Retinoid antagonists and uses thereof

Details Retinoid antagonists and uses thereof Retinoid antagonists and uses thereof

2000-12-08

2001-11-20

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S569000, C546S285000, C548S343500, C549S070000, C549S434000, C560S080000, C560S100000, C560S102000, C562S490000, C562S492000, C562S510000

Reexamination Certificate

active

06319948

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods for the minimization or prevention of post-surgical adhesion formation using retinoid antagonist compounds, particularly the retinoid antagonist compounds disclosed in U.S. Pat. No. 5,618,839; see also EP 661,259 A1 published Jul. 5, 1995. The above-mentioned U.S. patent is herein incorporated by reference in its entirety.
In another aspect the present invention provides a novel series of substituted (5,6)-dihydronaphthalenyl compounds which are also potent retinoid antagonists. These compounds are useful as antiinflammatory agents for chronic skin inflammatory diseases such as psoriasis and atopic dermatitis, as agents for the treatment of rheumatic diseases such as rheumatoid arthritis, as antitumor agents for the treatment of various tumors as well as non-malignant proliferative skin conditions and as agents for the minimization or prevention of post-surgical adhesion formation.
BACKGROUND OF THE INVENTION
Retinoic acid and its natural and synthetic analogs exert a wide array of biological effects. They have been shown to affect cellular growth and differentiation and are promising drugs for the treatment of several cancers.
U.S. Pat. No. 5,618,839 and EP 661,259 A1 published Jul. 5, 1995 disclose a series of substituted (5,6)-dihydronapthalenyl compounds of the formula
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
X is —O—CO—, —NH—CO—, —CS—NH—, —CO—O—, —CO—NH—, —COS—, —SCO—, —SCH
2
—, —CH
2
—CH
2
—, —C≡—C—, —CH
2
—NH—, —COCH
2
—, —NHCS—, —CH
2
S—, —CH
2
O—, —OCH
2
—, —NHCH
2
— or —CR
5
═CR
6
—;
R
m
and R
k
are independently hydrogen, halogen, C
1-6
alkyl, hydroxy, C
1-6
-alkyloxy or nitro;
n is zero or one;
R
4
is —(CH
2
)
t
—Y, C
1-6
alkyl, or C
3-6
cycloalkyl;
R
1
is —CO
2
Z, C
1-6
alkyl, CH
2
OH, —CONHR
y
, or CHO;
R
2
and R
3
are independently hydrogen or C
1-6
alkyl;
R
a
and R
b
are independently hydrogen or C
1-6
alkyl; but when n is one, R
a
and R
b
together can form a radical of the formula
Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C
1-6
alkyl or halogen;
Z is hydrogen or C
1-6
alkyl;
R
5
, R
6
and R
y
are independently hydrogen or C
1-6
alkyl; and
t is zero to six.
These compounds are reported to have retinoid-like activity and to be useful for preventing and/or treating various skin disorders such as acne, psoriasis and damage from irradiation, for treatment of various tumors and non-malignant proliferative skin diseases and for treatment of rheumatic diseases such as rheumatoid arthritis.
The present inventors have discovered that certain compounds included within the scope of EP 661,259A1 and U.S. Pat. No. 5,618,839 are retinoid antagonists, i.e., they bind to all three RAR retinoic acid receptor subtypes (&agr;, &bgr; and &ggr;) but do not activate at least two of the three subtypes when tested in a standard transactivation assay. These retinoid antagonist compounds have the general formula
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
X is —O—CO—, —NH—CO—, —CS—NH, —CO—O—, —CO—NH—, —COS—, —SCO—, —SCH
2
—, —CH
2
—CH
2
—, —C≡C, —CH
2
—NH—, —COCH
2
—, —NHCS—, —CH
2
S—, —CH
2
O—, —OCH
2
—, —NHCH
2
— or —CR
5
═CR
6
—;
R
m
and R
k
are independently hydrogen, halogen, C
1-6
alkyl, hydroxy, C
1-6
alkyloxy or nitro;
n is zero or one;
R
4
is —(CH
2
)
t
—Y;
R
1
is —CO
2
Z, —C
1-6
alkyl, CH
2
OH, —CONHR
y
or CHO;
R
2
and R
3
are independently hydrogen or C
1-6
alkyl;
R
a
and R
b
are independently hydrogen or C
1-6
alkyl; but when n is one, R
a
and R
b
together can form a radical of the formula
Y is phenyl or naphthyl and both radicals can be optionally substituted with one to three same or different C
1-6
alkyl or halogen groups;
Z is hydrogen or C
1-6
alkyl;
R
5
, R
6
and R
y
are independently hydrogen or C
1-6
alkyl; and
t is zero to six.
U.S. Pat. No. 5,534,261 discloses that retinoids, particularly all-trans retinoic acid, can be used to minimize or prevent adhesion formation following surgery. There is no illustration or suggestion, however, that a retinoid antagonist compound would have this same utility.
Published patent application WO 97/09297 discloses retinoid antagonist compounds of the general formula
wherein X is S, O or NR
1
where R
1
is H or alkyl of 1-6 carbons, or X is [C(R
1
)
2
]
n
where R
1
is independently H or alkyl of 1 to 6 carbons, and n is 0, 1 or 2;
R
2
is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF
3
, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R
3
is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is 0, 1, 2 or 3;
o is 0, 1, 2 or 3;
Z is —C≡C—,
—N═N—,
—N═CR
1
—,
—CR
1
═N,
—(CR
1
═CR
1
)
n′
where n′ is 0 or an integer of 1-5,
—CO—NR
1
—,
—CS—NR
1
—,
—NR
1
—CO,
—NR
1
—CS,
—COO—,
—OCO—,
—CSO—, or
—OCS—;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R
2
groups, or
when Z is —(CR
1
═CR
1
)
n′
and n′ is 3, 4 or 5, then Y represents a direct valence bond between said (CR
1
═CR
1
)
n′
group and B;
A is (CH
2
)
q
where q is 0 or an integer of 1-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR
8
, CONR
9
R
10
, —CH
2
OH, —CH
2
OR
11
, CH
2
OCOR
11
, CHO, CH(OR
12
)
2
, CHOR
13
O, —COR
7
, CR
7
(OR
12
)
2
, CR
7
OR
13
O, or tri-lower alkylsilyl, where R
7
is an alkyl, cycloalkyl or alkenyl group having 1-5 carbons, R
8
is an alkyl group of 1 to 10 carbons, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R
8
is phenyl or lower alkylphenyl, R
9
and R
10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R
11
, is lower alkyl, phenyl or lower alkylphenyl, R
12
is lower alkyl, and R
13
is a divalent alkyl radical of 2-5 carbons; and
R
14
is (R
15
)
r
-phenyl, (R
15
)
r
-naphthyl or (R
15
)
r
-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is 0 or an integer of 1-5; and R
15
is independently H, F, Cl, Br, I, NO
2
, N(R
8
)
2
, N(R
8
)COR
8
, NR
8
(CON(R
8
)
2
, OH, OCOR
8
, OR
8
, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 2 to 10 carbons and 1 to 3 double bonds, alkynyl group having 2-10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.
Also disclosed in this publication as retinoid antagonist compounds are compounds of the general formula
wherein X is S, O or NR
1
where R
1
is H or alkyl of 1-6 carbons, or
X is [C(R
1
)
2
]
n
, where R
1
is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
R
2
is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF
3
, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R
3
is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-3;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R
2
groups;
A is (CH
2
)
q
where q is 0-5, lower branche

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