.28, H, ArH), 7.36 (d, J=8.25,2H, ArH), 6.95 (m, J=2H,
ArH), 6.62 (m, H, ArH), 5.25 (t, H, vinylH), 5.10 (t, H, vinylH),
3.90 (s, 3H, OCH.sub.3), 3.49 (d, J=7.26, 2H, allylicH), 2.05 (s,
3H, CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS (ESI) m/z: 421
(M+H).sup.+, 443 (M+Na).sup.+.
[1222]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-nitrobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm) 8.22 (d, J=8.85, 2H, ArH), 8.10 (d, J=8.82, H, ArH), 7.62 (d,
J=8.82, H, ArH), 7.17 (m, 2H, ArH), 7.04 (m, J=2H, ArH), 6.62 (m,
H, ArH), 5.15 (t, H, vinylH), 5.10 (t, H, vinylH), 3.90 (s, 3H,
OCH.sub.3), 3.49 (d, J=7.26, 2H, allylicH), 2.05 (s, 3H, CH.sub.3),
1.60 (s, 2H, CH.sub.2). MS (ESI) m/z: 407 (M+H).sup.+, 430
(M+Na).sup.+.
[1223]
4-{2-[3-(3,7-Dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm) 7.56 (m, 3H, ArH), 7.55 (d, J=8.82, H, ArH), 7.28 (m, 3H,
ArH), 6.64 (m, 2H, ArH), 5.15 (t, H, vinylH), 5.10 (t, H, vinylH),
3.90 (s, 3H, OCH.sub.3), 3.49 (d, J=7.26, 2H, allylicH), 2.05 (s,
3H, CH.sub.3), 1.60 (s, 2H, CH.sub.2). MS (ESI) m/z: 388
(M+H).sup.+, 442 (M+Na).sup.+.
[1224]
2-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one: .sup.1H NMR (CDCl.sub.3--CD.sub.3OD, 300 MHz):
7.63-7.31 (m, 4H), 7.20-5.30 (m, 5H), 3.36 (s, 2H), 2.20 (s, 3H)
ppm. .sup.13CNMR (CDCl.sub.3--CD.sub.3OD, 75 MHz): 175.20, 161.55,
152.88, 147.94, 140.15, 134.77, 134.25, 133.35, 133.23, 132.72,
131.24, 130.74, 125.51, 125.12, 123.06, 119.49, 119.87, 118.87,
118.79, 20.56, 16.29 ppm. MS (m/z): 309 (MH.sup.+).
Example 29
Preparation of prenyl-/qeranyl-substituted, MOM Compounds of
Formula I
[1225] A mixture of the aldehyde (1.0 eq.), phosphonium salt (1.2
eq.), and EtOLi (1.2 eq.) was stirred at room temperature for 1.5
h. Workup and purification was carried out following a procedure
corresponding to the one described in Example 3. As such, the
following compounds were made:
[1226]
4-{2-[3,5-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.04 (d, J=8.37, H, ArH), 7.85 (d, J=8.40, H, ArH),
7.47 (d, J=16.11, 2H, ArH), 7.20 (d, J=8.4, H, ArH), 6.99 (d,
J=2.34, H, ArH), 6.78 (d, J=2.34, H, ArH), 6.71 (d, J=2.37, H,
ArH), 5.21 (s, 4H, OCH.sub.2O), 4.93 (s, H, vinylH), 3.93 (d,
J=15.9, 2H, allylicH), 3.50 (s, 3H, OCH.sub.3), 3.48 (s, 3H,
OCH.sub.3), 1.68 (s, 3H, CH.sub.3), 1.60 (s, 3H, CH.sub.3).
[1227]
4-{2-[3,5-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-nitrobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.24
(d, J=8.82, H, ArH), 8.14 (d, J=8.7, H, ArH), 8.04 (d, J=8.91, H,
ArH), 7.62 (d, J=8.76, H, ArH), 7.34 (d, J=8.4, H, ArH), 7.28 (d,
J=2.34, H, ArH), 7.25 (d, J=2.34, H, ArH) 6.99 (d, J=2.37, H, ArH)
5.21 (s, 4H, OCH.sub.2O), 4.93 (s, H, vinylH), 3.93 (d, J=15.9, 2H,
allylicH), 3.50 (s, 3H, OCH.sub.3), 3.48 (s, 3H, OCH.sub.3), 1.68
(s, 3H, CH.sub.3), 1.60 (s, 3H, CH.sub.3).
[1228]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. (ppm) 8.03 (d, J=8.37, 2H, ArH), 7.92 (d, J=8.34, 2H,
ArH) 7.57 (d, J=8.4, 2H, ArH), 7.37 (d, J=8.28, 2H, ArH), 7.13 (d,
J=14.52, 2H, ArH), 6.64 (d, J=8.37, H, ArH), 6.59 (d, J=6.69, 2H,
ArH), 5.24 (s, 4H, OCH.sub.2), 5.16 (t, H, vinylH), 5.08 (t, H,
vinylH), 4.13 (s, 3H, OCH.sub.3), 3.42 (s, 6H, OCH.sub.3), 3.39 (d,
J=6.96, 2H, ArCH.sub.2), 2.00 (q, 2H, geranylCH.sub.2), 1.95 (q,
2H, geranylCH.sub.2), 1.77 (s, 3H, geranylCH.sub.3), 1.64(s, 3H,
geranylCH.sub.3), 1.56 (s, 3H, geranylCH.sub.3). MS (ESI) m/z: 495
(M+H).sup.+, 517 (M+Na).sup.+.
[1229]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl-}-nitrobenzene. .sup.1H y NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.21 (d, J=8.37, 2H, ArH), 8.10 (d, J=8.34, 2H, ArH)
7.62 (d, J=8.4, 2H, ArH), 7.44 (d, J=8.28, 2H, ArH), 7.41 (d,
J=14.52, 2H, ArH), 6.99 (d, J=8.37, H, ArH), 6.62 (d, J=6.69, 2H,
ArH), 5.24 (s, 4H, OCH.sub.2), 5.16 (t, H, vinylH), 5.08 (t, H,
vinylH), 3.42 (s, 6H, OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2),
2.00 (q, 2H, geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77
(s, 3H, geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s,
3H, geranylCH.sub.3). MS (ESI) m/z: 482 (M+H).sup.+, 504
(M+Na).sup.+.
[1230]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzonitrile. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.:
8.21 (d, J=8.37, 2H, ArH), 8.10 (d, J=8.34, 2H, ArH) 7.62 (d,
J=8.4, 2H, ArH), 7.44 (d, J=8.28, 2H, ArH), 7.41 (d, J=14.52, 2H,
ArH), 6.99 (d, J=8.37, H, ArH), 6.62 (d, J=6.69, 2H, ArH), 5.24 (s,
4H, OCH.sub.2), 5.16 (t, H, vinylH), 5.08 (t, H, vinylH), 3.42 (s,
6H, OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2), 2.00 (q, 2H,
geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77 (s, 3H,
geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s, 3H,
geranylCH.sub.3). MS (ESI) m/z: 462 (M+H.sup.+), 484
(M+Na).sup.+.
[1231]
4-{2-[3,5-Bis-methoxymethoxy-2,6-bis-(3-methyl-but-2-enyl)-phenyl]--
vinyl}-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.04 (d, J=8.37, 2H, ArH), 8.01 (d, J=8.40, H, ArH),
7.54 (d, J=16.11, 2H, ArH), 7.34 (d, J=8.4, H, ArH), 7.08 (d,
J=2.34, H, ArH), 6.64 (d, J=2.34, H, ArH), 6.60 (d, J=2.37, H,
ArH), 5.24 (s, 4H, OCH.sub.2O), 4.99 (s, 2H, vinylH), 3.90 (d,
J=15.9, 4H, allylicH), 3.57 (s, 3H, OCH.sub.3), 3.49 (s, 3H,
OCH.sub.3), 1.76 (s, 6H, CH.sub.3), 1.60 (s, 6H, CH.sub.3).
[1232]
4-{2-[3,5-Bis-methoxymethoxy-2,6-bis-(3-methyl-but-2-enyl)-phenyl]--
vinyl}-nitrobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.:
8.13 (d, J=8.82, 2H, ArH), 7.08 (d, J=8.7, 2H, ArH), 6.95 (d,
J=8.91, H, ArH), 6.62 (d, J=8.76, 4H, ArH), 5.23 (s, 4H,
OCH.sub.2O), 5.11 (s, 2H, vinylH), 3.59 (d, J=15.9, 4H, allylicH),
3.50 (s, 3H, OCH.sub.3), 3.48 (s, 3H, OCH.sub.3), 1.76 (s, 6H,
CH.sub.3), 1.67 (s, 6H, CH.sub.3).
[1233]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.03 (d, J=8.41, H, ArH), 7.92 (d, J=6.67, H, ArH),
7.57 (d, J=8.43, H, ArH), 7.37 (d, J=8.28, H, ArH), 6.97 (s, H,
ArH), 6.57 (s, 2H, ArH), 6.64 (s, 1H, ArH), 5.25 (s, 4H,
OCH.sub.2), 5.22 (t, H, vinylH), 4.99 (s, 3H, OCH.sub.3), 3.91 (d,
2H, allylicH), 3.40 (s, 6H, OCH.sub.3), 1.77 (s, 3H, CH.sub.3),
1.71 (s, 3H, CH.sub.3). MS (ESI) m/z: 427 (M+H).sup.+, 449
(M+Na).sup.+.
[1234]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-nitrobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.22
(d, J=8.79, H, ArH), 8.10 (d, J=8.85, H, ArH), 7.59 (d, J=8.82, H,
ArH), 7.44 (d, J=8.82, H, ArH), 6.98 (s, 2H, ArH), 6.62 (s, 2H,
ArH), 6.59 (s, 1H, ArH), 5.25 (s, 4H, OCH.sub.2), 5.22 (t, H,
vinylH), 3.51 (s, 6H, OCH.sub.3), 3.42 (d, 2H, allylicH), 1.77 (s,
3H, CH.sub.3), 1.71 (s, 3H, CH.sub.3). MS (ESI) m/z: 414
(M+H).sup.+, 436 (M+Na).sup.+.
[1235]
4-{2-[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzonitrile. .sup.1H N MR (CDCl.sub.3, 300 MHz) .delta. (ppm)
7.54 (m, 3H, ArH), 7.38 (d, J=8.85, 2H, ArH), 7.36 (m, H, ArH),
6.64 (m, 2H, ArH), 5.25 (s, 4H, OCH.sub.2), 5.22 (t, H, vinylH),
3.51 (s, 6H, OCH.sub.3), 3.42 (d, 2H, allylicH), 1.77 (s, 3H,
CH.sub.3), 1.71 (s, 3H, CH.sub.3). MS (ESI) m/z: 394 (M+H).sup.+,
416 (M+Na).sup.+.
Example 30
Preparation of prenyl-/qeranyl-substituted, phenolic Compounds of
Formula I
[1236] MOM-hydrolysis reaction was carried out by following a
procedure corresponding to the one described in Example 4. As such
the following compounds were made:
[1237]
4-{2-[3,5-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
8.04 (d, J=8.37, H, ArH), 7.85 (d, J=8.40, H, ArH), 7.47 (d,
J=16.11, 2H, ArH), 7.20 (d, J=8.4, H, ArH), 6.99 (d, J=2.34, H,
ArH), 6.78 (d, J=2.34, H, ArH) 6.71 (d, J=2.37, H, ArH) 4.93 (t, H,
vinylH), 3.93 (d, J=15.9, 2H, allylicH), 1.68 (s, 3H, CH.sub.3),
1.60 (s, 3H, CH.sub.3). MS (ESI) m/z: 339 (M+H).sup.+.
[1238]
4-{2-[3,5-Dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-nitroben-
zene. Cis-isomer: .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
8.03 (d, J=1.83, 2H, ArH), 8.01 (d, J=1.8, H, ArH), 7.27 (d,
J=8.76, 2H, ArH), 6.87 (d, J=12.09, H, ArH), 6.66 (d, J=12.09, H,
ArH), 6.32 (d, J=2.4, H, ArH) 6.15 (d, J=2.4, H, ArH) 5.05 (t, H,
vinylH), 3.30 (d, J=15.9, 2H, allylicH), 1.78 (s, 3H, CH.sub.3),
1.67 (s, 3H, CH.sub.3). MS (ESI) m/z: 326 (M+H).sup.+, 348
(M+Na).sup.+. Trans-isomer: .sup.1H NMR (CDCl.sub.3, 300 MHz) 6
(ppm) 8.24 (d, J=8.76, 2H, ArH), 7.61 (d, J=7.76, 2H, ArH), 7.49
(d, J=16.05, 2H, ArH), 6.99 (d, J=16.02, H, ArH), 6.37 (d, J=2.37,
H, ArH), 5.21 (t, H, vinylH), 3.45 (d, J=6.63, 2H, allylicH), 1.83
(s, 3H, CH.sub.3), 1.75 (s, 3H, CH.sub.3). MS (ESI) m/z: 326
(M+H).sup.+, 348 (M+Na).sup.+.
[1239]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzoic acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 8.03 (d, J=8.37, 2H, ArH), 7.92 (d, J=8.34, 2H, ArH)
7.57 (d, J=8.4, 2H, ArH), 7.37 (d, J=8.28, 2H, ArH), 7.13 (d,
J=14.52, 2H, ArH), 6.64 (d, J=8.37, H, ArH), 6.59 (d, J=6.69, 2H,
ArH), 5.16 (t, H, vinylH), 5.08 (t, H, vinylH), 4.13 (s, 3H,
OCH.sub.3), 3.39 (d, J=6.96, 2H, ArCH.sub.2), 2.00 (q, 2H,
geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77 (s, 3H,
geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s, 3H,
geranylCH.sub.3). MS (ESI) m/z: 407 (M+H).sup.+, 429
(M+Na).sup.+.
[1240]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-nitrobenzene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.21
(d, J=8.37, 2H, ArH), 8.10 (d, J=8.34, 2H, ArH) 7.62 (d, J=8.4, 2H,
ArH), 7.44 (d, J=8.28, 2H, ArH), 7.41 (d, J=14.52, 2H, ArH), 6.99
(d, J=8.37, H, ArH), 6.62 (d, J=6.69, 2H, ArH), 5.16 (t, H,
vinylH), 5.08 (t, H, vinylH), 3.39 (d, J=6.96, 2H, ArCH.sub.2),
2.00 (q, 2H, geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77
(s, 3H, geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s,
3H, geranylCH.sub.3). MS (ESI) m/z: 394 (M+H.sup.+), 416
(M+Na.sup.+).
[1241]
4-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.21
(d, J=8.37, 2H, ArH), 8.10 (d, J=8.34, 2H, ArH) 7.62 (d, J=8.4, 2H,
ArH), 7.44 (d, J=8.28, 2H, ArH), 7.41 (d, J=14.52, 2H, ArH), 6.99
(d, J=8.37, H, ArH), 6.62 (d, J=6.69, 2H, ArH), 5.16 (t, H,
vinylH), 5.08 (t, H, vinylH), 3.39 (d, J=6.96, 2H, ArCH.sub.2),
2.00 (q, 2H, geranylCH.sub.2), 1.95 (q, 2H, geranylCH.sub.2), 1.77
(s, 3H, geranylCH.sub.3), 1.64(s, 3H, geranylCH.sub.3), 1.56 (s,
3H, geranylCH.sub.3). MS (ESI) m/z: 374 (M+H).sup.+, 396
(M+Na).sup.+.
[1242]
4-{2-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
8.03 (d, J=8.41, H, ArH), 7.92 (d, J=6.67, H, ArH), 7.57 (d,
J=8.43, H, ArH), 7.37 (d, J=8.28, H, ArH), 6.97 (s, H, ArH), 6.57
(s, 2H, ArH), 6.64 (s, 1H, ArH), 5.22 (t, H, vinylH), 4.99 (s, 3H,
OCH.sub.3), 3.91 (d, 2H, allylicH), 1.77 (s, 3H, CH.sub.3), 1.71
(s, 3H, CH.sub.3). MS (ESI) m/z: 338 (M+H).sup.+, 361
(M+Na).sup.+.
[1243]
4-{2-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-nitroben-
zene. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 8.22 (d,
J=8.76, H, ArH), 8.19 (d, J=8.85, H, ArH), 7.60 (d, J=8.82, H,
ArH), 7.43 (d, J=8.82, H, ArH), 7.07 (s, 2H, ArH), 6.63 (s, 2H,
ArH), 6.26 (s, 1H, ArH), 5.22 (t, H, vinylH), 3.42 (d, 2H,
allylicH), 1.77 (s, 3H, CH.sub.3), 1.71 (s, 3H, CH.sub.3). MS (ESI)
m/z: 326 (M+H).sup.+, 348 (M+Na).sup.+.
[1244]
4-{2-[3,5-Dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl-benzonitr-
ile. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 7.54 (m, 3H,
ArH), 7.38 (d, J=8.85, 2H, ArH), 7.36 (m, H, ArH), 6.64 (m, 2H,
ArH), 5.22 (t, H, vinylH), 3.42 (d, 2H, allylicH), 1.77 (s, 3H,
CH.sub.3), 1.71 (s, 3H, CH.sub.3). MS (ESI) m/z: 306 (M+H).sup.+,
328 (M+Na).sup.+.
Example 31
2-Bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol
[1245] 46
[1246] (3-Bromo-4-methoxymethoxy-phenyl)-methanol (250 mg) was
dissolved in DCM (20 mL), pyridine (0.15 mL) was added followed by
thionyl chloride (0.15 mL), and the mixture was stirred for 1 hour.
The mixture was partitioned with water and ethyl acetate. The
solvent removal gave
2-bromo-4-chloromethyl-1-methoxymethoxy-benzene as a clear oil,
which was used directly in next step. The oil was dissolved in
acetone, and sodium iodide (300 mg) was added. The mixture was
stirred overnight and a yellow precipitate was formed. Extraction
with ethyl acetate and water gave
2-iodo-4-chloromethyl-1-methoxymethoxy-benzene as a brown oil that
turned into solid after standing. .sup.1HNMR (CDCl.sub.3, 300 MHz):
7.58 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0, 8.5 Hz, 1H), 7.07 (d,
J=8.5 Hz, 1H), 5.25 (s, 2H), 4.39(s, 2H), 3.51 (s, 3H) ppm. The
iodide (170 mg) and trimethylphosphate (0.1 mL) were mixed and
stirred at 120.degree. C. for 1 hour. After cooling to room
temperature, the reaction mixture was directly applied to silica
gel column eluting with 5% MeOH in DCM to yield 150 mg of the
corresponding phosphonate.
[1247] To a mixture of phosphonate (200 mg) and
3-(3-methyl-but-2-enyl)-4-- (tetrahydro-pyran-2-yloxy)-benzaldehyde
(200 mg) in DMF (10 mL) was added NaH (80 mg). The mixture was
stirred at room temperature for 2 hours, and partitioned with ethyl
acetate and water. After evaporation of the solvent, purification
by flash chromatography eluted with 20% EtOAc in hexane, gave
2-[4-[2-(4-bromo-3-methoxymethoxy-phenyl)-vinyl]-2-(3-methyl-
-but-2-enyl)-phenoxy]-tetrahydro-pyran as an oil (200 mg). MS
(m/z): 509, 511 (MNa.sup.+).
[1248] The above MOM ether was stirred overnight in MeOH with
several drops of conc. HCl. After evaporation of the solvent and
purification by flash chromatography (hexane:EtOAc=1:1),
2-bromo-4-[4-hydroxy-3-(3-methyl- -but-2-enyl-phenyl)-vinyl]-phenol
(40 mg) was obtained. .sup.1HNMR (CDCl.sub.3, 300 MHz): 7.60-6.80
(m, 8H, aromatic), 5.53 (s, 1H, OH), 5.33 (m, 1H, vinyl), 5.25 (s,
1H, OH), 3.35 (d, J=3.1 Hz, 2H), 1.08 (s, 6H, 2Me) ppm. .sup.13CNMR
(CDCl.sub.3, 75 MHz): 154.16, 151.30, 135.13, 132.18, 129.98,
129.43, 128.16, 127.72, 125.63, 124.41, 121.54, 116.15, 116.07,
29.89, 25.84, 17.94 ppm. MS (m/z): 359, 361 (MH.sup.+).
Example 32
5-{4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydr-
o-pyrazol-3-one
[1249] 47
[1250] A solution of
3-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl-
}-3-oxo-propionic acid ethyl ester (400 mg) and hydrazine (excess)
in EtOH (30 mL) was stirred at 90.degree. C. for 5 hours.
Evaporation and purification by flash chromatography eluted with
5-10% MeOH in DCM gave
5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihyd-
ro-pyrazol-3-one as a yellow oil (260 mg). .sup.1H NMR (CDCl.sub.3,
300 MHz): 7.95 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H),
7.40-7.00(m, 7H), 6.90 (d, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.50 (d,
J=12.0 Hz, 1H) 5.21, 5.07(2s, 4H, MOM), 3.78(s, 2H), 33.51, 3.41
(2s, 6H, MOM) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz170.65, 154.82,
147.23, 147.15, 140.38, 138.53, 131.56, 129.84, 129.68, 129.29,
128.88, 126.17, 125.69, 123.72, 119.42, 117.83, 116.67, 56.69,
56.52, 40.03 ppm. MS: 459 (MH.sup.+).
Example 33
5-{4-[2-(3,4-Dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazol-
-3-one
[1251] A solution of
5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl-
}-2-phenyl-2,4-dihydro-pyrazol-3-one (the cruce reaction product
from Example 32) and conc. HCl in MeOH was stirred at room
temperature for overnight. Evaporation of the solvent and
purification by flash chromatography eluting with 10-15% MeOH in
DCM, gave
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazo-
l-3-one. .sup.1H NMR (CD.sub.3OD+CDCl.sub.3, 300 MHz): 7.75-6.45(m,
all aromatic peaks). .sup.13C NMR (CD.sub.3OD+CDCl.sub.3, 75 MHz):
168.65, 148.27, 144.57, 144.36, 142.01, 132.16, 130.44, 129.07,
128.75, 126.94, 121.37, 120.82, 115.66, 115.08, 113.49. MS: 347 and
371 (MH.sup.+).
Example 34
2-{4-[2-(4-Hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-p-
yrazol-3-one
[1252] 48
[1253] 34A. 2-(4-Bromo-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one
(105 mg) was dissolved in DME (ethylene glycol dimethyl ether, 2
mL), then Pd(PPh.sub.3).sub.4 (15 mg, 3%mol) was added. The air was
exchanged with argon and the mixture was stirred for 10 min. A
solution of 2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl-boronic
acid (90 mg) in DME (1 mL) was added followed by sodium carbonate
solution (2M, 0.75 mL). The mixture was stirred for 1 hour at
110.degree. C. After partitioning with ethyl acetate and water and
purification over silica gel eluting with 50% EtOAc in hexane gave
140 mg of 2-{4-[2-(3-methoxy-4-methoxymethoxy-phenyl-
)-vinyl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one as an oily
product, which was then hydrolyzed with conc. HCl in methanol.
Evaporation of the solvent and purification over silica gel gave
2-{4-[2-(4-hydroxy-3-methox-
y-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one as a
light yellow solid (90 mg). .sup.1HNMR (CDCl.sub.3, 300 MHz): 7.74
(d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 6.77 (s, 3H), 6.48 (s
2H), 5.66 (s, 1H), 3.63 (s, 3H), 3.42 (s, 2H), .sup.20, 19(s, 3H)
ppm. .sup.13CNMR (CDCl.sub.3--CD.sub.3OD, 75 MHz): 170.48, 156.45,
146.04, 144.89, 136.70, 134.28, 129.97, 129.41, 128.00, 122.47,
118.46, 114.21, 111.14, 55.72, 43.10, 17.05 ppm. MS (m/z): 323
(MH.sup.+).
[1254] 34B. Similarly, by following the procedure of Example 34A,
5-methyl-2-(4-styryl-phenyl)-2,4-dihydro-pyrazol-3-one was made.
.sup.1HNMR (DMSO-d.sub.6, 300 MHz): 8.10-7.00 (m, 11H), 5.5 (br.,
0.45H, contributed from enol form), 3.55(s, 1.55H, contributed from
amide form), 2.25 and 2.21 (2s, 3H, Me) ppm. .sup.13CNMR
(DMSO-d.sub.6, 75 MHz): 137.95, 134.32, 129.59, 128.72, 128.59,
128.42, 127.81, 127.27, 120.89, 14.84 ppm. MS (m/z): 277
(MH.sup.+).
Example 35
N-{4-[2-(3,4-Dihydroxyphenyl)-trans-vinyl]-benzenesulfonyl}-morpholine
[1255] 49
[1256] 35A. Preparation of N-(4-bromobenzenesulfonyl)morpholine. To
a solution of 4-bromobenzenesulfonylchloride (2.555 g, 10 mmol) in
CH.sub.2Cl.sub.2 (40 mL) was added a solution of triethylamine
(1.53 mL, 11 mmol) and morpholine (0.96 mL, 11 mmol) at room
temperature under argon atmosphere. The solution was stirred for 2
h and the mixture was purified by flash chromatography eluted with
mixed solvent of EtOAc: hexanes (1:2, v/v) to provide 3.028 g (9.89
mmol, yield 98.9%) of N-(4-bromobenzenesulfonyl)morpholine as a
white solid.
[1257] 35B. Preparation of N-(4-bromobenzenesulfonyl)piperidine.
Similarly, following the procedure of Example 35A and employing
commercially available 4-bromobenzenesulfonamide,
N-(4-bromobenzenesulfon- yl)piperidine was prepared in 99.3% yield.
MS (ESI) m/z: 304 and 306 (M+1).sup.+, and 326 and 328
(M+23).sup.+.
[1258] 35C. Preparation of 3,4-di(methoxymethoxy)styrene. A
solution of CH.sub.3PPh.sub.3Br (10.72 g, 30 mmol) in anhydrous DMF
(50 mL) under argon atmosphere was cooled to 0-5.degree. C. Sodium
hydride (2.0 g, 60% suspension in mineral oil, 50 mmol, 1.66 eq.)
was added in portions. The mixture was stirred at room temperature
for 1 hour and then 3,4-di-(methoxymethoxy)-benzaldehyde (6 g,
26.52 mmol) was added in portions. The resulting mixture was
stirred at room temperature until completion of the reaction (about
2 hours). The mixture was cooled again to 0-5.degree. C. and water
(5 mL) was slowly injected to decompose the excess NaH. After an
additional 10 min, the mixture was mixed with water (200 mL) and
extracted with CH.sub.2Cl.sub.2 (2.times.200 mL). The organic layer
was washed with water (200 mL), dried over anhydrous sodium
sulfate, filtered and evaporated. The residue was mixed with
hexanes and loaded to a silica gel column that was eluted with a
mixed solvent of hexane and EtOAc to afford, after evaporation,
3.974 g of 3,4-di(methoxymethoxy)styrene as a yellowish oil (17.72
mmol, yield 66.8%). MS (ESI) m/z: 225 (M+1).sup.+ and 247
(M+23).sup.+.
[1259] 35D. Preparation of
N-{4-[2-(3,4-di(methoxymethoxy)phenyl)-trans-vi-
nyl]benzene-sulfonyl}morpholine
N-(4-bromobenzenesulfonyl)morpholine (1.0 g, 3.266 mmol) was mixed
with (n-Bu).sub.4NBr (TBAB, 1.05 g, 3.266 mmol), K.sub.2CO.sub.3
(0.451 g, 3.266 mmol) and LiCl (0.1384 g, 3.266 mmol under argon
atmosphere. Then dry DMF (25 mL) and 3,4-di(methoxymethoxy)st-
yrene (0.7324 g, 3.226 mmol) were added, followed by the catalyst
Pd(OAc).sub.2 (73 mg, 0.3266 mmol). The mixture was heated between
80-90.degree. C. under argon atmosphere for 24 hours. After removal
of the DMF solvent, the residue obtained was loaded to a silica gel
column with CH.sub.2Cl.sub.2 as solvent. The column was eluted with
CH.sub.2Cl.sub.2/EtOAc (2:1, v/v) to yield 1.205 g of
N-(4-[2-(3,4-di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonyl}morpho-
line as a yellowish solid (2.6805 mmol, yield 82.1%). .sup.1H NMR
(CDCl.sub.3, 300.16 MHz) .delta. (ppm) 7.72 (d, J=8.5 Hz, 2H), 7.64
(d, J=8.5 Hz, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.20-7.13 (m, 3H), 7.00
(d, J=16.2 Hz, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 3.77-3.74 (m, 4H),
3.56 (s, 3H), 3.53 (s, 3H) and 3.04-3.01 (m, 4H). MS (ESI) m/z: 450
(M+1).sup.+ and 472 (M+23).sup.+.
[1260] 35E. Similarly, by following the procedure described in
Example 35D and substituting the sulfonamide accordingly, the
following compounds were obtained:
[1261]
N-{4-[2-(3,4-Di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonyl}
piperidine. .sup.1H NMR (CDCl.sub.3, 300.16 MHz) .delta. (ppm) 7.72
(d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.37 (d, J=1.7 Hz, 1H),
7.20-7.13 (m, 3H), 7.00 (d, J=16.3 Hz, 1H), 5.30 (s, 2H), 5.27 (s,
2H), 3.56 (s, 3H), 3.53 (s, 3H), 3.00 (m, 4H), 1.67-1.61 (m, 4H)
and 1.44-1.42 (m, 2H). MS (ESI) m/z: 448 (M+1).sup.+ and 470
(M+23).sup.+.
[1262]
4-[2-(3,4-Di(methoxymethoxy)phenyl)-trans-vinyl]benzenesulfonamide.
.sup.1H NMR (DMSO-d.sub.6, 300.16 MHz) .delta. (ppm) 7.78 (d, J=8.7
Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.39 (d, J=1.9 Hz, 1H), 7.33 (s,
2H), 7.32 (d, J=16.4 Hz, 1H), 7.22 (dd, J=8.4 & 2.0 Hz, 1H),
7.17 (d, J=16.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 5.24 (s, 2H), 5.20
(s, 2H), 3.42 (s, 3H) and 3.39 (s, 3H). MS (ESI) m/z:
380(M+1).sup.+, 397 (M+18).sup.+ and 402 (M+23).sup.+.
[1263] 35F. Preparation of
N-{4-[2-(3,4-Dihydroxyphenyl)-trans-vinyl]benze-
nesulfonyl}-morpholine
N-{4-[2-(3,4-Di(methoxymethoxy)phenyl)-trans-vinyl]-
benzenesulfonyl} morpholine (0.6 g, 1.3347 mmol) was dissolved in a
mixed solvent of MeOH (100 mL) and CH.sub.2Cl.sub.2 (60 mL). The
homogeneous solution was bubbled with argon gas. Water (0.2 g,
11.11 mmol) and concentrated hydrochloric acid (0.9 mL, 10.8 mmol)
were added and stirred for 45 hours. The solvents were removed by
evaporation and the solid residue was washed with water for several
times. The solid was dried under high vacuum in the presence of
Drierite providing 0.4388 g of
N-{4-[2-(3,4-dihydroxyphenyl)-trans-vinyl]benzenesulfonyl}-morpholine
as a yellowish solid (1.214 mmol, yield 91.0%). .sup.1H NMR
(Acetone-D.sub.6 and DMSO-d.sub.6, 300.16 MHz) .delta. (ppm) 9.05
& 9.03 (2s, 0.64H), 8.81 & 8.79 (2s, 0.65H), 7.81 (d, J=8.5
Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.32 (d, J=16.3 Hz, 1H), 7.13-7.04
(m, 2H), 6.96 (dd, J=8.2 & 1.9 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H),
3.68-3.65 (m, 4H) and 2.94-2.91 (m, 4H). MS (ESI) m/z: 362
(M+1).sup.+, 384 (M+23).sup.+ and 745 (2M+23).sup.+.
[1264] 35G. Similarly, by following the procedure described in 35F
and substituting the sulfonamide accordingly, the following
compounds were obtained:
[1265]
N-{4-[2-(3,4-Dihydroxyphenyl)-trans-vinyl]benzenesulfonyl}piperidin-
e. .sup.1H NMR (DMSO-d.sub.6, 300.16 MHz) .delta. (ppm) 9.27 (s,
1H), 9.01 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H),
7.25 (d, J=16.4 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J=16.4 Hz, 1H),
6.92 (dd, J=8.2 & 1.9 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H),
2.88-2.84 (m, 4H), 1.60-1.45 (m, 4H) and 1.40-1.30 (m, 4H). MS
(ESI) m/z: 360 (M+1).sup.+, 382 (M+23)+ and 741 (2M+23).sup.+.
[1266] 4-[2-(3,4-Dihydroxyphenyl)-trans-vinyl]benzenesulfonamide.
.sup.1H NMR (DMSO-d.sub.6, 300.16 MHz) .delta. (ppm) 9.24 (s, 1H),
9.01 (s, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.31
(s, 2H), 7.22 (d, J=16.3 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 6.97 (d,
J=16.3 Hz, 1H), 6.90 (dd, J=8.2 & 1.9 Hz, 1H) and 6.73 (d,
J=8.2 Hz, 1H). MS (ESI) m/z: 275 (M-16)+, 292 (M+1).sup.+, 314
(M+23).sup.+ and 605 (2M+23).sup.+.
Example 36
5-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl
[1267] 50
[1268] 36A. Preparation of 2-(tributyltin)pyridine A solution of
2-bromopyridine (9.48 g, 60 mmol) in absolute THF (100 mL) was
cooled to -78.degree. C. During 25 minutes, n-BuLi (25 mL, 2.5 M
hexanes solution, 62.5 mmol) was added slowly. The mixture was
stirred for additional 30 minutes and n-Bu.sub.3SnCl (18.6 mL with
96% purity, 66 mmol) was added dropwise. The reaction mixture was
stirred at -78.degree. C. for an additional 1 hour and was slowly
warmed to room temperature during 1 hour, then stirred at room
temperarture for 30 minutes. The solution was poured onto ice (200
g) and extracted with CH.sub.2Cl.sub.2 (2.times.200 mL). The
organic layer was washed with water, dried over anhydrous sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography eluted with hexanes:EtOAc (4:1, v/v) to afford
2-(tributyltin)pyridine as a yellowish liquid (18.35 g, 49.85 mmol,
yield 83.1%). .sup.1H NMR (CDCl.sub.3, 300.16 MHz) .delta. (ppm)
8.74-8.72 (m, 1H), 7.49-7.46 (m, 1H), 7.42-7.38 (m, 1H), 7.13-7.09
(m, 1H), 1.59-1.51 (m, 6H), 1.39-1.27 (m, 6H), 1.15-1.09 (m, 6H)
and 0.88 (t, J=7.4 Hz, 9H). MS (ESI) m/z=366, 368 and 370
(M+1).sup.+.
[1269] 36B. Preparation of 5-methyl-[2,2']bipyridinyl A solution of
2-(tributyltin)pyridine (9.20 g, 25 mmol) and
2-bromo-5-methylpyridine (4.3 g, 25 mmol) in toluene was bubbled
with argon gas for 10 min. The catalyst Pd(PPh.sub.3).sub.4 (0.29
g, 0.25 mmol, 1 mol %) was added and the mixture was refluxed under
argon atmosphere for 3 days. Removal of solvent gave an oil that
was purified by chromatography over silica gel eluted with
CH.sub.2Cl.sub.2 and then EtOAc. The brown liquid obtained was
dried overnight under high vacuum providing 4.1073 g of
5-methyl-[2,2']bipyridinyl as a brown liquid (24.13 mmol, yield
96.5%). .sup.1H NMR (CDCl3, 300.16 MHz) .delta. (ppm) 8.66 (ddd,
J=4.8, 1.8 & 0.9 Hz, 1H), 8.51 (dt, J=2.9 & 0.7 Hz, 1H),
8.35 (dt, J=8.0 & 1.1 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 7.80
(td, J 7.7 & 1.8 Hz, 1H), 7.63 (ddd, J=8.1, 1.5 & 0.7 Hz,
1H), 7.28 (ddd, J=7.5, 4.8 & 1.2 Hz, 1H) and 2.39 (s, 3H). MS
(ESI) m/z: 171 (M+1).sup.+ and (2M+23).sup.+.
[1270] 36C. Preparation of 5-(bromomethyl)-[2,2']bipyridinyl A
solution of 5-methyl-[2,2']bipyridinyl (3.96 g, 23.264 mmol) in
CCl4 (80 mL) was bubbled with argon gas. NBS (5.507 g, 30.94 mmol,
1.33 eq) and (PhCOO).sub.2 (0.2922 g, 1.21 mmol, 5 mol %) were
added. The mixture was refluxed under argon atmosphere for 2 days.
After being cooled to room temperature, the solid was removed by
filtration, the filtrate was evaporated, and the residue
chromatographed on a silica gel column eluted with a mixed solvent
of CH.sub.2Cl.sub.2 and EtOAc (1:1, v/v). A mixture of three
components was obtained (3.88 g). The mixture contained the desired
monobromide of 5-(bromomethyl)-[2,2']bipyridinyl (69.8 wt. %, 10.87
mmol, yield 46.7%), a dibromo by-product (20.2 wt. %, yield 10.3%)
and the unreacted starting methylbipyridine (10 wt. %, 9.8% of
starting amount). .sup.1H NMR (CDCl3, 300.16 MHz) for the
monobromide .delta. (ppm) 8.71-8.67 (m, 2H), 8.40 (d, J=8.0 Hz,
2H), 7.87-7.80 (m, 2H), 7.35-7.26 (m, 1H) and 4.54 (s, 2H) ppm. MS
for the monobromide (ESI) m/z: 249 and 251 (M.sup.+).
[1271] 36D. Preparation of (5-[2,2]bipyridinyl)methyl
triphenylphosphine bromide The mixture obtained in Example 36C
above (3.88 g, 10.87 mmol of the monobromide) was mixed with
toluene (100 mL) and filtered to remove insoluble solid. To the
filtrate was added triphenylphosphine (4.08 g, 15.55 mmol) and the
mixture was refluxed under argon atmosphere for 5.5 hours. After
being cooled to room temperature, the solid was collected by
filtration and washed with hexanes. The lightly brown solid was
pumped under high vacuum to afford 4.761 g of
(5-[2,2']bipyridinyl)methyl triphenylphosphine bromide (9.31 mmol,
yield 85.6%). MS (ESI) m/z: 431 (M.sup.+ without Br.sup.-).
[1272] 36E. Preparation of
5-{2-[3,4-bis(methoxymethoxy)phenyl]vinyl}-[2,2- ']bipyridinyl
(5-[2,2']Bipyridinyl)methyl triphenylphosphine bromide (2.00 g,
3.91 mmol) and 3,4-di(methoxymethoxy)-benzaldehyde (0.8847 g, 3.91
mmol) were mixed into absolute ethanol (50 mL) under argon
atmosphere. To this heterogenerous solution was added dropwise 5.5
mL of 1.0 M EtOLi solution in EtOH (5.5 mmol). The mixture became
homogeneous brown solution after the completion of the addition.
The reaction solution was stirred at room temperature for 6 hours.
Removal of the solvent gave oil that was flashed through a short
silica gel column to remove dark color and salts with EtOAc as
solvent. Ph.sub.3PO was yesprecipitated from a mixed solvent of
EtOAc and hexanes. The filtrate was concentrated and the resulting
oil was purified by chromatography over silica gel eluted with a
mixed solvent of EtOAc and hexanes (1:1, v/v). The resulting yellow
oil was pumped overnight under high vacuum to provide 1.29 g of
5-{2-[3,4-bis(methoxymethoxy) phenyl]vinyl}-[2,2']bipyridinyl
(3.409 mmol, yield 87.2%) as a Z/E mixture with the ratio of about
2:1. .sup.1H NMR (CDCl3, 300.16 MHz) .delta. (ppm) 8.75 (d, 0.45H),
8.70-8.67 (m, 0.37H), 8.66 (ddd, J=4.8,1.8 & 0.9 Hz, 1H), 8.56
(dt, J=2.2 & 0.7 Hz, 1H), 8.42-8.37 (m, 0.92H), 8.35 (dt, J=8.0
& 1.1 Hz, 1H), 8.26 (dd, J=8.2 & 0.4 Hz, 1H), 7.96 (dd,
0.47H), 7.83-7.77 (m, 1.44H), 7.72 (ddd, J=8.7, 2.2 & 0.5 Hz,
1H), 7.39 (d, 0.47H), 7.31-7.26 (m, 1.39H), 7.17-7.14 (m, 1.43H),
7.07 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.01 (d, 0.5H),
6.89 (ddd, J=2.0 & 0.5 Hz, 1H), 6.69 (d, J=12.1 Hz, 1H), 6.53
(d, J=12.1 Hz, 1H), 5.31 (s, 0.9H), 5.27 (s, 0.96H), 5.22 (s, 2H),
5.07 (s, 1.98H), 3.57 (s, 1.35H), 3.53 (s, 1.38H), 3.51 (s, 3.0H)
and 3.37 (s, 2.91H). MS (ESI) m/z: 379 (M+1).sup.+.
Example 37
5-{2-[3,4-Dihydroxyphenyl]vinyl}-[2,2']bipyridinyl
[1273] A solution of
5-{2-[3,4-bis(methoxymethoxy)phenyl]vinyl}-[2,2']bipy- ridinyl
(0.85 g, 2.246 mmol), concentrated hydrochloric acid (5 mL) and
water (2 mL) in methanol (100 mL) was stirred under argon
atmosphere at room temperature for 15 hoursw. Water (50 mL) was
added to the mixture and methanol was rotary evaporated. More water
(100 mL) was added and the resulting mixture was neutralized to pH
7 with sodium hydroxide solution. The solid precipitate was
collected by filtration and washed with water and a mixed solvent
of hexane and EtOAc (3:1, v/v). The resulting orange solid was
dried under high vacuum giving 0.5559 g of
5-{2-[3,4-dihydroxyphenyl]vinyl}-[2,2']bipyridinyl (1.915 mmol,
yield 85.3%) as a Z/E mixture. .sup.1H NMR (MeOH, 300.16 MHz): 8.71
(d, J=1.7 Hz, 0.70H), 8.65-8.62 (m, 1.56H), 8.51 (d, J=1.4 Hz,
1.03H), 8.31-8.23 (m, 2.29H), 8.16 (d, J=8.3 Hz, 1.0OH), 8.0 (dd,
J=2.0 Hz, 0.78H), 7.94-7.89 (m, 1.63H), 7.80 (dd, J=8.2 & 2.0
Hz, 1.04H), 7.44-7.40 (m, 1.52H), 7.23 (d, J=16.4 Hz, 0.74H), 7.08
(d, J=1.8 Hz, 0.71H), 7.00 (d, J=16.4 Hz, 0.74H), 6.95 (dd, J=8.2
& 1.8 Hz, 0.70H), 6.77 (d, J=8.2 Hz, 0.74H), 6.72-6.67 (m,
2.80H), 6.61 (dd, J=8.1 & 1.5 Hz, 1.01H), 6.47 (d, J=12.1 Hz,
1.0OH). UV-Vis (MeOH): E.sub.max=252 nm, 288 nm and 352 nm. MS
(ESI) m/z: 291 (M+1).sup.+.
Example 38
5-{2-[3,4-Bis(methoxymethoxy)phenyl]vinyl}-[2,2']Bipyridinyl,
Zn(II) Chloride
[1274] 51
[1275] 38A. To a solution of zinc(II) chloride (25.57 mg, 0.1876
mmol) in acetone (3 mL) was added a solution of
5-{2-[3,4-bis(methoxymethoxy)pheny- l]vinyl}-[2,2']bipyridinyl (71
mg, 0.1876 mmol), as prepared above, in methylene chloride (6 mL).
The mixture was stirred at room temperature in a sealed tube for 1
hour. Removal of solvents gave the title product as a bright yellow
solid that was pumped overnight under high vacuum. MS (ESI) m/z:
379 (M.sub.ligand+1).sup.+ and 539 (M.sub.complex+23).sup.+. UV-Vis
(CH.sub.2Cl.sub.2): E.sub.max=291 nm and 374 nm (for the ligand,
E.sub.max=248 nm and 336 nm in CH.sub.2Cl.sub.2).
[1276] 38B. Similarly, by following the procedure of Example 38A
and substituting zinc(II) chloride accordingly, there were
obtained:
[1277]
5-{2-[3,4-Bis(methoxymethoxy)phenyl]vinyl}-[2,2']bipyridinyl,
copper(II) chloride. MS (ESI) m/z=379 (M.sub.ligand+1).sup.+ and
500 (M.sub.complex+23-Cl).sup.+. UV-Vis (CH.sub.2Cl.sub.2):
E.sub.max=275 nm and 385 nm.
[1278]
5-{2-[3,4-Bis(methoxymethoxy)phenyl]vinyl}-[2,2']bipyridinyl,
manganese(III) acetate. MS (ESI) m/z 379 (M.sub.ligand+1).sup.+.
UV-Vis (CH.sub.2Cl.sub.2): E.sub.max=248 nm and 335 nm.
[1279] 38C. Similarly by following the procedure of Example 38A and
substituting
5-{2-[3,4-bis(methoxymethoxy)phenyl]vinyl}-[2,2']bipyridinyl with
5-{2-[3,4-dihydroxyphenyl]vinyl}-[2,2']bipyridinyl, and optionally
substituting zinc(II) chloride with the appropriate metal salts,
the following compounds were obtained:
[1280] {2-[3,4-Dihydroxyphenyl]vinyl}-[2,2']bipyridinyl, zinc(II)
chloride. MS (ESI) m/z: 291 (M.sub.ligand+1).sup.+ and 413
(M.sub.complex-Cl+Na).sup.+. UV-Vis (MeOH): E.sub.max=295 nm and
382 nm (for the ligand, E.sub.max=252 nm, 288 nm and 352 nm in
MeOH).
[1281] 5-[2-(3,4-Dihydroxyphenyl)vinyl]-[2,2']bipyridinyl,
copper(II) chloride. MS (ESI) m/z: 291 (M.sub.ligand+1).sup.+.
UV-Vis (MeOH): E.sub.max=245 nm, 293 nm, 316 nm, 360 nm and 485
nm.
[1282] 5-[2-(3,4-Dihydroxyphenyl)vinyl]-[2,2']bipyridinyl,
manganese(II) acetate. MS (ESI) m/z: 291 (M.sub.ligand+1).sup.+
from positive ESI; m/z=521 (M.sub.complex-1).sup.- from negative
ESI. UV-Vis (MeOH): E.sub.max=245 nm, 288 nm and 345 nm.
Example 39
1,3-Bis-methoxymethoxy-5-{2-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phen-
yl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene
[1283] 52
[1284] 39A. 4-Methoxymethoxy-3-(3-methyl-but-2-enyl)-benzaldehyde
To an ice cold solution of 1M NaOH (4.1 mmol) was added
4-hydroxy-benzaldehyde (500 mg, 4.1 mmol). After 5 minutes, prenyl
bromide (626 ul, 4.9 mmol) was added dropwise and the solution was
allowed to slowly come to room temperature for another two hours.
The pH was adjusted to 10 and the impurities were extracted out
with EtOAc, leaving the product and starting material in the
aqueous layer. The aqueous layer was made slightly acidic, and then
extracted with EtOAc, washed with H.sub.2O and brine, dried with
MgSO.sub.4 and evaporated yielding a yellow oil. After a quick
silica gel column (eluting with EtOAc:9Hexane and increased up to
8EtOAc:2Hexane) and evaporation, the prenylated benzaldehyde was
obtained as a thick yellow oil. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm): 9.81 (s, 1H), 7.66 (m, 2H), 6.97 (d, J=8.1, 1H),
5.33 (t, 1H), 3.41 (d, J=7.2, 2H), 1.77 (s, 6H). MS (ESI) m/z: 191
(M+H.sup.+), 213 (M+Na.sup.+). Prenylated benzaldehyde (1.2 g,
6.32) was dissolved in DMF, allowed to cool in an ice bath and
stirred. After slow addition of NaH (303 mg, 7.58 mmol),
methoxymethoxy chloride (576 ul, 7.58 mmol) was added dropwise.
This was left stirring at room temperature for 2 hours. Work up
with water, brine, extraction with EtOAc, and evaporation yielded
4-methoxymethoxy-3-(3-methyl-but-2-enyl)-benzaldehyde as a clear
dark yellow liquid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm): 9.81 (s, H), 7.16 (m, 2H), 7.05 (d, J=8.2, 1H), 5.30 (t,
1H), 5.20 (s, 2H) 3.48 (s, 3H), 3.36 (d, J=7.2, 2H), 1.77 (s, 6H)
ppm. MS (ESI) m/z: 234 (M+H).sup.+, 261 (M+Na).sup.+.
[1285] 39B. Methanesulfonic acid
3.5-bis-methoxymethoxy-4-(3-methyl-but-2-- enyl)-benzyl ester
[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]- -methanol
(2.09, 6.75 mmol) was dissolved in CH.sub.2Cl.sub.2 and placed in
an ice bath. Triethylamine (1.2 ml, 8.92 mmol) was added and
stirred until the reaction solution was at 0.degree. C., followed
by the dropwise addition of mesylate chloride (900 ul, 8.92 mmol).
After stirring in the ice bath for 1 hour, the reaction was
quenched with water, extracted with EtOAc, washed with brine, dried
with MgSO.sub.4, filtered and evaporated yielding methanesulfonic
acid 3,5-bis-methoxymethoxy-4-(3-methyl-but-2-en- yl)-benzyl ester
as a yellow oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm):
6.82 (s, 2H), 5.20 (t, 1H), 5.16 (s, 4H), 4.13 (s, 2H), 3.48 (s,
6H), 3.39 (d, 2H).sub.2, 96 (s, 3H), 1.78 (s, 3H), 1.65 (s, 3H). MS
(ESI) m/z: 375 (M+H).sup.+, 397 (M+Na).sup.+.
[1286] 39C.
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-benzyl)-triphen-
yl-phosphonium bromide Methanesulfonic acid
3,5-bis-methoxymethoxy-4-(3-me- thyl-but-2-enyl)-benzyl ester (100
mg, 0.27 mmol) was allowed to dissolve in acetone and stir as NaBr
(83 mg, 0.81 mmol) was added. The solvent was evaporated to dry and
the residue was washed with dichloro methane and filtered. The
solvents were evaporated to dry yielding yellow oil. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm): 6.81 (s, 2H), 5.20 (t, 1H),
5.16 (s, 4H), 4.44 (s, 2H), 3.48 (s, 6H), 3.39 (d, 2H), 1.78 (s,
3H), 1.65 (s, 3H). The bromide was converted to the triphenyl
phoshomium bromide following the procedure of Example 1.
[1287] 39D.
1,3-Bis-methoxymethoxy-5-{2-[4-methoxymethoxy-3-(3-methyl-but--
2-enyl)-phenyl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene To a
solution of
1,3-Bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-benzyl)-triphenyl-phosphon-
ium bromide (500 mg, 0.81 mmol) in DMF was added
4-methoxymethoxy-3-(3-met- hyl-but-2-enyl)-benzaldehyde (157 mg,
0.67 mmol) followed by stirring. NaH (32.4 mg, 1.2 mmol) was slowly
added and after 30 minutes of stirring at room temperature, it was
worked up with water, brine and EtOAc. This was dried with
MgSO.sub.4, filtered, and evaporated yielding a green oil. Column
purification yielded 1,3-bis-methoxymethoxy-5-{2-[4-methoxymethoxy-
-3-(3-methyl-but-2-enyl)-phenyl]-vinyl}-2-(3-methyl-but-2-enyl)-benzene
as a yellow oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) 6 (ppm): 7.28
(d, J=6.7, 1H), 7.01 (m, 2H), 6.95 (m, 3H, ArH), 6.65 (d, J=17.7,
1H), 6.45 (d, J=8.9, 1H), 5.32 (t, 1H), 5.24 (s, 2H), 5.17 (m, 4H),
3.48 (m, 6H), 3.37 (m, 3H), 3.39 (d, 2H), 3.22 (d, 2H), 1.78 (s,
6H), 1.65 (s, 6H). MS (ESI) m/z: 497 (M+H).sup.+, 519
(M+Na).sup.+.
[1288] 39E. Similarly the following compounds were prepared:
[1289]
1,3-Bis-methoxymethoxy-5-[2-(4-methoxymethoxy-3,5-dimethoxy-phenyl)-
-vinyl]-2-(3-methyl-but-2-enyl)-benzene .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. (ppm): 6.96 (d, J=4.65, 2H), 6.74 (s, 1H), 6.68
(s, 1H), 6.49 (m, 2H), 5.25 (s, 2H), 5.21 (t, 1H), 5.14 (s, 2H),
5.03 (s, 2H) 3.93 (s, 3H), 3.69 (s, 3H), 3.61 (s, 3H), 3.58 (s,
3H), 3.39 (s, 3H), 3.35 (d, J=6.88, 2H), 1.76 (m, 3H), 1.67 (m,
3H). MS (ESI) m/z: 489 (M+H), 511 (M+Na).
[1290]
1,3-Bis-methoxymethoxy-5-[2-(4-methoxymethoxy-3-methoxy-5-nitro-phe-
nyl)-vinyl]-2-(3-methyl-but-2-enyl)-benzene. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. (ppm): 7.46 (s, 0.5H), 7.21 (s,
0.5H), 6.97 (m, 2H), 6.64 (m, 1.5H), 6.45 (m, 1.5H), 5.24 (s, 2H),
5.20 (s, 2H), 5.05 (s, 2H), 3.98 (s, 3H), 3.64 (s, 3H), 3.53 (s,
3H), 3.41 (s, 3H), 1.79 (m, 3H), 1.63 (m 3H). MS (ESI) m/z: 504
(M+H), 526 (M+Na).
[1291]
1,3-Bis-methoxymethoxy-5-[2-(4-methoxymethoxy-3-nitro-phenyl)-vinyl-
]-2-(3-methyl-but-2-enyl)-benzene .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm): 7.76 (m, 3H), 6.97 (m, 4H), 5.31 (s, 2H), 5.26 (t,
1H) 5.24 (s, 2H), 5.04 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H), 3.38
(s, 3H), 1.79 (m, 3H), 1.66 (m 3H). MS (ESI) m/z: 474 (M+H), 496
(M+Na).
Example 40
4-[3-(3-Methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one
[1292] 53
[1293] To a solution of bis-(3,4-dimethoxy methyl oxy) benzaldehyde
(502 mg, 2.26 mmol-prepared from
3-(4-hydroxy-3-methoxy-phenyl)-propenal in a procedure as described
in Example 23B), 3-methyl-1-phenyl-2-pyrazolin-5-o- ne (392 mg,
2.25 mmol) and benzoic acid (26 mg, 0.21 mmol) in toluene (75 mL)
was added piperidine (19 mg, 0.22 mmol). The solution was refluxed
under nitrogen at 120.degree. C. with water-jacketed condensing for
9 hours. The solvent volume was reduced under reduced pressure and
EtOAc was added. The mixture was washed 3 times with aqueous NaCl
and 0.5 M HCl and dried over sodium sulfate for 2 hours. The
solvent was removed under reduced pressure and the residues were
chromatographed (silica gel, hexanes: EtOAc=5:2) to afford a dark
red product (372 mg, 44%). .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm): 9.90 (s, 0.03H), 8.45-8.10 (m, 1H), 7.96-7.93 (d,
J=9.9 Hz, 2H) 3-7.16 (m, 8H), 5.34-5.27 (2 d, J=6.2 Hz, combined
2H), 4.05-3.94 (2 s, combined 3H), 3.53 (s, 3H), 2.54-2.26 (m, 3H).
MS (ESI) m/z: 379 (M+H.sup.+, 100), 779 (M+M+Na.sup.+, 65).
Example 41
Determination of Activity Utilizing Neuronal Cell Stress Assay
[1294] A. Isolation and Culture of Primary Hippocampal Neuronal
Cells.
[1295] The following materials are employed:
[1296] Neurobasal/B27i: Neurobasal medium (available from
Invitrogen, San Diego, Calif.) with 1.times.B27 supplement
(Invitrogen), 0.5 .mu.M L-glutamine, 25 .mu.M L-glutamic acid, and
1.times. Penicillin/Streptomycin.
[1297] Hank's Basic Salt Solution (HBSS, Ca/Mg-free) is prepared by
preparing 1.times. Hanks CMF (Gibco) supplemented with HEPES (10
mM, pH 7.3), sodium bicarbonate (0.35%), 1.times.
Penicillin/Streptomycin, and 1 mM MEM sodium pyruvate.
[1298] Poly-D-lysine (Sigma, St. Louis, Mo.), 50 .mu.g/ml
solution.
[1299] Sigmacote (Sigma, St. Louis, Mo.).
[1300] Plastic Culture Flasks (T75 cm.sup.2) or 24-well cell
culture plates treated with Poly-D-Lysine (Sigma, St. Louis,
Mo.).
[1301] A pregnant female mouse (E18-E19) is euthanized with
CO.sub.2 followed by removal of the uterus, which is then placed in
a sterile plastic petri dish. The embryos are removed from the sac,
and the embryonic brains removed and immersed in cold (4.degree.
C.) Buffered Salt Solution (HBSS; Ca/Mg free; Life Technologies) in
a small petri dish. Hippocampi are then removed from the brains
under a dissecting microscope and placed on a paraffin-covered
dish. The meninges are stripped away and the dissected hippocampi
are collected in a small petri dish in HBSS. The hippocampi are
transferred to a 15-ml centrifuge tube (normally 10-12 brains)
filled with HBSS. The tube containing the brains is centrifuged at
1000 rpm for 2 min in a tabletop centrifuge. The supernatant is
removed, 2 ml of HBSS is added to the hippocampi in the tube, and
the resulting suspension is triturated 2 times each with
long-tipped siliconized glass pipettes having progressively smaller
apertures, starting with a pipette with a standard size opening
(approximately 1.0 mm diameter), following with one having an
aperture of half standard size (approximately 0.5 mm diameter),
then with one having an aperture about one-half that size (0.25 mm
diameter). The suspension is then centrifuged again at 1000 rpm for
2 min in a tabletop centrifuge, the supernatant is discarded, and 2
ml of Neurobasal/B27i (with antibiotics) is added to the tube. The
trituration procedure described above is then repeated on this
suspension.
[1302] The density of cells is determined on a small aliquot of
cells using standard counting procedures and correcting for cell
viability by trypan blue stain exclusion. Using this procedure, the
expected yield is 3.times.10.sup.5-6.times.10.sup.5 cells/brain.
Cells are then added to PDL-coated 24 well plates, flasks or MetTek
dishes in Neurobasal/B271 at a density of about 1.5.times.10.sup.6
cells (T75 flask) or about 100,000 cells/well of a 24-well plate.
Plated cells are incubated at 37.degree. C. in an atmosphere of 5%
CO.sub.2/95% O.sub.2. Media is renewed after 3-4 days by replacing
half of it with fresh Neurobasal/B27m medium, containing 5 .mu.M
cytosine arabinoside (Ara-C). Seven to eight days from the initial
culture, the media is renewed again, by removing one-half or it and
replacing with an equal amount of fresh Neurobasal/B27m medium
(without Ara-C).
[1303] B. Hippocampal Anoxia-Reoxygenation Cell Death Assay.
[1304] This assay is used to induce ischemia by
anoxia-reoxygenation in cultured hippocampal neuronal cells. Test
compounds are added to assess potency and efficacy against
ischemia-induced neuronal cell injury and cell death.
[1305] The following materials are employed:
[1306] a Neurobasal media, NoG neurobasal media, B27 supplement and
B27 Supplement minus AO (Invitrogen).
[1307] Neurobasal/B27 medium is prepared with 2.times.B27 minus AO
supplement, 0.5 mM L-glutamine and 0.25.times.
penicillin/streptomycin.
[1308] Cell Tracker Green was obtained from Molecular Probes and a
fresh 51AM solution was prepared from 10 mM stock just before
use.
[1309] NoG-Neurobasal contains NoG neurobasal medium plus 0.5 mM
glucose, 0.1 mM L-glutamine and 0.25.times.
Penicillin/Streptomycin.
[1310] Primary hippocampal neuronal cells were prepared according
to the methods described above and were cultured in poly-D-lysine
coated 24 well plates for 10-11 days prior to use.
[1311] Deoxygenated LoG-Neurobasal medium (100 ml) is prepared by
pre-equilibrating the medium in a T150 cm.sup.2 flask in a hypoxic
chamber overnight. Following pre-incubation under hypoxic
conditions, the LoG-Neurobasal media is lightly bubbled with 100%
N.sub.2 for 30 min to completely deoxygenate the media. An
additional 20 ml LoG-Neurobasal is pre-equilibrated in a T75
cm.sup.2 flask and 100 ml Neurobasal/B27AO is incubated in a normal
incubator (5% CO.sub.2) overnight. Reoxygenated medium is prepared
by placing medium overnight in the culture incubator (5%
CO.sub.2/95% O.sub.2) prior to use.
[1312] Existing culture medium (Neurobasal/B27m) is removed from
the cells by aspiration. Cells are washed once with 2 ml/well
(24-well culture plates) of glucose free-BSS. Neurons are
replenished 10-11 days after initial culture with deoxygenated
LoG-Neurobasal (1 ml per well for each well of a 24-well plate).
Test compounds are added directly to each well (3 concentrations of
the compound plus positive control, each in triplicate). Most test
compounds are dissolved in 100% DMSO; concentrations are adjusted
such that the final concentration of DMSO in the cell media never
exceeded 0.5%. Plates containing cells with test compounds are
placed in a hypoxic chamber for 5 hr with plate lids ajar. For
normoxia controls, pre-equilibrated normoxic LoG-Neurobasal medium
is added to each well of cells, and the plate is replaced in the
normal culture incubator for 5 hr. After 5 hr of hypoxia, the
existing media is carefully aspirated off, and 2 mL of new,
reoxygenated (pre-equilibrated) Neurobasal/B27AO is added to each
well. The same test compounds (in the same the concentrations) are
added back into the corresponding wells. Plates are placed in the
cell culture incubator (5% CO.sub.2/95% O.sub.2) and reoxygenated
for 20-24 hr. After reoxygenation for 20-24 hr, live neurons are
quantitated using the cell tracker green fluorescence method,
described below.
[1313] To test for cell viability, existing culture medium is
aspirated from each well of the 24 well plates, and neurons are
washed once with 2 ml of HBSS (pH 7.4, prewarmed to 30-37.degree.
C.). To each well is added one milliliter of 5 .mu.M Cell Tracker
Green fluorescent dye dissolved in HBSS. Plates are placed in the
dark at room temperature for 15 minutes, and are then washed with
two milliliters of HBSS. One milliliter of HBSS is then added to
each well, and fluorescent cells are counted using a fluorescent
microscope. Significantly increased cell viability compared to
control cells is indicative of a protective compound.
[1314] Results
[1315] When tested as described above, compounds of the present
invention, such as:
[1316] 2,6-di-tert-butyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1317] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[1318]
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzenesulfonamide-4-{2-[4-amino-
-sulfonyl)-phenyl]-vinyl}-benzene-1,2-diol;
[1319] 3,4-bis-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[1320] 4-[2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-vinyl]-benzoic
acid methyl ester;
[1321] 4-[2-(2,3,4-trihydroxy-phenyl)-vinyl]-benzonitrile;
[1322]
2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-di-
hydro-pyrazol-3-one;
[1323]
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium;
bromide;
[1324]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1325] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[1326]
4-[2-(3,4-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[1327]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzoic acid methyl ester;
[1328]
2-methoxymethoxy-1,3-dimethyl-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[1329]
1,2-bis-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benze-
ne;
[1330] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[1331]
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1332]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(3-nitro-4-meth-
oxymethoxy-5-methoxy-phenyl)-vinyl]-benzene;
[1333]
1-iodo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benz-
ene;
[1334]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[1335]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[1336]
5-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine--
2,4-dione;
[1337]
5-[4-methoxymethoxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidi-
ne-2,4-dione;
[1338]
5-[4-hydroxy-3-(3-methyl-but-2-enyl)-benzylidene]-thiazolidine-2,4--
dione;
[1339]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[1340]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-methoxymethoxy-benzylidene]-t-
hiazolidine-2,4-dione;
[1341]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[1342]
4-{2-[4,5-dihydroxy-2-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[1343]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[1344]
5-[2-(4-hydroxy-3-methoxy-5-nitro-phenyl)-vinyl]-2-(3-methyl-but-2--
enyl)-benzene-1,3-diol;
[1345]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzonitrile;
[1346] 4-[2-(4-nitro-phenyl)-vinyl-]benzene-1,2-diol;
[1347] 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
[1348] 2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1349] 2-chloro-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1350] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[1351] 4-[2-(2,5-dimethoxy-3,4-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[1352]
3-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-4H-isoxazol-5-one;
[1353]
2-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro--
pyrazol-3-one;
[1354] 4-[2-(6-nitro-benzo[1,3]dioxol-5-yl)-vinyl]-benzoic acid
methyl ester;
[1355]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[1356]
4-[2-(3-iodo-5-methoxy-4-methoxymethoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
[1357]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzoic acid methyl ester;
[1358] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester;
[1359] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid 3
,7-dimethyl-octa-2,6-dienyl ester;
[1360]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1361]
1,5-bis-methoxymethoxy-2,4-bis-(3-methyl-but-2-enyl)-3-[2-(4-nitro--
phenyl)-vinyl]-benzene;
[1362]
4-[2-(3-chloro-4-methoxymethoxy-phenyl)-vinyl]-benzonitrile;
[1363]
5-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl;
[1364]
4-(3,4-bis-methoxymethoxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydr-
o-pyrazol-3-one;
[1365]
5-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-[2,2']bipyridinyl,
Zn(II)chloride;
[1366]
4-{2-[4-hydroxy-3-methoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-be-
nzoic acid methyl ester;
[1367]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzoic acid methyl ester;
[1368]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[1369]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol;
[1370]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile; and
[1371]
5-{3-[3-methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-allylidene}-thia-
zolidine-2,4-dione,
[1372] provided protection against stressor-induced cell death in
at least about 20% of the cells tested, at concentrations ranging
from about 1 to 1000 .mu.M.
Example 42
Myocyte Calcium-Contractility Assay
[1373] A. Isolation and Culture of Primary Neonate Myocytes.
[1374] The following materials are employed:
[1375] 10.times. Heart Dissection Solution (HDS) contains the
following components (g/l) in tissue grade water: NaCl, 68; HEPES,
47.6; NaH.sub.2PO.sub.4, 2; Glucose, 10; KCl, 4; MgSO.sub.4, 1, pH
adjusted to 7.4. Prior to filter sterilization of diluted (1.times.
HDS) solution, 10 mg phenol red is added to each 500 milliliters of
medium,
[1376] Transferrin and Bovine Insulin (available from Life
Technologies) are resuspended at a concentration of 4 mg/ml in
tissue culture grade water.
[1377] DMEM-F12- DMEM/F12, powder, 1:1 containing glutamine and
pyridoxine hydrochloride (available from Life Technologies). To-one
liter equivalent of the powder is added 2.43 g of sodium
bicarbonate and 10 ml of 100.times. Penicillin/Streptomycin in 950
ml of tissue culture grade water with stirring. The pH is adjusted
to 7.2 with 1 M HCl and volume adjusted to 1 liter. The solution is
filter sterilized, followed by the addition of 2.5 ml of 4 mg/ml
Transferrin, 250 .mu.l 4 mg/ml Insulin and 30.7 mg of
bromodeoxyuridine.
[1378] DMEM-F12-5% FBS is also prepared for pre-coating the tissue
culture plates and initial suspension of the cardiomyocyte
pellet.
[1379] Collagenase solution-57.1 mg of collagenase is resuspended
in 140 ml 1.times. HDS.
[1380] Tissue culture ware is pre-coated with DMEM-F12-5%FBS by
incubating 50 .mu.l per well of a 96-well plate and 0.5 ml per
24-well plate at 37.degree. C.
[1381] Two-day old rat pups are removed from their mothers and
placed in a sterile container. Pups are dipped quickly into 70%
alcohol, then decapitated and the body placed in an empty sterile
tissue culture dish. An incision is made starting at the neck and
progressing towards the belly, cutting through the sternum. The
heart is removed and placed in a tissue culture dishes containing
1.times. HDS. The atria are trimmed, and the remaining ventricles
are placed into a separate tissue culture dish containing 1.times.
HDS, where they are sectioned into 3-4 pieces each. Ventricles are
then transferred to a sterile 250 ml glass flask and the 1.times.
HDS is removed. Twenty milliliters of pre-warmed collagenase
solution is added to the ventricles, followed by incubation at
37.degree. C. with shaking. After 20 minutes, the collagenase
solution is removed and replaced with 20 ml fresh pre-warmed
collagenase. Incubation is continued for an additional 20 minutes.
At the end of the incubation, any tissue chunks are allowed to
settle prior to removing the collagenase (containing the isolated
cardiomyocytes) from the disrupted tissue pieces. The isolated
myocytes are added to a 50 ml Falcon tube containing 2 ml Fetal
Bovine Serum (FBS). The remaining tissue pieces are subjected to a
second digestion by adding 20 ml fresh pre-warmed collagenase and
incubating as above for 20 minutes. This second digest is then
centrifuged at 1000 rpm for 5 minutes (tabletop centrifuge). The
resulting supernatant is discarded, and the cell pellet is
suspended with 4 ml FBS. The resulting cell suspension is placed in
the incubator at 37.degree. C. This step is repeated several
additional times to harvest additional material.
[1382] Percoll gradients are prepared by adding 2.5 ml of 10.times.
HDS to 22.5 ml of Percoll (Life Technologies) with mixing (Percoll
Stock). Top Gradient solution (11 ml Percoll Stock and 14 ml
1.times. HDS) and Bottom Gradient solution (13 ml Percoll Stock and
7 ml 1.times. HDS) are prepared. Four milliliters of the Top
Gradient solution is transferred into 6.times.15 ml sterile Falcon
tubes. Three milliliters of the Bottom Gradient solution is placed
in each tube by inserting a serological pipette to the bottom of
the tube and slowly adding the liquid.
[1383] All the digests (6) are pooled in one 50 ml Falcon tube and
centrifuged on a tabletop centrifuge at 1000 rpm for 10 minutes.
The supernatant is discarded, and the cell pellet is resuspended in
12 ml of 1.times. HDS. Two milliliters of the cell suspension is
added to the top of each gradient. The gradient tubes are then
centrifuged at 3000 rpm for 30 minutes without braking in a Beckman
Allegra 6 centrifuge (GH 3.8A rotor). Following centrifugation, the
cells segregate into two sharp bands at the two interfaces. The
lower band of the two bands is enriched for cardiomyocytes; there
is also a cardiomyocyte pellet at the bottom of the tube. The upper
band is enriched for fibroblasts and other non-cardiomyocytes. The
upper portion of the gradient is aspirated down to just above the
cardiomyocyte layer. The cardiomyocyte layer is then carefully
removed along with the pellet, and the two fractions are pooled in
a sterile 50 ml Falcon tube, along with corresponding fractions
from additional gradient tube; then 1.times. HDS is added to a
total volume of about 50 ml. The tube is centrifuged at 1000 rpm
for 10 minutes. The supernatant is discarded and resuspended in 10
ml 1.times. HDS. A further 40 ml of 1.times. HDS is added and the
centrifugation step is repeated. The cell pellet is resuspended
carefully but thoroughly in 50 ml of DMEMF 12-5% FBS.
[1384] A small aliquot of the cell suspension is counted in a
hemocytometer. The DMEM/F12-FBS coating medium is aspirated from
the tissue culture dishes. The cardiomyocytes are added to the
dishes at a plating density of 7.5.times.10.sup.4/well per 96-well
in 200 .mu.L and 6.times.10.sup.4/well per 24-well in 1 ml. The
cultures are incubated at 37.degree. C. with 5% CO.sub.2 overnight.
The original medium is removed, and add fresh DMEM/F12-5% FBS is
added to each culture, prior to incubation at 37.degree. C. with 5%
CO.sub.2 for a further 48 hours, before use.
[1385] B. Contractility Assay
[1386] The following materials are employed:
[1387] Complete DMEM-F12: DMEM/F12, powder, 1:1 containing
glutamine and pyridoxine hydrochloride (available from Life
Technologies-Invitrogen Life Technologies, Carlsbad, Calif.).
Powder sufficient to prepare one liter of buffer and 2.43 g of
sodium bicarbonate is mixed into 950 ml of tissue culture grade
water. The pH is adjusted to 7.2 with 1 M HCl and the remaining
water added to make 1 liter. Following filter sterilization, 10 ml
of 100.times. Penicillin/Streptomycin, 2.5 ml of 4 mg/ml
Transferrin, 250w 4 mg/ml Insulin and 30.7 mg of bromodeoxyuridine
are added, and the mixture is incubated at 37.degree. C. prior to
use.
[1388] 1 mM glucose in DMEM is made from DMEM without L-glutamine,
without glucose, without sodium pyruvate (available from Life
Technologies).
[1389] 20 .mu.M Fluo-4: Cell permanent AM ester of Fluo-4
(available as a dry powder to be stored at -20.degree. C., from
Molecular Probes--Eugene, Oreg.). This fluorescent dye is light
sensitive and should be made up fresh at 1 mM in DMSO prior to use
to prevent light degradation.
[1390] Neonatal cardiomyocytes are isolated as described above. The
cardiomyocytes are plated in 96-well format (black clear-bottomed
plates) at a density of 7.5.times.10.sup.4 per well and grown for 2
days in the presence of 5% FBS prior to use in the assay.
[1391] Physiological ischemia is simulated by placing the
cardiomyocytes in an anaerobic chamber (0% O.sub.2, 85% N.sub.2, 5%
CO.sub.2 & 10% H.sub.2) in DMEM containing 1 mM glucose.
Positive control cells are treated with DMEM-F12 containing 25 mM
Glucose, which protects against the anoxia.
[1392] The test compounds are made up in DMEM-1 mM glucose in 96
deep-well mother plates and appropriately diluted for use in the
assay. The media is removed from the cells and replaced with 200
.mu.l of either DMEM-F12 or 1 mM DMEM with or without test
compounds. The plates are then placed inside a 37.degree. C.
incubator in the anaerobic chamber and incubated for 16 hours. The
plates are then removed and reoxygenated by the addition of
pre-warmed DMEM-F12 containing 5% FBS. Since the anoxic treatment
may damage and/or kill the cells, causing them to dislodge from the
bottom of the wells gentle aspiration of media is required at this
step. The cells are then placed in a normal incubator at 37.degree.
C. and incubated for two hours to allow the cells to
reoxygenate.
[1393] A working solution of 20 .mu.M Fluo-4 is added to pre-warmed
1.times. HBSS. The cells are loaded with Fluo-4 by first removing
media from the cells and replacing with 100 .mu.l of 20 JIM Fluo-4.
Unloaded control cells are treated in parallel with 1.times. HBSS
alone. All cells are then incubated at 37.degree. C. for 30
minutes. Before fluorescence measurements are made, the cells are
washed in indicator-free medium (HBSS) to remove any dye that is
non-specifically associated with the cell surface. Cells are then
incubated for an additional 20 minutes at room temperature. Basal
Fluo-4 fluorescence is measured using the 485 nm excitation and 538
nm emission filter pair on a microplate flourometer (Fluorskan.TM.,
Thermo Labsystems Oy, Helsinki, Finland). Each well is read for 60
ms to obtain a baseline reading, then removed from the fluorimeter
and stimulated to contract by addition of 1.times. HBSS (which
contains 1.3 mM CaCl.sub.2), followed by incubation at 37.degree.
C. for 90 minutes. A second fluorescence reading is then taken.
Difference in pre vs. post stimulation fluorescence readings is
indicative of activity.
[1394] Results
[1395] When tested as described above, compounds of the present
invention, such as:
[1396] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[1397] 4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[1398] 4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-benzonitrile;
[1399] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid;
[1400] 5-(3,4-dihydroxy-benzylidene)-thiazolidine-2,4-dione;
[1401] 4-(2-nitro-vinyl)-benzene-1,2-diol;
[1402]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethy-
l)-benzamide;
[1403] 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phthalic acid
dimethyl ester;
[1404]
1-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-ph-
enyl)-vinyl]-benzene;
[1405]
1,3-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1406]
1,3-bis-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzene;
[1407]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[1408]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[1409] 2-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-thiazole;
[1410]
5-(3,4-bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione;
[1411]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzoic acid methyl ester;
[1412] 2,6-dimethyl-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1413] 2-bromo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1414] 4-[2-(4-hydroxy-3-iodo-5-methoxy-phenyl)-vinyl]-benzoic acid
methyl ester;
[1415]
4-[2-(3,4-dihydroxy-phenyl)-vinyl]-N,N-bis-(2-hydroxy-ethyl)-benzam-
ide;
[1416]
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol-
;
[1417]
1-carboxymethyl-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridinium,
bromide;
[1418]
1-(2-carboxy-2-oxo-ethyl)-4-[2-(3,4-dihydroxy-phenyl)-vinyl]-pyridi-
nium, bromide;
[1419] 4-[2-(5-methyl-thiophen-2-yl)-vinyl]-benzoic acid methyl
ester;
[1420] 2-[2-(3,4-dihydroxy-phenyl)-vinyl]-anthraquinone;
[1421] 4-[2-(1H-benzoimidazol-5-yl)-vinyl]-benzoic acid methyl
ester;
[1422] 2-methoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-phenol;
[1423]
4-{2-[3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester;
[1424]
4-{2-[3,4-bis-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester;
[1425]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzoic acid methyl ester;
[1426]
5-[2-(4-methoxycarbonyl-phenyl)-vinyl]-2-methoxymethoxy-benzoic
acid methoxymethyl ester;
[1427]
1,2-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1428]
2-(3,7-dimethyl-octa-2,6-dienyl)-1,3-bis-methoxymethoxy-5-[2-(4-nit-
ro-phenyl)-vinyl]-benzene;
[1429]
1-(3,7-dimethyl-octa-2,6-dienyl)-3-methoxy-2-methoxymethoxy-5-[2-(4-
-nitro-phenyl)-vinyl]-benzene;
[1430]
4-{2-[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzonitrile;
[1431]
{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-dimethyl-amine-
;
[1432]
{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-methyl-amine;
[1433]
4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-4'-methyl-[2,2']bipyrid-
inyl;
[1434]
2-methoxy-1-methoxymethoxy-4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-b-
enzene;
[1435]
4-(3,4-dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
-3-one;
[1436]
3-(3,4-bis-methoxymethoxy-benzylidene)-3H-benzofuran-2-one;
[1437]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[1438]
5-{4-[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chrom-
an-5-ylmethoxy]-benzylidene}-thiazolidine-2,4-dione;
[1439]
4-{2-[3,4-bis-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzoic acid methyl ester;
[1440]
1,2-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1441]
1,5-bis-methoxymethoxy-2-(3-methyl-but-2-enyl)-3-[2-(4-nitro-phenyl-
)-vinyl]-benzene;
[1442]
2-(3,7-dimethyl-octa-2,6-dienyl)-1,3-bis-methoxymethoxy-5-[2-(4-nit-
ro-phenyl)-vinyl]-benzene;
[1443]
1-(3,7-dimethyl-octa-2,6-dienyl)-3-methoxy-2-methoxymethoxy-5-[2-(4-
-nitro-phenyl)-vinyl]-benzene;
[1444]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-bis-methoxymethoxy-pheny-
l]-vinyl}-benzonitrile;
[1445]
4-{2-[3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-
-benzonitrile;
[1446]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-5-methoxy-4-methoxymethoxy-p-
henyl]-vinyl}-benzonitrile; and
[1447]
5-[2-(3,5-dimethoxy-4-methoxymethoxy-phenyl)-vinyl]-2-(3-methyl-but-
-2-enyl)-1,3-(bis-methoxymethoxy)-benzene,
[1448] showed the presence of calcium transients in amounts
indicative of ability guard against ischemic damage and allow the
cells to maintain their contractile function.
Example 43
Rat Middle Cerebral Artery Occlusion (MCAO) Model of Cerebral
Ischemia
[1449] A. Animal Preparation
[1450] Male Wistar rats (Harlan, Ind.) weighing 300-350 g are
commonly used in these experiments. Animals are allowed free access
to water and commercial rodent diet under standard laboratory
conditions. Room temperature is maintained at 20-23.degree. C. and
room illumination is on a 12/12-hour light/dark cycle. Animals are
acclimatized to the laboratory environment 5 to 7 days prior to the
study, and fasted (with free access to water) overnight before
surgery.
[1451] B. Middle Cerebral Artery Occlusion (MCAO)
[1452] Anesthesia is maintained by inhalation of 3.0% isoflurane
(Aerrane, Front Dodge, Iowa) in 0.8% oxygen. The animal's neck is
shaved and sterilized before operation. Body temperatures are
controlled and maintained at 37.5.degree. C.+/-1 degree via
external heating and cooling devices. To lower the body
temperature, animals are placed in a cooling chamber that uses ice
to cool circulating air. Throughout the study the body temperature
is recorded using a temperature transponder (BMDS Inc., Seaford,
DL) implanted subcutaneously at the time of MCAO between the rat
shoulder blades, which allows the user to read the body temperature
via a pocket scanner (BMDS Inc., Seaford, DL). The body temperature
can also be taken by inserting the temperature probe into the
animal's rectum. Body temperature is recorded every hour for 6
hours post-occlusion, but temperature is measured more frequently
to facilitate maintaining the animals' normothermic
temperature.
[1453] Animals are subjected to two hours MCAO using a modified
intraluminal filament technique, as follows. A midline incision on
the ventral part of the neck is made to expose external and
internal carotid arteries. The right external and common carotid
arteries are ligated by a suture (silk 5/0, Carlisle Laboratories,
Farmers Branch, Tex.) and the right internal artery is temporarily
ligated using a microvascular clip (Fine Science Tool Inc., Foster
City, Calif.). A small incision is made in the common carotid
artery. A nylon filament, its tip rounded by heating, is prepared
from a fishing line (Stren Fishing Lines, Wilmington, Del.) and is
inserted from the right common carotid artery. The filament is
advanced into the internal carotid artery 18-20 mm from the point
of bifurcation of internal and external arteries and a suture is
tightly ligated around the filament. Two hours post occlusion,
animals are re-anesthetized to allow reperfusion for the remaining
of the experiment by removal of the filament.
[1454] C. Drug Administration
[1455] Test compounds can be administered by any of a number of
routes, such as those described below. Compounds can be
administered before, during or after occlusion, as appropriate to
the protocol.
[1456] a) Intracerebroventricular (ICV) Infusion The anesthetized
animal is placed on a stereotaxic apparatus (Harvard Apparatus, S.
Natick, Mass.). Anesthesia is maintained by inhalation of 3.0%
isoflurane (Aerrane, Front Dodge, Iowa) in 0.8% oxygen throughout
the entire procedure. The scalp is shaved and sterilized prior to
surgery. A midline sagittal incision about 3 cm long is made
slightly behind the eyes to expose the skull. The skull is scraped
with a rounded end spatula to remove periosteal connective tissue.
A bur hole is placed 1.5 mm lateral, 1 mm posterior to the left of
the bregma to mark the left lateral ventricle. A brain infusion
cannula (ALZET-Alza, Palo Alto, Calif.) is inserted 4 mm deep into
the hole. The desired depth is adjusted by attaching spacers to the
cannula. The cannula, attached to a 4-cm silastic catheter (Helix
Medical Inc., Carpinteria, Calif.), is fixed in place with dental
cement (Ketac-cement, Norristown, Pa.). The catheter is either
attached to a primed osmotic pump placed subcutaneously between the
shoulder blades for permanent infusion or to a syringe for a short
infusion.
[1457] b) Intravenous (IV) Osmotic Pump Implantation into the
jugular vein Anesthesia is maintained by inhalation of 3.0%
isoflurane (Aerrane, Front Dodge, Iowa) in 0.8% oxygen throughout
the entire procedure. The animal's neck is shaved and sterilized
before operation. A midline incision is made on the ventral part of
the neck to exposes the jugular vein. The vein is isolated and
ligated with a suture (silk 5/0, Carlisle Laboratories, Farmers
Branch, Tex.) rostral to the point of the incision and a
microvascular clip (Fine Science Tool Inc., Foster City, Calif.) is
placed close to the heart. A small incision is made between the two
ligations. A 2-cm silastic catheter (Helix Medical Inc.) attached
to a PE-60 tube (Becton. Dickinson and Co. Sparks, Md.) connected
to an ALZET (Alza, Palo Alto, Calif.) pump is introduced and
advanced 2 mm into the jugular vein toward the heart. The
microvascular clip is removed and the catheter is secured in place
with a suture (silk 5/0, Carlisle Laboratories, Farmers Branch,
Tex.). The pump is placed into a pocket made subcutaneously between
the shoulder blades, allowing the catheter to reach over neck to
the jugular vein with sufficient slack to permit free movement of
neck and head.
[1458] c) IV infusion via femoral vein Anesthesia is maintained by
inhalation of 3.0% isoflurane (Aerrane, Front Dodge, Iowa) in 0.8%
oxygen throughout the entire procedure. The exterior site of the
right femoral vein is shaved and sterilized prior to surgery. A
3-cm incision is made in the right groin region and the femoral
vein is isolated. A small incision is made on the femoral vein,
temporarily ligated with a microvascular clip, to introduce and
advance a polyethylene (PE-50) catheter (Becton Dickinson and Co.
Sparks, Md.). The catheter is secured in place-with suture (silk
5/0, Carlisle Laboratories, Farmers Branch, Tex.). The other end of
the catheter is attached to a syringe filled with the heparinized
saline for the bolus injection. Using a hemostat, a pocket is made
subcutaneously on the back of the animal so the PE catheter can be
brought up to the exteriorization point at the nape of the neck for
either a bolus injection or a continuous injection by an osmotic
pump.
[1459] d) Intraperitoneal (IP) Injection An awake rat is held in a
standard hand hold position, a 23 3/4 G needle is injected into the
lower right quarter of the abdomen past the peritoneum, slightly
off the midline. To avoid organ injection, the plunger of the
syringe is slightly pulled back. If no fluid is withdrawn, the
content of the syringe is delivered into the abdominal cavity.
[1460] e) Gavage feeding A standard rat gavage tube (Popper &
Sons Inc., NY) is attached to a 3-cc hypodermic syringe. The animal
is held by the shoulder in a vertical position. The feeding tube is
placed into the mouth then advanced until it reaches the stomach
(the approximate insertion length of the tube was measured prior to
the feeding). The content of the syringe is slowly delivered, and
then the tube is withdrawn.
[1461] D. Behavioral Assessment
[1462] One hour after MCAO, the animal is gently held by its tail
and observed for forelimb flexion. Then the animal is placed on the
floor to be observed for walking pattern; only the animals that
score 3 on the Bederson grading system (Table 1) are included in
the study.
1TABLE 1 Bederson Grading System for Neurological Evaluation
Neurological deficit Grading Behavioral observation Normal grade 0:
No observable deficit Moderate grade 1: forelimb flexion Severe
grade 2: forelimb flexion, decreased resistance to lateral push
grade 3: forelimb flexion, decreased resistance to lateral push,
circle to paretic side
[1463] E. Evaluation of Ischemic Damage
[1464] Twenty-four hours post-MCAO, or longer in some experiments,
animals are sacrificed by CO.sub.2 asphyxiation (dry ice). The
brain is quickly removed from the skull, using standard procedures,
rinsed in chilled saline solution, and placed on a rat brain tissue
slicer (ASI instrument, MI). Seven 2-mm thick coronal slices are
cut from each brain using razor blades. The slices are immersed in
0.9% saline containing 1.0% 2,3,5-triphenyltetrazolume chloride
(TTC) (Sigma Chemical Co., St. Louis, Mo.) and incubated in a
37.degree. C. water bath for 30 minutes.
[1465] After staining, each 2-mm slice is photographed with a TMC-7
camera (J H Technologies, Ca) which is directly connected to a
desktop PC to capture and save the image of each brain slice. This
image is used for the measurements of the regions of interest using
a computer-based image processing system (Metamorph).
[1466] To measure each area, the region of interest is selected
using a freehand selection tool, the area is automatically computed
by selecting the measure command. The measurements for primary
regions of interest are right hemisphere, left hemisphere, total
infarct, subcortical infarct, total penumbra and subcortical
penumbra. After all regions of interest are measured for all seven
slices of the brain, they are sorted by slice number and the
corresponding regions of interest using an Excell macro called
statistic final. This macro also calculates the cortical penumbra,
cortical infarct and total ischemic damage for each slice; the
corresponding areas of each rat brain are added together to produce
a single measurement for each area. Since the ipsilateral
hemisphere is swollen following MCAO, edema volume is calculated
and reported as the volumetric differences between the right and
left hemispheres of each brain slice. Using the % of hemispheric
swelling all the volumes are corrected for the edema.
[1467] The volume of the damage is determined using the
calculations below for each rat's brain.
2 Measurement Equation Corrected Value(s) Cortical Total Penumbra-
Total Penumbra (T.P..sub.corr) = (T.P. .times. Penumbra Subcortical
% H.S./100) (C.P.) Penumbra C.P..sub.corr = C.P. - (C.P. .times. %
H.S./100) S.P..sub.corr = S.P. - (S.P. .times. % H.S./100) Cortical
Infarct Total Infarct- T.I..sub.corr = T.I. - (T.I. .times. %
H.S./100) Subcortical S.I..sub.corr = S.I. - (S.I. .times. %
H.S./100) Infarct C.I..sub.corr = C.I. - (C.I. .times. % H.S./100)
Total Ischemic Total Penumbra + T.I.D..sub.corrected = T.I.D. -
(T.I.D. .times. Damage Total Infarct % H.S./100) (T.I.D.) Total
Each value is Volume (mm.sup.3) multiplied by 2 (the thickness of
the tissue). Edema Volume The volumetric differences be- tween the
sum of right and left hemispheres de- termines the edema volume. %
Hemispheric Edema .times. 100/left swelling (H.S.) hemisphere
[1468] F. Statistical Analysis
[1469] Sample size is chosen to achieve a 90% probability of
significant results. The measurements representing theisame region
of interest in seven slices of each rat's brain are added together
to yield a single measurement for total infarct, subcortical
infarct, cortical infarct, total penumbra, subcortical penumbra,
cortical penumbra, total ischemic damage and edema in each animal.
Group data are presented as means +/-SEM. Differences at the level
of p<0.05 are considered statistically significant. Between
groups, comparisons of each region of interest are carried out by
unpaired student t test (between two groups) or one way ANOVA
followed by post hoc Bonferroni's multiple comparisons or by the
nonparametric Dunnett's test (between control and the drug treated
groups).
[1470] Results
[1471] When tested as described above, compounds of the present
invention, such as:
[1472] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[1473] 4-[2-(phenyl-1,2-diol)vinyl]-benzoic acid methyl ester,
zinc(II)chloride; and
[1474]
2-Methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol,
[1475] provided a reduction in total infarct volume of at least
about 20% at doses in the range of less than about 1 .mu.g/kg to
about 10 mg/kg that is less than about 10 mg/kg.
Example 44
Model of Myocardial Infarction: Left Coronary Ligation (Rat)
[1476] Animal Preparation: Male Sprague-Dawley weighing 250-320 g
are allowed free access to water and commercial rodent diet under
standard laboratory conditions. Room temperature is maintained at
20-23.degree. C. and room illumination is on a 12/12-hour
light/dark cycle. Animals are acclimatized to the laboratory
environment 5 to 7 days prior to the study and are fasted overnight
prior to surgery.
[1477] Surgical Procedure for Acute Studies: Rats are anaesthetized
with Urethane (1.2-1.5 gm/kg). Core body temperature is maintained
at 37.degree. C. by using a heating blanket. The surgical area is
shaved, and a ventral midline incision is made to expose the
trachea and jugular area. A catheter (PE50) is placed in the
jugular for administration of compound and maintenance anesthesia.
The trachea is incised and a 14-16-gauge modified intravenous
catheter is inserted and tied in place as an endotracheal tube. The
animal is placed in right lateral recumbency and initially placed
on a Harvard ventilator with a tidal volume of 5-10 ml/kg. 100%
O.sub.2 is delivered to the animals by the ventilator. ECG
electrodes are placed to record a standard Lead II ECG. The
surgical site is cleaned with alcohol swab, and a skin incision is
made over the rib cage over the 4.sup.th-5.sup.th intercostal
space. The underlying muscles are dissected with care to avoid the
lateral thoracic vein, to expose the intercostal muscles. The chest
cavity is entered through the 4.sup.th-5.sup.th intercostal space,
and the incision expanded to allow visualization of the heart. The
pericardium is opened to expose the heart. A 6-0 silk suture with a
taper needle is passed around the left coronary artery near its
origin, which lies in contact with the left margin of the pulmonary
cone, at about 1 mm from the insertion of the left auricular
appendage. A piece of tubing is placed over the suture to form an
occluder. The coronary artery is occluded for 30 minutes by sliding
the tube towards the heart until resistance is felt and holding it
in place with a vascular clamp. The ECG is monitored for S-T
changes indicative of ischemia. After 30 minutes, the occluder is
removed, leaving the suture in place. The ECG is monitored for the
first 10 minutes of reperfusion. The rat is transferred to the
pressure control ventilator for the remainder of the protocol. The
rats are ventilated by a small animal ventilator with a peak
inspiratory pressure of 10-15 cm H.sub.2O and respiratory rate
60-110 breaths/min. The heart is allowed to reperfuse for 90
minutes.
[1478] Surgical procedure for 24 hour study: Rats are anaesthetized
with Ketamine/Xylazine IP (95 and 5 mg/kg) and intubated with a
14-16-gauge modified intravenous catheter. Anesthesia level is
checked every 15 minutes by toe pinch. Core body temperature is
maintained at 37.degree. C. by using a heating blanket. The
surgical area is shaved and scrubbed. A ventral midline incision is
made to expose the jugular vein. A catheter (PE50) is placed in the
jugular for administration of compound and maintenance anesthesia.
The animal is placed in right lateral recumbency and initially
placed on a ventilator with a tidal volume of 5-10 ml/kg H.sub.2O
or a pressure controlled ventilator with a peak inspiratory
pressure of 8-15 cm H.sub.2O and respiratory rate 60-110
breaths/min. 100% O.sub.2 is delivered to the animals by the
ventilator. ECG electrodes are placed to record a standard Lead II
ECG. The surgical site is cleaned with surgical scrub and alcohol.
A skin incision is made over the rib cage over the
4.sup.th-5.sup.th intercostal space. The underlying muscles are
dissected with care to avoid the lateral thoracic vein, to expose
the intercostal muscles. The chest cavity is entered through
4.sup.th-5.sup.th intercostal space, and the incision expanded to
allow visualization of the heart. The pericardium is opened to
expose the heart. A 6-0 silk suture with a taper needle is passed
around the left coronary artery near its origin, which lies in
contact with the left margin of the pulmonary cone, at about 1 mm
from the insertion of the left auricular appendage. A piece of
tubing is placed over the suture to form an occluder. The coronary
artery is occluded for 30 minutes by sliding the tube towards the
heart until resistance is felt and holding it in place with a
vascular clamp. The ECG is monitored for S-T changes indicative of
ischemia. After 30 minutes, the occluder is removed, leaving the
suture in place. The ECG is monitored for the first 10 minutes of
reperfusion. The incision is closed in three layers. The IV
catheter is removed or tunneled under the skin and exteriorized
between the shoulder blades to allow for blood withdrawal or
further drug therapy. The rat is ventilated until able to ventilate
on its own. The rats are extubated and recovered on a heating pad.
Once awake, they are returned to their cage(s). Animals may receive
Buprenorphine (0.01-0.05 mg/kg SQ) for post-operative analgesia.
After the designated reperfusion time (24 hours) the animals are
anesthetized and the hearts removed under deep anesthesia.
[1479] Treatment Protocols
[1480] Diet Animals are fed a custom diet prior to or after
coronary ligation. The length of treatment varies with the study.
Doses are calculated based on the average consumption of 15 gms of
feed per day for a 300 gm rat. Rat weights are monitored during the
study. Feed not consumed is weighed to estimate consumption
rates.
[1481] GavageAnimals are dosed orally by gavage. Length and
frequency of treatment vary with the study. A standard rat gavage
tube (Popper & Sons Inc, NY) is attached to a 3-cc hypodermic
syringe. The animal is held by the shoulder in a vertical position.
The feeding tube is placed into the mouth then advanced until it
reaches the stomach (the approximate insertion length of the tube
is measured prior to the feeding). The content of the syringe is
slowly delivered, and then the tube is withdrawn.
[1482] IV Treatment A ventral incision is made to expose the
jugular area. A catheter (PE50) is placed in the jugular vein for
administration of compound. Animals are dosed by bolus injection
and/or continuous infusion. The time and duration of treatment
varies with the protocol.
[1483] Tissue Processing
[1484] After reperfusion, each animal receives 200 units of heparin
IV under general anesthesia and the heart is removed and placed in
cold saline. After removal the coronary artery is ligated with the
suture that is already in place. The heart is placed on a perfusion
apparatus and Evans Blue dyed is infused delineate the area at
risk. The heart is then cut into five 2-mm thick transverse slices
from apex to base. The slices are incubated in 1%
triphenyltetrazolium chloride (TTC) in 0.9% saline for 20 minutes
at 37.degree. C. Tetrazolium reacts with NADH in the presence of
dehydrogenase enzymes causing viable tissue to stain a deep red
color and that is easily distinguished from the infarcted
pale-unstained necrotic tissue. The slices are placed apex side
down in the lid of a small petri dish for the staining procedure.
The bottom of the dish is placed over the slices to keep them flat.
The slices are photographed in order from apex to base, with the
base side up. The areas of infarcted tissue, area at risk and the
whole left ventricle are determined using a computerized image
analysis system. The total area for each region is added together
to give a total for the entire heart. Infarct size is expressed
both as a percentage of the total ventricle and the area at
risk.
[1485] Statistical Analysis
[1486] Group data is represented as means +/-SEM. Comparisons
between treatment groups are made using ANOVA with p<0.05
considered significant. Post hoc comparisons may be made using
either Dunnett's test or Tukey's test.
[1487] Results
[1488] The compounds of the present invention show activity when
tested by this method.
Example 45
Evaluations of Sensorimotor Behavior
[1489] A. Fore and Hindlimb Grip Strength Test in Rats
[1490] Animals with cerebral infarction induced by transient or
permanent unilateral occlusion of the middle cerebral artery (MCA)
and sham-operated rats are tested for grip strength, a standard
model of neuromuscular function and sensorimotor integration, using
a Computerized Grip Strength Meter for Rats (Dual Stand Model,
Columbus Instruments, Columbus, Ohio).
[1491] Animals are moved into the testing room for 30 minutes
before testing. Prior to testing, each gauge is calibrated with a
set of known weights and the apparatus is adjusted for the size of
animal, according to manufacturer's instructions. The forelimb
measurements are carried out with the meter in the tension peak
mode to freeze the reading as the subject is pulled away from the
grip bar. The hindlimb measurements are carried out with the meter
in the compression peak mode to freeze the reading as the subject's
hindlimbs are pulled over the bar toward the meter. Each animal is
hand-held by the investigator as pulled past the grip bars, using a
consistent technique, leaving the fore and hind limbs free to grasp
the grip bars.
[1492] Testing is carried out on postoperative day 2 and repeated,
in a blind-randomized fashion, twice weekly for a defined interval.
Typically, three successive readings are taken for each animal with
an intertrial interval long enough to record the data and zero both
meters for the next trail.
[1493] B. Rota-Rod Test in Rats
[1494] Apparatus: Rota-Rod Treadmill for Rats (7750 Accelerating
Model, from UGO BASILE, COMERIO-ITALY).
[1495] Procedure: Animals with cerebral infarction induced by
transient or permanent unilateral occlusion of the middle cerebral
artery (MCA) and sham-operated rats are tested in this study, using
a Rota-Rod Treadmill for Rats (7750 Accelerating Model, UGO Basile,
Comerio, Italy). The animals are moved into the testing room 30
minutes before testing. Every rat receives 2-3 training runs of 1-2
minutes at intervals of 2-3 hours before testing.
[1496] The cylinder on the apparatus is set in motion before
placing the rats in position. The motor is set at a constant
selected speed in 7700 on RESET mode, and the rats are placed, one
by one, in their sections.
[1497] Testing is carried out on postoperative day 2 and repeated,
in a blind-randomized fashion, twice weekly for a defined interval.
Typically, three successive readings are taken for each animal with
an intertrial interval long enough to record the data and zero both
meters for the next trail.
[1498] The compounds of the present invention show activity when
tested by this method.
Example 46
Left Coronary Artery Occlusion Model of Congestive Heart
Failure
[1499] Experimental preparation
[1500] 225-275 g male Sprague-Dawley CD (Charles River) rats are
used for this experiment. Animals are allowed free access to water
and commercial rodent diet under standard laboratory conditions.
Room temperature is maintained at 20-23.degree. C. and room
illumination is on a 12/12-hour light/dark cycle. Animals are
acclimatized to the laboratory environment 5 to 7 days prior to the
study. The animals are fasted overnight prior to surgery.
[1501] Animals are anaesthetized with ketamine/xylazine (95 mg/kg
and 5 mg/kg) and intubated with a 14-16-gauge modified intravenous
catheter. Anesthesia level is checked by toe pinch. Core body
temperature is maintained at 37.degree. C. by using a heating
blanket. The surgical area is clipped and scrubbed. The animal is
placed in right lateral recumbency and initially placed on a
ventilator with a peak inspiratory pressure of 10-15 cm H.sub.2O
and respiratory rate 60-110 breaths/min. 100% O.sub.2 is delivered
to the animals by the ventilator. ECG electrodes are placed to
record a standard Lead II ECG. The surgical site is scrubbed with
surgical scrub and alcohol. An incision is made over rib cage over
the 4.sup.th-5.sup.th intercostal space. The underlying muscles are
dissected with care to avoid the lateral thoracic vein, to expose
the intercostal muscles. The chest cavity is entered through
4.sup.th-5.sup.th intercostal space, and the incision expanded to
allow visualization of the heart. The pericardium is opened to
expose the heart. A 6-0 silk suture with a taper needle is passed
around the left coronary artery near its origin, which lies in
contact with the left margin of the pulmonary cone, at about 1 mm
from the insertion of the left auricular appendage. The coronary
artery is occluded by tying the suture around the artery. The ECG
is monitored for S-T changes indicative of ischemia. If the animal
develops ventricular fibrillation, gentle cardiac massage is used
to convert the animal to a normal rhythm. The incision is closed in
three layers. The rat is ventilated until are able to ventilate on
their own. The rats are extubated and recovered on a heating pad.
Animals receive buprenorphine (0.01-0.05 mg/kg SQ) for post
operative analgesia. Once awake, they are returned to their cage.
Animals are monitored daily for signs of infection or distress.
Infected or moribund animals are euthanized. Animals are weighed
once a week.
[1502] Treatment Protocols
[1503] Diet Animals are fed a custom diet prior to or after
coronary ligation. The length of treatment will vary with the
study. Doses are calculated based on the average consumption of
feed per day. Rat weights are monitored during the study. Feed not
consumed is weighed to estimate consumption rates.
[1504] GavageAnimals are dosed orally by gavage. Length and
frequency of treatment will vary with the study. A standard rat
gavage tube (Popper & Sons Inc, NY) is attached to a 3-cc
hypodermic syringe. The animal is held by the shoulder in a
vertical position. The feeding tube is placed into the mouth then
advanced until it reaches the stomach (the approximate insertion
length of the tube is measured prior to the feeding). The content
of the syringe is slowly delivered, and then the tube is
withdrawn.
[1505] Drinking Water Compound can also be dissolved in the
drinking water. Water consumption is monitored. In the case of a
bitter tasting compound, flavoring agents may be added to the water
of both vehicle and treated groups. In the case of insoluble
compounds, solubilizing agents may be used (i.e. 0.015% cremophor.
0.015% alcohol).
[1506] Alzet Pumps Alzet pumps can be implanted using aseptic
techniques into the peritoneum or subcutaneously behind the
shoulder blades. Pumps are implanted using Isoflurane anesthesia.
Serial implantation can be used for extended studies.
[1507] Measurements
[1508] In vivo After 6-12 weeks the animals are anesthetized with
Ketamine/Xylazine (95 mg/kg and 5 mg/kg), and a catheter is placed
in the right carotid artery and advanced into the left ventricle
for hemodynamic measurements. The catheter is attached to a
pressure transducer calibrated against a mercury manometer
immediately prior to use. Recordings are made by a DATAQ data
analysis system. Pressure traces are recorded and analyzed for
heart rate, left ventricular systolic and diastolic pressure, left
ventricular developed pressure, and dP/dt max and min. An average
of at least five peaks is used to determine values for left
ventricular systolic and end diastolic pressure. Left ventricular
developed pressure is determined by subtracting end diastolic
pressure from left ventricular systolic pressure. Heart rate is
determined from the frequency spectrum of a 5 second sample. After
measurements are taken, 2 ml blood is removed and placed in serum
and plasma tubes for possible analysis.
[1509] Ex vivo After removal, the heart is placed in cold saline to
stop the beating, then trimmed and weighed. Heart weight is
presented as total weight and as a percentage of total body weight.
After removal of the heart, lungs and liver are weighed and dried
overnight for determination of wet to dry ratios.
[1510] The heart is sliced and slice #3 is incubated in 1%
triphenyltetrazolium chloride (TTC) in 0.9% saline for 20 minutes
at 37.degree. C. Tetrazolium reacts with NADH in the presence of
dehydrogenase enzymes causing viable tissue to stain a deep red
color that is easily distinguished from the infarcted
pale-unstained necrotic tissue. The slice is placed apex side down
in the lid of a small petri dish for the staining procedure. The
bottom of the dish is placed over the slice to keep it flat. The
slice is photographed. The areas of infarcted tissue, left and
right ventricle are determined using a computerized image analysis
system. Infarct size is expressed as a percentage of the total
ventricle. Total areas of the left and right ventricle are
measured. The remaining sections are divided into right and left
ventricle and frozen for TBARS and glutathione assays.
[1511] Statistical Analysis
[1512] Group data is presented as means +/-SEM. Comparisons between
treatment groups are made using ANOVA with p<0.05 considered
significant. Post hoc comparisons use either Dunnett's test or
Tukey's test. Survival curves are generated using Graph Pad Prism.
For each X value (time) Prism shows the fraction still alive. It
also shows standard error. Prism calculates survival fractions
using the product limit or Kaplan-Meier method.
[1513] The compounds of the present invention show activity when
tested by this method.
Example 47
Skin Protection Assay
[1514] Cytoprotective activity for skin can be evaluated in cell
culture using the Epiderm Skin Model (EPI-100) from the Mattek
Corporation of Ashland, Mass. Cell cultures of neonatal foreskin
are cultured in accordance with the manufacturer's directions, and
are assayed for percent cellular viability by measuring the amount
of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) dye taken up by the cells. Viable cells take up this dye and
convert it to insoluble formazin crystals that resides in the
mitochondria of the cells until extracted with alcohol. The amount
of MTT converted to extractable formazin crystals is directly
proportional to the viability of the cell culture. MTT is measured
spectrophotometrically.
[1515] Cells are exposed to UV light at a rate of 1.5 Minimal
Erythemal Dose (MED) per hour per square centimeter, for a total
dose of about 31.5 mJ/cm.sup.2, from a solar simulator (filtered to
yield wavelengths in the region of 290-400 nm) in the presence of
the cytoprotective compound or mixtures thereof to measure the
effect of test compounds to protect the cell culture from the
generation of free radicals resulting from the ultraviolet
light.
[1516] The controls for this study are cell cultures without added
test compound (positive control). All cell cultures are also
compared to cultures that are not exposed to UV light and do not
include the cytoprotective agents or blends in order to determine
percent cellular viability (negative control). This latter
measurement is assumed to be equal to 100% viability.
[1517] Cell cultures treated with the cytoprotective compounds of
the invention show greater survival than do positive control cell
cultures, when tested as described above.
Example 48
Rat Paw Edema Assay
[1518] Animal Preparation: Male Sprague-Dawley rats weighing
between 175 to 200 g are used in this study. Animals are allowed
free access to water and commercial rodent diet under standard
laboratory conditions. Room temperature is maintained at
20-23.degree. C. and room illumination is on a 12/12-hour
light/dark cycle. Animals are acclimatized to the laboratory
environment 5 to 7 days prior to the study.
[1519] Experimental Procedure:
[1520] Each animal is treated by administration of vehicle,
reference or test substance one hour prior to carrageenan
injection, as follows:
[1521] I.V. Infusion via Femoral Vein: Anesthesia is maintained by
inhalation of 3.0% isoflurane (Aerrane, Front Dodge, Iowa) in
oxygen throughout the entire procedure. The exterior site of the
right femoral vein is shaved and sterilized prior to surgery. A
3-cm incision is made in the right groin region and the femoral
vein is isolated. The femoral vein is temporarily ligated with a
micro-vascular clip, and a small incision is made on the femoral
vein to introduce and advance a polyethylene (PE-50) catheter
(Becton. Dickinson and Co., Sparks, Md.). The catheter is secured
in place with suture (silk 5/0, Carlisle Laboratories, Farmers
Branch, Tex.). The other end of the catheter is attached to a
syringe filled with the saline for the bolus injection. Using a
hemostat, a pocket is made subcutaneously on the back of the animal
so the PE catheter can be brought up to the exteriorization point
between the shoulder blade for either a bolus injection or a
continuous injection by an osmotic pump.
[1522] I.P. Injection: An awake rat is held in a standard hand held
position. A 23 3/4 G needle is injected into the lower right
quarter of the abdomen pass the peritoneum, slightly off the
midline. To avoid organ injection, the plunger of the syringe is
slightly pulled back. If no fluid is withdrawn, the content of the
syringe is delivered into the abdominal cavity.
[1523] Gavage Feeding: A standard rat gavage tube (Popper &
Sons Inc, NY) is attached to a 3-cc hypodermic syringe. The animal
is held in a vertical position. The feeding tube is placed into the
mouth and then gently advanced until it reaches the stomach (the
approximate insertion length of the tube should be measured prior
to feeding). The content of the syringe is slowly delivered, and
then the tube is withdrawn.
[1524] One hour post treatment each animal is anesthetized with
3.0%.isoflurane (Aerrane, Front Dodge, Iowa) in oxygen and
administered 100 .mu.l of 1% Carrageenan Lambda type IV (Sigma
Chemical Company, St. Louis, Mo.) suspension in saline, into the
intraplantar surface of the right hind paw. Paw edema is measured
four hours after carrageenan injection, either by measuring the
increase in paw volume using a plethysmometer or the increase in
paw weight using a fine scale. Immediately prior to edema
measurement, the animals are euthanized via CO.sub.2 asphyxiation
and 500 .mu.l blood is withdrawn by cardiac puncture for later
analysis. Paw volume is determined by the extent to which water is
displaced by the paw from a pre-calibrated chamber. The volume of
the left hind paw (control) is subtracted from the volume of the
right hind paw (carrageenan-treated) to determine the volume of
carrageenan-induced edema. To measure the weight difference between
paws, both hind paws were removed and weighed separately.
[1525] To minimize the variation in the model following steps are
taken:
[1526] Carrageenan is made fresh every day prior to the study
(2-3hours before injection).
[1527] The plethysmometer is calibrated each day prior to the
study.
[1528] If carrageenan injection causes significant bleeding or a
hematoma on the treated foot, the animal is excluded from the
study.
[1529] Each paw is marked at the tibio-tarsal joint across the
ankle prior to measurements, to ensure each paw is submerged at the
same level.
[1530] If reading on the volume needs to be repeated, the paw must
be dried off completely.
[1531] Statistical Analysis
[1532] The difference of the weight or the volume between right and
left paw is calculated for each animal for the analysis. Group data
are presented as means +/-SEM and p<0.05 are considered
significant. Inter-group comparisons are carried out by unpaired
student t test (between two groups) or one-way ANOVA followed by
post hoc Bonferroni's multiple comparisons.
[1533] Results
[1534] The compounds of the present invention, such as:
[1535] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[1536] 4-{2-[4-(2-nitro-vinyl)-phenyl]-vinyl}-benzene-1,2-diol;
[1537] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[1538] 4-[2-(3,4-Bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid
tetradecyl ester;
[1539]
4-[2-(3,4-Bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-viny-
l]-benzoic acid ethyl ester;
[1540]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[1541]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[1542]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol; and
[1543]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol,
[1544] showed significant reduction in edema (10 to 70%, p<0.05)
when tested by this method.
Example 49
Mouse Ear Inflammatory Response to Topical Arachidonic Acid
[1545] Animals: Balb C Mice 23-28gms, from Simonsen Labs, Gilroy,
Calif.
[1546] Materials:
[1547] Arachidonic Acid, 99% pure from Porcine Liver (Sigma
Aldrich) reconstituted in acetone 2 mg/20 ul (200 mg/ml).
[1548] Inhalation anesthesia: Isoflurane 3% (Baxter).
[1549] Blood Sample tubes: Microtainer tubes w/heparin (Becton
Dickinson).
[1550] TNFa Elisa assay (R&D Science).
[1551] Experimental Procedure
[1552] Test compounds, positive control (arachidonic acid only) and
standard (Dexamethasone @ 0.1 mg/kg) prepared in solutions of
acetone, ethanol or aqueous ethanol, are applied to both sides of
the right ear with an Eppendorf repipettor pipette, in a volume of
10 .mu.l each side (20 .mu.l total). 30 Minutes later, 10 .mu.l of
arachidonic acid is applied to both sides of the right ear (20
.mu.l total). One hour after the application of arachidonic acid,
the mice are deeply anesthetized with isoflurane and a blood sample
is taken via the orbital sinuses and placed in Microtainer tubes.
The animals are then euthanized by CO.sub.2 inhalation and the
right ears removed at the base. A uniform plug of ear tissue is
obtained using a 8 mm dermal punch. The earplugs are quickly
weighed to the nearest 0.1 mg and then flash frozen for TNF.alpha.
determination.
[1553] The earplugs are thawed and placed in 1 ml PBS, and
homogenized using a mortar and pestle. The homogenates are placed
in 15 ml centrifuge tubes and spun at 5000 g for 10 minutes. The
supernatant of each sample is aspirated and placed in 1.5 ml
centrifuge tubes and flash frozen. The samples are stored at
-70.degree. C. until assayed for TNF.alpha..
[1554] Statistical Analysis:
[1555] Group data are presented as means +/-SEM and p<0.05 is
considered significant. Inter-group comparisons are carried out by
unpaired student t tests (between two groups) or ANOVA (three or
more groups) followed by post hoc Dunnet's test.
[1556] Results
[1557] The compounds of the present invention, such as:
[1558] 4-12-(4-nitro-phenyl)-vinyl]-benzene-1,2-diol;
[1559] 4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2,3-triol;
[1560]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[1561]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol;
[1562]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile;
[1563]
4-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-5-methyl-2-phe-
nyl-2,4-dihydro-pyrazol-3-one;
[1564]
5-[3-(3-methoxy-4-methoxymethoxy-phenyl)-allylidene]-thiazolidine-2-
,4-dione;
[1565]
3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-5-hydroxy-3H-benzofuran-
-2-one;
[1566]
4-{2-[4-(3,7-dimethyl-octa-2,6-dienyl)-3,5-dihydroxy-phenyl]-vinyl}-
-benzonitrile;
[1567] 2-hydroxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid;
[1568] 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-4-nitro-phenol;
[1569] 2-iodo-6-methoxy-4-[2-(4-nitro-phenyl)-vinyl]-phenol;
[1570] 5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-diol;
[1571] 4-[2-(3,4-dihydroxy-phenyl)-vinyl]-benzoic acid methyl
ester;
[1572] 4-[2-(4-hydroxy-3,5-dimethyl-phenyl)-vinyl]-benzoic acid
methyl ester;
[1573]
5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro--
pyrazol-3-one;
[1574] 5-methyl-2-(4-styryl-phenyl)-2,4-dihydro-pyrazol-3-one;
[1575]
2-{4-[2-(3,4-dihydro-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-py-
razol-3-one
[1576]
4-{2-[4-(5-hydroxy-1H-pyrazol-3-yl)-phenyl]-vinyl}-benzene-1,2-diol-
;
[1577]
4-[3-(4-hydroxy-3-methoxy-phenyl)-allylidene]-5-methyl-2-phenyl-2,4-
-dihydro-pyrazol-3-one;
[1578] 4-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-benzene-1,2-diol;
[1579]
4-{2-[3-methoxy-4-methoxymethoxy-5-(3-methyl-but-2-enyl)-phenyl]-vi-
nyl}-benzoic acid methyl ester;
[1580] 2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-benzoic acid
methoxymethyl ester;
[1581]
1-bromo-3-methoxy-2-methoxymethoxy-5-[2-(4-nitro-phenyl)-vinyl]-ben-
zene;
[1582]
5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-
-dihydro-pyrazol-3-one
[1583]
4-{2-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-5-methoxy-phenyl]--
vinyl}-benzonitrile;
[1584]
4-(3,4-dihydroxy-benzylidene)-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
-3-one;
[1585]
5-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-thiazolidine-2,4-dione;
[1586]
5-[3-(3,7-dimethyl-octa-2,6-dienyl)-4-hydroxy-benzylidene]-thiazoli-
dine-2,4-dione;
[1587]
5-[3-methoxy-4-methoxymethoxy-5-(3-methoxy-4-methoxymethoxy-1-(thia-
zolidine-2,4-dionyl)-benzylidene-5-yl)-benzylidene]-thiazolidine-2,4-dione-
;
[1588]
4-{2-[3,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[1589]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzoic
acid methyl ester;
[1590]
2-methoxy-6-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-phen-
ol;
[1591]
3-(3-methyl-but-2-enyl)-4-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[1592]
3-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,2-di-
ol;
[1593]
4-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[1594]
2-(3,7-dimethyl-octa-2,6-dienyl)-6-methoxy-4-[2-(4-nitro-phenyl)-vi-
nyl]-phenol;
[1595]
2-(3,7-dimethyl-octa-2,6-dienyl)-5-[2-(4-nitro-phenyl)-vinyl]-benze-
ne-1,3-diol;
[1596]
2-(3-methyl-but-2-enyl)-5-[2-(4-nitro-phenyl)-vinyl]-benzene-1,3-di-
ol;
[1597]
4-{2-[3,5-dihydroxy-4-(3-methyl-but-2-enyl)-phenyl]-vinyl}-benzonit-
rile; and
[1598]
2-bromo-4-[4-hydroxy-3-(3-methyl-but-2-enyl-phenyl)-vinyl]-phenol,
[1599] showed significant reduction in edema (15 to 80%, p<0.05)
when tested by this method.
[1600] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective, spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto. All patents and publications cited above are
hereby incorporated by reference.
* * * * *