U.S. patent application number 11/485940 was filed with the patent office on 2006-11-16 for 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders.
Invention is credited to Lee K. Hoong, Charles Q. Meng, Liming Ni, James A. Sikorski.
Application Number | 20060258735 11/485940 |
Document ID | / |
Family ID | 26907449 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258735 |
Kind Code |
A1 |
Meng; Charles Q. ; et
al. |
November 16, 2006 |
1,3-Bis-(substituted-phenyl)-2-propen-1-ones and their use to treat
VCAM-1 mediated disorders
Abstract
It has been discovered certain
1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds
of formula (I) inhibit the expression of VCAM-1, and thus can be
used to treat a patient with a disorder mediated by VCAM-1.
Examples of inflammatory disorders that are mediated by VCAM-1
include, but are not limited to arthritis, asthma, dermatitis,
cystic fibrosis, post transplantation late and chronic solid organ
rejection, multiple sclerosis, systemic lupus erythematosis,
inflammatory bowel diseases, autoimmune diabetes, diabetic
retinopathy, rhinitis, ischemia-reperfusion injury,
post-angioplasty restenosis, chronic obstructive pulmonary disease
(COPD), glomerulonephritis, Graves disease, gastrointestinal
allergies, conjunctivitis, atherosclerosis, coronary artery
disease, angina and small artery disease.
Inventors: |
Meng; Charles Q.;
(Alpharetta, GA) ; Ni; Liming; (Duluth, GA)
; Sikorski; James A.; (Alpharetta, GA) ; Hoong;
Lee K.; (Suwanee, GA) |
Correspondence
Address: |
Madeline I. Johnston, Esq.;KING & SPALDING LLP
34th Floor
1180 Peachtree Street
Atlanta
GA
30309-3521
US
|
Family ID: |
26907449 |
Appl. No.: |
11/485940 |
Filed: |
July 13, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10443470 |
May 21, 2003 |
7078431 |
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11485940 |
Jul 13, 2006 |
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09886348 |
Jun 20, 2001 |
6608101 |
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10443470 |
May 21, 2003 |
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60212769 |
Jun 20, 2000 |
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60255934 |
Dec 15, 2000 |
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Current U.S.
Class: |
514/443 ;
514/252.1; 514/263.1; 514/307; 514/311; 514/381; 514/394; 514/396;
514/411; 514/416; 514/419 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 1/04 20180101; C07D 333/56 20130101; A61P 27/02 20180101; C07D
317/44 20130101; C07D 493/04 20130101; A61P 9/10 20180101; A61P
11/02 20180101; C07C 205/45 20130101; C07C 49/796 20130101; A61P
1/00 20180101; A61P 13/12 20180101; A61P 11/00 20180101; C07C
49/813 20130101; A61P 37/08 20180101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 31/44 20130101; A61P 3/10 20180101; A61K
31/381 20130101; C07C 49/86 20130101; A61K 31/381 20130101; C07C
49/835 20130101; A61K 9/0031 20130101; C07C 49/84 20130101; C07D
309/06 20130101; A61P 37/06 20180101; A61P 29/00 20180101; A61P
17/06 20180101; C07D 409/10 20130101; A61K 31/513 20130101; A61P
11/06 20180101; A61P 9/00 20180101; A61P 19/02 20180101; C07D
417/10 20130101; A61K 31/505 20130101; C07D 333/16 20130101; A61K
9/0034 20130101; A61K 31/513 20130101; A61K 31/505 20130101; C07D
413/10 20130101; A61P 17/00 20180101; A61P 25/00 20180101; A61P
37/02 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/443 ;
514/263.1; 514/252.1; 514/311; 514/307; 514/419; 514/396; 514/381;
514/416; 514/394; 514/411 |
International
Class: |
A61K 31/381 20060101
A61K031/381 |
Claims
1. A compound of the formula (I): ##STR545## or its
pharmaceutically acceptable salt, wherein: i) the wavy line
indicates that the compound can be in the form of the E or Z
isomer; ii) R.sup.22 and R.sup.23 are independently hydrogen or
(C.sub.1-C.sub.4)alkyl; iii) R.sup.2.alpha., R.sup.3.alpha.,
R.sup.4.alpha., R.sup.5.alpha., R.sup.6.alpha., R.sup.2.beta.,
R.sup.3.beta., R.sup.4.beta., R.sup.5.beta. and R.sup.6.beta. are
independently hydrogen, alkyl, carbocycle, aryl, heteroaryl,
heterocycle, cycloalkyl, alkoxy, aryloxy, arylalkoxy,
heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl,
haloalkylthio, acyl, haloalkyl, aryloxy, amido, acylamino, amino,
dialkylamino, aminodialkyl, trifluoroalkoxy, alkylsulfonyl,
haloalkylsulfonyl, aminocarbonyl, alkenyl, alkynyl, halogen,
hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate, sulfate,
sulfinic acid, sulfenic acid, sulfamide, sulfonamide, sulfoxide,
metal sulfinate, phosphate, phosphonate, metal phosphonate,
phosphinate, alditol, carbohydrate, amino acid,
OC(R.sup.1).sub.2CO.sub.2H, SC(R.sup.1).sub.2CO.sub.2H,
NHCHR.sup.1CO.sub.2H, CO--R.sup.2, CO.sub.2R.sup.1,
polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl,
lower alkyl S(O)-lower alkyl, lower alkyl-S(O).sub.2-lower alkyl;
hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower
alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl,
heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl,
heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio
lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl,
heteroarylamino lower alkyl, heterocycloamino lower alkyl,
arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which
can be optionally substituted with a moiety that does not adversely
affect the biological properties of the molecule;
--C(O)(CH.sub.2).sub.2CO.sub.2.sup.-M.sup.+, --SO.sub.3M.sup.+, or
lower alkyl-O--R, wherein R is PO.sub.2(OH).sup.-M.sup.+,
PO.sub.3(OH).sup.-M.sup.+ or --SO.sub.3M.sup.+, wherein M.sup.+ is
a pharmaceutically acceptable cation; -lower alkylcarbonyl-lower
alkyl; carboxy lower alkyl; lower alkylamino-lower alkyl;
N,N-di-substituted amino lower alkyl-, wherein the substituents
each independently represent lower alkyl; iv) R.sup.1 is H, lower
alkyl, an optionally substituted carbocycle, aryl, heteroaryl,
heterocycle, alkylaryl, alkylheteroaryl, alkylheteroaryl or
alkylheterocycle; v) R.sup.2 is an optionally substituted alkyl,
alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle,
alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle;
vi) alternatively, R.sup.22 and R.sup.6.alpha. or R.sup.23 and
R.sup.6.alpha. can join together to form a bridged carbocycle,
aryl, heterocycle or heteroaromatic; vii) R.sup.2.alpha. and
R.sup.3.alpha., R.sup.3.alpha. and R.sup.4.alpha., R.sup.4.alpha.
and R.sup.5.alpha., R.sup.5.alpha. and R.sup.6.alpha.,
R.sup.2.beta. and R.sup.3.beta., R.sup.3.beta. and R.sup.4.beta.,
R.sup.4.beta. and R.sup.5.beta. or R.sup.5.beta. and R.sup.6.beta.
can independently join to form a bridged compound selected from the
group consisting of an optionally substituted carbocycle, an
optionally substituted cycloalkenyl, an optionally substituted
cycloalkylcarbonyl, an optionally substituted cycloalkenylcarbonyl;
an optionally substituted aryl, an optionally substituted
heterocylic or an optionally substituted heteroaromatic, or
alkylenedioxy or wherein the ring can include a carbonyl, cyclic
ester, amide, amine, sulfonate, or phosphonate; viii) at least one
of R.sup.2.alpha., R.sup.3.alpha., R.sup.4.alpha., R.sup.5.alpha.,
R.sup.6.alpha., R.sup.2.beta., R.sup.3.beta., R.sup.4.beta.,
R.sup.5.beta. or R.sup.6.beta. is, or R.sup.2.alpha. and
R.sup.3.alpha., R.sup.3.alpha. and R.sup.4.alpha., R.sup.4.alpha.
and R.sup.5.alpha., R.sup.5.alpha. and R.sup.6.alpha.,
R.sup.2.beta. and R.sup.3.beta., R.sup.3.beta. and R.sup.4.beta.,
R.sup.4.beta. and R.sup.5.beta. or R.sup.5.beta. and R.sup.6.beta.
come together to be, an heterocycle or heteroaromatic; and ix) at
least one of R.sup.2.alpha., R.sup.3.alpha., R.sup.4.alpha.,
R.sup.5.alpha., or R.sup.6.alpha., and at least one of
R.sup.2.beta., R.sup.3.beta., R.sup.4.beta., R.sup.5.beta. or
R.sup.6.beta. is a substituent other than hydrogen.
2. The compound of claim 1 of formula (II): ##STR546## or its
pharmaceutically acceptable salt.
3. The compound of claim 1, wherein R.sup.1 is independently H or
lower alkyl, R.sup.2 is an optionally substituted alkyl; and at
least one of R.sup.2.alpha., R.sup.3.alpha., R.sup.4.alpha.,
R.sup.5.alpha., or R.sup.6.alpha., and at least one of
R.sup.2.beta., R.sup.3.beta., R.sup.4.beta., R.sup.5.beta. or
R.sup.6.beta. is a substituent other than hydrogen.
4. The compound of claim 1, wherein R.sup.4.beta. or R.sup.5.beta.
is optionally substituted heteroaryl or heterocycle; and at least
one of R.sup.2.alpha., R.sup.3.alpha., R.sup.4.alpha.,
R.sup.5.alpha., or R.sup.6.alpha. is a substituent other than
hydrogen.
5. The compound of claim 1, wherein R.sup.4.alpha. or
R.sup.5.alpha. is optionally substituted heteroaryl or heterocycle;
and at least one of R.sup.2.alpha., R.sup.3.alpha., R.sup.4.alpha.,
R.sup.5.alpha., or R.sup.6.alpha. is a substituent other than
hydrogen.
6. The compound of claim 1, wherein R.sup.5.beta. is optionally
substituted thienyl or benzothienyl; R.sup.2.alpha.,
R.sup.3.alpha., R.sup.4.alpha., R.sup.5.alpha., R.sup.6.alpha., or
R.sup.2.beta., R.sup.3.beta., R.sup.4.beta., and R.sup.6.beta. are
independently hydrogen, methoxy, ethoxy, propoxy, benzyloxy,
4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy, 4-aminobenzyloxy,
fluoro, chloro, bromo, iodo, hydroxy, OCH.sub.2CO.sub.2H,
SCH.sub.2CO.sub.2H, NHCH.sub.2CO.sub.2H, CO.sub.2H,
pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy;
thien-2-ylmethoxy, thien-3-ylmethoxy, fur-2-ylmethoxy,
fur-3-ylmethoxy, and at least one of R.sup.2.alpha.,
R.sup.3.alpha., R.sup.4.alpha., R.sup.5.alpha., or R.sup.6.alpha.
is a substituent other than hydrogen.
7. The compound of claim 1 wherein at least one of R.sup.2.alpha.,
R.sup.3.alpha., R.sup.4.alpha., R.sup.5.alpha., R.sup.6.alpha.,
R.sup.2.beta., R.sup.3.beta., R.sup.4.beta., R.sup.5.beta. or
R.sup.6.beta., is or R.sup.2.alpha. and R.sup.3.alpha.,
R.sup.3.alpha. and R.sup.4.alpha., R.sup.4.alpha. and
R.sup.5.alpha., R.sup.5.alpha. and R.sup.6.alpha., R.sup.2.beta.
and R.sup.3.beta., R.sup.3.beta. and R.sup.4.beta., R.sup.4.beta.
and R.sup.5.beta. or R.sup.5.beta. and R.sup.6.beta. join to form a
carbocycle, aryl, heterocycle or heteroaromatic in which the
carbocycle, aryl, heteroaryl or heterocycle is a 5, 6 or 7 membered
ring, optionally conjugated to another carbocycle, aryl, heteroaryl
or heterocycle.
8. The compound of claim 1, wherein R.sup.3.alpha. and
R.sup.4.alpha. or R.sup.5.alpha. and R.sup.4.alpha. join to form a
5-membered methylendioxyphenyl group.
9. The compound of claim 1, wherein a heteroaryl or heteroaryl is
on the A ring.
10. The compound of claim 1, wherein a heteroaryl or heteroaromatic
is on the B ring.
11. The compound of claim 1, wherein the compound has a substituent
that increases the water solubility of the compound.
12. The compound of claim 11, wherein the water solubilizing moiety
is selected from the group consisting of alkoxy, alditol,
carbohydrate, amino acid, OC(R.sup.1).sub.2CO.sub.2H,
SC(R.sup.1).sub.2CO.sub.2H, NHCHR.sup.1CO.sub.2H, CO--R.sup.2 and
CO.sub.2R.sup.1.
13. The compound of claim 11, wherein the solubilizing substituent
is a residue of glycolic acid.
14. The compound of claim 11, wherein the optionally subtituted
heteroaryl or heterocyclic attached to the A or B phenyl ring is
selected from the group consisting of pyrrolidinyl,
tetrahydrofuryl, piperazinyl, piperidinyl, morpholino,
thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl,
pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl. aziridinyl,
furyl, furanyl, pyridyl, pyrimidinyl, benzoxazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl
and 1,3,5-triazinyl.
15. The compound of claim 11, wherein the optionally substituted
heteroaryl or heterocyclic attached to the A or B phenyl ring is
selected from the group consisting of thienyl, isothiazolyl,
imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl,
isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl,
isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl,
xanthinyl, hypoxanthinyl, pyrazole, and imidazole.
16. The compound of claim 11, wherein the optionally substituted
heteroaryl or heterocyclic attached to the A or B phenyl ring is
selected from the group consisting of 1,2,3-triazole,
1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine and
pteridinyl.
17. The compound of claim 1 the formula: ##STR547## or its
pharmaceutically acceptable salt thereof.
18. The compound of claim 1 of the formula: ##STR548## or its
pharmaceutically acceptable salt.
19. The compound of claim 1 of the formula: ##STR549## or its
pharmaceutically acceptable salt.
20. The compound of claim 1 of the formula: ##STR550## or its
pharmaceutically acceptable salt.
21. The compound of claim 1 of the formula: ##STR551## or its
pharmaceutically acceptable salt.
22. The compound of claim 1 of the formula: ##STR552## or its
pharmaceutically acceptable salt.
24. The compound of claim 1 of the formula: ##STR553## or its
pharmaceutically acceptable salt.
25. The compound of claim 1, wherein the compound is of the
formula: ##STR554## or its pharmaceutically acceptable salt.
26. The compound of claim 1 of the formula: ##STR555## or its
pharmaceutically acceptable salt.
27. The compound of claim 1 of the formula: ##STR556## or its
pharmaceutically acceptable salt thereof.
28. The compound of claim 1 of the formula: ##STR557## or its
pharmaceutically acceptable salt thereof.
29. The compound of claim lof the formula: ##STR558## or its
pharmaceutically acceptable salt.
30. The compound of claim 1, the formula: ##STR559## or its
pharmaceutically acceptable salt.
31. The compound of claim 1 of the formula: ##STR560## or its
pharmaceutically acceptable salt.
32. The compound of claim 1 of the formula: ##STR561## or its
pharmaceutically acceptable salt.
33. The compound of claim 1 of the formula: ##STR562## wherein Y is
a phenyl ring fused to another heteroaromatic or heterocycle.
34. The compound of claim 1 of the formula: ##STR563## wherein Y is
a phenyl ring fused to another heteroaromatic or heterocycle.
35. The compound of claim 1 of the formula: ##STR564## or its
pharmaceutically acceptable salt thereof, wherein Y is a phenyl
ring fused to another heteroaromatic or heterocycle.
36. The compound of claim 1, wherein the compound is of the
formula: ##STR565## or its pharmaceutically acceptable salt.
37. The compound of claim 1, wherein the compound is of the
formula: ##STR566## or its pharmaceutically acceptable salt.
38. The compound of claim 1, wherein the compound is of the
formula: ##STR567## or its pharmaceutically acceptable salt.
39. The compound of claim 1, wherein the compound is of the
formula: ##STR568## or its pharmaceutically acceptable salt.
40. The compound of claim 1, wherein the compound is of the
formula: ##STR569## or its pharmaceutically acceptable salt.
41. The compound of claim 1, wherein the compound is of the
formula: ##STR570## or its pharmaceutically acceptable salt.
42. The compound of claim 1, wherein the compound is of the
formula: ##STR571## or its pharmaceutically acceptable salt.
43. The compound of claim 1, wherein the compound is of the
formula: ##STR572## or its pharmaceutically acceptable salt
thereof.
44. The compound of claim 1, wherein the compound is of the formula
##STR573## or its pharmaceutically acceptable salt.
45. The compound of claim 1, wherein the compound is of the
formula: ##STR574## or its pharmaceutically acceptable salt,
wherein Y is selected from the group consisting of: ##STR575##
##STR576##
46. The compound of claim 1 of the formula: ##STR577## wherein
R.sup.4.beta. is a heteroaryl or heterocycle.
47. The compound of claim 1 of the formula: ##STR578## wherein
R.sup.4.beta. is a heteroaryl or heterocycle.
48. The compound of claim 1 of the formula: ##STR579## or its
pharmaceutically acceptable salt, wherein R.sup.4.beta. is a
heteroararyl or heterocyclic.
49. The compound of claim 1 of the formula: ##STR580## or its
pharmaceutically acceptable salt, wherein R.sup.4.beta. is a
heteroaryl or heterocycle.
50. The compound of claim 1 of the formula: ##STR581## or its
pharmaceutically acceptable salt.
51. The compound of claim 1 of the formula: ##STR582## or its
pharmaceutically acceptable salt.
52. The compound of claim 1, wherein the compound is of the
formula: ##STR583## or its pharmaceutically acceptable salt.
53. The compound of claim 1, wherein the compound is of the
formula: ##STR584## or its pharmaceutically acceptable salt.
54. A compound selected from the group consisting of:
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-
methoxyphenyl)-2-propen-1-one sodium salt;
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyp-
henyl)-2-propen-1-one;
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyp-
henyl)-2-propen-1-one sodium salt;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-
phenyl)-2-propen-1-one;
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)--
2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-
methoxyphenyl)-2-propen-1-one;
3-[2,4-dimethoxy-5-(thien-2-yl)-phenyl]-1-(4-carboxymethoxy-3,5-dimethoxy-
phenyl)-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(2,3,4-trimethoxyphenyl)-
-2-propen-1-one;
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-p-
ropen-1-one;
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one;
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxyp-
henyl)-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxyphenyl)-2-propen-1-one-
;
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-pro-
pen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-pro-
pen-1-one sodium salt;
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one;
3-[3,4-dimethoxy-5-(3-pyridyl)phenyl]-1-(3,4,5-trimethoxyphenyl-
)-2-propen-1-one;
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-prope-
n-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,5-dimethoxyphenyl)-2-pro-
pen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-iodo-2-methoxyphenyl)-2-propen-1--
one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(4-pyridylmethoxyp-
henyl)-2-propen-1-one, hydrochloride salt;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxyphenyl-
)-2-propen-1-one hydrochloride salt;
3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-2--
propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-pro-
pen-1-one;
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one;
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxypheny-
l)-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxphenyl)-
-2-propen-1-one;
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-
-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-
phenyl)-2-propen-1-one sodium salt;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(3-pyridylmethoxphenyl)-
-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(4-methoxyphenyl)-2-propen-1-
-one;
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxyphenyl)-2-
-propen-1-one;
3-[5-(5-acetylthien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimetoxyphenyl)--
2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-methoxyphenyl)-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,6-dimethoxyphenyl)-2-propen-1-one-
;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-o-
ne;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,4,6-trimethoxyphenyl)-2-prope-
n-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2--
propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-ethoxycarbonylenzyloxy)-3-meth-
oxyphenyl]-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[4-(2,3-isopropylidenedi-
oxy-1-propoxy)-3,5-dimethoxyphenyl]-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[3-methoxy-4-(4-pyridylmethoxy)pheny-
l]-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-propen--
1-one;
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyph-
enyl)-2-propen-1-one;
3-(4-ethoxy-3-fluorophenyl)-1-[2-methoxy-5-(thien-2-yl)phenyl]-2-propen-1-
-one;
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,-
5-trimethoxyphenyl)-2-propen-1-one sodium salt;
3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one sodium salt;
3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one;
3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one sodium salt;
3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one sodium salt;
3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-buten-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-carboxybenzyloxy)-3-methoxyphe-
nyl]-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-difluorophenyl)-2-propen-1-one;
3-[4-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-aminobenzyloxy)-3-methoxypheny-
l]-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-
-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(2,3,4-trimethox-
yphenyl)-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[3,5-dimethoxy-4-(2-morp-
holinoethoxy)phenyl]-2-propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[2-methoxy-4-(3-methoxyphenyl)phenyl-
]-2-propen-1-one;
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4-dimethoxyphenyl)-2--
propen-1-one;
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxy-4-(thien-2-ylmethoxy)-
phenyl)-2-propen-1-one;
3-[4-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;
3-[2-methoxy-4-(thien-2-yl)-phenyl]-1-[2-methoxy-4-(thien-2-yl)phenyl)-2--
propen-1-one phenyl]-2-propen-1-one;
55. A pharmaceutical composition for the treatment of a VCAM-1
mediated disorder in a host, comprising an effective amount of
compound of claims 1-54 in a pharmaceutically acceptable
carrier.
56. The pharmaceutical composition of claim 55 further comprising a
second biologically active agent selected from the group consisting
of heparin, frusemide, ranitidine, DNAase, an immunosuppressive
agent, IV gamma globulin, troleandomycin, cyclosporin (Neoral),
methotrexate, FK-506, Myochrysine (gold sodium thiomalate),
platelet activating factor (PAF) antagonist, thromboxane inhibitor,
leukotriene-D.sub.4-receptor antagonist, Accolate (zafirlukast),
Ziflo (zileuton), leukotriene C.sub.1 or C.sub.2 antagonist,
inhibitor of leukotriene synthesis, zileuton or an inducible nitric
oxide synthase inhibitor, prophylactic agent, sodium cromoglycate,
Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic
Crolom), Tilade (nedocromil, nedocromil sodium), ketotifen,
.beta..sub.2-adrenergic agonist, corticosteriod, antihistimine
(H.sub.1 receptor antagonist), xanthines and methylxanthines,
Theo-24 (theophylline, Slo-Phylline, Uniphyllin, Slobid, Theo-Dur),
Choledyl (oxitriphylline), aminophylline; anticholinergic agent
(antimuscarinic agent), belladonna alkaloids, Atrovent (ipratropium
bromide), atropine, oxitropium bromide; phosphodiesterase
inhibitors, zardaverine; calcium antagonists, nifedipine; potassium
activators, cromakalim, P38 kinase inhibitors, tricyclic
antidepressents, cJun kinase inhibitors and cylcooxygenase-2
(COX-2) inhibitors.
57. The pharmaceutical composition of claim 56, wherein the
.beta..sub.2-adrenergic agonist is selected from the group
consisting of albuterol (salbutamol, Proventil, Ventolin),
terbutaline, Maxair (pirbuterol), Serevent (salmeterol),
epinephrine, metaproterenol (Alupent, Metaprel), Brethine
(Bricanyl, Brethaire, terbutaline sulfate), Tomalate (bitolterol),
isoprenaline, ipratropium bromide, bambuterol hydrochloride,
bitolterol meslyate, broxaterol, carbuterol hydrochloride,
clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol
fumarate, ephedra (source of alkaloids), ephedrine (ephedrine
hydrochloride, ephedrine sulfate), etafedrine hydrochloride,
ethylnoradrenaline hydrochloride, fenoterol hydrochloride,
hexoprenaline hydrochloride, isoetharine hydrochloride,
isoprenaline, mabuterol, methoxyphenamine hydrochloride,
methylephedrine hydrochloride, orciprenaline sulphate,
phenylephrine acid tartrate, phenylpropanolamine
(phenylpropanolamine polistirex, phenylpropanolamine sulphate),
pirbuterol acetate, procaterol hydrochloride, protokylol
hydrochloride, psuedoephedrine (psuedoephedrine polixtirex,
psuedoephedrine tannate, psuedoephedrine hydrochloride,
psuedoephedrine sulphate), reproterol hydrochloride, rimiterol
hydrobromide, ritodrine hydrochloride, salmeterol xinafoate,
terbutaline sulphate, tretoquinol hydrate and tulobuterol
hydrochloride.
58. The pharmaceutical composition of claim 56, wherein the
corticosteriod is selected from the group consisting of
glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort
(triamcinolone acetonide), Beclovet (Vanceril, beclomethasone
dipropionate), Flovent (fluticasone), Pulmicort (budesonide),
prednisolone, hydrocortisone, adrenaline, Alclometasone
Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,
Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone
Benzoate, Betamethasone Dipropionate, Betamethasone Sodium
Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,
Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate,
Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol,
Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate),
Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone
Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate,
Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium
Phosphate), Dichlorisone Acetate, Diflorasone Diacetate,
Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone,
Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,
Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone
Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone
(Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone
(Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone,
Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide,
Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride,
Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate,
Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,
Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,
Hydrocortisone Valerate), Medrysone, Meprednisone,
Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone,
Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone
Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate
Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone
Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,
Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium
Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate,
Prednisolone Tebutate), Prednisone (Prednisone Acetate),
Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex,
Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,
Triamcinolone Diacetate and Triamcinolone Hexacetonide).
59. The pharmaceutical composition of claim 56, wherein the
antihistimine (H.sub.1 receptor antagonist) is selected from the
group consisting of Chlortrimeton (Teldrin, chlorpheniramine),
Atrohist (brompheniramine, Bromarest, Bromfed, Dimetane), Actidil
(triprolidine), Dexchlor (Poladex, Polaramine,
dexchlorpheniramine), Benadryl (diphen-hydramine), Tavist
(clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ
(tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec
(cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra
(fexofenadine), Hismanal (astemizole), Claritin (loratadine),
Seldane (terfenadine), Periactin (cyproheptadine), Nolamine
(phenindamine, Nolahist), Phenameth (promethazine, Phenergan),
Tacaryl (methdilazine) and Temaril (trimeprazine).
60. A method for the treatment or prophylaxis of a VCAM-1 mediated
disorder in a host, comprising administering an effective amount of
compound of claims 1-54.
61. The method of claim 60, wherein the VCAM-1 mediated disorder is
arthritis,
62. The method of claim 60, wherein the VCAM-1 mediated disorder is
asthma.
63. The method of claim 60, wherein the VCAM-1 mediated disorder is
dermatitis.
64. The method of claim 60, wherein the VCAM-1 mediated disorder is
psoriasis.
65. The method of claim 60, wherin the VCAM-1 mediated disorder is
cystic fibrosis.
66. The method of claim 60, wherein the VCAM-1 mediated disorder is
post transplantation late or chronic solid organ rejection.
67. The method of claim 60, wherein the VCAM-1 mediated disorder is
multiple sclerosis.
68. The method of claim 60, wherein the VCAM-1 mediated disorder is
atherosclerosis.
69. The method of claim 60, whereint he VCAM-1 mediated disorder is
post-angioplasty restenosis.
70. The method of claim 60, wherein the VCAM-1 mediated disorder is
coronary artery disease.
71. The method of claim 60, wherein the VCAM-1 mediated idsorder is
angina or small artery disease.
72. The method of claim 60, wherein the VCAM-1 mediated arthritis
is systemic lupus erythematosus.
73. The method of claim 60, wherein the VCAM-1 mediated disorder is
Crohn's disease.
74. The method of claim 60, wherein the VCAM-1 mediated disorder is
rheumatoid arthritis.
75. The method of claim 60, wherein the VCAM-1 mediated disorder is
inflammatory bowel diseases.
76. The method of claim 60, wherein the VCAM-1 mediated disorder is
autoimmune diabetes.
77. The method of claim 60, wherein the VCAM-1 mediated disorder is
diabetic retinopathy.
78. The method of claim 60, wherein the VCAM-1 mediated disorder is
rhinitis.
79. The method of claim 60, wherein the VCAM-1 mediated disorder is
ischemia-reperfusion injury.
80. The method of claim 60, wherein the VCAM-1 mediated disorder is
chronic obstructive pulmonary disease (COPD).
81. The method of claim 60, wherein the VCAM-1 mediated disorder is
glomerulonephritis.
82. The method of claim 60, wherein the VCAM-1 mediated disorder is
Graves disease.
83. The method of claim 60, wherein the VCAM-1 mediated disorder is
gastrointestinal allergies.
84. The method of claim 60, wherein the VCAM-1 mediated disorder is
conjunctivitis.
85. The method of claim 60, further comprising administering the
compound in alternation or combination with an effective amount of
a second biologically active agent.
Description
[0001] This application is a continuation U.S. Ser. No. 09/886,348,
filed Jun. 20, 2001, which claims priority to U.S. Ser. No.
60/212,769, filed on Jun. 20, 2000, and U.S. Ser. No. 60/255,934
filed on Dec. 15, 2000, the disclosures of which are hereby
incorporated by reference in their entirety.
[0002] The present invention includes novel heteroaryl or
heterocyclic 1,3-bis-(substituted-phenyl)-2-propen-1-ones as well
as methods and compositions for the treatment of disorders mediated
by VCAM-1 or MCP-1 and for the treatment of inflammatory disorders
generally that include the administration of a
1,3-bis-(substituted-phenyl)-2-propen-1-one that has at least one
phenyl substituent that is an aryl, heteroaryl or heterocyclic
moiety.
BACKGROUND OF THE INVENTION
[0003] Adhesion of leukocytes to the endothelium represents a
fundamental, early event in a wide variety of inflammatory
conditions, autoimmune disorders and bacterial and viral
infections. Leukocyte recruitment to endothelium is mediated in
part by the inducible expression of adhesion molecules on the
surface of endothelial cells that interact with counterreceptors on
immune cells. Endothelial cells determine which types of leukocytes
are recruited by selectively expressing specific adhesion
molecules, such as vascular cell adhesion molecule-1 (VCAM-1),
intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1
binds to the integrin VLA-4 expressed on lymphocytes, monocytes,
macrophages, eosinophils, and basophils but not neutrophils. This
interaction facilitates the firm adhesion of these leukocytes to
the endothelium. VCAM-1 is an inducible gene that is not expressed,
or expressed at very low levels, in normal tissues. VCAM-1 is
upregulated in a number of inflammatory diseases, including
arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post
transplantation late and chronic solid organ rejection, multiple
sclerosis, systemic lupus erythematosis, inflammatory bowel
diseases, autoimmune diabetes, diabetic retinopathy, rhinitis,
ischemia-reperfusion injury, post-angioplasty restenosis, chronic
obstructive pulmonary disease (COPD), glomerulonephritis, Graves
disease, gastrointestinal allergies, conjunctivitis,
atherosclerosis, coronary artery disease, angina and small artery
disease.
[0004] Coronary heart disease (CHD), primarily as a result of
atherosclerosis, remains the leading cause of death in
industrialized countries. Atherosclerosis is a disease
characterized by vascular inflammation, deposition of lipids in the
arterial vessel wall and smooth muscle cell proliferation resulting
in a narrowing of the vessel passages. In advanced stages of the
disease atherosclerotic lesions can become unstable resulting in
plaque rupture, thrombosis, myocardial infarction and ischemic
heart disease. It is now well accepted that the initiating events
in atherosclerosis are local injury to the arterial endothelium
that results in the induction of VCAM-1 and recruitment of
mononuclear leukocytes that express the integrin counterreceptor,
VLA-4, (O'Brien, et al., J. Clin. Invest., 92: 945-951, 1993).
Subsequent conversion of leukocytes to foamy macrophages results in
the synthesis of a wide variety of inflammatory cytokines, growth
factors, and chemoattractants that help propagate formation of the
mature atheromatous plaque by further inducing endothelial
activation, leukocyte recruitment, smooth muscle cell
proliferation, and extracellular matrix deposition. Pharmacological
inhibition of VCAM-1 expression has been shown to inhibit
atherosclerosis in several animal models (Sundell et al.,
Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1
has also been shown to inhibit neointimal formation in a mouse
model of arterial wall injury (Oguchi, S., et al., Arterioscler.
Thromb. Vasc. Biol., 20: 1729-1736, 2000).
[0005] Asthma, which is increasing in prevalence and morbidity
world-wide, is a chronic inflammatory disease characterized by lung
eosinophilia and bronchial hyperreactivity. The interaction between
VCAM-1 on lung endothelial cells and VLA-4, which is the integrin
counterreceptor expressed on eosinophils, is thought to be
important for selective eosinophil recruitment. Eosinophils have
been considered an important effector cell in the pathogenesis of
asthma and other allergic diseases. Activated eosinophils release
proteins such as major basic protein (MBP) that have been
demonstrated to induce bronchial hyperreactivity, one of the
defining criteria of asthma (Bousquot, et al., N. Engl. J. Med.,
323: 1033-1039, 1990). It has been demonstrated that VCAM-1 is
markedly upregulated on human bronchial vascular endothelium of
subjects with asthma who have air flow limitation, when compared
with subjects without asthma (Pilewski, et al., Am. J. Respir. Cell
Mol. Biol., 12, 1-3,1995; Ohkawara, Y., et al., Am. J. Respir. Cell
Mol. Biol., 12, 4-12, 1995; Gosset, P., et al., Int. Arch. Allergy
Immunol. 106: 69-77, 1995; Hacken, N. H., et al., Clin. Exp.
Allergy, 28 (12): 1518-1525, 1998). An elevation in serum soluble
VCAM-1 levels has also been demonstrated in patients undergoing a
bronchial asthma attack compared with levels under stable
conditions (Montefort, S., Koizumi, A., Clin. Exp. Immunol., 101:
468-73, 1995). Several animal studies further demonstrate a spatial
and temporal association between VCAM-1 and asthma. In a mouse
model of allergic asthma, VCAM-1 expression was shown to be induced
by allergen challenge, and administration of an anti-VCAM-1
antibody was effective in inhibiting eosinophil infiltration that
occurred in this model (Metzger, W. J., et al., J. Allergy Clin.
Immunol., 93: 183, 1994). Further evidence for the importance of
VCAM-1 in allergic asthma comes from work in IL-12 knockout mice.
IL-12 knockout mice had fewer eosinophils and VCAM-1 expression
than wildtype mice; however, administration of recombinant IL-12 at
the time of ova sensitization and challenge restored lung VCAM-1
expression and eosinophilia (Wang, S., et al., J. Immunol.,
166:2741-2749, 2001). There are several examples where blocking the
integrin receptors for VCAM-1 have had positive effects on animal
models of asthma (Rabb et al., Am. J. Respir. Care Med. 149:
1186-1191, 1994; Abraham, W, et al., Am. J. Respir. Crit. Care Med.
156: 696-703. 1997) further demonstrating the importance of
VCAM-1/VLA-4 interactions in allergic inflammation. Eosinophils are
also important effector cells in allergic rhinitis. VCAM-1 has been
demonstrated to be upregulated 24 hrs after nasal allergen
provocation in patients with seasonal allergic rhinitis but not in
normal subjects (Braunstahl, G. J., et al., J. Allergy Clin.
Immunol., 107: 469-476, 2001).
[0006] Rheumatoid arthritis (RA) is a clinical syndrome of unknown
cause characterized by symmetric, polyarticular inflammation of
synovial-lined joints. The role of adhesion molecules in the
pathogenesis of rheumatoid arthritis (RA) has also been well
documented, and VCAM-1 expression on synovial fibroblasts is a
clinical hallmark of RA (Li, P., et al., J. Immunol. 164: 5990-7,
2000). VLA-4/VCAM-1 interactions may be the predominant mechanism
for recruitment of leukocytes to the synovium (Dinther-Janssen, et
al., J. Immunol. 147: 4207-4210, 1991; Issekeutz and Issekeutz,
Clin. Immunol. Immunopathol. 61:436-447, 1991; Morales-Ducret et
al., J. Immunol. 149:1424-1431, 1992; Postigo et al., J. Clin.
Invest. 89:1445-1452, 1992; Matsuyama, T., et al, Hum. Cell, 9:
187-192,1996). In support of this, increased VCAM-1 expression has
been found in RA synovial tissue compared with osteoarthritis and
control tissue (Wilkinson et al., Lab. Invest. 69:82-88, 1993;
Furuzawa-Carballeda, J., et al., Scand. J. Immunol. 50: 215-222;
1999). Soluble VCAM-1 is higher in RA patients than in control
subjects (Kolopp-Sarda, M. N., et al., Clin. Exp. Rheumatol. 19:
165-70, 2001). Soluble VCAM-1 has been shown to be chemotactic for
T cells (Kitani, A., et al., J. Immun. 161: 4931-8, 1998), and in
addition to being a possible diagnostic marker for RA, may
contribute to its pathogenesis by inducing migration and
recruitment of T cells. VCAM-1 expressed on fibroblast-like
synoviocytes has also been implicated in enhanced survival of
activated synovial fluid B cells (Marinova, Mutafcheia, L.,
Arthritis Rheum. 43: 638-644, 2000) that may further contribute to
RA pathogenesis.
[0007] Chronic inflammation and accompanying vascular complications
and organ damage characterize systemic lupus erythematosis (SLE).
Recent studies suggest that VCAM-1 plays a role in SLE. Expression
of VCAM-1 is increased on dermal vessel endothelial cells in
patients with active systematic lupus erythematosus (Jones, S. M.,
British J. Dermatol. 135: 678-686, 1996) and correlates with
increased disease severity (Belmont et al., Arthritis Rheum.
37:376-383, 1994). SLE muscle samples with perivascular infiltrate
have greater endothelial cell expression of VCAM-1 compared with
SLE patients without a perivascular infiltrate or with control
samples (Pallis et al., Ann. Rheum. Dis. 52:667-671, 1993).
Increased expression of VCAM-1 has also been demonstrated in
kidneys of lupus-prone MRL/1pr mice compared to nonautoimmune
strains and its expression increased with disease severity (McHale,
J. F., et al., J. Immunol. 163: 3993-4000, 1999). VCAM-1 expression
on mesangial cells in vitro can be stimulated by IL-1, TNF-.alpha.,
and INF.gamma. exposure as well as by anti-endothelial cell IgG
fraction and anti-DNA autoantibodies from SLE patients (Wuthrich,
Kidney Int. 42: 903-914, 1992; Papa, N. D., et al., Lupus, 8:
423-429, 1999; Lai, K. N., et al., Clin Immunol Immunopathol, 81:
229-238, 1996). Furthermore, soluble VCAM-1 is higher in SLE
patients than in normal subjects (Mrowka, C., et al., Clin.
Nephrol. 43: 288-296, 1995; Baraczka, K., et al., Acta. Neurol.
Scand. 99: 95-99, 1999; Kaplanski, G., et al., Arthritis Rheumol.
43: 55-64, 2000; Ikeda, Y., Lupus, 7: 347-354, 1998) and correlates
with disease activity (Scudla, V., Vnitr. Lek., 43: 307-311,
1997).
[0008] Increased VCAM-1 expression has also been demonstrated in
solid organ transplant rejection. Acute transplant rejection occurs
when the transplant recipient recognizes the grafted organ as
"non-self" and mounts an immune response characterized by massive
infiltration of immune cells, edema, and hemorrage that result in
the death of the transplanted organ. Acute rejection occurs in a
matter of hours or days and has been correlated with increased
levels of VCAM-1 in tissues and in plasma (Tanio et al.,
Circulation, 89:1760-1768, 1994; Cosimi et al., J. Immunol. 144:
4604-4612, 1990; Pelletier, R., et al., Transplantation, 55: 315,
1992). A monoclonal antibody to VCAM-1 has been shown to inhibit
cardiac allograft rejection in mice (Pelletier, R., J. Immunol.,
149: 2473-2481, 1992; Pelletier, R., et al., Transplantation
Proceedings, 25: 839-841, 1993; Orosz, C. G., et al., J. Heart and
Lung Transplantation, 16: 889-904, 1997) and when given for 20 days
can cause complete inhibition of rejection and long-term graft
acceptance (Orosz C. G., et al., Transplantation, 56: 453-460,
1993). Chronic graft rejection also known as allograft vasculopathy
is distinct from acute transplant rejection and is a leading cause
of late graft loss after renal and heart transplantation.
Histologically it is characterized by concentric neointimal growth
within vessels that is largely due to smooth muscle migration and
proliferation. It is thought to be the result of endothelial damage
brought about by several factors including: ischemia-reperfusion
injury, immune complexes, hypertension, hyperlipidemia and viruses.
All of these factors have been associated with induction of VCAM-1
in endothelial cells. There is also a strong correlation of soluble
and tissue VCAM-1 levels with chronic rejection (Boratynska, M.,
Pol. Arch. Med. Wewn, 100: 410-410, 1998; Zembala, M., et al., Ann.
Transplant. 2: 16-9, 1998; Solez K., et al., Kidney International.,
51: 1476-1480, 1997; Koskinen P. K., et al., Circulation, 95:
191-6, 1997).
[0009] Multiple sclerosis is a common demyelinating disorder of the
central nervous system, causing patches of sclerosis (plaques) in
the brain and spinal cord. It occurs in young adults and has
protean clinical manifestations. It is well documented that VCAM-1
is expressed on brain microvascular endothelial cells in active
lesions of multiple sclerosis (Lee S. J., et al., J. Neuroimmunol.,
98: 77-88, 1998). Experimental therapy of experimental autoimmune
encephalomyelitis, which is an animal model for multiple sclerosis,
using antibodies against several adhesion molecules, including
VCAM-1, clearly shows that adhesion molecules are critical for the
pathogenesis of the disease (Benveniste et al., J. Neuroimmunol.
98:77-88, 1999). A time and dose dependent expression of VCAM-1 and
release of soluble VCAM-1 were detected in cultures of human
cerebral endothelial cells induced by TNF.alpha., but not in
peripheral blood mononuclear cells (Kallmann et al., Brain,
123:687-697, 2000). Clinical data also show that adhesion molecules
in blood and cerebrospinal fluid are up-regulated throughout the
clinical spectrum of multiple sclerosis (Baraczka, K., et al.,
Acta. Neurol. Scand. 99: 95-99, 1999; Reickmann, P., et al., Mult.
Scler., 4: 178-182, 1998; Frigerio, S., et al., J. Neuroimmunol.,
87: 88-93, 1998) supporting the notion that therapies which
interfere with cell adhesion molecules such as VCAM-1 may be
beneficial in modifying this disease (Elovaara et al., Arch.
Neurol. 57:546-551, 2000).
[0010] Diabetes mellitus is a metabolic disease in which
carbohydrate utilization is reduced and that of lipid and protein
is enhanced. Evidence has accumulated that increased levels of
adhesion molecules may play a functional pathophysiological role in
diabetes (Wagner and Jilma, Hormone and Metabolic Research, 29:
627-630, 1997; Kado, S., Diabetes Res. Clin. Pract., 46: 143-8,
1999). It is caused by an absolute or relative deficiency of
insulin and is characterized by chronic hyperglycemia, glycosuria,
water and electrolyte loss, ketoacidosis, and coma. Elevated
circulating adhesion molecules including VCAM-1 have been detected
in patients with diabetes and in experimental models of diabetes in
animals (Lorini et al., Hormone Research, 48: 153, 1997; Otsuki et
al., Diabetologia, 40: A440, 1997; Hart et al., FASEB J. 11:A340,
1997; Albertini et al., Diabetologia, 39: A240, 1996; Wagner et
al., Diabetologia, 39: A205, 1996; Enghofer et al., Diabetologia,
39: A97, 1996; Koga M., Diabet. Med., 15: 661-667, 1998). In
addition, complications of diabetes often include peripheral
vasculopathies such as diabetic retinopathy and diabetic
nephropathy. It is believed that adhesion of leukocytes to the
peripheral vasculature plays a central role in the vasculopathies
often associated with diabetes.
[0011] Crohn's disease, also known as regional enteritis, is a
subacute chronic inflammatory condition of unknown cause, involving
the internal ileum and less frequently other parts of the
gastrointestinal tract. It is characterized by patchy deep ulcers
that may cause fistulas, and narrowing and thickening of the bowel
by fibrosis and lymphocytic infiltration. Ulcerative colitis is a
chronic disease of unknown cause characterized by ulceration of the
colon and rectum, with rectal bleeding, mucosal crypt abscesses,
inflammatory pseudopolyps, abdominal pain, and diarrhea. It has
been reported that serum VCAM-1 reflects the grade of intestinal
inflammation in patients with Crohn's disease or ulcerative colitis
(Jones, et al., Gut, 36: 724-30, 1995; Goggins et al.,
Gastroenterology, 108: A825, 1995; Goeke and Manns,
Gastroenterology, 106: A689, 1994; Goeke et al., J.
Gasterokenterol. 32:480-486, 1997; Loftus et al., Gastroenterology,
108: A684, 1995; Tahami et al., Gastroenterology, 118: A344, 2000).
Antibodies to VCAM-1 have been shown to ameliorate
experimentally-induced colitis in mice (Soriano, A., Lab. Invest.
80: 1541-1551, 2000).
[0012] Psoriasis is a chronic skin disease characterized by
erythematous scaling plaques as a result of keratinocyte
hyperplasia, influx of immune cells and endothelial activation
(Nickoloff, B. J., et al., J. Invest. Dermatol., 127: 871-884,
1991). VCAM-1 is upregulated in psoriatic skin as compared to
normal skin (Groves, R. W., J. Am. Acad. Dermatol., 29: 67-72,
1993; Uyemura, K., et al., J. Invest. Dermatol. 101: 701-705, 1993)
and levels of circulating VCAM-1 correlate with disease activity
(Schopf, R. E., Br. J. Dermatol., 128: 34-7, 1993).
[0013] U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959;
5,773,231, and 5,773,209 to Medford, et al., as well as the
corresponding WO95/30415 to Emory University indicate that
polyunsaturated fatty acids ("PUFAs") and their hydroperoxides
("ox-PUFAs"), which are important components of oxidatively
modified low-density-lipoprotein (LDL), induce the expression of
VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or
E-selectin in human aortic endothelial cells, through a mechanism
that is not mediated by cytokines or other noncytokine signals.
This is a fundamental discovery of an important and previously
unknown biological pathway in VCAM-1 mediated immune responses. As
non-limiting examples, linoleic acid, linolenic acid, arachidonic
acid, linoleyl hydroperoxide (13-HPODE) and arachidonic
hydroperoxide (15-HPETE) induce cell-surface gene expression of
VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as
stearic acid) and monounsaturated fatty acids (such as oleic acid)
do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
[0014] PCT WO 98/51662, filed by AtheroGenics, Inc. and listing as
inventors Russell M. Medford, Patricia K. Somers, Lee K. Hoong, and
Charles Q. Meng, claims priority to provisional application U.S.
Ser. No. 60/047,020, filed on May 14, 1997. This application
discloses the use of a broad group of compounds as cardiovascular
protectants that exhibit at least one, and sometimes a composite
profile, of reducing cholesterol, lowering LDL, and inhibiting the
expression of VCAM-1.
[0015] U.S. Pat. No. 5,155,250 to Parker, et al. discloses that
2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same
compounds are disclosed as serum cholesterol lowering agents in PCT
Publication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat.
No. 5,608,095 to Parker, et al. discloses that
alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower
plasma cholesterol, and inhibit the expression of VCAM-1, and thus
are useful in the treatment of atherosclerosis.
[0016] PCT WO 98/51289, which claims priority to provisional
application U.S. Ser. No. 60/047,020, filed on May 14, 1997 by
Emory University listing Patty Somers as sole inventor, discloses
the use of a group of compounds as cardiovascular protectants and
antiinflammatory agents which exhibit at least one, and sometimes a
composite profile, of reducing cholesterol, lowering LDL, and
inhibiting the expression of VCAM-1 and thus can be used as
antiinflammatory and cardivascular treat agents.
[0017] U.S. Pat. Nos. 5,380,747; 5,792,787; 5,783,596; 5,750,351;
5,821,260; 5,807,884; 5,811,449; 5,846,959; 5,877,203; and
5,773,209 to Medford, et al., teach the use of dithiocarbamates of
the general formula A-SC(S)-B for the treatment of cardiovascular
and other inflammatory diseases. Examples include sodium
pyrrolidine-N-carbodithioate, tri-sodium
N,N-di(carboxymethyl)-N-carbodithioate, and sodium
N,N-diethyl-N-carbodithioate. The patents teach that the compounds
inhibit the expression of VCAM-1.
[0018] PCT WO 98/23581 discloses the use of benzamidoaldehydes and
their use as cysteine protease inhibitors.
[0019] PCT WO 97/12613 of Cornicelli et al. discloses compounds for
the inhibition of 15-lipogenase to treat and prevent inflammation
or atherosclerosis. Compounds disclosed include benzopyranoindole,
benzimidazole, catacholes, benzoxadiazines, benzo[a]phenothiazine,
or related compounds thereof.
[0020] Japanese Patent No. 06092950 to Masahiko et al. discloses
preparation of epoxy compounds wherein electron deficient olefins
such as acylstyrene derivatives, styrene derivatives, and
cyclohexenone derivatives are efficiently oxidized by a hydrogen
peroxide derivative in the presence of a primary or secondary amine
in an organic solvent to give said epoxides which are useful
intermediates for pharmaceutical and flavoring materials.
[0021] U.S. Pat. No. 5,217,999 to Levitzki et al. discloses
substituted styrene compound as a method of inhibiting cell
proliferation.
[0022] Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are
natural products related to flavonoids. PCT WO 99/00114
(PCT/DK98/00283) discloses the use of certain chalcones,
1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and
1,3-bisaromatic-prop-2-yn-1-ones for the preparation of
pharmaceutical compositions for the treatment of prophylaxis of a
number of serious diseases including i) conditions relating to
harmful effects of inflammatory cytokines, ii) conditions involving
infection by Helicobacter species, iii) conditions involving
infections by viruses, iv) neoplastic disorders, and v) conditions
cause by microorganisms or parasites.
[0023] PCT WO 00/47554 filed by Cor Therapeutics describes a broad
class of substituted unsaturated compounds for use as
antithrombotic agents.
[0024] PCT 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one
derivatives of the formula: ##STR1## which act as PAF antagonists
or 5-lipoxygenase inhibitors. The compounds are used in the
prevention and treatment of inflammatory and allergic disorders
mediated by platelet-activating factor and/or leukotrienes.
[0025] U.S. Pat. No. 4,085,135 discloses
2'-(carboxymethoxy)-chalcones with antigastric and antiduodenal
ulcer activities.
[0026] U.S. Pat. No. 5,744,614 to Merkle et al. discloses a process
for preparing 3,5-diarylpyrazoles and various derivatives thereof
by reacting hydrazine hydrate with 1,3-diarylpropenone in the
presence of sulfuric acid and an iodine compound.
[0027] U.S. Pat. No. 5,951,541 to Wehlage et al. discloses the use
of salts of aromatic hydroxy compounds, such as
(hydroxyaryl)alkenone salts, as brighteners in aqueous acidic
electroplating baths. In addition the invention discloses that such
compounds have a lower vapor pressure than the known brighteners,
as a single substance and in the electroplating baths, in order to
avoid losses of substance. They also have high water solubility
properties.
[0028] Japanese Patent No. 07330814 to Shigeki et al. discloses
benzylacetophenone compounds as photoinitiator compounds.
[0029] Japanese Patent No. 04217621 to Tomomi discloses siloxane
chalcone derivatives in sunscreens.
[0030] U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a
process for preparation of 2'-(carboxymethoxy)-chalcones having
antigastric and anti duodenal activities with low toxicity and high
absorptive ratio in the body. This patent suggests that the high
absorptive ratio in the body is due to the 2'-carboxymethoxy group
attached to the chalcone derivative.
[0031] U.S. Pat. No. 4,855,438 discloses the process for
preparation of optically active 2-hydroxyethylazole derivatives
which have fungicidal and plant growth-regulating action by
reacting an .alpha.-.beta.-unsaturated ketone which could include a
chalcone or a chalcone derivative with an enantiomerically pure
oxathiolane in the presence of a strongly basic organometallic
compound and at temperatures ranging from -80 to 120.degree. C.
[0032] European Patent No 307762 assigned to Hofmann-La Roche
discloses substituted phenyl chalcones.
[0033] E. Bakhite et al. in J. Chem. Tech. Biotech. 1992, 55,
157-161, have disclosed a process for the preparation of some
phenyloxazole derivatives of chalcone by condensing
5-(p-acetylphenyl)-2-phenyloxazole with aromatic aldehydes.
[0034] Herencia, et al., in Synthesis and Anti-inflammatory
Activity of Chalcone Derivatives, Bioorganic & Medicinal
Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone
derivatives with anti-inflammatory activity.
[0035] Hsieh, et al., Synthesis and Antiinflammatory Effect of
Chalcones, J. Pharm. Pharmacol. 2000, 52; 163-171 describes that
certain chalcones have potent antiinflammatory activity.
[0036] Zwaagstra, et al., Synthesis and Structure-Activity
Relationships of Carboxylated Chalcones: A Novel Series of CysLT1
(LT4) Receptor Antagonists; J. Med. Chem., 1997, 40, 1075-1089
discloses that in a series of 2-, 3-, and 4-(2-quinolinylmethoxy)-
and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2', 3', 4', or
5' carboxylated chalcones, certain compounds are CysLT1 receptor
antagonists.
[0037] JP 63010720 to Nippon Kayaku Co., LTD discloses that
chalcone derivatives of the following formula (wherein R1 and R2
are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase
inhibitors and can be used in treating allergies. ##STR2##
[0038] JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan,
discloses chalcones of the following structure as 5-lipoxygenase
inhibitors, wherein R is acyl and R1-R5 are hydrogen, lower alkyl,
lower alkoxy or halo, and specifically that in which R is acyl and
R1-R5 are hydrogen. ##STR3##
[0039] U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses
heterocyclic ring-containing chalcones of the following formula as
antiallergic agents, wherein A represents a substituted or
unsubstituted phenyl group, a substituted or unsubstituted naphthyl
group, or a group: ##STR4## in which X represents a hydrogen or
halogen atom or a hydroxyl, lower alkyl or lower alkoxyl group and
B represents --CH.dbd.CH--, --N(R6)-, R6 is a lower alkyl group or
a lower alkoxyalkyl group, --O-- or --S--; W represents
--CH.dbd.CH-- or --CH2O--, and R1-5 is the same or different and
each independently represent a hydrogen or halogen atom, a
hydroxyl, a lower alkyl, lower alkoxyl, carboxyl, cyano,
alkyloxycarbonyl or tetrazolyl group, a group --CONHR7 in which R7
represents a hydrogen atom or a lower alkyl group, or a group
--O(CH2)n R8 in which R8 represents a carboxyl, alkyloxycarbonyl or
tetrazolyl group and n is from 1 to 4, with the proviso that at
least one of the groups R1-S represents a carboxyl, cyano,
alkyloxycarbonyl or tetrazolyl group, the group --CONHR7 or the
group --O(CH2)nR8; or a salt or solvate thereof. ##STR5##
[0040] Reported bioactivies of chalcones have been reviewed by
Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal
Chemistry 1999, 6, 1125-1149.
[0041] Given that VCAM-1 is a mediator of chronic inflammatory
disorders, it is a goal of the present work to identify new
compounds, compositions and methods that can inhibit the expression
of VCAM-1. A more general goal is to identify selective compounds
and methods for suppressing the expression of redox sensitive genes
or activating redox sensitive genes that are suppressed.
[0042] It is therefore an object of the present invention to
provide new compounds for the treatment of disorders mediated by
VCAM-1.
[0043] It is also an object to provide new pharmaceutical
compositions for the treatment of diseases and disorders mediated
by the expression of VCAM-1.
[0044] It is a further object of the invention to provide compounds
and methods of treating disorders and diseases mediated by VCAM-1,
including cardiovascular and inflammatory diseases.
[0045] It is another object of the invention to provide compounds,
compositions and methods to treat arthritis.
[0046] It is yet another object of the invention to provide
compounds, compositions and methods to treat asthma.
[0047] It is another object of the invention to provide compounds,
methods and compositions to inhibit the progression of
atherosclerosis.
[0048] It is still another object of the invention to provide
compounds, compositions, and methods to treat or prevent transplant
rejection.
[0049] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of lupus.
[0050] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
inflammatory bowel disease.
[0051] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of autoimmune
diabetes.
[0052] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of multiple
sclerosis.
[0053] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of diabetic
retinopathy.
[0054] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
rhinitis.
[0055] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
ischemia-reperfusion injury.
[0056] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
post-angioplasty restenosis.
[0057] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of chronic
obstructive pulmonary disease (COPD).
[0058] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
glomerulonephritis.
[0059] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of Graves
disease.
[0060] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
gastrointestinal allergies.
[0061] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
conjunctivitis.
[0062] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
dermatitis.
[0063] It is a further object of the present invention to provide
compounds, methods and compositions for the treatment of
psoriasis.
SUMMARY OF THE INVENTION
[0064] It has been discovered certain
1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds
of formula (I) inhibit the expression of VCAM-1, and thus can be
used to treat a patient with a disorder mediated by VCAM-1.
Examples of inflammatory disorders that are mediated by VCAM-1
include, but are not limited to arthritis, asthma, dermatitis,
cystic fibrosis, post transplantation late and chronic solid organ
rejection, multiple sclerosis, systemic lupus erythematosis,
inflammatory bowel diseases, autoimmune diabetes, diabetic
retinopathy, rhinitis, ischemia-reperfusion injury,
post-angioplasty restenosis, chronic obstructive pulmonary disease
(COPD), glomerulonephritis, Graves disease, gastrointestinal
allergies, conjunctivitis, atherosclerosis, coronary artery
disease, angina and small artery disease.
[0065] The compounds disclosed herein can also be used in the
treatment of inflammatory skin diseases that are mediated by
VCAM-1, as well as human endothelial disorders that are mediated by
VCAM-1, which include, but are not limited to psoriasis,
dermatitis, including eczematous dermatitis, Kaposi's sarcoma,
multiple sclerosis, as well as proliferative disorders of smooth
muscle cells.
[0066] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0067] In one embodiment, the compounds of the present invention
are selected for the prevention or treatment of tissue or organ
transplant rejection. Treatment and prevention of organ or tissue
transplant rejection includes, but is not limited to treatment of
recipients of heart, lung, combined heart-lung, liver, kidney,
pancreatic, skin, spleen, small bowel, or corneal transplants. The
compounds can also be used in the prevention or treatment of
graft-versus-host disease, such as sometimes occurs following bone
marrow transplantation.
[0068] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0069] In addition to inhibiting the expression of VCAM-1, the
1,3-bis-(substituted-phenyl)-2-propen-1-ones have the additional
properties of inhibiting monocyte chemoattractant protein-1 (MCP-1)
and smooth muscle proliferation. MCP-1 is a chemoattractant protein
produced by endothelial cells, smooth muscle cells as well as
macrophages. MCP-1 promotes integrin activation on endothelial
cells thereby facilitating adhesion of leukocytes to VCAM-1, and
MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to
play a role in leukocyte recruitment in a number of chronic
inflammatory diseases including atherosclerosis, rheumatoid
arthritis, and asthma. Its expression is upregulated in these
diseases and as such inhibition of MCP-1 expression represents a
desirable property of anti-inflammatory therapeutics. Furthermore,
smooth muscle cell hyperplasia and resulting tissue remodeling and
decreased organ function is yet another characteristic of many
chronic inflammatory diseases including atherosclerosis, chronic
transplant rejection and asthma. Inhibition of the
hyperproliferation of smooth muscle cells is another desirable
property for therapeutic compounds.
[0070] In one embodiment, the invention provides a compound of the
formula (I) ##STR6##
[0071] or its pharmaceutically acceptable salt, wherein: [0072] i)
the wavy line indicates that the compound can be in the form of the
E or Z isomer; [0073] ii) R22 and R23 are independently hydrogen or
(C1-C4)alkyl; [0074] iii) R2.alpha., R3.alpha., R4.alpha.,
R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and
R6.beta. are independently [0075] iv) hydrogen, alkyl, carbocycle,
aryl, heteroaryl, heterocycle, cycloalkyl, alkoxy, aryloxy,
arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino,
aminoalkyl, haloalkylthio, acyl, haloalkyl, aryloxy, amido,
acylamino, amino, dialkylamino, aminodialkyl, trifluoroalkoxy,
alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl, alkynyl,
halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate,
sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide,
sulfoxide, metal sulfinate, phosphate, phosphonate, metal
phosphonate, phosphinate, alditol, carbohydrate, amino acid,
OC(R1)2CO2H, SC(R1)2CO2H, NHCHR1CO2H, CO--R2, CO2R1,
polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl,
lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl;
hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower
alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl,
heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl,
heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio
lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl,
heteroarylamino lower alkyl, heterocycloamino lower alkyl,
arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which
can be optionally substituted with a moiety that does not adversely
affect the biological properties of the molecule;
--C(O)(CH2)2CO2-M+, --SO3M+, or -lower alkyl-O--R, wherein R is
PO2(OH)-M+, PO3(OH)-M+ or --SO3M+, wherein M+ is a pharmaceutically
acceptable cation; -lower alkylcarbonyl-lower alkyl; carboxy lower
alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino
lower alkyl-, wherein the substituents each independently represent
lower alkyl; [0076] v) R1 is H, lower alkyl, an optionally
substituted carbocycle, aryl, heteroaryl, heterocycle, alkylaryl,
alkylheteroaryl, alkylheteroaryl or alkylheterocycle; [0077] vi) R2
is an optionally substituted alkyl, alkenyl, alkynyl, aryl,
carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl,
alkylheteroaryl or alkylheterocycle; [0078] vii) alternatively, R22
and R6.alpha. or R23 and R6.alpha. can join together to form a
bridged carbocycle, aryl, heterocycle or heteroaromatic; [0079]
viii) R2.alpha. and R3.alpha., R3.alpha. and R4.alpha., R4.alpha.
and R5.alpha., R5.alpha. and R6.alpha., R2.beta. and R3.beta.,
R3.beta. and R4.beta., R4.beta. and R5.beta. or R5.beta. and
R6.beta. can independently join to form a bridged compound selected
from the group consisting of an optionally substituted carbocycle,
an optionally substituted cycloalkenyl, an optionally substituted
cycloalkylcarbonyl, an optionally substituted cycloalkenylcarbonyl;
an optionally substituted aryl, an optionally substituted
heterocylic or an optionally substituted heteroaromatic, or
alkylenedioxy or wherein the ring can include a carbonyl, cyclic
ester, amide, amine, sulfonate, or phosphonate; [0080] ix) at least
one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha.,
R2.beta., R3, R4.beta., R5.beta. or R6.beta. is, or R2.alpha. and
R3.alpha., R3.alpha. and R4.alpha., R4.alpha. and R5.alpha.,
R5.alpha. and R6.alpha., R2.beta. and R3.beta., R3.beta. and
R4.beta., R4.beta. and R5.beta. or R5.beta. and R6.beta. join
together to be, an aryl, heterocycle or heteroaromatic; and [0081]
x) at least one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., or
R6.alpha., and at least one of R2.beta., R3.beta., R4.beta.,
R5.beta. or R6.beta. is a substituent other than hydrogen. In
another embodiment, the compound is of the formula (II):
##STR7##
[0082] or its pharmaceutically acceptable salt.
[0083] In another embodiment, R1 is independently H or lower alkyl,
R2 is an optionally substituted alkyl; and at least one of
R2.alpha., R3.alpha., R4.alpha., R5.alpha., or R6.alpha., and at
least one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. is
a substituent other than hydrogen.
[0084] In another embodiment, R4.beta. or R5.beta. is optionally
substituted heteroaryl or heterocycle; and at least one of
R2.alpha., R3.alpha., R4.alpha., R5.alpha., or R6.alpha. is a
substituent other than hydrogen.
[0085] In another embodiment, R4.alpha. or R5.alpha. is optionally
substituted heteroaryl or heterocycle; and at least one of
R2.beta., R3.beta., R4.beta., R5.beta., or R6.beta. is a
substituent other than hydrogen.
[0086] In a particular embodiment, R5.beta. is optionally
substituted thienyl or benzothienyl; R2.alpha., R3.alpha.,
R4.alpha., R5.alpha., R6.alpha., or R2.beta., R3.beta., R4.beta.,
and R6.beta. are independently hydrogen, methoxy, ethoxy, propoxy,
benzyloxy, 4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy,
4-aminobenzyloxy, fluoro, chloro, bromo, iodo, hydroxy, OCH2CO2H,
SCH2CO2H, NHCH2CO2H, CO2H, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,
pyrid-4-ylmethoxy; thien-2-ylmethoxy, thien-3-ylmethoxy,
fur-2-ylmethoxy, fur-3-ylmethoxy and at least one of R2.alpha.,
R3.alpha., R4.alpha., R5.alpha., or R6.alpha. is a substituent
other than hydrogen.
[0087] In another embodiment, at least one of R2.alpha., R3.alpha.,
R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta.,
R5.beta. or R6.beta., is or R2.alpha. and R3.alpha., R3.alpha. and
R4.alpha., R4.alpha. and R5.alpha., R5.alpha. and R6.alpha.,
R2.beta. and R3.beta., R3.beta. and R4.beta., R4.beta. and R5.beta.
or R5.beta. and R6.beta. join to form a carbocycle, aryl,
heterocycle or heteroaromatic in which the carbocycle, aryl,
heteroaryl or heterocycle is a 5, 6 or 7 membered ring, optionally
conjugated to another carbocycle, aryl, heteroaryl or
heterocycle.
[0088] In one embodiment, the heteroaryl group is not an
oxazole.
[0089] In yet another embodiment, either R3.alpha. and R4.alpha. or
R5.alpha. and R4.alpha. join to form a 5-membered
methylendioxyphenyl group.
[0090] In one alternative embodiment, one of the A or B rings has
only hydrogen substituents.
[0091] While it has been known that certain chalcones exhibit
antiinflammatory properties, it has not been reported that the
presently disclosed class of
1,3-di-(substituted-phenyl)-2-propenones inhibit the expression of
VCAM-1, and are useful anti-inflammatory agents.
[0092] One of the challenges of the prior biological use of
chalcones has been that the phenyl groups of the chalcone can be
metabolized by ring hydroxylation (by oxidizing enzymes, including
but not limited to cytochrome P450) or via break down of the
chalcone double bond. As part of the invention, the present
chalcones include a heteroaryl, aryl or heterocyclic group attached
to one of the phenyl rings to increase the half life and thus
bioavailability of the compound. However, the addition of the
heteroaryl, aryl or heterocyclic group can decrease the water
solubility of the compound, which has the effect of actually
limiting the bioavailability of the compound. Therefore, in a
preferred embodiment, the chalcone contains both a heterocycle,
heteroaromatic or aryl group on at least one of the A and B phenyl
rings to limit the metabolism of the compound, and at least one
group that increases the water solubility of the compound. Since
phenyl hydroxylation typically occurs at the para position, in a
preferred embodiment, the aryl, heteroaryl or heterocyclic group is
positioned at the para position, or at a meta position that blocks
para-hydroxylation. Alternatively, halogen, especially fluorine,
increases metabolic stability when placed in the position(s) most
susceptible to hydroxylation. Bulky alkoxy groups like cyclopropyl
methoxy, heteroarylalkoxy (for example, thienyl methoxy, furryl
methoxy and pyridyl methoxy) and heterocyclealkoxy also increase
metabolic stability when placed at the meta or para position. It
has been observed that adding the group that increases water
solubility to the B ring typically increases the water solubility
more than when the same group is added to the A ring, however, this
trend may not hold true in all cases. Preferred water solubilizing
groups are alkoxy, such as methoxy, OC(R1)2CO2H, SC(R1)2CO2H,
NHC(R1)2CO2H or OC(R1)2CO2H, wherein R1 is H or lower alkyl. In a
more general embodiment, any group that increases the water
solubility of the compound can be used as substituents for
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta.,
R3.beta., R4.beta., R5.beta. and R6.beta., specifically including
but not limited to [0093] alkoxy, alkylthio, alkylamino,
aminoalkyl, haloalkylthio, acyl, amido, acylamino, amino,
dialkylamino, aminodialkyl, trifluoroalkoxy, alkylsulfonyl,
haloalkylsulfonyl, aminocarbonyl, hydroxyl, thiol, cyano, nitro,
sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid,
sulfamide, sulfonamide, sulfoxide, metal sulfinate, phosphate,
phosphonate, metal phosphonate, phosphinate, alditol, carbohydrate,
amino acid, CO--R2, CO2-R2, polyoxyalkylene, polyol alkyl, NH2.HCl,
oxyalkylamino, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl,
lower alkyl-S(0)2-lower alkyl; imidazolyl lower alkyl, morpholinyl
lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl,
imidazolylcarbonyl, morpholinyl carbonyl, (lower
alkyl)-aminocarbonyl, N-pyrrylpyridinyl-lower alkyl;
pyridylthio-lower alkyl; morpholinyl-lower alkyl;
hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl;
imidazolylthio-lower alkyl; triazolylthio-lower alkyl;
triazolylphenylthio-lower alkyl; tetrazolylthio-lower alkyl;
tetrazolylphenylthio-lower alkyl; aminophenylthio-lower alkyl;
N,N-di-substituted aminophenylthio-lower alkyl wherein the amine
substituents each independently represent lower alkyl;
amidinophenylthio-lower alkyl; phenylsulfinyl-lower alkyl;
phenylsulfonyl lower alkyl; -lower alkyl-O--R, wherein R is
PO2(OH)-M+ or PO3(OH)-M+wherein M+ is a pharmaceutically acceptable
cation; --C(O)(CH2)2CO2-M+; --SO3M+; -lower alkylcarbonyl-lower
alkyl; -carboxy lower alkyl; -lower alkylamino-lower alkyl;
N,N-di-substituted amino lower alkyl-, wherein the substituents
each independently represent lower alkyl; pyridyl-lower alkyl;
imidazolyl-lower alkyl; imidazolyl-Y-lower alkyl wherein Y is thio
or amino; morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl;
thiazolinyl-lower alkyl; piperidinyl-lower alkyl; morpholinyl-lower
hydroxyalkyl; N-pyrryl; piperazinyl-lower alkyl; N-substituted
piperazinyl-lower alkyl, wherein the amine substituent is lower
alkyl; triazolyl-lower alkyl; tetrazolyl-lower alkyl;
tetrazolylamino-lower alkyl; or thiazolyl-lower alkyl;
hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower
alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl,
heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl,
heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio
lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl,
heteroarylamino lower alkyl, heterocycloamino lower alkyl,
arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which
can be optionally substituted with a moiety that does not adversely
affect the biological properties of the molecule;
[0094] In a preferred embodiment, after the target biological
activity, metabolic stability and water solubility have been
jointly optimized, substituent groups that do not contribute to
these factors or contribute another attribute are removed.
BRIEF DESCRIPTION OF THE FIGURES
[0095] FIG. 1 is an illustration of non-limiting examples of
compounds of the present invention.
[0096] FIG. 2 is a bar chart graph of the inhibition of eosinophil
recruitment (percent eosinophils in the peritoneal fluid) by 50
mg/kg/dose of
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one. Balb/C mice (n=10) were sensitized to ovalbumin on
days 0 and 7 with a subcutaneous injection of ovalbumin absorbed in
aluminum hydroxide. They were then challenged with an
intraperitoneal injection of ovalbumin and sacrificed 48 hrs
post-challenge. Peritoneal fluid was then collected and spun down
onto slides. Slides were stained with DiffQuik and a differential
performed. The test compound was administered by subcutaneously
injection -24, -2, +2 and +6 hrs around the time of ovalbumin
challenge. This is a model of allergic inflammation as eosinophils
are the major leukocyte recruited into the peritoneum.
[0097] FIG. 3 is a bar chart graph of the inhibition of paw edema
in a mouse model of delayed type hypersensitivity by 50 mg/kg/dose
of
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one. Balb/C mice (n=5) were sensitized intradermally on
day 0 with methylated BSA (metBSA). They were then challenged with
metBSA on day 7 in the right hind paw. The animals were sacrificed
24 hours later and the left and right hind paws weighed. The left
hindpaw weight is subtracted from the right hind paw to give the
paw weight increase. The test compound was administered by
intraperitoneal injection -24, -2 and +6 hrs around the time of
metBSA challenge.
DETAILED DESCRIPTION OF THE INVENTION
[0098] It has been discovered that compounds of formula (I) inhibit
the expression of VCAM-1, and thus can be used to treat a patient
with a disorder mediated by VCAM-1. These compounds can be
administered to a host as monotherapy, or if desired, in
combination with another compound of formula (I) or another
bioloigically active agent, as described in more detail below.
[0099] The compounds can be used to treat inflammatory disorders
that are mediated by VCAM-1 including, but not limited to
arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post
transplantation late and chronic solid organ rejection, multiple
sclerosis, systemic lupus erythematosis, inflammatory bowel
diseases, autoimmune diabetes, diabetic retinopathy, rhinitis,
ischemia-reperfusion injury, post-angioplasty restenosis, chronic
obstructive pulmonary disease (COPD), glomerulonephritis, Graves
disease, gastrointestinal allergies, conjunctivitis,
atherosclerosis, coronary artery disease, angina and small artery
disease.
[0100] The compounds disclosed herein can be used in the treatment
of inflammatory skin diseases that are mediated by VCAM-1, and in
particular, human endothelial disorders that are mediated by
VCAM-1, which include, but are not limited to, psoriasis,
dermatitis, including eczematous dermatitis, and Kaposi's sarcoma,
as well as proliferative disorders of smooth muscle cells.
[0101] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0102] In yet another embodiment, the compounds of the present
invention can be selected for the prevention or treatment of tissue
or organ transplant rejection. Treatment and prevention of organ or
tissue transplant rejection includes, but are not limited to
treatment of recipients of heart, lung, combined heart-lung, liver,
kidney, pancreatic, skin, spleen, small bowel, or corneal
transplants. They are also indicated for the prevention or
treatment of graft-versus-host disease, which sometimes occurs
following bone marrow transplantation.
[0103] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0104] In another aspect the invention provides pharmaceutical
compositions for the treatment of diseases or disorders mediated by
VCAM-1 wherein such compositions comprise a VCAM-1 inhibiting
amount of a chalcone derivatives of the formula (I) or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0105] In another aspect the invention provides a method for
treating a disease or disorder mediated by VCAM-1 comprising
administering to a patient a VCAM-1 inhibiting effective amount of
a compound of formula (I) or a pharmaceutically acceptable salt
thereof.
[0106] In another aspect the invention provides a method for
treating cardiovascular and inflammatory disorders in a patient in
need thereof comprising administering to said patient an VCAM-1
inhibiting effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0107] In another aspect the invention provides a method and
composition for treating asthma or arthritis in a patient in need
thereof comprising administering to said patient an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
I. COMPOUNDS OF THE PRESENT INVENTION
[0108] In one embodiment, the invention provides compounds of
formula (I) and their pharmaceutically acceptable salts or
prodrugs: ##STR8##
[0109] or its pharmaceutically acceptable salt, wherein: [0110] xi)
the wavy line indicates that the compound can be in the form of the
E or Z isomer; [0111] xii) R22 and R23 are independently hydrogen
or (C1-C4)alkyl, [0112] xiii) R2.alpha., R3.alpha., R4.alpha.,
R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and
R6.beta. are independently [0113] xiv) hydrogen, alkyl, carbocycle,
aryl, heteroaryl, heterocycle, aryloxy; arylalkoxy; heteroaryloxy;
heteroarylalkoxy, cycloalkyl, alkoxy, alkylthio, alkylamino,
aminoalkyl, haloalkylthio, acyl, haloalkyl, aryloxy, amido,
acylamino, amino, dialkylamino, aminodialkyl, trifluoroalkoxy,
alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl, alkynyl,
halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate,
sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide,
sulfoxide, metal sulfinate, phosphate, phosphonate, metal
phosphonate, phosphinate, alditol, carbohydrate, amino acid,
OC(R1)2CO2H, SC(R1)2CO2H, NHCHR1CO2H, CO--R2, CO2R1,
polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl,
lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl;
hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower
alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl,
heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl,
heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio
lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl,
heteroarylamino lower alkyl, heterocycloamino lower alkyl,
arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which
can be optionally substituted with a moiety that does not adversely
affect the biological properties of the molecule;
--C(O)(CH2)2CO2-M+, --SO3M+, or -lower alkyl-O--R, wherein R is
PO2(OH)-M+, PO3(OH)-M+ or --SO3M+, wherein M+ is a pharmaceutically
acceptable cation; -lower alkylcarbonyl-lower alkyl; carboxy lower
alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino
lower alkyl-, wherein the substituents each independently represent
lower alkyl; [0114] xv) R1 is H, lower alkyl, an optionally
substituted carbocycle, aryl, heteroaryl, heterocycle, alkylaryl,
alkylheteroaryl, alkylheteroaryl or alkylheterocycle; [0115] xvi)
R2 is an optionally substituted alkyl, alkenyl, alkynyl, aryl,
carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl,
alkylheteroaryl or alkylheterocycle; [0116] xvii) alternatively,
R22 and R6.alpha. or R23 and R6.alpha. can join together to form a
bridged carbocycle, aryl, heterocycle or heteroaromatic; [0117]
xviii) R2.alpha. and R3.alpha., R3.alpha. and R4.alpha., R4.alpha.
and R5.alpha., R5.alpha. and R6.alpha., R2.beta. and R3.beta.,
R3.beta. and R4.beta., R4.beta. and R5.beta. or R5.beta. and
R6.beta. can independently join to form a bridged compound selected
from the group consisting of an optionally substituted carbocycle,
an optionally substituted cycloalkenyl, an optionally substituted
cycloalkylcarbonyl, an optionally substituted cycloalkenylcarbonyl;
an optionally substituted aryl, an optionally substituted
heterocylic or an optionally substituted heteroaromatic, or
alkylenedioxy or wherein the ring can include a carbonyl, cyclic
ester, amide, amine, sulfonate, or phosphonate; [0118] xix) at
least one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha.,
R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. is, or R2.alpha.
and R3.alpha., R3.alpha. and R4.alpha., R4.alpha. and R5.alpha.,
R5.alpha. and R6.alpha., R2.beta. and R3.beta., R3.beta. and
R4.beta., R4.beta. and R5.beta. or R5.beta. and R6.beta. come
together to be, an aryl, heterocycle or heteroaromatic; and [0119]
xx) at least one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., or
R6.alpha., and at least one of R2.beta., R3.beta., R4.beta.,
R5.beta. or R6.beta. is a substituent other than hydrogen. In
another embodiment, the compound is of the formula (II):
##STR9##
[0120] or its pharmaceutically acceptable salt.
[0121] In another embodiment, R1 is independently H or lower alkyl,
R2 is an optionally substituted alkyl; and at least one of
R2.alpha., R3.alpha., R4.alpha., R5.alpha., or R6.alpha., and at
least one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. is
a substituent other than hydrogen.
[0122] In another embodiment, R4.beta. or R5.beta. is optionally
substituted heteroaryl or heterocycle; and at least one of
R2.alpha., R3.alpha., R4.alpha., R5.alpha., or R6.alpha. is a
substituent other than hydrogen.
[0123] In another embodiment, R4.alpha. or R5.alpha. is optionally
substituted heteroaryl or heterocycle; and at least one of
R2.beta., R3.beta., R4.beta., R5.beta., or R6.beta. is a
substituent other than hydrogen.
[0124] In one alternative embodiment, one of the A or B rings has
only hydrogen substituents.
[0125] In a particular embodiment, R5.beta. is optionally
substituted thienyl or benzothienyl; R2.alpha., R3.alpha.,
R4.alpha., R5.alpha., R6.alpha., or R2.beta., R3.beta., R4.beta.,
and R6.beta. are independently hydrogen, methoxy, ethoxy, propoxy,
benzyloxy, 4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy,
4-aminobenzyloxy, fluoro, chloro, bromo, iodo, hydroxy, OCH2CO2H,
SCH2CO2H, NHCH2CO2H, CO2H, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,
pyrid-4-ylmethoxy; thien-2-ylmethoxy, thien-3-ylmethoxy,
fur-2-ylmethoxy, fur-3-ylmethoxy and at least one of R2.alpha.,
R3.alpha., R4.alpha., R5.alpha., or R6.alpha. is a substituent
other than hydrogen.
[0126] In another embodiment, at least one of R2.alpha., R3.alpha.,
R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta.,
R5.beta. or R6.beta., is or R2.alpha. and R3.alpha., R3.alpha. and
R4.alpha., R4.alpha. and R5.alpha., R5.alpha. and R6.alpha.,
R2.beta. and R3.beta., R3.beta. and R4.beta., R4.beta. and R5.beta.
or R5.beta. and R6.beta. join to form a carbocycle, aryl,
heterocycle or heteroaromatic in which the carbocycle, aryl,
heteroaryl or heterocycle is a 5, 6 or 7 membered ring, optionally
conjugated to another carbocycle, aryl, heteroaryl or heterocycle.
In yet another embodiment, either R3.alpha. and R4.alpha. or
R5.alpha. and R4.alpha. join to form a 5-membered
methylendioxyphenyl group.
[0127] In a primary embodiment, the compounds of the formula (I)
are of the more specific formula (II): ##STR10## or its
pharmaceutically acceptable salt or prodrug thereof, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta.,
R3.beta., R4.beta., R5.beta. and R6.beta. are defined above.
[0128] In a particular embodiment, the optionally substituted
carbocycle, aryl, heteroaryl or heterocycle is a 5, 6 or 7 membered
ring, optionally substituted or conjugated to another optionally
substituted carbocycle, aryl, heteroaryl or heterocycle.
[0129] In another sub-embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof wherein;
[0130] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
independently selected from alkyl, alkoxy, hydroxy, halogen,
preferably chloro, heterocycle, heteroaromatic, OC(R1)2CO2H wherein
R1 is H, or lower alkyl, O-alkylheteroaryl and R2.beta., R3.beta.,
R4.beta., R5.beta. and R6.beta. are independently selected from
alkyl, alkoxy, hydroxy, halogen, preferably F or Br, carbocycle,
aryl, heterocycle and heteroaryl, preferably thienyl or
benzothienyl.
[0131] In one embodiment the invention provides trans compounds of
formula (II) and a pharmaceutically acceptable salts or prodrugs
that exhibit a sufficient solubility in water and an in vitro
inhibition of fifty percent of VCAM expression at 10 micromolar
concentration.
[0132] In another embodiment, at least one of R2.alpha., R3.alpha.,
R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta.,
R5.beta. and R6.beta. is selected from halogen, alkoxy, hydroxy,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt; R1 is H, or lower alkyl; the remaining
R.alpha./.beta. groups are selected independently from H; halogen,
thio, cyano, nitro, optionally substituted alkyl; cycloalkyl;
hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl, haloalkylthio;
haloalkyl; carboxyl derivatives; aryloxy; arylalkoxy;
heteroaryloxy; heteroarylalkoxy, amido; acylamino; amino,
dialkylamino; trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl;
sulfonic acid; sulfonate, sulfate, sulfinic acid, sulfenic acid,
sulfamide, sulfonamide; sulfoxide, metal sulfinate, phosphate,
phosphonate, metal phosphonate, phosphinate aminocarbonyl; alkenyl;
alkynyl; alditol, carbohydrate, carbocycle, aryl, heteroaryl, and
heterocycle; or
[0133] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally conjugated to another optionally
substituted carbocycle, aryl, heteroaryl.
[0134] In a preferred embodiment the invention provides trans
compounds of formula (II) and a pharmaceutically acceptable salts
or prodrugs that increase the solubility of the molecule while
maintaining or increasing the inhibition of VCAM expression
wherein:
[0135] at least one of the R2.beta., R3.beta., R4.beta., R5.beta.
and R6.beta. is selected from OC(R1)2CO2H, SC(R1)2CO2H,
NHC(R1)2CO2H or their salts;
[0136] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
selected independently from H; halogen, thio, cyano, nitro,
optionally substituted alkyl; cycloalkyl; hydroxy; alkoxy;
alkylthio; alkylamino, aminoalkyl, haloalkylthio; haloalkyl;
carboxyl derivatives; aryloxy; arylalkoxy; heteroaryloxy;
heteroarylalkoxy, amido; acylamino; amino, dialkylamino;
trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl; sulfonic acid;
sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide,
sulfonamide; sulfoxide, metal sulfinate, phosphate, phosphonate,
metal phosphonate, phosphinate aminocarbonyl; alkenyl; alkynyl;
alditol, carbohydrate, carbocycle, aryl, heteroaryl and
heterocycle; or
[0137] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally conjugated to another optionally
substituted carbocycle, aryl, heteroaryl.
[0138] In yet another preferred embodiment the invention provides
trans compounds of formula (II) and a pharmaceutically acceptable
salts or prodrugs that increase the solubility of the molecule
while maintaining or increasing the inhibition of VCAM
expression
wherein:
[0139] R2.beta. is selected from OC(R1)2CO2H, SC(R1)2CO2H, or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0140] R1 is H, or lower alkyl;
[0141] R3.beta., R4.beta., R5.beta., R6.beta., R2.alpha.,
R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are selected
independently from H; halogen, thio, cyano, nitro, optionally
substituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio;
alkylamino, aminoalkyl, haloalkylthio; thio; cyano; halo;
haloalkyl; nitro; carboxyl derivatives; aryloxy; arylalkoxy;
heteroaryloxy; heteroarylalkoxy, amido; acylamino; amino,
dialkylamino; trifluoroalkoxy; alkylsulfonyl, haloalkylsulfonyl;
sulfonic acid; sulfonate, sulfate, sulfinic acid, sulfenic acid,
sulfamide, sulfonamide; sulfoxide, metal sulfinate, phosphate,
phosphonate, metal phosphonate, phosphinate aminocarbonyl; alkenyl;
alkynyl; alditol, carbohydrate, carbocycle, aryl, heteroaryl, and
heterocycle; or
[0142] R2.alpha. and R3.alpha., R3.alpha. and R4.alpha., R4.alpha.
and R5.alpha., R5.alpha. and R6.alpha., R3.beta. and R4.beta.,
R4.beta. and R5.beta. or R5.beta. and R6.beta. can join to form a
5, 6 or 7 membered optionally substituted carbocycle, aryl,
heteroaryl or heterocycle, optionally conjugated to another
optionally substituted carbocycle, aryl, heterocycle or
heteroaryl.
[0143] In yet another embodiment the invention provides compounds
of the formula (II) and a pharmaceutically acceptable salts or
prodrugs that are metabolically stable:
wherein:
[0144] R4.alpha. and R4.beta. are independently selected from
cyano; halo; nitro; substituted or unsubstituted alkyl; cycloalkyl;
alkoxy; alkylthio; alkylamino; aminoalkyl; haloalkylthio;
haloalkyl; carboxyl derivatives; aryloxy; arylalkoxy;
heteroaryloxy; heteroarylalkoxy, amido; acylamino; amino,
dialkylamino; trifluoroalkoxy; aminocarbonyl; alkenyl; alkynyl;
alditol; carbohydrate; aryl; heteroaryl; and heterocycle; or
[0145] R3.alpha. and R4.alpha.; R4.alpha. and R5.alpha.; R3.beta.
and R4.beta.; or R4.beta. and R5.beta.; independently form a 5-7
membered optionally substituted carbocyclic, aryl; heteroaryl or
heterocyclic ring;
[0146] the remaining R.alpha./.beta. groups are selected
independently from H; halogen, thio, cyano, nitro, optionally
substituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio;
alkylamino, aminoalkyl, haloalkylthio; haloalkyl; carboxyl
derivatives; aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy,
amido; acylamino; amino, dialkylamino; trifluoroalkoxy;
alkylsulfonyl, haloalkylsulfonyl; sulfonic acid; sulfonate,
sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide;
sulfoxide, metal sulfinate, phosphate, phosphonate, metal
phosphonate, phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,
carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or
[0147] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally conjugated to another optionally
substituted carbocycle, aryl, heteroaryl, and
[0148] R1 is H; or lower alkyl; or
[0149] In a preferred embodiment the invention provides trans
compounds of formula (II) and a pharmaceutically acceptable salts
or prodrugs that are metabolically stable:
wherein:
[0150] R4.alpha. and R4.beta. independently from each other are
selected from halogen preferably F or heteroaryl preferably thienyl
and benzothienyl and, and R3.beta., R5.beta., R6.beta., R2.alpha.,
R3.alpha., R5.alpha. and R6.alpha. are selected from H, cyano;
nitro; halo preferably F; optionally substituted alkyl; cycloalkyl;
alkoxy; alkylthio; alkylamino; aminoalkyl; haloalkylthio;
haloalkyl; carboxyl derivatives; aryloxy; amido; acylamino; amino,
dialkylamino; trifluoroalkoxy; aminocarbonyl; alkenyl; alkynyl;
alditol; carbohydrate; aryl; heteroaryl; and heterocycle; or
[0151] R3.alpha. and R4.alpha., R4.alpha. and R5.alpha., R3.beta.
and R4.beta., or R4.beta. and R5.beta. independently can join to
form a 5-7 membered optionally substituted carbocylic; aryl;
heteroaryl; or heterocyclic ring; and
[0152] the remaining R.alpha./.beta. groups are selected
independently from H; halogen, thio, cyano, nitro, optionally
substituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio;
alkylamino, aminoalkyl, haloalkylthio; haloalkyl; carboxyl
derivatives; aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy,
amido; acylamino; amino, dialkylamino; trifluoroalkoxy;
alkylsulfonyl, haloalkylsulfonyl; sulfonic acid; sulfonate,
sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide;
sulfoxide, metal sulfinate, phosphate, phosphonate, metal
phosphonate, phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,
carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or
[0153] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally conjugated to another optionally
substituted carbocycle, aryl, heteroaryl, and
[0154] R1 is H; or lower alkyl.
[0155] In another embodiment the invention provides trans compounds
of formula (II) and a pharmaceutically acceptable salts or
prodrugs:
wherein:
[0156] at least one of the following pairs R3.alpha. and R4.alpha.,
R4.alpha. and R5.alpha., R3.beta. and R4.beta., or R4.beta. and
R5.beta. comes together to form a 5, 6 or 7 membered optionally
substituted heteroaryl or optionally substituted heterocycle,
optionally conjugated to another optionally substituted carbocycle,
optionally substituted aryl, or heteroaryl, wherein the heteroatom
of the ring is selected from O, S or N; and
[0157] the remaining R.alpha./.beta. groups are independently
selected from H; halogen, thio, cyano, nitro, optionally
substituted alkyl; cycloalkyl; hydroxy; alkoxy; alkylthio;
alkylamino, aminoalkyl, haloalkylthio; haloalkyl; carboxyl
derivatives; aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy,
amido; acylamino; amino, dialkylamino; trifluoroalkoxy;
alkylsulfonyl, haloalkylsulfonyl; sulfonic acid; sulfonate,
sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide;
sulfoxide, metal sulfinate, phosphate, phosphonate, metal
phosphonate, phosphinate aminocarbonyl; alkenyl; alkynyl; alditol,
carbohydrate, carbocycle, aryl, heteroaryl and heterocycle; or
[0158] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally conjugated to another optionally
substituted carbocycle, aryl, heteroaryl.
[0159] In another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0160] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
independently selected from alkyl, alkoxy, halogen, preferably Cl,
Br or I, heteroaryl, O-alkylheterocycle, O-akylheteroaryl,
carboxyalkyl;
[0161] R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are
independently selected from alkyl, alkoxy, halogen, preferably F or
Br, or heteroaryl, preferably benzothienyl.
[0162] In one preferred embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein:
[0163] R3.beta. and R6.beta. are independently H;
[0164] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
independently selected from H, OH, OR(R is lower alkyl), halogen,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0165] R2.beta., R4.beta. and R5.beta. are independently selected
from O-alkyl, OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its
pharmaceutically acceptable salt; and
[0166] R1 is H, or lower alkyl.
[0167] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein:
[0168] R2.alpha., R6.alpha., R3.beta. and R6.beta. are H;
[0169] R3.alpha., R5.alpha., R3.beta. and R6.beta. are OMe;
[0170] R4.alpha. is OC(R1)2CO2H, CO2H, SC(R1)2CO2H or NHC(R1)2CO2H;
or its pharmaceutically acceptable salt;
[0171] R1 is H or lower alkyl; and
[0172] R5.beta. is a heteroaryl or heterocycle.
[0173] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0174] R2.alpha., R6.alpha., R3.beta. and R6.beta. are H;
[0175] R3.alpha., R4.alpha., R5.alpha. and R4.beta. are OMe;
[0176] R2.beta. is selected from OC(R1)2CO2H, CO2H, SC(R1)2CO2H or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0177] R1 is H or lower alkyl; and
R5.beta. is a heteroaryl or heterocycle.
[0178] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0179] R2.alpha., R6.alpha., R3.beta. and R6.beta. are H;
[0180] R3.alpha., R4.alpha., R5.alpha., R2.beta. and R4.beta. are
OMe; and
R5.beta. is a heteroaryl or heterocycle.
[0181] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0182] R2.alpha., R6.alpha., R2.beta. and R6.beta. are H;
[0183] R3.alpha., R4.alpha., R5.alpha., R3.beta. and R4.beta. are
OMe; and
R5.beta. is a heteroaryl or heterocycle.
[0184] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0185] R3.beta. and R6.beta. are H;
[0186] R2.beta. and R4.beta. are OMe and,
[0187] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
independently selected from H, OH, SH, halo, alkyl, CF3, O-alkyl,
CO2H, NH2, aminoalkyl, aminodialkyl, SO3H, sulfonamine,
sulfonaminodi- and mono-alkyl, .alpha.-aminoacid, heterocycle,
OC(R1)2CO2H, CO2H, SC(R1)2CO2H or NHC(R1)2CO2H; or its
pharmaceutically acceptable salt;
[0188] R1 is H or lower alkyl; and
[0189] R5.beta. is a heteroaryl.
[0190] In another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0191] R3.beta., R5.beta. and R6.beta. are H;
[0192] R4.beta. is OMe and,
[0193] R2.beta. is OC(R1)2CO2H, CO2H, SC(R1)2CO2H or NHC(R1)2CO2H;
or its pharmaceutically acceptable salt;
[0194] R2.alpha., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
independently selected from H, OH, SH, halo, alkyl, CF3, O-alkyl,
CO2H, NH2, aminoalkyl, aminodialkyl, SO3H, sulfonamine,
sulfonaminodi- and mono-alkyl, .alpha.-aminoacid, heterocycle,
heteroaryl, OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its
pharmaceutically acceptable salt; and
[0195] R1 is H, or lower alkyl.
[0196] In yet another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0197] R2.alpha. and R6.alpha. are H and,
[0198] R4.beta., R3.alpha., R4.alpha. and R5.alpha. are OMe
and,
[0199] R2.beta. is OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or
its pharmaceutically acceptable salt;
[0200] R3.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, OC(R1)2CO2H,
SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically acceptable
salt; and
[0201] R1 is H, or lower alkyl.
[0202] In yet another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0203] R2.alpha., and R6.alpha. are independently H and,
[0204] R4.beta., R3.alpha., R4.alpha., R5.alpha. and R6.alpha. are
OMe and,
[0205] R3.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0206] R1 is H, or lower alkyl.
[0207] In yet another preferred embodiment, the invention provides
trans compounds of formula (II) and their pharmaceutically
acceptable salts or prodrugs thereof:
wherein;
[0208] R2.alpha. and R6.alpha. are H and,
[0209] R3.beta., R4.beta., R3.alpha., R4.alpha. and R5.alpha. are
OMe and,
[0210] R2.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0211] R1 is H, or lower alkyl.
[0212] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0213] R3.beta., R4.beta. and R6.beta. are H;
[0214] R4.beta. is OMe and,
[0215] R2.beta. is C(R1)2CO2H, OC(R1)2CO2H, SC(R1)2CO2H, or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0216] R2.alpha.-R6.alpha. are independently selected from H, OH,
SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,
sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0217] R1 is H, or lower alkyl.
[0218] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0219] R3.beta., R5.beta. and R6.beta. are H;
[0220] R2.beta. and R4.beta. are OMe;
[0221] R2.alpha.-R6.alpha. are independently selected from H, OH,
SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,
sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0222] R1 is H, or lower alkyl
[0223] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0224] R2.beta., R5.beta. and R6.beta. are H;
[0225] R3.beta. and R4.beta. are OMe;
[0226] R2.alpha.-R6.alpha. are independently selected from H, OH,
SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,
sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0227] R1 is H, or lower alkyl.
[0228] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0229] R2.alpha., R3.alpha. and R6.alpha. are H;
[0230] R4.beta. is OMe and,
[0231] R4.alpha. and R5.alpha. together form a five or six membered
substituted heterocylic ring and,
[0232] R2.beta. is OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or
its pharmaceutically acceptable salt;
[0233] R3.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, sulfonic acid, sulfonamine, sulfonaminodi- and
mono-alkyl, .alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt; and
[0234] R1 is H, or lower alkyl.
[0235] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0236] R2.alpha., R3.alpha. and R6.alpha. are H;
[0237] R4.alpha. and R5.alpha. together form a five or six membered
substituted heterocylic ring;
[0238] R2.beta. and R4.beta. are methoxy;
[0239] R3.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, sulfonic acid, sulfonamine, sulfonaminodi- and
mono-alkyl, .alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt; and
[0240] R1 is H, or lower alkyl.
[0241] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0242] R2.alpha., R3.alpha. and R6.alpha. are H;
[0243] R4.alpha. and R5.alpha. together form a five or six membered
substituted heterocylic ring;
[0244] R3.beta. and R4.beta. are methoxy;
[0245] R2.beta., R5.beta. and R6.beta. are independently selected
from H, OH, SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl,
aminodialkyl, SO3H, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt; and
[0246] R1 is H, or lower alkyl.
[0247] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0248] R3.beta. and R6.beta. are H;
[0249] R2.beta. is methoxy and,
[0250] R4.beta. is selected from OC(R1)2CO2H, SC(R1)2CO2H, or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0251] R2.alpha.-6.alpha. are independently selected from H, OH,
SH, halo, alkyl, CF3, O-alkyl, CO2H, NH2, aminoalkyl, aminodialkyl,
sulfonic acid, sulfonamine, sulfonaminodi- and mono-alkyl,
.alpha.-aminoacid, heterocycle, heteroaryl, C(R1)2CO2H,
OC(R1)2CO2H, SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically
acceptable salt;
[0252] R1 is H, or lower alkyl.
[0253] In yet another embodiment, the invention provides trans
compounds of formula (II) and their pharmaceutically acceptable
salts or prodrugs thereof:
wherein;
[0254] R3.beta., R6.alpha. and R6.beta. are H;
[0255] R4.beta. is OMe;
[0256] R2.beta. is selected from OC(R1)2CO2H, SC(R1)2CO2H, or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0257] R1 is H, or lower alkyl; and
[0258] (R2.alpha. and R3.alpha.), (R3.alpha. and R4.alpha.) or
(R4.alpha. and R5.alpha.) join to form a 5 or 6 membered optionally
substituted heteroaryl or heterocycle, or optionally conjugated to
another optionally substituted carbocycle, aryl, or heteroaryl.
[0259] In yet another embodiment the invention provides trans
compounds of formula (II) and a pharmaceutically acceptable salts
or prodrugs:
wherein;
[0260] R5.beta. is heteroaryl preferably 2-benzothienyl and,
2-thienyl and,
[0261] R2.beta. and R4.beta. are independently H, or OMe and,
[0262] R3.beta. and R6.beta. and R6.alpha. are H and,
[0263] R2.alpha., R3.alpha., R4.alpha. and R5.alpha. are
independently H, OH, alkoxy, halo, heteroaryl group, or OCHR1 CO2H;
or its pharmaceutically acceptable salt; and
[0264] R1 is H, or lower alkyl.
[0265] In another preferred embodiment the invention provides trans
compounds of formula (II) and a pharmaceutically acceptable salts
or prodrugs:
wherein;
[0266] R4.alpha. is alkoxy, halo, preferably F, OC(R1)2CO2H,
SC(R1)2CO2H, or NHC(R1)2CO2H; or its pharmaceutically acceptable
salt;
[0267] R1 is H, or lower alkyl, preferably methyl;
[0268] R2.alpha., R6.alpha., R3.beta. and R6.beta. are H and,
[0269] R3.alpha., R5.alpha., R2.beta. and R4.beta. are selected
from electron donating groups including but not limited to amino,
thiol, alkylthio, alkoxy, preferably OMe;
[0270] R5.beta. is an heteroaryl including furanyl, pyrrolyl,
thienyl or pyridinyl, but preferably benzothienyl.
[0271] In another preferred embodiment the invention provides trans
compounds of formula (II) and a pharmaceutically acceptable salts
or prodrugs:
wherein;
[0272] R2.beta. is H, alkoxy, hydroxyl, OC(R1)2CO2H, SC(R1)2CO2H,
or NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0273] R1 is H, or lower alkyl, preferably Me;
R4.beta., R5.alpha. and R3.alpha. are independently hydroxy or
alkoxyl, preferably methoxy;
[0274] R2.alpha., R6.alpha., R3.beta. and R6.beta. are
independently H; and
R4.alpha. is hydroxy, alkoxy or halogen, preferably F.
[0275] In another preferred embodiment the compounds of the formula
(II) and a pharmaceutically acceptable salts or prodrugs:
wherein;
[0276] R2.beta. is H, hydroxy, alkoxy, OC(R1)2CO2H, SC(R1)2CO2H, or
NHC(R1)2CO2H; or its pharmaceutically acceptable salt;
[0277] R1 is H, or lower alkyl, preferably methyl;
R4.beta. and R3.alpha. are independently hydroxyl or alkoxy,
preferably methoxy;
[0278] R2.alpha., R6.alpha., R3.beta. and R6.beta. are H;
[0279] R5.beta. is heteroaryl, preferably 2-thienyl or
2-benzo[b]thienyl; and
[0280] R4.alpha. and R5.alpha. join to form a 5, 6 or 7 membered
optionally substituted carbocycle, aryl, heteroaryl or heterocycle,
optionally conjugated to another optionally substituted carbocycle,
aryl, or heteroaryl.
[0281] In another preferred embodiment the trans compounds of the
formula (II) and a pharmaceutically acceptable salts or
prodrugs:
wherein;
[0282] R3.alpha., R5.alpha., R6.alpha., R2.beta., R5.beta. and
R6.beta. are H;
[0283] R2.alpha., R3.beta. and R4.beta. are independently halo,
preferably F, hydroxyl or alkoxy, preferably methoxy; and
[0284] R4.alpha. is an heteroaryl preferably 2-thienyl.
[0285] In another preferred embodiment the trans compounds of
formula (II) and a pharmaceutically acceptable salts or
prodrugs:
wherein;
[0286] R3.alpha., R5.alpha., R6.alpha., R2.beta. and R4.beta. are
independently hydroxy or alkoxy, preferably methoxy;
[0287] R2.alpha., R6.alpha., R3.beta. and R6.alpha. are H;
[0288] R4.alpha. is OC(R1)2heterocycle or its pharmaceutically
acceptable salt;
[0289] R1 is H, or lower alkyl; and
[0290] R5.beta. is heteroaryl preferably benzo[b]thienyl.
[0291] In another alternative embodiment the trans compounds of
formula (II) and a pharmaceutically acceptable salts or
prodrugs:
wherein;
[0292] at least one of R3.alpha., R4.alpha., R4.beta., or R5.beta.
is selected from a group consisting of the moieties in the
following table (1): TABLE-US-00001 TABLE 1 ##STR11## ##STR12##
##STR13## ##STR14## ##STR15## ##STR16## ##STR17## ##STR18##
##STR19## ##STR20## ##STR21## ##STR22## ##STR23## ##STR24##
##STR25## ##STR26## ##STR27## ##STR28## ##STR29## ##STR30##
##STR31## ##STR32## ##STR33## ##STR34## ##STR35## ##STR36##
##STR37## ##STR38## ##STR39## ##STR40## ##STR41## ##STR42##
##STR43##
and the remaining R.alpha./.beta. groups are selected independently
from H; halogen, thio, cyano, nitro, optionally substituted alkyl;
cycloalkyl; hydroxy; alkoxy; alkylthio; alkylamino, aminoalkyl,
haloalkylthio; haloalkyl; carboxyl derivatives; aryloxy;
arylalkoxy; heteroaryloxy; heteroarylalkoxy, amido; acylamino;
amino, dialkylamino; trifluoroalkoxy; alkylsulfonyl,
haloalkylsulfonyl; sulfonic acid; sulfonate, sulfate, sulfinic
acid, sulfenic acid, sulfamide, sulfonamide; sulfoxide, metal
sulfinate, phosphate, phosphonate, metal phosphonate, phosphinate
aminocarbonyl; alkenyl; alkynyl; alditol, carbohydrate, carbocycle,
aryl, heteroaryl and heterocycle; or
[0293] the remaining R.alpha./.beta. groups can join to form a 5, 6
or 7 membered optionally substituted carbocycle, aryl, heteroaryl
or heterocycle, optionally fused to another optionally substituted
carbocycle, aryl, heteroaryl, or heterocycle.
[0294] Examples of active chalcone derivatives prepared in this
invention are listed in Table 2. TABLE-US-00002 TABLE 2 ##STR44## X
Z 4-carboxymethoxy-3,5- 2,4-dimethoxy-5-(benzo[b]thien-2-
dimethoxy, sodium salt yl) 2,4,6-trimethoxy 2,4-difluoro
2,3-dichloro-4-methoxy 5-bromo-2-methoxy 2,4,6-trimethoxy
4-hydroxy-3,5-dimethoxy 3,5-dimethoxy-4-(4- 3,4,5-trimethoxy
methoxybenzyloxy) 3,4,5-trimethoxy 5-bromo-2-methoxy
2,3,4-trimethoxy 3-bromo-4,5-dimethoxy 3,4,5-trimethoxy
3,4-dimethoxy-5-phenyl 4-hydroxy-3,5-dimethoxy
2,4-dimethoxy-5-(benzo[b]thien-2- yl) 4-carboxymethoxy-3,5-
2,4-dimethoxy-5-(benzo[b]thien-2- dimethoxy yl) 2,3,4-trimethoxy
5-(benzo[b]thien-2-yl)-3,4- dimethoxy 3,4,5-trimethoxy
2-methoxy-5-(4-methylthien-2-yl) 3,4-dimethoxy
2-methoxy-5-(5-methylthien-2-yl) 3,4,5-trimethoxy
2-methoxy-5-(5-methylthien-2-yl) 3,5-dimethoxy-4-(1,4-
3,4,5-trimethoxy benzodioxan-3-methoxy) 2,5-dimethoxy
2-methoxy-5-(thien-2-yl) 3,4,5-trimethoxy
3,4-dimethoxy-5-(thien-2-yl) 3,4-dichloro-2-hydroxy, sodium
2-methoxy-5-(thien-2-yl) salt 3,4-dimethoxy
2-methoxy-5-(4-methylthien-2-yl) 3,4,5-trimethoxy
3,4-dimethoxy-5-(3-pyridyl) 3,4,5-trimethoxy
2,4-dimethoxy-5-(thien-2-yl) 3,4,5-trimethoxy 5-bromo-2,4-dimethoxy
3,5-dimethoxy 2-methoxy-5-(thien-2-yl) 4-iodo-2-methoxy
2-methoxy-5-(thien-2-yl) 4-(3,4-dimethoxybenzyloxy)-3-
3,4,5-trimethoxy methoxy 4-(3,4-dimethoxybenzyloxy)-
3,4,5-trimethoxy 3,5-dimethoxy 2,4,5-trimethoxy 3,4,5-trimethoxy
3,4,5-trimethoxy 2-bromo-4,5-dimethoxy 3,4-dichloro-2-hydroxy
5-bromo-2-methoxy 3-methoxy-4-(3,4,5- 3,4,5-trimethoxy
trimethoxybenzyloxy) 3-methoxy-4-(4- 2-methoxy-5-(thien-2-yl)
pyridylmethoxy), hydrogen chloride 3-methoxy-4-(2-
2-methoxy-5-(thien-2-yl) pyridylmethoxy), hydrogen chloride
2-methoxy-4-(thien-2-yl) 3,4-difluoro 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-2-methoxy 3,4-dichloro-2-hydroxy
2-methoxy-5-(thien-2-yl) 3,4-dimethoxy
5-(benzo[b]thien-2-yl)-2-methoxy 2,3,4-trimethoxy
2,4-dimethoxy-5-(thien-2-yl) 3-methoxy-4-(2-
2-methoxy-5-(thien-2-yl) pyridylmethoxy) 4-(fur-2-ylmethoxy)-3,5-
3,4,5-trimethoxy dimethoxy 4-iodo-2-methoxy 3,4,5-trimethoxy
2,4,6-trimethoxy 3-bromo-4,5-dimethoxy 3,4-methylenedioxy
2-methoxy-5-(5-methylthien-2-yl) 4-hydroxy-3,5-dimethoxy,
2,4-dimethoxy-5-(benzo[b]thien-2- sodium salt yl) 3-methoxy-4-(3 -
2-methoxy-5-(thien-2-yl) pyridylmethoxy) 4-methoxy
5-(benzo[b]thien-2-yl)-2-methoxy 3,5-dimethoxy-4-(3,4-
3,4,5-trimethoxy methylenedioxybenzyloxy) 3,5-dimethoxy-4-(thien-2-
3,4,5-trimethoxy ylmethoxy) 3,4,5-trimethoxy 3-fluoro-4-methoxy
3,4-dimethoxy 3-bromo-4,5-dimethoxy 2,3,4-trimethoxy
3,4-dimethoxy-5-(thien-2-yl) 3,5-dimethoxy-4-(3,4,5-
3,4,5-trimethoxy trimethoxybenzyloxy) 3,4,5-trimethoxy
5-(5-acetylthien-2-yl)-3,4- dimethoxy 4-methoxy
2-methoxy-5-(thien-2-yl) 2,6-dimethoxy 2-methoxy-5-(thien-2-yl)
3,4-dimethoxy 2-methoxy-5-Qhien-2-yl) 2,4,6-trimethoxy
2-methoxy-5-Qhien-2-yl) 3,4,5-trimethoxy 2-methoxy-5-(thien-2-yl)
5-(2,4-dimethoxyphenyl) 3,4,5-trimethoxy 2-bromo-4,5-dimethoxy
2-bromo-4,5-dimethoxy 3,4,5-trimethoxy 4-hydroxy 3-methoxy-4-(4-
3,4,5-trimethoxy methoxybenzyloxy) 4-(4-ethoxycarbonyl-
2-methoxy-5-(thien-2-yl) benzyloxy)-3-methoxy
4-(2,3-isopropylidenedioxy-1- 5-(benzo[b]thien-2-yl)-2,4-
propoxy)-3,5-dimethoxy dimethoxy 3-methoxy-4-(4-
2-methoxy-5-(thien-2-yl) pyridylmethoxy)
4-(3-acetylphenyl)-2-methoxy 3,4,5-trimethoxy 3,4,5-trimethoxy
3-bromo-4,5-dimethoxy 3,4-methylenedioxy 5-bromo-2-methoxy
3,4-methylenedioxy 2-methoxy-5-(thien-2-yl) 3,4-methylenedioxy
2-methoxy-5-(4-methylthien-2-yl) 2-methoxy-5-(thien-2-yl)
4-ethoxy-3-fluoro 3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2-
carboxymethoxy-4-methoxy, sodium salt 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-3,4- dimethoxy 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-2,4- dimethoxy 4-(4-carboxybenzyloxy)-3-
2-methoxy-5-(thien-2-yl) methoxy 3,5-dimethoxy-4-(2-
3,4,5-trimethoxy methoxyethoxy) 2,3,4-trimethoxy
5-(4-formylphenyl)-3,4-dimethoxy 2,4-dimethoxy 4-trifluoromethyl
3,4-difluoro 2-methoxy-5-(thien-2-yl) 3,4,5-trimethoxy hydrogen
4-(3-chlorophenyl) 3,4,5-trimethoxy 3,4,5-trimethoxy 4-(thien-2-yl)
5-(3-chlorophenyl)-2,4- 3,4,5-trimethoxy dimethoxy
4-(4-aminobenzyloxy)-3- 2-methoxy-5-(thien-2-yl) methoxy
3-methoxy-4-(3,4- 3,4,5-trimethoxy methylenedioxybenzyloxy)
4-hydroxy-3-methoxy 2-methoxy-5-(thien-2-yl) 2,3,4-trimethoxy
5-(benzo[b]thien-2-yl)-2,4- dimethoxy 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-2- carboxymethoxy-4-methoxy
3,5-di-tert-butyl-4-methoxy hydrogen 3,5-dimethoxy-4-(2-
5-(benzo[b]thien-2-yl)-2,4- morpholinoethoxy) dimethoxy
2-methoxy-4-(3- 2-methoxy-5-(thien-2-yl) methoxyphenyl)
3,4-dimethoxy 5-(benzo[blthien-2-yl)-2,4- dimethoxy
3,4,5-trimethoxy 4-bromo 2,5-dimethoxy-4-(thien-2-yl-
2-methoxy-5-(thien-2-yl) methoxy) 3,4-dimethoxy 4-(thien-2-yl)
2,4-dihydroxy 4-hydroxy 5-bromo-2,4-dimethoxy 3,4,5-trimethoxy
2,4,5-triethoxy 3-bromo-4,5-dimethoxy 4-methoxy 3,4-dimethoxy
2-methoxy-4-(thien-2-yl) 2-methoxy-4-(thien-2-yl)
3,5-di-tert-butyl-4-methoxy 4-methoxy hydrogen hydrogen 4-fluoro
4-fluoro hydrogen 4-nitro 4-methoxy hydrogen 3,4-dichloro-2-hydroxy
5-(benzo[b]thien-2-yl)-2-methoxy 3-chloro hydrogen
3,5-di-tert-butyl-4-hydroxy 4-methoxy 4-methyl
3,5-di-tert-butyl-4-hydroxy hydrogen 3,5-di-tert-butyl-4-hydroxy
3-methoxy-4-(4-tert-butyloxy- 2-methoxy-5-(thien-2-yl)
carbonylaminobenzyloxy) hydrogen 2,4,6-triisopropyl 4-bromo
3,4,5-trimethoxy 4-benzyloxy-3,5-dimethoxy 3-bromo-4,5-dimethoxy
3,5-dimethoxy-4- 5-(benzo[b]thien-2-yl)-2,4- ##STR45##
dimethoxy
[0295] Alternative embodiments include the compounds illustrated
below, or their pharmaceutically acceptable salts, wherein the
variables are as defined above. ##STR46## ##STR47## ##STR48##
[0296] wherein Y is a phenyl ring conjugated to another
heteroaromatic or heterocycle. ##STR49## ##STR50## In yet another
embodiment, the compound is selected from the following: [0297]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-
methoxyphenyl)-2-propen-1-one sodium salt; [0298]
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyp-
henyl)-2-propen-1-one; [0299]
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-carboxymethoxy-3,5-dimethoxyp-
henyl)-2-propen-1-one sodium salt; [0300]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-
phenyl)-2-propen-1-one; [0301]
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3,5-dimethoxyphenyl)--
2-propen-1-one; [0302]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-
methoxyphenyl)-2-propen-1-one; [0303]
3-[2,4-dimethoxy-5-(thien-2-yl)-phenyl]-1-(4-carboxymethoxy-3,5-dimethoxy-
phenyl)-2-propen-1-one; [0304]
3-[5-(benzo[b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(2,3,4-trimethoxyphenyl)-
-2-propen-1-one; [0305]
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxy
phenyl)-2-propen-1-one; [0306]
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one; [0307]
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4,5-trimethoxy
phenyl)-2-propen-1-one; [0308]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxyphenyl)-2-propen-1-one-
; [0309]
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxypheny-
l)-2-propen-1-one; [0310]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-pro-
pen-1-one sodium salt; [0311]
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one; [0312]
3-[3,4-dimethoxy-5-(3-pyridyl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-
-1-one; [0313]
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-prope-
n-1-one; [0314]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,5-dimethoxyphenyl)-2-propen-1-one-
; [0315]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-iodo-2-methoxyphenyl)-2-
-propen-1-one; [0316]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(4-pyridylmethoxyphenyl-
)-2-propen-1-one, hydrochloride salt; [0317]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxyphenyl-
)-2-propen-1-one hydrochloride salt; [0318]
3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one;
[0319]
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one; [0320]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dichloro-2-hydroxyphenyl)-2-pro-
pen-1-one; [0321]
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(3,4-dimethoxyphenyl)-2-prop-
en-1-one; [0322]
3-[2,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxyphenyl)-2-prope-
n-1-one; [0323]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(2-pyridylmethoxphenyl)-
-2-propen-1-one; [0324]
3-[2-methoxy-5-(5-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-
-propen-1-one; [0325]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-
phenyl)-2-propen-1-one sodium salt; [0326]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3-methoxy-4-(3-pyridylmethoxphenyl)-
-2-propen-1-one; [0327]
3-[5-(benzo[b]thien-2-yl)-2-methoxyphenyl]-1-(4-methoxyphenyl)-2-propen-1-
-one; [0328]
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(2,3,4-trimethoxyphenyl)-2-prope-
n-1-one; [0329]
3-[5-(5-acetylthien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one; [0330]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-methoxyphenyl)-2-propen-1-one;
[0331]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,6-dimethoxyphenyl)-2-prop-
en-1-one; [0332]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one-
; [0333]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,4,6-trimethoxyphenyl)-2-
-propen-1-one; [0334]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1--
one; [0335]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-ethoxycarbonylenzyloxy)-3-meth-
oxyphenyl]-2-propen-1-one; [0336]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[4-(2,3-isopropylidenedi-
oxy-1-propoxy)-3,5-dimethoxyphenyl]-2-propen-1-one; [0337]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[3-methoxy-4-(4-pyridylmethoxy)pheny-
l]-2-propen-1-one; [0338]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-propen--
1-one; [0339]
3-[2-methoxy-5-(4-methylthien-2-yl)phenyl]-1-(3,4-methylenedioxyphenyl)-2-
-propen-1-one; [0340]
3-(4-ethoxy-3-fluorophenyl)-1-[2-methoxy-5-(thien-2-yl)phenyl]-2-propen-1-
-one; [0341]
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one sodium salt; [0342]
3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one; [0343]
3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one sodium salt; [0344]
3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one; [0345]
3-[2-carboxymethoxy-4-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one sodium salt; [0346]
3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one sodium salt; [0347]
3-[4-carboxymethoxy-2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyph-
enyl)-2-propen-1-one; [0348]
3-[5-(benzo[b]thien-2-yl)-3,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one; [0349]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one; [0350]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-buten-1-one; [0351]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-carboxybenzyloxy)-3-methoxyphe-
nyl]-2-propen-1-one; [0352]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(3,4-difluorophenyl)-2-propen-1-one;
[0353]
3-[4-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-o-
ne; [0354]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[4-(4-aminobenzyloxy)-3-methoxypheny-
l]-2-propen-1-one; [0355]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-
-1-one; [0356]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(2,3,4-trimethoxyphenyl)-
-2-propen-1-one; [0357]
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one; [0358]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-[3,5-dimethoxy-4-(2-morp-
holinoethoxy)phenyl]-2-propen-1-one; [0359]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[2-methoxy-4-(3-methoxyphenyl)phenyl-
]-2-propen-1-one; [0360]
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4-dimethoxyphenyl)-2--
propen-1-one; [0361]
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(2,5-dimethoxy-4-(thien-2-ylmethoxy)-
phenyl)-2-propen-1-one; [0362]
3-[4-(thien-2-yl)phenyl]-1-(3,4-dimethoxyphenyl)-2-propen-1-one;
[0363]
3-[2-methoxy-4-(thien-2-yl)-phenyl]-1-[2-methoxy-4-(thien-2-yl)phenyl)-2--
propen-1-one phenyl]-2-propen-1-one; [0364]
2-[[3,4-dimethoxy-5-(thien-2-yl)phenyl]ethylene]-3,4-dihydro-6,7-dimethox-
y-1 (2H)-naphthalenone. Stereoisomerism and Polymorphism
[0365] It is appreciated that compounds of the present invention
having a chiral center may exist in and be isolated in optically
active and racemic forms. Some compounds may exhibit polymorphism.
It is to be understood that the present invention encompasses any
racemic, optically-active, diastereomeric, polymorphic, or
stereoisomeric form, or mixtures thereof, of a compound of the
invention, which possess the useful properties described herein, it
being well known in the art how to prepare optically active forms
(for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active
starting materials, by chiral synthesis, or by chromatographic
separation using a chiral stationary phase).
[0366] Examples of methods to obtain optically active materials are
known in the art, and include at least the following. [0367] i)
physical separation of crystals--a technique whereby macroscopic
crystals of the individual enantiomers are manually separated. This
technique can be used if crystals of the separate enantiomers
exist, i.e., the material is a conglomerate, and the crystals are
visually distinct; [0368] ii) simultaneous crystallization--a
technique whereby the individual enantiomers are separately
crystallized from a solution of the racemate, possible only if the
latter is a conglomerate in the solid state; [0369] iii) enzymatic
resolutions--a technique whereby partial or complete separation of
a racemate by virtue of differing rates of reaction for the
enantiomers with an enzyme; [0370] iv) enzymatic asymmetric
synthesis--a synthetic technique whereby at least one step of the
synthesis uses an enzymatic reaction to obtain an enantiomerically
pure or enriched synthetic precursor of the desired enantiomer;
[0371] v) chemical asymmetric synthesis--a synthetic technique
whereby the desired enantiomer is synthesized from an achiral
precursor under conditions that produce asymmetry (i.e., chirality)
in the product, which may be achieved using chiral catalysts or
chiral auxiliaries; [0372] vi) diastereomer separations--a
technique whereby a racemic compound is reacted with an
enantiomerically pure reagent (the chiral auxiliary) that converts
the individual enantiomers to diastereomers. The resulting
diastereomers are then separated by chromatography or
crystallization by virtue of their now more distinct structural
differences and the chiral auxiliary later removed to obtain the
desired enantiomer; [0373] vii) first- and second-order asymmetric
transformations--a technique whereby diastereomers from the
racemate equilibrate to yield a preponderance in solution of the
diastereomer from the desired enantiomer or where preferential
crystallization of the diastereomer from the desired enantiomer
perturbs the equilibrium such that eventually in principle all the
material is converted to the crystalline diastereomer from the
desired enantiomer. The desired enantiomer is then released from
the diastereomer; [0374] viii) kinetic resolutions--this technique
refers to the achievement of partial or complete resolution of a
racemate (or of a further resolution of a partially resolved
compound) by virtue of unequal reaction rates of the enantiomers
with a chiral, non-racemic reagent or catalyst under kinetic
conditions; [0375] ix) enantiospecific synthesis from non-racemic
precursors--a synthetic technique whereby the desired enantiomer is
obtained from non-chiral starting materials and where the
stereochemical integrity is not or is only minimally compromised
over the course of the synthesis; [0376] x) chiral liquid
chromatography--a technique whereby the enantiomers of a racemate
are separated in a liquid mobile phase by virtue of their differing
interactions with a stationary phase. The stationary phase can be
made of chiral material or the mobile phase can contain an
additional chiral material to provoke the differing interactions;
[0377] xi) chiral gas chromatogaphy--a technique whereby the
racemate is volatilized and enantiomers are separated by virtue of
their differing interactions in the gaseous mobile phase with a
column containing a fixed non-racemic chiral adsorbent phase;
[0378] xii) extraction with chiral solvents--a technique whereby
the enantiomers are separated by virtue of preferential dissolution
of one enantiomer into a particular chiral solvent; [0379] xiii)
transport across chiral membranes--a technique whereby a racemate
is placed in contact with a thin membrane barrier. The barrier
typically separates two miscible fluids, one containing the
racemate, and a driving force such as concentration or pressure
differential causes preferential transport across the membrane
barrier. Separation occurs as a result of the non-racemic chiral
nature of the membrane which allows only one enantiomer of the
racemate to pass through.
II. DEFINITIONS
[0380] The term alkyl, as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic, primary,
secondary, or tertiary hydrocarbon, including but not limited to
those of C1 to C10, and preferably C1-C4, including methyl, ethyl,
propyl, isopropyl, cyclopropyl, methylcyclopropyl, butyl, isobutyl,
t-butyl, sec-butyl, cyclobutyl, and (cyclopropyl)methyl. The alkyl
group specifically includes fluorinated alkyls such as CF3 and
other halogenated alkyls such as CH2CF2, CF2CF3, the chloro
analogs, and the like.
[0381] The alkyl group can be optionally substituted with one or
more moieties selected from the group consisting of aryl,
heteroaryl, heterocyclic, carbocycle, alkoxy, heterocycloxy,
heterocylalkoxy, aryloxy; arylalkoxy; heteroaryloxy;
heteroarylalkoxy, carbohydrate, amino acid, amino acid esters,
amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl,
acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino,
nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl,
sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid,
amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether,
oxime, hydrazine, carbamate, phosphonic acid, phosphate,
phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic
acid, sulfonylimide, substituted or unsubstituted urea connected
through nitrogen including but not limited to NHCONH2 and NHCONHR;
or any other desired functional group that does not inhibit the
pharmacological activity of this compound, either unprotected, or
protected as necessary, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991, hereby
incorporated by reference.
[0382] The term aryl, as used herein, and unless otherwise
specified, refers to phenyl, biphenyl, or naphthyl, and preferably
phenyl. The aryl group can be optionally substituted with one or
more of the moieties selected from the group consisting of alkyl,
heteroaryl, heterocyclic, carbocycle, alkoxy, aryloxy, aryloxy;
arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino
acid, amino acid esters, amino acid amides, alditol, halo,
haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido,
alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide,
sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl,
carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl,
phosphoryl, thioester, thioether, oxime, hydrazine, carbamate,
phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido,
carboxamido, hydroxamic acid, sulfonylimide or any other desired
functional group that does not inhibit the pharmacological activity
of this compound, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in
Greene, et al., "Protective Groups in Organic Synthesis," John
Wiley and Sons, Second Edition, 1991. Alternatively, adjacent
groups on the aryl ring may combine to form a 5 to 7 membered
carbocyclic, aryl, heteroaryl or heterocylic ring. In another
embodiment, the aryl ring is substituted with an optionally
substituted cycloalkyl (such as cyclopentyl or cylcohexyl), or an
alkylene dioxy moiety (for example methylenedioxy).
[0383] The term heterocyclic refers to a nonaromatic cyclic group
that may be partially (contains at least one double bond) or fully
saturated and wherein there is at least one heteroatom, such as
oxygen, sulfur, nitrogen, or phosphorus in the ring. The term
heteroaryl or heteroaromatic, as used herein, refers to an aromatic
that includes at least one sulfur, oxygen, nitrogen or phosphorus
in the aromatic ring. Nonlimiting examples of heterocylics and
heteroaromatics are pyrrolidinyl, tetrahydrofuryl, piperazinyl,
piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl,
imidazolyl, pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or
1,4-dioxanyl. aziridinyl, furyl, furanyl, pyridyl, pyrimidinyl,
benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-thiadiazole, indazolyl, 1,3,5-triazinyl, thienyl,
isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl,
isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl,
xanthinyl, hypoxanthinyl, pyrazole, imidazole, 1,2,3-triazole,
1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine, or
pteridinyl wherein said heteroaryl or heterocyclic group can be
optionally substituted with one or more substituent selected from
the same substituents as set out above for aryl groups. Functional
oxygen and nitrogen groups on the heteroaryl group can be protected
as necessary or desired. Suitable protecting groups can include
trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and
t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups,
acyl groups such as acetyl and propionyl, methanesulfonyl, and
p-toluenelsulfonyl.
[0384] The term thienyl refers to a five member cyclic group
wherein the ring contains one sulfur atom and two double bonds. The
thienyl group can optionally be substituted with one or more
moieties selected from the group consisting of those described
above for aryl substituents.
[0385] The term benzothienyl refers to a five member cyclic group
wherein the ring contains one sulfur atom and two double bonds
fused to a phenyl ring. The benzothienyl group can optionally be
substituted with one or more moieties selected from the group
consisting of those described above for aryl substituents.
[0386] The term aralkyl, as used herein, and unless otherwise
specified, refers to an aryl group as defined above linked to the
molecule through an alkyl group as defined above. The aryl and
alkyl portions can be optionally substituted as described
above.
[0387] The term heteroaralkyl, as used herein, and unless otherwise
specified, refers to an heteroaryl group as defined above linked to
the molecule through an alkyl group as defined above.
[0388] The term heterocyclealkyl, as used herein, refers to a
heterocyclic group bound to the molecule through an alkyl group.
The heterocyclic group and the alkyl group can be optionally
substituted as described above.
[0389] The term aryloxy, as used herein, refers to an aryl group
bound to the molecule through an oxygen atom. The aryl group can be
optionally substituted as set out above for aryl groups.
[0390] The term heteroaryloxy, as used herein, refers to a
heteroaryl group bound to the molecule through an oxygen atom. The
heteroaryl group can be optionally substituted as set out above for
aryl groups.
[0391] The term aralkoxy refers to an aryl group attached to an
alkyl group which is attached to the molecule through an oxygen
atom. The aryl and alkyl groups can be optionally substituted as
described above.
[0392] The term heterocyclearalkoxy refers to a heterocyclic group
attached to an aryl group attached to an alkyl-O-- group. The
heterocyclic, aryl and alkyl groups can be optionally substituted
as described above.
[0393] The term halo or halogen, as used herein, includes chloro,
bromo, iodo and fluoro.
[0394] The term alkoxy, as used herein, and unless otherwise
specified, refers to a moiety of the structure --O-alkyl, wherein
alkyl is as defined above. The alkyl group can be optionally
substituted as described above. Alkoxy groups can include OCF3,
OCH2CF3, OCF2CF3 and the like.
[0395] The term alkylthio as used herein refers to an alkyl group
attached to the molecule through a sulfur atom. The alkyl group can
be optionally substituted as described above.
[0396] The term acyl, as used herein, refers to a group of the
formula C(O)R', wherein R' is an alkyl, aryl, alkaryl or aralkyl
group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein
these groups are as defined above.
[0397] The term "alditol," as referred to herein, and unless
otherwise specified, refers to a carbohydrate in which the aldehyde
or ketone group has been reduced to an alcohol moiety. The alditols
of the present invention can also be optionally substituted or
deoxygenated at one or more positions. Exemplary substituents
include hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino,
amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino,
alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,
sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid,
amide, amino acid, amino acid esters and amides, phosphonyl,
phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine,
carbamate, phosphonic acid, phosphonate, or any other viable
functional group that does not inhibit the pharmacological activity
of this compound. Particular exemplary substituents include amine
and halo, particularly fluorine. The substituent or alditol can be
either unprotected, or protected as necessary, as known to those
skilled in the art, for example, as taught in Greene, et al.,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second
Edition, 1991, hereby incorporated by reference.
[0398] The alditol may have 3, 4, 5, 6 or 7 carbons. Examples of
useful alditols are those derived from reduction of
monosaccharides, including specifically those derived from the
reduction of pyranose and furanose sugars.
[0399] The term "carbohydrate," as referred to herein, and unless
otherwise specified, refers to a compound of carbon, hydrogen and
oxygen that contains an aldehyde or ketone group in combination
with at least two hydroxyl groups. The carbohydrates of the present
invention can also be optionally substituted or deoxygenated at one
or more positions. Carbohydrates thus include substituted and
unsubstituted monosaccharides, disaccharides, oligosaccharides, and
polysaccharides. The saccharide can be an aldose or ketose, and may
comprise 3, 4, 5, 6, or 7 carbons. In one embodiment the
carbohydrates are monosaccharides. In another embodiment the
carbohydrates are pyranose and furanose sugars.
[0400] Non limiting examples of pyranose and furanose sugars
include threose, ribulose, ketose, gentiobiose, aldose,
aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose,
ketopentose, erythrose, threose, ribose, deoxyribose, arabinose,
xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose,
glactose, talose, erythrulose, ribulose, xylulose, psicose,
fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose,
cellulose, aldose, amylose, palatinose, trehalose, turanose,
cellobiose, amylopectin, glucosamine, mannosamine, fucose,
phamnose, glucuronate, gluconate, glucono lactone, muramic acid,
abequose, rhamnose, gluconic acid, glucuronic acid, and
galactosamine.
[0401] The carbohydrate can be optionally deoxygenated at any
corresponding C-position, and/or substituted with one or more
moieties such as hydrogen, halo, haloalkyl, carboxyl, acyl,
acyloxy, amino, amido, carboxyl derivatives, alkylamino,
dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic
acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl,
ester, carboxylic acid, amide, amino acid, amino acid esters,
amides, phosphonyl, phosphinyl, phosphoryl, thioester, thioether,
oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any
other viable functional group that does not inhibit the
pharmacological activity of this compound. Particular exemplary
substituents include anine and halo, particularly fluorine. The
substituent or carbohydrate can be either unprotected, or protected
as necessary, as known to those skilled in the art, for example, as
taught in Greene, et al., Protective Groups in Organic Synthesis,
John Wiley and Sons, Second Edition, 1991, hereby incorporated by
reference.
[0402] The term "protected" as used herein and unless otherwise
defined refers to a group that is added to an oxygen, nitrogen, or
phosphorus atom to prevent its further reaction or for other
purposes. A wide variety of oxygen and nitrogen protecting groups
are known to those skilled in the art of organic synthesis. The
term aryl, as used herein, and unless otherwise specified, refers
to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl
group can be optionally substituted with one or more moieties
selected from the group consisting of hydroxyl, amino, alkylamino,
arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,
phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as necessary, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991.
[0403] As used herein, the term "patient" refers to warm-blooded
animals or mammals, and in particular humans, who are in need of
the therapy described herein. The term host, as used herein, refers
to a unicellular or multicellular organism, including cell lines
and animals, and preferably a human.
III. PHARMACEUTICALLY ACCEPTABLE SALT FORMULATIONS
[0404] In cases where compounds are sufficiently basic or acidic to
form stable nontoxic acid or base salts, administration of the
compound as a pharmaceutically acceptable salt may be appropriate.
The term "pharmaceutically acceptable salts" or "complexes" refers
to salts or complexes that retain the desired biological activity
of the compounds of the present invention and exhibit minimal
undesired toxicological effects.
[0405] Examples of pharmaceutically acceptable salts are organic
acid addition salts formed with acids, which form a physiological
acceptable anion, for example, tosylate, methanesulfonate, acetate,
citrate, malonate, tartarate, succinate, benzoate, ascorbate,
.alpha.-ketoglutarate and .alpha.-glycerophosphate. Suitable
inorganic salts may also be formed, including, sulfate, nitrate,
bicarbonate and carbonate salts. Alternatively, the
pharmaceutically acceptable salts may be made with sufficiently
basic compounds such as an amine with a suitable acid affording a
physiologically acceptable anion. Alkali metal (for example,
sodium, potassium or lithium) or alkaline earth metal (for example
calcium) salts of carboxylic acids can also be made.
[0406] Nonlimiting examples of such salts are (a) acid addition
salts formed with inorganic acids (for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
the like), and salts formed with organic acids such as acetic acid,
oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic
acid, and polygalcturonic acid; (b) base addition salts formed with
metal cations such as zinc, calcium, bismuth, barium, magnesium,
aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and
the like, or with a cation formed from ammonia,
N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or
ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc
tannate salt or the like. Also included in this definition are
pharmaceutically acceptable quaternary salts known by those skilled
in the art, which specifically include the quaternary ammonium salt
of the formula --NR+A-, wherein R is as defined above and A is a
counterion, including chloride, bromide, iodide, --O-alkyl,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or
carboxylate (such as benzoate, succinate, acetate, glycolate,
maleate, malate, citrate, tartrate, ascorbate, benzoate,
cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0407] Pharmaceutically acceptable prodrugs refer to a compound
that is metabolized, for example hydrolyzed or oxidized, in the
host to form the compound of the present invention. Typical
examples of prodrugs include compounds that have biologically
labile protecting groups on a functional moiety of the active
compound. Prodrugs include compounds that can be oxidized, reduced,
aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed,
dehydrolyzed, alkylated, dealkylated, acylated, deacylated,
phosphorylated, dephosphorylated to produce the active compound.
The compounds of this invention possess anti-inflammatory activity,
or are metabolized to a compound that exhibits such activity.
[0408] Any of the compounds described herein can be administered as
a prodrug to increase the activity, bioavailability, stability or
otherwise alter the properties of the compound. A number of prodrug
ligands are known. In general, alkylation, acylation or other
lipophilic modification of the compound will increase the stability
of the chalcone. Examples of substituent groups that can replace
one or more hydrogens on the compound are alkyl, aryl, steroids,
carbohydrates, including sugars, 1,2-diacylglycerol and alcohols.
Many are described in R. Jones and N. Bischofberger, Antiviral
Research, 27 (1995) 1-17. Any of these can be used in combination
with the disclosed compounds to achieve a desired effect.
IV. INFLAMMATORY DISEASES
[0409] The compounds of the present invention can be used to treat
any disorder that is mediated by VCAM. VCAM is upregulated in a
wide variety of disease states, including but not limited to
arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post
transplantation late and chronic solid organ rejection, multiple
sclerosis, systemic lupus erythematosis, inflammatory bowel
diseases, autoimmune diabetes, diabetic retinopathy, rhinitis,
ischemia-reperfusion injury, post-angioplasty restenosis, chronic
obstructive pulmonary disease (COPD), glomerulonephritis, Graves
disease, gastrointestinal allergies, and conjunctivitis.
[0410] Nontlimiting examples of arthritis include rheumatoid (such
as soft-tissue rheumatism and non-articular rheumatism,
fibromyalgia, fibrositis, muscular rheumatism, myofascil pain,
humeral epicondylitis, frozen shoulder, Tietze's syndrome,
fascitis, .quadrature.endonitis, tenosynovitis, bursitis), juvenile
chronic, spondyloarthropaties (ankylosing spondylitis),
osteoarthritis, hyperuricemia and arthritis associated with acute
gout, chronic gout and systemic lupus erythematosus.
[0411] Human endothelial disorders mediated by VCAM-1 include
psoriasis, eczematous dermatitis, Kaposi's sarcoma, as well as
proliferative disorders of smooth muscle cells.
[0412] In yet another embodiment, the compounds disclosed herein
can be selected to treat anti-inflammatory conditions that are
mediated by mononuclear leucocytes.
[0413] In one embodiment, the compounds of the present invention
are selected for the prevention or treatment of tissue or organ
transplant rejection. Treatment and prevention of organ or tissue
transplant rejection includes, but are not limited to treatment of
recipients of heart, lung, combined heart-lung, liver, kidney,
pancreatic, skin, spleen, small bowel, or corneal transplants. The
compounds can also be used in the prevention or treatment of
graft-versus-host disease, such as sometimes occurs following bone
marrow transplantation.
[0414] In an alternative embodiment, the compounds described herein
are useful in both the primary and adjunctive medical treatment of
cardiovascular disease. The compounds are used in primary treatment
of, for example, coronary disease states including atherosclerosis,
post-angioplasty restenosis, coronary artery diseases and angina.
The compounds can be administered to treat small vessel disease
that is not treatable by surgery or angioplasty, or other vessel
disease in which surgery is not an option. The compounds can also
be used to stabilize patients prior to revascularization
therapy.
[0415] In addition to inhibiting the expression of VCAM-1, the
disubstituted 1,3-bis-(substituted-phenyl)-2-propen-1-ones have the
additional properties of inhibiting monocyte chemoattractant
protein-1 (MCP-1) and smooth muscle proliferation. MCP-1 is a
chemoattractant protein produced by endothelial cells, smooth
muscle cells as well as macrophages. MCP-1 promotes integrin
activation on endothelial cells thereby facilitating adhesion of
leukocytes to VCAM-1, and MCP-1 is a chemoattractant for monocytes.
MCP-1 has been shown to play a role in leukocyte recruitment in a
number of chronic inflammatory diseases including atherosclerosis,
rheumatoid arthritis, and asthma. Its expression is upregulated in
these diseases and as such inhibition of MCP-1 expression
represents a desirable property of anti-inflammatory therapeutics.
Furthermore, smooth muscle cell hyperplasia and resulting tissue
remodeling and decreased organ function is yet another
characteristic of many chronic inflammatory diseases including
atherosclerosis, chronic transplant rejection and asthma.
Inhibition of the hyperproliferation of smooth muscle cells is
another desirable property for therapeutic compounds.
V. COMBINATION AND ALTERNATION THERAPY
[0416] Any of the compounds disclosed herein can be administered in
combination or alternation with a second biologically active agent
to increase its effectiveness against the target disorder.
[0417] In combination therapy, effective dosages of two or more
agents are administered together, whereas during alternation
therapy an effective dosage of each agent is administered serially.
The dosages will depend on absorption, inactivation and excretion
rates of the drug as well as other factors known to those of skill
in the art. It is to be noted that dosage values will also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens and schedules should be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions.
[0418] The efficacy of a drug can be prolonged, augmented, or
restored by administering the compound in combination or
alternation with a second, and perhaps third, agent that induces a
different biological pathway from that caused by the principle
drug. Alternatively, the pharmacokinetics, biodistribution or other
parameter of the drug can be altered by such combination or
alternation therapy. In general, combination therapy is typically
preferred over alternation therapy because it induces multiple
simultaneous stresses on the condition.
[0419] Any method of alternation can be used that provides
treatment to the patient. Nonlimiting examples of alternation
patterns include 1-6 weeks of administration of an effective amount
of one agent followed by 1-6 weeks of administration of an
effective amount of a second agent. The alternation schedule can
include periods of no treatment. Combination therapy generally
includes the simultaneous administration of an effective ratio of
dosages of two or more active agents.
[0420] Illustrative examples of specific agents that can be used in
combination or alternation with the chalcones of the present
invention are described below in regard to asthma and arthritis.
The agents set out below or others can alternatively be used to
treat a host suffering from any of the other disorders listed in
Section IV or that are mediated by VCAM or MCP-1. Illustrative
second biologically active agents for the treatment of
cardiovascular disease are also provided below.
Asthma
[0421] In one embodiment, the compound of the present invention is
administered in combination or alternation with heparin, frusemide,
ranitidine, an agent that effects respiratory function, such as
DNAase, or immunosuppressive agents, IV gamma globulin,
troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold
compounds such as Myochrysine (gold sodium thiomalate), platelet
activating factor (PAF) antagonists such as thromboxane inhibitors,
leukotriene-D4-receptor antagonists such as Accolate (zafirlukast),
Ziflo (zileuton), leukotriene C1 or C2 antagonists and inhibitors
of leukotriene synthesis such as zileuton for the treatment of
asthma, or an inducible nitric oxide synthase inhibitor.
[0422] In another embodiment, the active compound is administered
in combination or alternation with one or more other prophylactic
agent(s). Examples of prophylactic agents that can be used in
alternation or combination therapy include but are not limited to
sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom,
Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium)
and ketotifen.
[0423] In another embodiment, the active compound is administered
in combination or alternation with one or more other
.beta.2-adrenergic agonist(s) (.beta. agonists). Examples of
.beta.2-adrenergic agonists (.beta. agonists) that can be used in
alternation or combination therapy include but are not limited to
albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair
(pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol
(Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline
sulfate), Tomalate (bitolterol), isoprenaline, ipratropium bromide,
bambuterol hydrochloride, bitolterol meslyate, broxaterol,
carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline
hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids),
ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine
hydrochloride, ethylnoradrenaline hydrochloride, fenoterol
hydrochloride, hexoprenaline hydrochloride, isoetharine
hydrochloride, isoprenaline, mabuterol, methoxyphenamine
hydrochloride, methylephedrine hydrochloride, orciprenaline
sulphate, phenylephrine acid tartrate, phenylpropanolamine
(phenylpropanolamine polistirex, phenylpropanolamine sulphate),
pirbuterol acetate, procaterol hydrochloride, protokylol
hydrochloride, psuedoephedrine (psuedoephedrine polixtirex,
psuedoephedrine tannate, psuedoephedrine hydrochloride,
psuedoephedrine sulphate), reproterol hydrochloride, rimiterol
hydrobromide, ritodrine hydrochloride, salmeterol xinafoate,
terbutaline sulphate, tretoquinol hydrate and tulobuterol
hydrochloride.
[0424] In another embodiment, the active compound is administered
in combination or alternation with one or more other
corticosteriod(s). Examples of corticosteriods that can be used in
alternation or combination therapy include but are not limited to
glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort
(triamcinolone acetonide), Beclovet (Vanceril, beclomethasone
dipropionate), Flovent (fluticasone), Pulmicort (budesonide),
prednisolone, hydrocortisone, adrenaline, Alclometasone
Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,
Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone
Benzoate, Betamethasone Dipropionate, Betamethasone Sodium
Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,
Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate,
Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol,
Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate),
Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone
Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate,
Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium
Phosphate), Dichlorisone Acetate, Diflorasone Diacetate,
Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone,
Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,
Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone
Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone
(Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone
(Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone,
Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide,
Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride,
Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate,
Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,
Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,
Hydrocortisone Valerate), Medrysone, Meprednisone,
Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone,
Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone
Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate
Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone
Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,
Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium
Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate,
Prednisolone Tebutate), Prednisone (Prednisone Acetate),
Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex,
Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,
Triamcinolone Diacetate and Triamcinolone Hexacetonide).
[0425] In another embodiment, the active compound is administered
in combination or alternation with one or more other
antihistimine(s) (H1 receptor antagonists). Examples of
antihistimines (H1 receptor antagonists) that can be used in
alternation or combination therapy include alkylamines,
ethanolamines ethylenediamines, piperazines, piperidines or
phenothiazines. Some non-limiting examples of antihistimes are
Chlortrimeton (Teldrin, chlorpheniramine), Atrohist
(brompheniramine, Bromarest, Bromfed, Dimetane), Actidil
(triprolidine), Dexchlor (Poladex, Polaramine,
dexchlorpheniramine), Benadryl (diphen-hydramine), Tavist
(clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ
(tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec
(cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra
(fexofenadine), Hismanal (astemizole), Claritin (loratadine),
Seldane (terfenadine), Periactin (cyproheptadine), Nolamine
(phenindamine, Nolahist), Phenameth (promethazine, Phenergan),
Tacaryl (methdilazine) and Temaril (trimeprazine).
[0426] Alternatively, the compound of the present invention is
administered in combination or alternation with [0427] (a)
xanthines and methylxanthines, such as Theo-24 (theophylline,
Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl
(oxitriphylline), aminophylline; [0428] (b) anticholinergic agents
(antimuscarinic agents) such as belladonna alkaloids, Atrovent
(ipratropium bromide), atropine, oxitropium bromide; [0429] (c)
phosphodiesterase inhibitors such as zardaverine; [0430] (d)
calcium antagonists such as nifedipine; or [0431] (e) potassium
activators such as cromakalim for the treatment of asthma.
Arthritic Disorders
[0432] In one embodiment, the compound of the present invention can
also be administered in combination or alternation with apazone,
amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam,
fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan
(hyaluronate), misoprostol, paracetamol, superoxide dismutase
mimics, TNF.alpha. receptor antagonists, TNF.alpha. antibodies, P38
Kinase inhibitors, tricyclic antidepressents, cJun kinase
inhibitors or immunosuppressive agents, IV gamma globulin,
troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold
compounds such as Myochrysine (gold sodium thiomalate), platelet
activating factor (PAF) antagonists such as thromboxane inhibitors,
leukotriene-D4-receptor antagonists such as Accolate (zafirlukast),
Ziflo (zileuton), leukotriene C1, C2 antagonists and inhibitors of
leukotriene synthesis such as zileuton for the treatment of
arthritic disorders, inducible nitric oxide sythase inhibitors.
[0433] In another embodiment, the active compound is administered
in combination or alternation with one or more other
corticosteriod(s). Examples of corticosteriods that can be used in
alternation or combination therapy include but are not limited to
glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort
(triamcinolone acetonide), Beclovet (Vanceril, beclomethasone
dipropionate), Flovent (fluticasone), Pulmicort (budesonide),
prednisolone, hydrocortisone, adrenaline, Alclometasone
Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate,
Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone
Benzoate, Betamethasone Dipropionate, Betamethasone Sodium
Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone,
Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate,
Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol,
Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate),
Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone
Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate,
Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium
Phosphate), Dichlorisone Acetate, Diflorasone Diacetate,
Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone,
Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate,
Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone
Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone
(Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone
(Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone,
Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide,
Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride,
Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate,
Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate,
Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate,
Hydrocortisone Valerate), Medrysone, Meprednisone,
Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone,
Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone
Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate
Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone
Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate,
Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium
Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate,
Prednisolone Tebutate), Prednisone (Prednisone Acetate),
Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex,
Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide,
Triamcinolone Diacetate and Triamcinolone Hexacetonide).
[0434] In another embodiment, the active compound is administered
in combination or alternation with one or more other non-steroidal
anti-inflammatory drug(s) (NSAIDS). Examples of NSAIDS that can be
used in alternation or combination therapy are carboxylic acids,
propionic acids, fenamates, acetic acids, pyrazolones, oxicans,
alkanones, gold compounds and others that inhibit prostaglandin
synthesis, preferably by selectively inhibiting cylcooxygenase-2
(COX-2). Some nonlimiting examples of COX-2 inhibitors are Celebrex
(celecoxib) and Vioxx (rofacoxib). Some non-limiting examples of
NSAIDS are aspirin (acetylsalicylic acid), Dolobid (diflunisal),
Disalcid (salsalate, salicylsalicylate), Trisilate (choline
magnesium trisalicylate), sodium salicylate, Cuprimine
(penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil,
Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxen sodium),
Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen),
Daypro (oxaprozin), meclofenamate (meclofanamic acid, Meclomen),
mefenamic acid, Indocin (indomethacin), Clinoril (sulindac),
tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac,
Butazolidin (phenylbutazone), Tandearil (oxyphenbutazone),
piroxicam (Feldene), Relafen (nabumetone), Myochrysine (gold sodium
thiomalate), Ridaura (auranofin), Solganal (aurothioglucose),
acetaminophen, colchicine, Zyloprim (allopurinol), Benemid
(probenecid), Anturane (sufinpyrizone), Plaquenil
(hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide,
Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin,
Amfenac Sodium, Amidopyrine, Aminopropylone, Ammonium Salicylate,
Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin,
Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac
Lysine), Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine,
Hydrochloride, Bornyl Salicylate, Bromfenac Sodium, Bufexamac,
Bumadizone Calcium, Butibufen Sodium, Capsaicin, Carbaspirin
Calcium, Carprofen, Chlorthenoxazin, Choline Magnesium
Trisalicylate, Choline Salicylate, Cinmetacin, Clofexamide,
Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene, Diacerein,
Diclofenac (Diclofenac Diethylammonium Salt, Diclofenac Potassium,
Diclofenac Sodium), Diethylamine Salicylate, Diethylsalicylamide,
Difenpiramide, Diflunisal, Dipyrone, Droxicam, Epirizole,
Etenzamide, Etersalate, Ethyl Salicylate, Etodolac, Etofenamate,
Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium, Fentiazac,
Fepradinol, Feprazone, Floctafenine, Flufenamic, Flunoxaprofen,
Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen, Glafenine,
Glucametacin, Glycol Salicylate, Gold Keratinate, Harpagophytum
Procumbens, Ibufenac, Ibuprofen, Ibuproxam, Imidazole Salicylate,
Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone,
Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol,
Lithium Salicylate, Lonazolac Calcium, Lomoxicam, Loxoprofen
Sodium, Lysine Aspirin, Magnesium Salicylate, Meclofenamae Sodium,
Mefenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl
Gentisate, Methyl Salicylate, Metiazinic Acid, Metifenazone,
Mofebutazone, Mofezolac, Morazone Hydrochloride, Morniflurnate,
Morpholine Salicylate, Nabumetone, Naproxen (Naproxen Sodium),
Nifenazone, Niflumic Acid, Nimesulide, Oxametacin, Oxaprozin,
Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone, Phenyramidol
Hydrochloride, Picenadol Hydrochloride, Picolamine Salicylate,
Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen,
Pranosal, Proglumetacin Maleate, Proquazone, Protizinic Acid,
Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide,
Salix, Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate,
Sodium Salicylate, Sodium Thiosalicylate, Sulindac, Superoxide
Dismutase (Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone,
Tenidap Sodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate,
Tiaprofenic, Tiaramide Hydrochloride, Tinoridine Hydrochloride,
Tolfenamic Acid, Tometin Sodium, Triethanolamine Salicylate,
Ufenamate, Zaltoprofen, Zidometacin and Zomepirac Sodium.
Cardiovascular Disease
[0435] Compounds useful for combining with the compounds of the
present invention for the treatment of cardiovascular disease
encompass a wide range of therapeutic compounds.
[0436] Ileal bile acid transporter (IBAT) inhibitors, for example,
are useful in the present invention, and are disclosed in patent
application no. PCT/US95/10863, herein incorporated by reference.
More IBAT inhibitors are described in PCT/US97/04076, herein
incorporated by reference. Still further IBAT inhibitors useful in
the present invention are described in U.S. application Ser. No.
08/816,065, herein incorporated by reference. More IBAT inhibitor
compounds useful in the present invention are described in WO
98/40375, and WO 00/38725, herein incorporated by reference.
Additional IBAT inhibitor compounds useful in the present invention
are described in U.S. application Ser. No. 08/816,065, herein
incorporated by reference.
[0437] In another aspect, the second biologically active agent is a
statin. Statins lower cholesterol by inhibiting of
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a key
enzyme in the cholesterol biosynthetic pathway. The statins
decrease liver cholesterol biosynthesis, which increases the
production of LDL receptors thereby decreasing plasma total and LDL
cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo,
A. J. Lipid Res. 33, 1569 (1992)). Depending on the agent and the
dose used, statins may decrease plasma triglyceride levels and may
increase HDLc. Currently the statins on the market are lovastatin
(Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and
fluvastatin (Sandoz). A fifth statin, atorvastatin
(Parke-Davis/Pfizer), is the most recent entrant into the statin
market. Any of these statins or thers can be used in combination
with the chalcones of the present invention.
[0438] MTP inhibitor compounds useful in the combinations and
methods of the present invention comprise a wide variety of
structures and functionalities. Some of the MTP inhibitor compounds
of particular interest for use in the present invention are
disclosed in WO 00/38725, the disclosure from which is incorporated
by reference. Descriptions of these therapeutic compounds can be
found in Science, 282, 23 Oct. 1998, pp. 751-754, herein
incorporated by reference.
[0439] Cholesterol absorption antagonist compounds useful in the
combinations and methods of the present invention comprise a wide
variety of structures and functionalities. Some of the cholesterol
absorption antagonist compounds of particular interest for use in
the present invention are described in U.S. Pat. No. 5,767,115,
herein incorporated by reference. Further cholesterol absorption
antagonist compounds of particular interest for use in the present
invention, and methods for making such cholesterol absorption
antagonist compounds are described in U.S. Pat. No. 5,631,365,
herein incorporated by reference.
[0440] A number of phytosterols suitable for the combination
therapies of the present invention are described by Ling and Jones
in "Dietary Phytosterols: A Review of Metabolism, Benefits and Side
Effects," Life Sciences, 57 (3), 195-206 (1995). Without
limitation, some phytosterols of particular use in the combination
of the present invention are Clofibrate, Fenofibrate, Ciprofibrate,
Bezafibrate, Gemfibrozil. The structures of the foregoing compounds
can be found in WO 00/38725.
[0441] Phytosterols are also referred to generally by Nes
(Physiology and Biochemistry of Sterols, American Oil Chemists'
Society, Champaign, Ill., 1991, Table 7-2). Especially preferred
among the phytosterols for use in the combinations of the present
invention are saturated phytosterols or stanols. Additional stanols
are also described by Nes (Id.) and are useful in the combination
of the present invention. In the combination of the present
invention, the phytosterol preferably comprises a stanol. In one
preferred embodiment the stanol is campestanol. In another
preferred embodiment the stanol is cholestanol. In another
preferred embodiment the stanol is clionastanol. In another
preferred embodiment the stanol is coprostanol. In another
preferred embodiment the stanol is 22,23-dihydrobrassicastanol. In
another embodiment the stanol is epicholestanol. In another
preferred embodiment the stanol is fucostanol. In another preferred
embodiment the stanol is stigmastanol.
[0442] Another embodiment the present invention encompasses a
therapeutic combination of a compound of the present invention and
an HDLc elevating agent. In one aspect, the second HDLc elevating
agent can be a CETP inhibitor. Individual CETP inhibitor compounds
useful in the present invention are separately described in WO
00/38725, the disclosure of which is herein incorporated by
reference. Other individual CETP inhibitor compounds useful in the
present invention are separately described in WO 99/14174,
EP818448, WO 99/15504, WO 99/14215, WO 98/04528, and WO 00/17166,
the disclosures of which are herein incorporated by reference.
Other individual CETP inhibitor compounds useful in the present
invention are separately described in WO 00/18724, WO 00/18723, and
WO 00/18721, the disclosures of which are herein incorporated by
reference. Other individual CETP inhibitor compounds useful in the
present invention are separately described in WO 98/35937, the
disclosure of which is herein incorporated by reference.
[0443] In another aspect, the second biologically active agent can
be a fibric acid derivative. Fibric acid derivatives useful in the
combinations and methods of the present invention comprise a wide
variety of structures and functionalities which have been reported
and published in the art.
[0444] In another embodiment the present invention encompasses a
therapeutic combination of a compound of the present invention and
an antihypertensive agent. Hypertension is defined as persistently
high blood pressure. In another embodiment, the chalcone is
administered in combination with an ACE inhibitor, a beta
andrenergic blocker, alpha andrenergic blocker, angiotensin II
receptor antagonist, vasodilator and diuretic.
VI. PHARMACEUTICAL COMPOSITIONS
[0445] Any host organism, including a pateint, mammal, and
specifically a human, suffering from any of the above-described
conditions can be treated by the administration of a composition
comprising an effective amount of the compound of formula (I) or a
pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
[0446] The composition can be administered in any desired manner,
including oral, topical, parenteral, intravenous, intradermal,
intra-articular, intra-synovial, intrathecal, intra-arterial,
intracardiac, intramuscular, subcutaneous, intraorbital,
intracapsular, intraspinal, intrasternal, topical, transdermal
patch, via rectal, vaginal or urethral suppository, peritoneal,
percutaneous, nasal spray, surgical implant, internal surgical
paint, infusion pump, or via catheter. In one embodiment, the agent
and carrier are administered in a slow release formulation such as
an implant, bolus, microparticle, microsphere, nanoparticle or
nanosphere. For standard information on pharmaceutical
formulations, see Ansel, et al., Pharmaceutical Dosage Forms and
Drug Delivery Systems, Sixth Edition, Williams & Wilkins
(1995).
[0447] An effective dose for any of the herein described conditions
can be readily determined by the use of conventional techniques and
by observing results obtained under analogous circumstances. In
determining the effective dose, a number of factors are considered
including, but not limited to: the species of patient; its size,
age, and general health; the specific disease involved; the degree
of involvement or the severity of the disease; the response of the
individual patient; the particular compound administered; the mode
of administration; the bioavailability characteristics of the
preparation administered; the dose regimen selected; and the use of
concomitant medication. Typical systemic dosages for all of the
herein described conditions are those ranging from 0.1 mg/kg to 500
mg/kg of body weight per day as a single daily dose or divided
daily doses. Preferred dosages for the described conditions range
from 5-1500 mg per day. A more particularly preferred dosage for
the desired conditions ranges from 25-750 mg per day. Typical
dosages for topical application are those ranging from 0.001 to
100% by weight of the active compound.
[0448] The compound is administered for a sufficient time period to
alleviate the undesired symptoms and the clinical signs associated
with the condition being treated.
[0449] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutic amount of compound in vivo in the absence
of serious toxic effects.
[0450] The concentration of active compound in the drug composition
will depend on absorption, inactivation, and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
dosage ranges set forth herein are exemplary only and are not
intended to limit the scope or practice of the claimed composition.
The active ingredient may be administered at once, or may be
divided into a number of smaller doses to be administered at
varying intervals of time.
[0451] A preferred mode of administration of the active compound
for systemic delivery is oral. Oral compositions will generally
include an inert diluent or an edible carrier. They may be enclosed
in gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches or capsules. Pharmaceutically compatible binding agents,
and/or adjuvant materials can be included as part of the
composition.
[0452] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, Primogel, or corn
starch; a lubricant such as magnesium stearate or Sterotes; a
glidant such as colloidal silicon dioxide; a sweetening agent such
as sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0453] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials which modify the physical form of the dosage unit, for
example, coatings of sugar, shellac, or other enteric agents.
[0454] The compound or its salts can be administered as a component
of an elixir, suspension, syrup, wafer, chewing gum or the like. A
syrup may contain, in addition to the active compounds, sucrose as
a sweetening agent and certain preservatives, dyes and colorings
and flavors.
[0455] The compound can also be mixed with other active materials
that do not impair the desired action, or with materials that
supplement the desired action. The compounds can also be
administered in combination with nonsteroidal antiinflammatories
such as ibuprofen, indomethacin, fenoprofen, mefenamic acid,
flufenamic acid, sulindac. The compound can also be administered
with corticosteriods.
[0456] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. pH can be adjusted with acids or
bases, such as hydrochloric acid or sodium hydroxide. The
parenteral preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0457] If administered intravenously, preferred carriers are
physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF,
Parsippany, N.J.) or phosphate buffered saline (PBS).
[0458] In a preferred embodiment, the active compounds are prepared
with carriers that will protect the compound against rapid
elimination from the body, such as a controlled release
formulation, including implants and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters and polylactic acid. Methods for
preparation of such formulations will be apparent to those skilled
in the art. The materials can also be obtained commercially from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to infected cells with
monoclonal antibodies to viral antigens) are also preferred as
pharmaceutically acceptable carriers. These may be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidyl choline, arachadoyl phosphatidyl choline, and
cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin film of dried lipid on the surface of the
container. An aqueous solution of the compound is then introduced
into the container. The container is then swirled by hand to free
lipid material from the sides of the container and to disperse
lipid aggregates, thereby forming the liposomal suspension.
[0459] Suitable vehicles or carriers for topical application can be
prepared by conventional techniques, such as lotions, suspensions,
ointments, creams, gels, tinctures, sprays, powders, pastes,
slow-release transdermal patches, suppositories for application to
rectal, vaginal, nasal or oral mucosa. In addition to the other
materials listed above for systemic administration, thickening
agents, emollients and stabilizers can be used to prepare topical
compositions. Examples of thickening agents include petrolatum,
beeswax, xanthan gum, or polyethylene, humectants such as sorbitol,
emollients such as mineral oil, lanolin and its derivatives, or
squalene.
[0460] Any of the compounds described herein for combination or
alternation therapy can be administered as any derivative that upon
administration to the recipient, is capable of providing directly
or indirectly, the parent compound, or that exhibits activity
itself Nonlimiting examples are the pharmaceutically acceptable
salts (alternatively referred to as "physiologically acceptable
salts"), and a compound which has been alkylated or acylated at an
appropriate position. The modifications can affect the biological
activity of the compound, in some cases increasing the activity
over the parent compound. This can easily be assessed by preparing
the derivative and testing its anti-inflammatory activity according
to known methods.
VII. SYNTHESIS OF THE ACTIVE COMPOUNDS
[0461] A number of the compounds of the general formula (I) are
known, whereas many of the compounds of the general formula (I) are
novel compounds. The known compounds may be isolated or synthesized
in accordance with methods from literature or methods analogous
thereto, an non-limiting example is taught by Wade et al, Organic
Chemistry Third Edition, 1995. The novel compounds may, likewise,
be produced by methods known per se or methods which are analogous
to such methods.
[0462] Compounds of general formula (I) are prepared by reacting an
aryl or cyclic substituted ketone with an aryl or cyclic
substituted aldehyde. This reaction, which is a condensation
reaction, is suitably carried out under acid or base catalyzed
conditions. The reaction may be suitably carried out in water or
protic organic solvents such as lower alcohols (e.g. methanol,
ethanol, or tert-butanol), or lower carboxylic acid (e.g. formic
acid, glacial acetic acid, or propionic acid), or in aprotic
organic solvents such as ethers (e.g. tetrahydrofuran, dioxane, or
diethyl ether), liquid amides (e.g. dimethylformamide, or
hexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons
(e.g. toluene or benzene), or mixtures of such solvents. When
carrying out the reaction under basic conditions, the base may be
selected from sodium, lithium, potassium, barium, calcium,
magnesium, aluminum, ammonium, or quarternary ammonium hydroxides,
lower alkoxides (e.g. methoxides, ethoxides, tert-butoxides),
carbonates, borates, oxides, hydrides, or amides of lower secondary
amines (e.g. diisopropyl amides or methylphenyl amides). Primary
aromatic amines such as aniline, free secondary amines such as
dimethyl amine, diethyl amine, piperidine, or pyrrolidine as well
as basic ion exchange resins may also be used.
[0463] Acid catalysts may be selected from hydrogen chloride,
hydrogen bromide, hydrogen iodide, sulfuric acid, sulfonic acids
(such as paratoluenesulfonic or methansulfonic acid), lower
carboxylic acid (such as formic, acetic, or propionic acid), lower
halogenated carboxylic acid (such as trifluoroacetic acid), Lewis
acids (such as BF3, POCl3, PCl5, FeCl3), or acid ion exchange
resins.
[0464] The reaction may be carried out at temperatures in the range
of 0-100.degree. C., preferrably at room temperature. The time of
reaction may be from 30 minutes to 24 hours.
[0465] In the above reactions, it may be preferred or necessary to
protect various sensitive or reactive groups present in the
starting materials so as to prevent said groups from interfering
with the reactions. Such protection may be carried out in a
well-known manner as taught by Theodora Green et al., in
"Protective Groups in Organic Chemistry" or of the like. The
protecting group may be removed after the reaction in a manner
known per se.
1,3-Bis-(substituted-phenyl)-2-propen-1-ones
[0466] The 1,3-bis-(substituted-phenyl)-2-propen-1-one compounds of
formula (I) and formula (II) can be prepared by known procedures
and techniques, or routine modifications thereof. General
procedures for preparing compounds of formula (I) are set forth in
Schemes 1 through 6.
Generic Syntheses
[0467] The 1,3-bis-(substituted-phenyl)-2-propen-1-one compounds of
the present invention can be readily prepared by someone skilled in
the art of organic synthesis using commonly known methods, many of
which are described by D. N. Dnar in The Chemistry of Chalcones and
Related Compounds (Wiley-Interscience, New York, 1981), that is
incorporated herein by reference. As shown in Scheme 1 through
Scheme 6, typically a substituted acetophenone is condensed with a
substituted benzaldehyde in the presence of a suitable base in a
common procedure known as an aldol condensation reaction. A variety
of organic and inorganic bases can be used. Sodium hydroxide is a
preferred inorganic base. The reaction can be carried out in a
variety of different solvents. Either protoic or aprotic solvents
may be used. Ethanol is preferred in the presence of an inorganic
base. On either or both of the phenyl rings there is a halogen
substutution, with iodo and bromo being preferred.
[0468] A heteroaryl or heterocyclic ring is then introduced to
replace the halogen substitution on either one or both of the
phenyl rings through a metal-catalyzed cross-coupling carbon-carbon
bond forming reaction well known in the art of organic chemistry. A
variety of metal-catalyzed cross coupling carbon-carbon bond
forming reactions can be used. The palladium-catalyzed Suzuki
reaction is preferred, and general methods for this procedure are
described by A. Suzuki in Recent Advances in the Cross-Coupling
Reactions of Organoboron Derivatives with Organic Electrophiles,
1995-1998 (J. Organomet. Chem. (1999), 576(1-2), 147-168),
incorporated herein by reference. For the Suzuki reaction, a
variety of solvents can be used. The preferred solvent for the
Suzuki coupling is ethylene glycol dimethyl ether (DME). As shown
in Schemes 1 and 5, this cross-coupling reaction can be done on
either phenyl ring after the
1,3-bis-(substituted-phenyl)-2-propen-1-one skeleton has been
assembled to provide 1,3-bis-(substituted-phenyl)-2-propen-1-ones
containing one or more heteroaryl or heterocyclic ring.
Alternatively, the cross-coupling reaction can be done on the
individual acetophenone or benzaldehyde intermediates prior to the
aldol condensation, as shown in Schemes 2 and 4. Most of the
compounds of this invention are made by either one of these two
methods.
[0469] As shown in Scheme 3, the aldol condensation reaction can
also be carried out in an aquaeous solution using a surfactant. A
variety of surfactants can be used. Cetyltrimethylammonium chloride
is the preferred surfactant. This method is particularly useful
when there are one or more hydroxyl substitutions on either one or
both of the phenyl rings.
[0470] As shown in Scheme 6, the aldol condensation reaction can
also be carried out in an aprotic solvent such as tetrahydrofuran
(THF) with an organic base. The preferred solvent is THF and the
preferred base is lithium diisopropylamide (LDA). In this manner an
aldol reaction may take place first and the subsequent dehydration
reaction may take place during aqueous workup.
[0471] Some acetophenones and benzaldehydes are not commercially
available. They can be readily prepared by someone skilled in the
art of organic synthesis. Since the acetophenones or benzaldehydes
may also contain one or more water solubilizing groups (amines,
acohols, carboxylates, phosphates, phosphonates, sulfonates,
sulfates, etc) that may interfere in the reaction or that may
complicate isolation of the desired product, one normally skilled
in the art may choose to protect these solubilizing groups prior to
the reaction using methods commonly known in the literature such as
those described by T. W. Greene and P. G. M. Wuts in Protective
Groups in Organic Synthesis (Wiley, New York, 1999) and A. J.
Pearson and W. R. Roush in Handbook of Reagents for Organic
Synthesis: Activating and Agents and Protecting Groups (Wiley,
Chichester, UK, 1999), incorporated herein by reference. Preferable
protecting groups include acetates to protect alcohols, esters to
protect carboxylic acids, and amides or carbamates to protect
amines. Compounds of the present invention include the resulting
protected intermediates. One skilled in the art can selectively
remove these protecting groups using well established and known
procedures to give the desired deprotected heteroaryl or
heterocyclic 1,3-bis-(substituted-phenyl)-2-propen-1-one products.
Some protecting groups such as carboxylic esters may be removed
during the aldol condensation reaction. Formation of the resulting
carboxylate salts, e.g. the sodium salt, may facilitate isolation
of the desired heteroaryl or heterocyclic
1,3-bis-(substituted-phenyl)-2-propen-1-one products from the
reaction mixture. Alternatively, acidification of the reaction
mixture prior to or during workup may facilitate the isolation of
the desired free carboxylic, phosphonic, phosphinic or sulfonic
acid derivatives. Various salts of the compounds of this invention
can be prepared by someone skilled in the art of organic synthesis.
Such salts, e.g. amine hydrochlorides, can be directly isolated
from the reaction mixture after acidification or formed separately
after isolation of the corresponding free amine.
[0472] The chemical reactions described above are generally
disclosed in terms of their broadest applications to the
preparation of the compounds of the present invention.
Occasionally, the reactions may not be applicable as described to
each compound included within the disclosed scope. The compounds
for which this occurs will be readily recognized by those skilled
in the art. In all such cases, either the reactions can
successfully performed by conventional modifications recognized by
those skilled in the art, e.g., by appropriate protection and
deprotection of interfering groups, by changing to alternative
conventional solvents or reagents, by routine modification of
reaction conditions and the like, or other conventional reactions
will be applicable to the preparation of the corresponding
compounds of the present invention. In all preparative methods, all
starting materials are known or readily prepared from known
starting materials.
VIII. EXAMPLES
[0473] The following examples are understood to be illustrative
only and are not intended to limit the scope of the present
invention in any way. All intermediates and final products have
been completely characterized by conventional proton NMR and
standard analytical methods known to those skilled in the art.
##STR51##
Example 1
[0474] ##STR52##
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-
-1-one
[0475] Ex-IA: 3',4',5'-Trimethoxyacetophenone (1.47 g, 6.9 mmol)
and 3-bromo-4,5-dimethoxybenzaldehyde (1.64 g, 0.67 mmol) were
suspended in ethanol (50 mL). Sodium hydroxide solution (50%, 1 mL)
was added dropwise. The mixture was stirred at room temperature for
2 h. Water (20 mL) was added. The precipitate was filtered out,
washed with water and dried over an oil pump to give 1.91 g (65%)
of the desired product,
3-(3-bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one-
, as a slightly yellow residue.
[0476]
3-(3-Bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-prope-
n-1-one (0.105 g, 0.2 mmol) from Ex-1A was dissolved in ethylene
glycol dimethyl ether (20 mL).
Tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1 mmol) was
added, and the mixture was stirred at room temperature under
nitrogen for 5 min. 2-Thiopheneboronic acid (0.128 g) and sodium
carbonate solution (2 M, 0.5 mL) were added. The mixture was
stirred at reflux under nitrogen overnight. Upon cooling to room
temperature it was poured into water (100 mL) and extracted with
dichloromethane (100 mL). The organic phase was dried over sodium
sulfate and evaporated. Silica gel chromatography (hexane/ethyl
acetate, 4:1, 2:1) gave 0.079 g (90%) of the desired
3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-prope-
n-1-one product as a slightly yellow residue. 1H-NMR (300 MHz,
CDCl3): 7.79 (d, 1H), 7.56 (m, 2H), 7.42 (d, 1H), 7.39 (d, 1H),
7.29 (s, 2H), 7.10-7.16 (m, 2H), 3.89-4.00 (m, 15H). Anal.
Calculated for C24H24O6S C: 65.44; H, 5.49, S: 7.28; found C,
65.69; H, 5.59, S: 6.99.
[0477] Additional substituted
1-phenyl-3-[(heteroaryl)phenyl]-2-propen-1-ones can be prepared by
one skilled in the art using similar methods, as shown in Example
Table 1. TABLE-US-00003 EXAMPLE TABLE 1 ##STR53## Substituted
1-Phenyl-3-[(Heteroaryl)phenyl]-2-propen-1-ones. Ex. No. X Z
Melting point (.degree. C.) 2 2,3,4-trimethoxy 3,4-dimethoxy-5-
94-97 (thien-2-yl) 3 3,4,5-trimethoxy 5-(5-acetylthien-2- 109-112
yl)-3,4-dimethoxy 4 3,4,5-trimethoxy 5-(benzo[b]thien-2- 150-151
yl)-3,4-dimethoxy 5 3,4,5-trimethoxy 2,4-dimethoxy-5- 75-80
(thien-2-yl)
[0478] ##STR54##
Example 6
[0479] ##STR55##
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)--
2-propen-1-one
[0480] Ex-6A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol)
was dissolved in ethylene glycol dimethyl ether (50 mL).
Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was
added, and the mixture was stirred at room temperature under
nitrogen for 5 min. Benzo[b]thiophene-2-boronic acid (4.27 g, 24
mmol) and sodium carbonate solution (2 M, 20 mL) were added. The
mixture was stirred at reflux under nitrogen for 24 hours. Upon
cooling to room tempaerature, it was poured into water and
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate and evaporated. Silica gel chromatography
(hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the
desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde.
[0481] 3',4',5'-Trimethoxyacetophenone (1.62 g, 7.7 mmol) was
dissolved in ethanol (50 mL). Sodium hydroxide solution (50%, 4 mL)
was added and the mixture was stirred at room temperature for 30
minutes. 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (2.2 g,
7.7 mmol) from Ex-6A was added, and the mixture was stirred at room
temperature overnight. The resulting yellow precipitate was
filtered out, rinsed with water and dried over an oil pump to give
3.4 g (92%) of the desired
3-[5-(benzo[b]thien-2-yl)-2,4-di-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl-
)-2-propen-1-one product as a solid, m.p. 194-196.degree. C. 1H-NMR
(300 MHz, CDCl3): 8.09 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.78
(d, 1H), 7.67 (s, 1H), 7.52 (d, 1H), 7.25-7.38 (m, 4H), 6.57 (s,
1H), 3.9-4.1 (m, 15H). Anal. Calculated for C28H26O6S: C, 68.55, H,
5.34; S, 6.53; found C, 68.48; H, 5.43, S: 6.52.
[0482] Additional substituted
1-[(heteroaryl)phenyl]-3-phenyl-2-propen-1-ones and substituted
3-[(heteroaryl)phenyl]-1-phenyl-2-propen-1-ones can be prepared by
one skilled in the art using similar methods, as shown in Example
Tables 2a and 2b. TABLE-US-00004 EXAMPLE TABLE 2a Substituted
1-[(Heteroaryl)phenyl]-3-phenyl-2-propen-1-ones and Substituted
3-[Heteroary)phenyl]-1-phenyl-2-propen-1-ones. ##STR56## Example
Melting point No. X Z (.degree. C.) 7 3,4,5-trimethoxy
2-methoxy-5-(thien-2-yl) 47-53 8 2,4,6-trimethoxy
2-methoxy-5-(thien-2-yl) 173-180 9 3,4-dimethoxy
2-methoxy-5-(thien-2-yl) 124-127 10 2,6-dimethoxy
2-methoxy-5-(thien-2-yl) 171-173 11 4-methoxy
2-methoxy-5-(thien-2-yl) 65-85 12 3,4,5-trimethoxy 4-(thien-2-yl)
135-140 13 3,4-dimethoxy 4-(thien-2-yl) 170-180 14 3,5-dimethoxy
2-methoxy-5-(thien-2-yl) 135-140 15 2,5-dimethoxy
2-methoxy-5-(thien-2-yl) 96-100 16 3,4,5-trimethoxy
3,4-dimethoxy-5-(3- Oil pyridyl) 17 2,5-dimethoxy-4-(thien-2-
2-methoxy-5-(thien-2-yl) 54-73 yl-methoxy) 18 4-iodo-2-methoxy
2-methoxy-5-(thien-2-yl) 150-155 19 3-methoxy-4-(2-
2-methoxy-5-(thien-2-yl) 92-94 pyridylmethoxy) 20 3,4-dimethoxy
5-(benzo[b]thien-2-yl)- 159-161 2,4-dimethoxy 21
2-methoxy-4-(3-methoxy- 2-methoxy-5-(thien-2-yl) 97-107 phenyl) 22
3,4-methylenedioxy 2-methoxy-5-(thien-2-yl) 140-145 23
4-(4-ethyloxy- 2-methoxy-5-(thien-2-yl) 62-65 carbonylbenzyloxy)-3-
methoxy 24 4-(4-tert-butyloxy- 2-methoxy-5-(thien-2-yl) 50-60
carbonylaminobenzyloxy)- 3-methoxy 25 4-(4-aminobenzyl-oxy)-3-
2-methoxy-5-(thien-2-yl) 67-80 methoxy 26 3-methoxy-4-(3-
2-methoxy-5-(thien-2-yl) 220-255 pyridylmethoxy) 27 3-methoxy-4-(4-
2-methoxy-5-(thien-2-yl) 165-170 pyridylmethoxy) 28
3,4,5-trimethoxy 2-methoxy-5-(5- 111-115 methylthien-2-yl) 29
3,4-dimethoxy 2-methoxy-5-(5- 119-124 methylthien-2-yl) 30
3,4-methylenedioxy 2-methoxy-5-(5- 115-117 methylthien-2-yl) 31
3,4,5-trimethoxy 2-methoxy-5-(4- 103-105 methylthien-2-yl) 32
3,4-dimethoxy 2-methoxy-5-(4- 82-90 methylthien-2-yl) 33
3,4-methylenedioxy 2-methoxy-5-(4- 143-146 methylthien-2-yl) 34
4-(4-carboxy-benzyloxy- 2-methoxy-5-(thien-2-yl) Oil 3-methoxy 35
3,4-difluoro 2-methoxy-5-(thien-2-yl) 100-105 36
3,4-dichloro-2-hydroxy 2-methoxy-5-(thien-2-yl) 152-163 37
3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2- 150-151 methoxy 38
3,4-dimethoxy 5-(benzo[b]thien-2-yl)-2- 155-162 methoxy 39
4-methoxy 5-(benzo[b]thien-2-yl)-2- 173-176 methoxy 40
2-methoxy-5-(thien-2-yl) 4-ethoxy-3-fluoro Oil 41 2,3,4-trimethoxy
2,4-dimethoxy-5-(thien- 132-133 2-yl) 42 3,4-dichloro-2-hydroxy
5-(benzo[b]thien-2-yl)-2- 203-210 methoxy 43 3,5-dimethoxy-4-(2-
5-(benzo[b]thien-2-yl)- 111-113 morpholino-ethyloxy) 2,4-dimethoxy
44 4-carboxymethoxy-3,5- 5-(benzo[b]thien-2-yl)- 145-153 dimethoxy
2,4-dimethoxy 45 2,3,4-trimethoxy 5-(benzo[b]thien-2-yl)- 145-147
2,4-dimethoxy 46 2,3,4-trimethoxy 5-(benzo[b]thien-2-yl)-2- 195-200
carboxymethoxy-4- methoxy 47 3,5-dimethoxy-4-
5-(benzo[b]thien-2-yl)- Oil ##STR57## 2,4-dimethoxy 48
4-(2,3-isopropylidene- 5-(benzo[b]thien-2-yl)- 131-135
dioxy-1-propoxy)-3,5- 2,4-dimethoxy dimethoxy 49 2,3,4-trimethoxy
5-(benzo[b]thien-2-yl)- 120-124 3,4-dimethoxy 50 3-methoxy-4-(4-
2-methoxy-5-(thien-2-yl) 173-175 pyridylmethoxy), hydrogen chloride
51 3-methoxy-4-(2- 2-methoxy-5-(thien-2-yl) 168-171
pyridylmethoxy), hydrogen chloride 52 3,4-dichloro-2-hydroxy,
2-methoxy-5-(thien-2-yl) >260 sodium salt
[0483] TABLE-US-00005 EXAMPLE TABLE 2b Cyclic Substituted
1-[(Heteroaryl)phenyl]-3-phenyl-2-propen-1- ones and Substituted
3-[(Heteroaryl)phenyl]-1-phenyl-2-propen-1-ones. Example No.
Structure m.p.(.degree. C.) 53 ##STR58## 216-222 54 ##STR59##
192-205 55 ##STR60## 164-172
[0484] ##STR61##
Example 56
[0485] ##STR62##
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen--
1-one
[0486] To a suspension of 2-methoxy-5-(thien-2-yl)benzaldehyde (0.5
g, 2.3 mmol), obtained in the same manner as described in Ex-6A, in
5 N KOH solution was added cetyltrimethyl-ammonium chloride (CTACl,
25% in water, 4 mL, 3.0 mmol) followed by the addition of
4'-hydroxy-3'-methoxyacetophenone (0.38 g, 2.3 mmol). The mixture
was stirred at room temperature overnight. Then it was acidified to
about pH 1 with 6 M sulfuric acid, saturated with sodium chloride,
and extracted with dichloromethane. The organic phase was washed
with brine, dried and evaporated. Silica gel chromatography
(hexane/ethyl acetate, 3:1 then 1:1) gave 0.61 g (73%) of a foam as
the desired
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-
-1-one product, m.p. 142-144.degree. C. 1H-NMR (300 MHz, CDCl3):
8.21 (d, 1H), 7.82 (s, 1H), 7.55-7.75 (m, 4H), 6.85-7.15 (m, 4H),
6.14 (s, 1H), 4.00 (s, 3H), 3.95 (s, 3H). ##STR63##
Example 57
[0487] ##STR64##
3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one
[0488] Ex-57a: 4'-iodo-2'-methoxyacetophenone (1.08 g, 3.9 mmol) in
ethylene glycol dimethyl ether (50 ml) was degassed for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol),
thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonate
solution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred at
reflux under nitrogen for 24 hours. Upon cooling to room
temperature, it was poured into water and extracted with
dichloromethane. The organic phase was dried over sodium sulfate
and evaporated. Silica gel chromatography (hexane/ethyl acetate,
3:1) gave 0.88 g (98%) of the desired
2'-methoxy-4'-(thien-2-yl)acetophenone.
[0489] The 2'-methoxy-4'-(thien-2-yl)acetophenone (0.30 g, 1.3
mmol) from Ex-57A and 3,4-difluorobenzaldehyde 0.19 g, 1.3 mmol)
were mixed in tetrahydrofuran (THF, 10 mL). Cesium carbonate (1.2
g, 3.9 mmol) was added, and the mixture was stirred at reflux
overnight. Upon cooling to room temperature, the mixture was
filtered, the filtrate was treated with 0.5 M HCl, and extracted
with dichloromethane. The organic phase was dried and evaporated.
Silica gel chromatography gave 0.32 g (69%) of the desired
3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-prope-
n-1-one product, m.p. 73-79.degree. C. 1H-NMR (300 MHz, CDCl3):
7.70 (d, 1H), 7.25-7.40 (m, 2H), 6.98-7.15 (m, 7H), 6.49 (d, 1H),
3.89 (s, 3H). ##STR65##
Example 58
[0490] ##STR66##
3-[2-Methoxy-5-(thien-2-yl)phenyl]-1-[(2-methoxy-4-(thien-2-yl)phenyl]-2-p-
ropen-1-one
[0491] The
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-iodo-2-methoxyphenyl)-2-propen-1--
one (0.28 g, 0.59 mmol) from Example 18 was dissolved in toluene
(60 mL) and ethanol (10 mL), and the solution was degassed for 10
minutes. Then tetrakis(triphenyl-phosphine)palladium(0) (0.07 g,
0.05 mmol) was added, and the mixture was stirred at room
temperature under nitrogen for 5 min. 2-Thiopheneboronic acid (0.11
g, 0.88 mmol) and sodium carbonate solution (2 M, 1.5 mL) were
added. The mixture was stirred at reflux under nitrogen overnight.
The solvent was evaporated. Silica gel chromatography (hexane/ethyl
acetate 3:1) of the resulting residue gave 0.21 g (81%) of the
desired
3-[2-methoxy-5-(thien-2-yl)phenyl]-1-[(2-methoxy-4-(thien-2-yl)phenyl]-2--
propen-1-one product as a solid, m.p. 30-50.degree. C. 1H-NMR (300
MHz, CDCl3): 7.80 (d, 1H), 7.70 (d, 1H), 7.55 (d, 1H), 7.46 (m,
2H), 7.25 (d, 1H), 7.18 (d, 1H), 6.95-7.08 (m, 6H), 6.80 (d, 1H),
6.76 (d, 1H), 3.96 (s, 3H), 3.85 (s, 3H). ##STR67##
Example 59
[0492] ##STR68##
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyp-
henyl)-2-propen-1-one
[0493] Ex-59A: To a solution of
4'-hydroxy-3',5'-dimethoxyacetophenone (1 g, 5.1 mmol) in
N,N-dimethylformamide were added tert-butyldimethylsilyl chloride
(1.15 g, 7.6 mmol) and imidazole (0.69 g, 10.2 mmol). The mixture
was stirred at room temperature overnight. Upon quenching with 1 M
sulfuric acid solution, the mixture was extracted with
dichloromethane. The organic phase was washed with saturated sodium
bicarbonate and brine. It was dried and evaporated. Water (2 mL)
was added to the residue, and the precipitate was filtered out and
dried over an oil pump to give 1.28 g (81%) of
3',5'-dimethoxy-4'-(tert-butyldimethylsiloxy)acetophenone as a
white solid, m.p. 90-92.degree. C.
[0494] Ex-59B: To a solution of
3',5'-dimethoxy-4'-(tert-butyldimethylsiloxy)acetophenone, from
Ex-59A (0.5 g, 1.6 mmol) in tetrahydrofuran (10 mL) chilled with
ice/water was added lithium diisopropylamide (2 M, 0.8 mL, 1.6
mmol). The mixture was stirred for 20 minutes while chilled. Then
5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde, from Ex-6A, (0.48
g, 1.6 mmol) in tetrahydrofuran (6 mL) was added, and the mixture
was stirred at room temperature for 2 hours. Upon quenching with
water, the mixture was extracted with dichloromethane. The organic
phase was dried and evaporated. Crystallization from ethanol gave
0.19 g (20%) of the desired
3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldime-
thylsiloxy-3,5-dimethoxyphenyl)-2-propen-1-one as a yellow
solid.
[0495] To a solution of
3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethyl-sil-
oxy-3,5-dimethoxyphenyl)-2-propen-1-one, from Ex-59B, (0.135 g,
0.228 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium
fluoride (0.061 g. 0.228 mmol), and the mixture was stirred at room
temperature for two hours. Upon quenching with water, the mixture
was extracted with dichloromethane. The organic phase was dried and
evaporated. Silica gel chromatography (hexane/ethyl acetate, 1:1)
gave 0.05 g (46%) of the desired
3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-di-
methoxy-phenyl)-2-propen-1-one product as a yellow solid, m.p.
85-105.degree. C.
Example 60
[0496] ##STR69##
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyp-
henyl)-2-propen-1-one, sodium salt
[0497]
3-[5-(Benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dim-
ethoxyphenyl)-2-propen-1-one from Example 59 was treated with 5 N
NaOH and the desired
3-[5-(Benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxyp-
henyl)-2-propen-1-one sodium salt product precipitated out
following the addition of dichloromethane, m.p. 209-215.degree.
C.
Example 61
[0498] ##STR70##
3-[5-(Benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-dim-
ethoxyphenyl)-2-propen-1-one, sodium salt
[0499] Ex-61A: 3',5'-Dimethoxy-4'-hydroxyacetophenone (6.03 g, 31
mmol) and triphenylphosphine (8.05 g, 31 mmol) were stirred in 124
mL of tetrahydrofuran (THF). The mixture was treated with ethyl
glycolate (3.2 g, 31 mmol) and diethylazodicarboxylate (4.83 mL, 31
mmol). The reaction mixture was stirred under reflux for about 3.5
h and then evaporated. The residue was crystallized from
hexane/ethyl acetate. The mother liquor was concentrated to give a
crude product which was purified by recrystallization from EtOH
twice to give 3.14 g of
4'-ethoxycarbonyl-methoxy-3',5'-dimethoxyacetophenone. Solvent
removal from the mother liquor provided additional crude product
which was purified by silica gel chromatography (hexane/ethyl
acetate, 1:1) to give additional product (4.2 g). The total amount
of pure material isolated was 7.34 g (90% yield). mp. 81-83.degree.
C.; Anal. Calcd. for C14H18O6: C, 59.57; H, 6.43; Found: C, 59.60;
H, 6.34; MS (direct probe): Calcd for C14H18O6: m/z=282, found:
m/z=282.
[0500] 4'-Ethoxycarbonylmethoxy-3',5'-dimethoxyacetophenone from
Ex-61A (3.15 g; 11.2 mmol) and
5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-6A (3.33
g; 11.2 mmol) were suspended in 250 mL of absolute ethanol. The
mixture was stirred and heated to give a clear solution then
treated dropwise with 50% NaOH (4 mL). A yellow precipitate
gradually formed after the addition of the base. The mixture was
stirred under reflux for ca. 30 minutes and then cooled to room
temperature and stirred for 5 hours. The yellow precipitate was
isolated by filtration, washed with EtOH/H2O (1:1), acetone, and
hexanes. Final solvent removal under reduced pressure gave 2.4 g
(39%) of the desired
3-[5-(Benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(4-carboxymethoxy-3,5-di-
-methoxyphenyl)-2-propen-1-one sodium salt product as a yellow
solid, m.p. 191-196.degree. C. (decomp.). 1H-NMR (300 MHz,
DMSO-d6): 8.30 (s, 1H), 7.65-8.02 (m, 5H), 7.31 (m, 4H), 6.85 (s,
1H), 4.11 (s, 2H), 4.02 (s, 3H), 4.00 (s, 6H), 3.84 (s, 6H). Anal.
Calcd. for C29H25NaO8S.2.5H2O: C, 57.90; H, 5.03; S, 5.33; Found:
C, 57.53; H, 4.62; S, 5.34; MS (Neg. Ion ES): Calcd. for C29H25O8S:
m/z=533, found: m/z=534.
Example 62
[0501] ##STR71##
3-[5-(Benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trime-
thoxyphenyl)-2-propen-1-one, sodium salt
[0502] Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03
g, 20 mmol) in 25 mL of dichloromethane was cooled to 0.degree. C.
and treated dropwise with a solution of bromine (3.41 g, 21 mmol)
in 10 mL of dichloromethane. The reaction mixture was stirred at
0.degree. C. for 1.5 hours. The solvent was removed by rotary
evaporation to give a residue. The residue was taken up in EtOAc
and washed with 3 portions of water. The organic layer was dried
over MgSO4. The drying agent was removed by filtration, and solvent
was removed by rotary evaporation to give 3.9 g of the desired
5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p.
111-115.degree. C.
[0503] Ex-62B: A stream of N2 was bubbled through a solution of
5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A
in 30 mL of ethylene glycol dimethyl ether for 15 min.
Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was
added along with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10
mL of Na2CO3 (2M aqueous solution). The resulting mixture was
stirred under reflux overnight. The solvent was removed by rotary
evaporation and the residue was treated with saturated NaHCO3 and
extracted with dichloromethane. The organic phase was washed with
brine, dried over MgSO4, and filtered to remove drying agent.
Solvent was removed by rotary evaporation. Purification of the
crude material by silica gel chromatography (hexanes/EtOAc, 2:1)
gave 1.04 g of the desired
5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde.
[0504] Ex-62C: A solution of
5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde (1 g, 3.5
mmol) from Ex-62B and triphenylphosphine (1.0 g, 3.9 mmol) in 20 mL
of THF was stirred and treated with ethyl glycolate (0.4 g, 3.9
mmol) and diethyl azodicarboxylate (0.7 mL, 3.9 mmol), The
resulting mixture was stirred under reflux for 2 h. The solvent was
removed by rotary evaporation and the residue was recrystallized
from hexanes/EtOAc to give 0.34 g of product. The mother liquor was
concentrated and purified by silica gel column chromatography
(hexanes/EtOAc, 3:1)) to give an additional 0.07 g of product,
providing a total of 0.4 g of the desired
5-(benzo[b]thien-2-yl)-2-ethoxycarbonylmethoxy-4-methoxybenzaldehyde.
[0505] A solution of
5-(benzo[b]thien-2-yl)-2-ethoxycarbonylmethoxy-4-methoxybenzaldehyde
(0.49 g, 1.32 mmol) from Ex-62C in 100 mL of absolute EtOH was
treated with 3',4',5'-trimethoxyacetophenone (0.31 g, 1.5 mmol) and
0.5 mL of NaOH (50% aqueous solution). The yellow solution was
stirred overnight. The resulting yellow precipitate was filtered
and washed with 50% EtOH in water, followed by acetone. Removal of
residual solvent under vacuum gave 0.66 g of the desired,
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-methoxyphenyl]-1-(3,4,5-trim-
ethoxyphenyl)-2-propen-1-one sodium salt product, m.p.
255-257.degree. C. 1H-NMR (300 MHz, DMSO-d6): 8.50 (d, 1H), 8.09
(s, 1H), 7.75-7.90 (m, 4H), 7.51 (s, 2H), 7.28 (m, 2H), 6.72 (s,
1H), 4.32 (s, 2H), 3.99 (s, 3H), 3.91 (s, 6H), 3.73 (s, 3H). Anal.
Calculated for C29H25NaO8S.2.5H2O: C, 57.85, H, 4.97, S, 5.32;
found C: 57.78, H, 4.74, S: 5.24. MS (Neg. Ion ES): Calcd. for
C29H25O8S: m/z=533, found: m/z=534.
[0506] Using one or more of the preceding methods, additional
substituted 1-[(heteroaryl or
heterocyclic)phenyl]-3-phenyl-2-propen-1-ones and substituted
3-[(heteroaryl or heterocyclic)phenyl]-1-phenyl-2-propen-1-ones can
be prepared by one skilled in the art using similar methods, as
shown in Example Table 3 through 29. TABLE-US-00006 EXAMPLE TABLE 3
Substituted 3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-
methoxyphenyl]-1-phenyl-2-propen-1-ones. ##STR72## EXAMPLE NUMBER
R2.alpha. R3.alpha. R4.alpha. R5.alpha. R6.alpha. 63 H OMe
OCH2-cyclopropyl OMe H 64 OMe H H H H 65 H OMe H H H 66 H H F H H
67 F H H H H 68 H F H H H 69 F F F F F 70 F H F H H 71 H F F H H 72
H F H F H 73 H OMe OCF3 OMe H 74 F H OMe H H 75 H F OMe H H 76 OH H
F H H 77 OH H H F H 78 OMe H F H H 79 OMe H H F H 80 OMe H CH3 H H
81 OMe H H CH3 H 82 OMe CH3 H H H 83 OMe H H H CH3 84 H OMe F OMe H
85 H OMe Cl OMe H 86 H OMe COOH OMe H 87 H OMe OCH2COOH OMe H 88 H
OMe CH2COOH OMe H 89 H OMe SCH2COOH OMe H 90 H OMe SO3H OMe H 91 H
OMe SO2NH2 OMe H 92 H OMe SO2N(Me)2 OMe H 93 H OMe OCH2CH(NH2)COOH
OMe H 94 H OMe NH2 OMe H 95 H OMe N(CH3)2 OMe H 96 H OMe
N(H)CH2COOH OMe H 97 H OMe ##STR73## OMe H 98 H OMe ##STR74## OMe H
99 H OMe ##STR75## OMe H 100 H OMe ##STR76## OMe H 101 H OMe CH3
OMe H 102 H OMe CF3 OMe H 103 H H H H H
[0507] TABLE-US-00007 EXAMPLE TABLE 4 Substituted
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-
phenyl-2-propen-1-ones. ##STR77## EXAMPLE NUMBER R2.alpha.
R3.alpha. R4.alpha. R5.alpha. R6.alpha. 104 H OMe OCH2-cyclopropyl
OMe H 105 OMe H H H H 106 H OMe H H H 107 H H F H H 108 F H H H H
109 H F H H H 110 F F F F F 111 F H F H H 112 H F F H H 113 H F H F
H 114 H OMe OCF3 OMe H 115 F H OMe H H 116 H F OMe H H 117 OH H F H
H 118 OH H H F H 119 OMe H F H H 120 OMe H H F H 121 OMe H CH3 H H
122 OMe H H CH3 H 123 OMe CH3 H H H 124 OMe H H H CH3 125 H OMe F
OMe H 126 H OMe Cl OMe H 127 H OMe COOH OMe H 128 H OMe CH2COOH OMe
H 129 H OMe SCH2COOH OMe H 130 H OMe SO3H OMe H 131 H OMe SO2NH2
OMe H 132 H OMe SO2N(Me)2 OMe H 133 H OMe OCH2CH(NH2)COOH OMe H 134
H OMe NH2 OMe H 135 H OMe N(CH3)2 OMe H 136 H OMe N(H)CH2COOH OMe H
137 H OMe ##STR78## OMe H 138 H OMe ##STR79## OMe H 139 H OMe
##STR80## OMe H 140 H OMe ##STR81## OMe H 141 H OMe CH3 OMe H 142 H
OMe CF3 OMe H 143 H H H H H
[0508] TABLE-US-00008 EXAMPLE TABLE 5 Substituted
3-[5-(thien-2-yl)-3,4-dimethoxyphenyl]-1-phenyl-2- propen-1-ones.
##STR82## EXAMPLE NUMBER R2.alpha. R3.alpha. R4.alpha. R5.alpha.
R6.alpha. 144 H H H H H 145 OMe H H H H 146 H OMe H H H 147 H H F H
H 148 F H H H H 149 H F H H H 150 F F F F F 151 F H F H H 152 H F F
H H 153 H F H F H 154 H OMe OCF3 OMe H 155 F H OMe H H 156 H F OMe
H H 157 OH H F H H 158 OH H H F H 159 OMe H F H H 160 OMe H H F H
161 OMe H CH3 H H 162 OMe H H CH3 H 163 OMe CH3 H H H 164 OMe H H H
CH3 165 H OMe F OMe H 166 H OMe Cl OMe H 167 H OMe COOH OMe H 168 H
OMe OCH2COOH OMe H 169 H OMe CH2COOH OMe H 170 H OMe SCH2COOH OMe H
171 H OMe SO3H OMe H 172 H OMe SO2NH2 OMe H 173 H OMe SO2N(Me)2 OMe
H 174 H OMe OCH2CH(NH2)COOH OMe H 175 H OMe NH2 OMe H 176 H OMe
N(CH3)2 OMe H 177 H OMe N(H)CH2COOH OMe H 178 H OMe ##STR83## OMe H
179 H OMe ##STR84## OMe H 180 H OMe ##STR85## OMe H 181 H OMe
##STR86## OMe H 182 H OMe CH3 OMe H 183 H OMe CF3 OMe H
[0509] TABLE-US-00009 EXAMPLE TABLE 6 Substituted 3-[5-(heteroaryl
or heterocyclic)-2,4-dimethoxyphenyl]-
1-[(3,5-dimethoxy)-4-carboxymethoxyphenyl]-2-propen-1-ones.
##STR87## Ex. No. R5.beta. 184 ##STR88## 185 ##STR89## 186
##STR90## 187 ##STR91## 188 ##STR92## 189 ##STR93## 190 ##STR94##
191 ##STR95## 192 ##STR96## 193 ##STR97## 194 ##STR98## 195
##STR99## 196 ##STR100## 197 ##STR101## 198 ##STR102## 199
##STR103## 200 ##STR104## 201 ##STR105## 202 ##STR106## 203
##STR107## 204 ##STR108## 205 ##STR109## 206 ##STR110## 207
##STR111## 208 ##STR112## 209 ##STR113## 210 ##STR114## 211
##STR115## 212 ##STR116## 213 ##STR117## 214 ##STR118## 215
##STR119## 674 ##STR120##
[0510] TABLE-US-00010 EXAMPLE TABLE 7 3-[5-(Heteroaryl or
Heterocyclic)-2-carboxymethoxy-4-
methoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.
##STR121## Ex. No. R5.beta. 216 ##STR122## 217 ##STR123## 218
##STR124## 219 ##STR125## 220 ##STR126## 221 ##STR127## 222
##STR128## 223 ##STR129## 224 ##STR130## 225 ##STR131## 226
##STR132## 227 ##STR133## 228 ##STR134## 229 ##STR135## 230
##STR136## 231 ##STR137## 232 ##STR138## 233 ##STR139## 234
##STR140## 235 ##STR141## 236 ##STR142## 237 ##STR143## 238
##STR144## 239 ##STR145## 240 ##STR146## 241 ##STR147## 242
##STR148## 243 ##STR149## 244 ##STR150## 245 ##STR151## 246
##STR152## 247 ##STR153## 248 ##STR154##
[0511] TABLE-US-00011 EXAMPLE TABLE 8 3-[5-(Heteroaryl or
Heterocyclic)-2,4-dimethoxyphenyl]-
1-[(3,4,5-trimethoxy)pbenyl]-2-propen-1-ones. ##STR155## Ex. No.
R5.beta. 249 ##STR156## 250 ##STR157## 251 ##STR158## 252
##STR159## 253 ##STR160## 254 ##STR161## 255 ##STR162## 256
##STR163## 257 ##STR164## 258 ##STR165## 259 ##STR166## 260
##STR167## 261 ##STR168## 262 ##STR169## 263 ##STR170## 264
##STR171## 265 ##STR172## 266 ##STR173## 267 ##STR174## 268
##STR175## 269 ##STR176## 270 ##STR177## 271 ##STR178## 272
##STR179## 273 ##STR180## 274 ##STR181## 275 ##STR182## 276
##STR183## 277 ##STR184## 278 ##STR185## 279 ##STR186## 280
##STR187## 281 ##STR188##
[0512] TABLE-US-00012 EXAMPLE TABLE 9 3-[5-(Heteroaryl or
Heterocyclic)-3,4-dimethoxyphenyl]-1-
[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones. ##STR189## Ex. No.
R5.beta. 282 ##STR190## 283 ##STR191## 284 ##STR192## 285
##STR193## 286 ##STR194## 287 ##STR195## 288 ##STR196## 289
##STR197## 300 ##STR198## 301 ##STR199## 302 ##STR200## 303
##STR201## 304 ##STR202## 305 ##STR203## 306 ##STR204## 307
##STR205## 308 ##STR206## 309 ##STR207## 310 ##STR208## 311
##STR209## 312 ##STR210## 313 ##STR211## 314 ##STR212## 315
##STR213## 316 ##STR214## 317 ##STR215## 318 ##STR216## 319
##STR217## 320 ##STR218## 321 ##STR219## 322 ##STR220## 675
##STR221## 676 ##STR222##
[0513] TABLE-US-00013 EXAMPLE TABLE 10 Substituted
3-[5-(benzo[b]thien-2-yl)-4-methoxyphenyl]-
1-[(3,5-dimethoxy)phenyl]-2-buten-1-ones. ##STR223## Example No.
R4.alpha. R2.beta. 323 OMe OMe 324 OCH2COOH OMe 325 OMe
OCH2COOH
[0514] TABLE-US-00014 EXAMPLE TABLE 11 1-[4-(Heteroaryl or
Heterocyclic)-phenyl]-3-
[(2-carboxymethoxy-4-methoxy)phenyl]-2-propen-1-ones. ##STR224##
EXAMPLE NO. R2.alpha. R3.alpha. R4.alpha. R5.alpha. R6.alpha. 326 H
H ##STR225## H H 327 H H ##STR226## H H 328 H H ##STR227## H H 329
H H ##STR228## H H 330 H H ##STR229## H H 331 H H ##STR230## H H
332 H H ##STR231## H H 333 H H ##STR232## H H 334 H H ##STR233## H
H 335 H H ##STR234## H H 336 H H ##STR235## H H 337 H H ##STR236##
H H 338 H H ##STR237## H H 339 H H ##STR238## H H 340 H H
##STR239## H H 341 H H ##STR240## H H 342 H H ##STR241## H H 343 H
H ##STR242## H H 344 H H ##STR243## H H 345 H H ##STR244## H H 346
H H ##STR245## H H 347 H H ##STR246## H H 348 H H ##STR247## H H
349 H H ##STR248## H H 350 H H ##STR249## H H 351 H H ##STR250## H
H 352 H H ##STR251## H H 353 H H ##STR252## H H 354 H H ##STR253##
H H 355 H H ##STR254## H H 356 H H ##STR255## H H 357 H H
##STR256## H H 358 H H ##STR257## H H 359 H H ##STR258## H H 360 H
H ##STR259## H H 361 H H ##STR260## H H 362 H H ##STR261## H H 363
H H ##STR262## H H 364 H H ##STR263## H H
[0515] TABLE-US-00015 EXAMPLE TABLE 12 3-[3 or
6-(Heteroaryl)-2-carboxymethoxy-4-methoxy)phenyl]-
1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones. ##STR264## Example
Number R3.beta. R5.beta. R6.beta. 365 H H ##STR265## 366 H H
##STR266## 367 ##STR267## H H 368 ##STR268## H H
[0516] TABLE-US-00016 EXAMPLE TABLE 13 3-[3 or
6-(Heteroaryl)-2,4-dimethoxy)phenyl]-1-[(3,4,5-
trimethoxy)phenyl]-2-propen-1-ones. ##STR269## Example Number
R3.beta. R5.beta. R6.beta. 369 H H ##STR270## 370 H H ##STR271##
371 ##STR272## H H 372 ##STR273## H H
[0517] TABLE-US-00017 EXAMPLE TABLE 14 3-[2- or
6-(Heteroaryl)-3,4-dimethoxy)phenyl]-[(3,4,5-
trimethoxy)phenyl]-2-propen-1-ones. ##STR274## Example Number
R3.beta. R5.beta. R6.beta. 373 H H ##STR275## 374 H H ##STR276##
375 ##STR277## H H 376 ##STR278## H H
[0518] TABLE-US-00018 EXAMPLE TABLE 15 Substituted 1-[2- or
3-(Heteroary)-phenyl]-3-[(2-
carboxymethoxy)-4-methoxy]-2-propen-1-ones. ##STR279## EX- AMPLE
NUM- BER R2.alpha. R3.alpha. R4.alpha. R5.alpha. R6.alpha. 377
##STR280## F H H H 378 ##STR281## H F H H 379 H ##STR282## F H H
380 H ##STR283## F H H
[0519] TABLE-US-00019 EXAMPLE TABLE 16 Substituted 1-[2- or
3-(Heteroaryl)-phenyl]-3-[(2,4- dimethoxy)phenyl]-2-propen-1-ones.
##STR284## EXAMPLE NUMBER R2.alpha. R3.alpha. R4.alpha. R5.alpha.
R6.alpha. 381 ##STR285## H F H H 382 ##STR286## H F H H 383 H
##STR287## F H H 384 H ##STR288## F H H
[0520] TABLE-US-00020 EXAMPLE TABLE 17 Substituted 1-[2- or
3-(Heteroaryl)-phenyl]-3-[(3,4- dimethoxy)phenyl]-2-propen-1-ones.
##STR289## EXAMPLE NUMBER R2.alpha. R3.alpha. R4.alpha. R5.alpha.
R6.alpha. 385 ##STR290## H F H H 386 ##STR291## H F H H 387 H
##STR292## F H H 388 H ##STR293## F H H
[0521] TABLE-US-00021 EXAMPLE TABLE 18 Substituted 3-[3-, 5- or
6-(Heteroaryl)-2-(carboxymethoxy)-
4-methoxyphenyl]-1-phenyl-2-propen-1-ones. ##STR294## Example
Number R3.beta. R5.beta. R6.beta. 389 H ##STR295## H 390 H
##STR296## H 391 H H ##STR297## 392 H H ##STR298## 393 ##STR299## H
H 394 ##STR300## H H
[0522] TABLE-US-00022 EXAMPLE TABLE 19 Substituted 3-[3-, 5- or
6-(Heteroaryl)-2,4-dimethoxyphenyl]- 1-phenyl-2-propen-1-ones.
##STR301## Example Number R3.beta. R5.beta. R6.beta. 395 H
##STR302## H 396 H ##STR303## H 397 H H ##STR304## 398 H H
##STR305## 399 ##STR306## H H 400 ##STR307## H H
[0523] TABLE-US-00023 EXAMPLE TABLE 20 Substituted 3-[2-, 5- or
6-(Heteroaryl)-3,4-dimethoxyphenyl]- 1-phenyl-2-propen-1-ones.
##STR308## Example Number R3.beta. R5.beta. R6.beta. 401 H
##STR309## H 402 H ##STR310## H 403 H H ##STR311## 404 H H
##STR312## 405 ##STR313## H H 406 ##STR314## H H
[0524] TABLE-US-00024 EXAMPLE TABLE 21 Substituted
3-[5-(benzo[b]thien-2-yl)-4-carboxymethoxy-2-
methoxypbenyl]-1-phenyl-2-propen-1-ones. ##STR315## EXAMPLE NUMBER
R2.alpha. R3.alpha. R4.alpha. R5.alpha. R6.alpha. 407 H OMe OCH2-
OMe H cyclopropyl 408 OMe H H H H 409 H OMe H H H 410 H H F H H 411
F H H H H 412 H F H H H 413 F F F F F 414 F H F H H 415 H F F H H
416 H F H F H 417 H OMe OCF3 OMe H 418 F H OMe H H 419 H F OMe H H
420 OH H F H H 421 OH H H F H 422 OMe H F H H 423 OMe H H F H 424
OMe H CH3 H H 425 OMe H H CH3 H 426 OMe CH3 H H H 427 OMe H H H CH3
428 H OMe F OMe H 429 H OMe Cl OMe H 430 H OMe COOH OMe H 431 H OMe
OCH2COOH OMe H 432 H OMe CH2COOH OMe H 433 H OMe SCH2COOH OMe H 434
H OMe SO3H OMe H 435 H OMe SO2NH2 OMe H 436 H OMe SO2N(Me)2 OMe H
437 H OMe OCH2CH(NH2) OMe H COOH 438 H OMe NH2 OMe H 439 H OMe
N(CH3)2 OMe H 440 H OMe N(H)CH2COOH OMe H 441 H OMe ##STR316## OMe
H 442 H OMe ##STR317## OMe H 443 H OMe ##STR318## OMe H 444 H OMe
##STR319## OMe H 445 H OMe CH3 OMe H 446 H OMe CF3 OMe H 447 H OMe
OMe OMe H 448 OMe OMe OMe H H 449 H OMe OMe H H
[0525] TABLE-US-00025 EXAMPLE TABLE 22 Substituted
3-[5-(benzo[b]thien-2-yl)-2-carboxymethoxy-4-
methoxyphenyl]-1-phenyl-2-propen-1-ones. ##STR320## Ex. No. Y 450
##STR321## 451 ##STR322## 452 ##STR323## 453 ##STR324## 454
##STR325## 455 ##STR326## 456 ##STR327## 457 ##STR328## 458
##STR329## 459 ##STR330## 460 ##STR331## 461 ##STR332## 462
##STR333## 463 ##STR334## 464 ##STR335## 465 ##STR336## 466
##STR337## 467 ##STR338## 468 ##STR339## 469 ##STR340## 470
##STR341## 471 ##STR342## 472 ##STR343## 473 ##STR344## 474
##STR345## 475 ##STR346## 476 ##STR347## 477 ##STR348## 478
##STR349## 479 ##STR350## 480 ##STR351## 481 ##STR352## 482
##STR353## 483 ##STR354## 484 ##STR355## 485 ##STR356## 486
##STR357## 487 ##STR358## 488 ##STR359## 489 ##STR360##
[0526] TABLE-US-00026 EXAMPLE TABLE 23 Substituted 3-[4-(heteroaryl
or heterocyclic)-2,4-
dimethoxyphenyl]-1-[(3,5-dimethoxy)-4-carboxymethoxyphenyl]-
2-propen-1-ones. ##STR361## Ex. No. R4.beta. 490 ##STR362## 491
##STR363## 492 ##STR364## 493 ##STR365## 494 ##STR366## 495
##STR367## 496 ##STR368## 497 ##STR369## 498 ##STR370## 499
##STR371## 500 ##STR372## 501 ##STR373## 502 ##STR374## 503
##STR375## 504 ##STR376## 505 ##STR377## 506 ##STR378## 507
##STR379## 508 ##STR380## 509 ##STR381## 510 ##STR382## 511
##STR383## 512 ##STR384## 513 ##STR385## 514 ##STR386## 515
##STR387## 516 ##STR388## 517 ##STR389## 518 ##STR390## 519
##STR391## 520 ##STR392## 521 ##STR393## 522 ##STR394##
[0527] TABLE-US-00027 EXAMPLE TABLE 24 3-[4-(Heteroaryl or
Heterocyclic)-2-carboxymethoxy-4-
methoxyphenyl]-1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones.
##STR395## Ex. No. R4.beta. 523 ##STR396## 524 ##STR397## 525
##STR398## 526 ##STR399## 527 ##STR400## 528 ##STR401## 529
##STR402## 530 ##STR403## 531 ##STR404## 532 ##STR405## 533
##STR406## 534 ##STR407## 535 ##STR408## 536 ##STR409## 537
##STR410## 538 ##STR411## 539 ##STR412## 540 ##STR413## 541
##STR414## 542 ##STR415## 543 ##STR416## 544 ##STR417## 545
##STR418## 546 ##STR419## 547 ##STR420## 548 ##STR421## 549
##STR422## 550 ##STR423## 551 ##STR424## 552 ##STR425## 553
##STR426## 554 ##STR427## 555 ##STR428##
[0528] TABLE-US-00028 EXAMPLE TABLE 25 3-[4-(Heteroaryl or
Heterocyclic)-2,4-dimethoxyphenyl]-
1-[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones. ##STR429## Ex. No.
R4.beta. 556 ##STR430## 557 ##STR431## 558 ##STR432## 559
##STR433## 560 ##STR434## 561 ##STR435## 562 ##STR436## 563
##STR437## 564 ##STR438## 565 ##STR439## 566 ##STR440## 567
##STR441## 568 ##STR442## 569 ##STR443## 570 ##STR444## 571
##STR445## 572 ##STR446## 573 ##STR447## 574 ##STR448## 575
##STR449## 576 ##STR450## 577 ##STR451## 578 ##STR452## 579
##STR453## 580 ##STR454## 581 ##STR455## 582 ##STR456## 583
##STR457## 584 ##STR458## 585 ##STR459## 586 ##STR460## 587
##STR461## 588 ##STR462##
[0529] TABLE-US-00029 EXAMPLE TABLE 26 3-[4-(Heteroaryl or
Heterocyclic)-3,5-dimethoxyphenyl]-1-
[(3,4,5-trimethoxy)phenyl]-2-propen-1-ones. ##STR463## Ex. No.
R4.beta. 589 ##STR464## 590 ##STR465## 591 ##STR466## 592
##STR467## 593 ##STR468## 594 ##STR469## 595 ##STR470## 596
##STR471## 597 ##STR472## 598 ##STR473## 599 ##STR474## 600
##STR475## 601 ##STR476## 602 ##STR477## 603 ##STR478## 604
##STR479## 605 ##STR480## 606 ##STR481## 607 ##STR482## 608
##STR483## 609 ##STR484## 610 ##STR485## 611 ##STR486## 612
##STR487## 613 ##STR488## 614 ##STR489## 615 ##STR490## 616
##STR491## 617 ##STR492## 618 ##STR493## 619 ##STR494## 620
##STR495## 621 ##STR496##
[0530] TABLE-US-00030 EXAMPLE TABLE 27 Substituted
3-[4-(pyran-2-yl)phenyl]-1-[(3,5-
dimethoxy)phenyl]-2-propen-1-ones. ##STR497## Example Number
R4.alpha. R2.beta. R3.beta. R5.beta. 622 F OMe H OMe 623 OCH2COOH
OMe OMe H 624 F OCH2COOH H OMe
[0531] TABLE-US-00031 EXAMPLE TABLE 28 Substituted
3-[4-(pyran-4-yl)phenyl]-1-[(3,5-
dimethoxy)phenyl]-2-propen-1-ones. ##STR498## Example Number
R4.alpha. R2.beta. R3.beta. R5.beta. 625 F OMe H OMe 626 OCH2COOH
OMe OMe H 627 F OCH2COOH H OMe
[0532] TABLE-US-00032 EXAMPLE TABLE 29 Substituted
3-[5-(benzo[b]thien-2-yl)-2-(2-carboxy-2-
propoxy)-4-methoxyphenyl]-1-phenyl-2-propen-1-ones. ##STR499## Ex.
No. Y 629 ##STR500## 630 ##STR501## 631 ##STR502## 632 ##STR503##
633 ##STR504## 634 ##STR505## 635 ##STR506## 636 ##STR507## 637
##STR508## 638 ##STR509## 639 ##STR510## 640 ##STR511## 641
##STR512## 642 ##STR513## 643 ##STR514## 644 ##STR515## 645
##STR516## 646 ##STR517## 647 ##STR518## 648 ##STR519## 649
##STR520## 650 ##STR521## 651 ##STR522## 652 ##STR523## 653
##STR524## 654 ##STR525## 655 ##STR526## 656 ##STR527## 657
##STR528## 658 ##STR529## 659 ##STR530## 660 ##STR531## 661
##STR532## 662 ##STR533## 663 ##STR534## 664 ##STR535## 665
##STR536## 666 ##STR537## 667 ##STR538## 668 ##STR539##
VIII. BIOLOGICAL ACTIVITY OF ACTIVE COMPOUNDS
[0533] The ability of a compound described herein to inhibit the
expression of VCAM-1 in a host can be assessed using any known
method, including that described in detail below.
Preparing Vascular Endothelial Cells:
[0534] Two to four confluent P150 plates were trypsinized and the
cells transferred to a 50 mL conical centrifuge tube. The cells
were pelleted, resuspended and counted using the trypan blue
exclusion method.
[0535] Cells were resuspended at a concentration of 36,000 cells/mL
and 1 mL was aliquoted per well.
[0536] Cells were split into 24 well tissue culture plates. The
cells in each well should be approximately 90-95% confluent by the
following day. Cells should not be older than passage 8.
Water Soluble Compounds
[0537] Compounds were initially screened at 50 .mu.M and 10 .mu.M.
A 50 mM stock solution for each compound was prepared in culture
medium. The stock solution was diluted to 5 mM and 1 mM. When 10
.mu.L of the 5 mM solution was added to the well (1 mL
medium/well), the final concentration was 50 .mu.M. Adding 10 .mu.L
of the 1 mM solution to the well provides a final concentration of
10 .mu.M.
Water Insoluble Compounds
[0538] Compounds which will not go into solution in culture medium
were resuspended in DMSO at a concentration of 25 mM. The stock
solution was then diluted to the final concentration in culture
medium. The old medium was aspirated and 1 mL of the new medium
with the compound was added. For example, if the final
concentration was 50 .mu.M, the 2 .mu.L of the 25 mM stock was
added per mL of culture medium. The 50 mM solution was diluted for
lower concentrations.
Example 669
In Vitro MCP-1 Activity Assay
[0539] Cultured human endothelial cells were seeded in 96-well
plates. On the following day cells were stimulated with TNF-.alpha.
(1 ng/ml) in the presence or absence of compounds dissolved in
DMSO. To establish a dose curve and IC50 for each compound,
multiple concentrations in 2-fold increments were used. Cells were
exposed to TNF-.alpha. and compounds for approximately 16 hours.
The next day the cells were visually examined via light microscopy
to score for visual signs of toxicity. Cell culture media, diluted
1:10, was analyzed by an MCP-1 immunoassay kit (R & D Systems).
This assay is a sandwich immunoassay using immobilized anti-MCP-1
antibody in 96-well plate to capture secreted MCP-1 in cell culture
media. Captured MCP-1 is subsequently detected with a horse radish
peroxidase-conjugated anti-MCP-1 antibody for color development.
Results are expressed as IC50 values (the amount of compound
(.quadrature.M) required to achieve a 50% reduction compared to
control (cells stimulated with TNF-.alpha. only)).
Example 670
In Vitro Smooth Muscle Cell Activity Assay
[0540] Cultured human aortic smooth muscle cells were seeded in
24-well plates. When cells reached 80% confluency, they were made
quiescent by changing media to 0.2% serum (as compared to 5% serum
in normal culture media) for 48 hours. The cells were then
stimulated by addition of 5% serum in the presence or absence of
compounds dissolved in DMSO. To establish a dose curve and IC50 for
each compound, multiple concentrations in 5-fold increments were
used. After 20 hr incubation, 3H-thymidine (0.5 .mu.Ci/per well)
was added to the cells for 4 hours of labeling. Washed cells were
then lysed in NaOH and, the amount of 3H-thymidine incorporation
was determined. Results are expressed as IC50 values (the amount of
compound (.quadrature.M) required to achieve a 50% reduction
compared to control (cells stimulated with 5% serum only)).
TABLE-US-00033 TABLE 3 Smooth Muscle Cell EXAMPLE MCP-1 Activity
Activity NUMBER IC50 (.quadrature.M) IC50 (.quadrature.M) 61 ND
0.45 5 ND 0.45 50 >50 0.94 51 20 1.25 41 ND 1.25 2 5 0.4 11 10
4.53 9 10 1.15 7 8 1.53 23 ND 2.33 62 ND 1.25 6 >50 0.33 ND =
Not determined
Example 671
In Vitro VCAM-1 Assay
[0541] The compounds were added to the plate (each compound is done
in duplicate). One plate was prepared for VCAM expression and one
plate was prepared for ICAM expression.
[0542] Immediately after the compounds weree added, TNF was added
to each well 100 units/mL TNF was usually added to each well. Since
each lot of TNF varies in the number of units, each new lot was
titrated to determine the optimum concentration. Therefore this
concentration changed. If 100 units/mL was being used, TNF was
dilted to 10 units/.mu.L and 10 .mu.L added to each well.
[0543] The plates were incubated at 37.degree. C., 5% CO2 overnight
(approximately 16 hours). The next day the plates were checked
under the microscope to see if there were any visual signs of
toxicity. Records were made of any cell death, debris, or
morphology changes, as well as insoluble compounds (particulate or
turbity).
[0544] The degree of inhibition of the compounds of formula (I) was
determined by the assays. The results are provided in Table 4.
TABLE-US-00034 TABLE 4 ##STR540## VCAM-1 IC50 X Z (.quadrature.M)
4-carboxymethoxy-3,5- 2,4-dimethoxy-5-(benzo[b]thien-2- 0.7
dimethoxy, sodium salt yl) 2,4,6-trimethoxy 2,4-difluoro 0.7
2,3-dichloro-4-methoxy 5-bromo-2-methoxy 1 2,4,6-trimethoxy
4-hydroxy-3,5-dimethoxy 1 3,5-dimethoxy-4-(4- 3,4,5-trimethoxy 1
methoxybenzyloxy) 3,4,5-trimethoxy 5-bromo-2-methoxy 1
2,3,4-trimethoxy 3-bromo-4,5-dimethoxy 1 3,4,5-trimethoxy
3,4-dimethoxy-5-phenyl 1 4-hydroxy-3,5-dimethoxy
2,4-dimethoxy-5-(benzo [b]thien-2- 1.2 yl) 4-carboxymethoxy-3,5-
2,4-dimethoxy-5-(benzo[b]thien-2- 1.3 dimethoxy yl)
2,3,4-trimethoxy 5-(benzo[b]thien-2-yl)-3,4- 1.4 dimethoxy
3,4,5-trimethoxy 2-methoxy-5-(4-methylthien-2-yl) 1.5 3,4-dimethoxy
2-methoxy-5-(5-methylthien-2-yl) 1.5 3,4,5-trimethoxy
2-methoxy-5-(5-methylthien-2-yl) 1.5 3,5-dimethoxy-4-(1,4-
3,4,5-trimethoxy 1.5 benzodioxan-3-methoxy) 2,5-dimethoxy
2-methoxy-5-(thien-2-yl) 1.5 3,4,5-trimethoxy
3,4-dimethoxy-5-(thien-2-yl) 1.5 3,4-dichloro-2-hydroxy, sodium
2-methoxy-5-(thien-2-yl) 1.6 salt 3,4-dimethoxy
2-methoxy-5-(4-methylthien-2-yl) 2 3,4,5-trimethoxy
3,4-dimethoxy-5-(3-pyridyl) 2 3,4,5-trimethoxy
2,4-dimethoxy-5-(thien-2-yl) 2 3,4,5-trimethoxy
5-bromo-2,4-dimethoxy 2 3,5-dimethoxy 2-methoxy-5-(thien-2-yl) 2
4-iodo-2-methoxy 2-methoxy-5-(thien-2-yl) 2
4-(3,4-dimethoxybenzyloxy)-3- 3,4,5-trimethoxy 2 methoxy
4-(3,4-dimethoxybenzyloxy)- 3,4,5-trimethoxy 2 3,5-dimethoxy
2,4,5-trimethoxy 3,4,5-trimethoxy 2 3,4,5-trimethoxy
2-bromo-4,5-dimethoxy 2 3,4-dichloro-2-hydroxy 5-bromo-2-methoxy 2
3-methoxy-4-(3,4,5- 3,4,5-trimethoxy 2 trimethoxybenzyloxy)
3-methoxy-4-(4- 2-methoxy-5-(thien-2-yl) 2 pyridylmethoxy),
hydrogen chloride 3-methoxy-4-(2- 2-methoxy-5-(thien-2-yl) 2
pyridylmethoxy), hydrogen chloride 2-methoxy-4-(thien-2-yl)
3,4-difluoro 2.1 3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2-methoxy
2.1 3,4-dichloro-2-hydroxy 2-methoxy-5-(thien-2-yl) 2.3
3,4-dimethoxy 5-(benzo[b]thien-2-yl)-2-methoxy 2.4 2,3,4-trimethoxy
2,4-dimethoxy-5-(thien-2-yl) 2.4 3-methoxy-4-(2-
2-methoxy-5-(thien-2-yl) 2.5 pyridylmethoxy)
4-(fur-2-ylmethloxy)-3,5- 3,4,5-trimethoxy 2.5 dimethoxy
4-iodo-2-methoxy 3,4,5-trimethoxy 2.5 2,4,6-trimethoxy
3-bromo-4,5-dimethoxy 2.5 3,4-methylenedioxy
2-methoxy-5-(5-methylthien-2-yl) 2.5 4-hydroxy-3,5-dimethoxy,
2,4-dimethoxy-5-(benzo[b]thien-2- 2.5 sodium salt yl)
3-methoxy-4-(3- 2-methoxy-5-(thien-2-yl) 2.6 pyridylmethoxy)
4-methoxy 5-(benzo[b]thien-2-yl)-2-methoxy 2.9
3,5-dimethoxy-4-(3,4- 3,4,5-trimethoxy 3 methylenedioxybenzyloxy)
3,5-dimethoxy-4-(thien-2- 3,4,5-trimethoxy 3 ylmethoxy)
3,4,5-trimethoxy 3-fluoro-4-methoxy 3 3,4-dimethoxy
3-bromo-4,5-dimethoxy 3 2,3,4-trimethoxy
3,4-dimethoxy-5-(thien-2-yl) 3 3,5-dimethoxy-4-(3,4,5-
3,4,5-trimethoxy 3 trimethoxybenzyloxy) 3,4,5-trimethoxy
5-(5-acetylthien-2-yl)-3,4- 3 dimethoxy 4-methoxy
2-methoxy-5-(thien-2-yl) 3 2,6-dimethoxy 2-methoxy-5-(thien-2-yl) 3
3,4-dimethoxy 2-methoxy-5-(thien-2-yl) 3 2,4,6-trimethoxy
2-methoxy-5-(thien-2-yl) 3 3,4,5-trimethoxy
2-methoxy-5-(thien-2-yl) 3 5-(2,4-dimethoxyphenyl) 3,4,5-trimethoxy
3 2-bromo-4,5-dimethoxy 2-bromo-4,5-dimethoxy 3 3,4,5-trimethoxy
4-hydroxy 3.5 3-methoxy-4-(4- 3,4,5-trimethoxy 3.7
methoxybenzyloxy) 4-(4-ethoxycarbonyl- 2-methoxy-5-(thien-2-yl) 3.7
benzyloxy)-3-methoxy 4-(2,3-isopropylidenedioxy-1-
5-(benzo[b]thien-2-yl)-2,4- 3.8 propoxy)-3,5-dimethoxy dimethoxy
3-methoxy-4-(4- 2-methoxy-5-(thien-2-yl) 4 pyridylmethoxy)
4-(3-acetylphenyl)-2-methoxy 3,4,5-trimethoxy 4 3,4,5-trimethoxy
3-bromo-4,5-dimethoxy 4 3,4-methylenedioxy 5-bromo-2-methoxy 4
3,4-methylenedioxy 2-methoxy-5-(thien-2-yl) 4 3,4-methylenedioxy
2-methoxy-5-(4-methylthien-2-yl) 4 2-methoxy-5-(thien-2-yl)
4-ethoxy-3-fluoro 4.3 3,4,5-trimethoxy 5-(benzo[b]thien-2-yl)-2-
4.3 carboxymethoxy-4-methoxy, sodium salt 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-3,4- 5 dimethoxy 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-2,4- 5 dimethoxy 4-(4-carboxybenzyloxy)-3-
2-methoxy-5-(thien-2-yl) 5 methoxy 3,5-dimethoxy-4-(2-
3,4,5-trimethoxy 5 methoxyethoxy) 2,3,4-trimethoxy
5-(4-formylphenyl)-3,4-dimethoxy 5 2,4-dimethoxy 4-trifluoromethyl
5.3 3,4-difluoro 2-methoxy-5-(thien-2-yl) 6 3,4,5-trimethoxy
hydrogen 6 4-(3-chlorophenyl) 3,4,5-trimethoxy 6 3,4,5-trimethoxy
4-(thien-2-yl) 6 5-(3-chlorophenyl)-2,4- 3,4,5-tnmethoxy 6
dimethoxy 4-(4-aminobenzyloxy)-3- 2-methoxy-5-(thien-2-yl) 7
methoxy 3-methoxy-4-(3,4- 3,4,5-trimethoxy 7
methylenedioxybenzyloxy) 4-hydroxy-3-methoxy
2-methoxy-5-(thien-2-yl) 7 2,3,4-trimethoxy
5-(benzo[b]thien-2-yl)-2,4- 8.1 dimethoxy 3,4,5-trimethoxy
5-(benzo[b]thien-2-yl)-2- 8.3 carboxymethoxy-4-methoxy
3,5-di-tert-butyl-4-methoxy hydrogen 9 3,5-dimethoxy-4-(2-
5-(benzo[b]thien-2-yl)-2,4- 10 morpholinoethoxy) dimethoxy
2-methoxy-4-(3 - 2-methoxy-5-(thien-2-yl) 11 methoxyphenyl)
3,4-dimethoxy 5-(benzo[b]thien-2-yl)-2,4- 11 dimethoxy
3,4,5-trimethoxy 4-bromo 11 2,5-dimethoxy-4-(thien-2-yl-
2-methoxy-5-(thien-2-yl) 12 methoxy) 3,4-dimethoxy 4-(thien-2-yl)
12 2,4-dihydroxy 4-hydroxy 12 5-bromo-2,4-dimethoxy
3,4,5-trimethoxy 12.5 2,4,5-triethoxy 3-bromo-4,5-dimethoxy 15
4-methoxy 3,4-dimethoxy 15 2-methoxy-4-(thien-2-yl)
2-methoxy-4-(thien-2-yl) 16 2,4-di-tert-butyl-3-methoxy 4-methoxy
17 hydrogen hydrogen 23 4-fluoro 4-fluoro 25 hydrogen 4-nitro 30
4-methoxy hydrogen 32 3,4-dichloro-2-hydroxy
5-(benzo[b]thien-2-yl)-2-methoxy 50 3-chloro hydrogen 57
3,5-di-tert-butyl-4-hydroxy 4-methoxy >50 4-methyl
3,5-di-tert-butyl-4-hydroxy >50 hydrogen
3,5-di-tert-butyl-4-hydroxy >50 3-methoxy-4-(4-tert-butyloxy-
2-methoxy-5-(thien-2-yl) >50 carbonylaminobenzyloxy) hydrogen
2,4,6-triisopropyl >50 4-bromo 3,4,5-trimethoxy >50
4-benzyloxy-3,5-dimethoxy 3-bromo-4,5-dimethoxy >50
3,5-dimethoxy-4- 5-(benzo[b]thien-2-yl)-2,4- >50 ##STR541##
dimethoxy
[0545] Alternatively, the degree of inhibition of the compounds of
formula (I) was determined and tabulated in Table 5. TABLE-US-00035
TABLE 5 Ex. VCAM-1 No. Structure (.quadrature.M) 53 ##STR542##
>50 54 ##STR543## 2 55 ##STR544## >50
Example 672
Mouse Peritonitis Model
[0546] FIG. 2 is a bar chart graph of the inhibition of eosinophil
recruitment (percent eosinophils in the peritoneal fluid) by 50
mg/kg/dose of
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one. Balb/C mice (n=10) were sensitized to ovalbumin on
days 0 and 7 with a subcutaneous injection of ovalbumin absorbed in
aluminum hydroxide. They were then challenged with an
intraperitoneal injection of ovalbumin and sacrificed 48 hrs
post-challenge. Peritoneal fluid was then collected and spun down
onto slides. Slides were stained with DiffQuik and a differential
performed. The test compound wase administered by subcutaneously
injection -24, -2, +2 and +6 hrs around the time of ovalbumin
challenge. This is a model of allergic inflammation as eosinophils
are the major leukocyte recruited into the peritoneum.
Example 673
Paw Edema Model
[0547] FIG. 3 is a bar chart graph of the inhibition of paw edema
in a mouse model of delayed type hypersensitivity by 50 mg/kg/dose
of
3-[5-(benzo[b]thien-2-yl)-2,4-dimethoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-
-2-propen-1-one. Balb/C mice (n=5) were sensitized intradermally on
day 0 with methylated BSA (metBSA). They were then challenged with
metBSA on day 7 in the right hind paw. The animals were sacrificed
24 hours later and the left and right hind paws weighed. The left
hindpaw weight is subtracted from the right hind paw to give the
paw weight increase. The test compound was administered by
intraperitoneal injection -24, -2 and +6 hrs around the time of
metBSA challenge.
[0548] Modifications and variations of the present invention
relating to compounds that inhibit the suppression of VCAM-1 and
methods of treating diseases mediated by the expression of VCAM-1
will be obvious to those skilled in the art from the foregoing
detailed description of the invention. Such modifications and
variations are intended to come with the scope of the appended
claims.
* * * * *