5,6-dihydronaphthalenyl derivatives having retinoid-like...

Details 5,6-dihydronaphthalenyl derivatives having retinoid-like... 5,6-dihydronaphthalenyl derivatives having retinoid-like...

1999-09-16

2001-02-27

Woodward, Michael P. (Department: 1631)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06194601

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a series of 5,6-dihydronaphthalenyl derivatives which exhibits unexpectedly good therapeutic indexes in the treatment of skin disorders such as, but not limited to, acne and damage from age or irradiation and chronic skin inflammatory diseases such as psoriasis and atopic dermatitis. The compounds are also useful as antitumor agents for the treatment of, but not limited to, breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, blood and lymphatic system cancers.
BACKGROUND OF THE INVENTION
Compounds which have retinoid-like activity are well known in the art and are described in numerous patents and scientific publications. It is generally accepted that pharmaceutical compositions having a retinoid-like compound are useful for treating and/or preventing skin-related diseases such as, but not limited to acne, actinic keratosis, psoriasis, eczema and atopic dermatitis. It is also known that they are useful to reverse or treat the effects of age and photo damage to the skin and to prevent and/or treat cancerous or precancerous conditions.
One of the most significant drawbacks associated with the use of retinoids, especially in the topical treatment of dermatological diseases, is local irritation. Retinoids or compounds having retinoid-like activity that combine good topical efficacy and cutaneous tolerability are not very common. Recently, the new drug adapalene (“Differin”, CIRD Galderma) was reported to offer these favorable characteristics and it has been launched in several countries as a water-based gel formulation.
U.S. Pat. No. 5,648,514 describes a series of substituted (5,6)-dihydronaphthalene derivatives having retinoid-like biological activity of the formula
wherein
R
1
is hydrogen or alkyl of 1 to 10 carbons;
R
2
and R
3
are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus;
m is an integer having the value of 0-3;
o is an integer having the value 0-3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R
2
groups;
A is (CH
2
)
n
where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, 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 trilower alkylsilyl, where R
7
is an alkyl, cycloalkyl or alkenyl group containing 1 to 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 divalent alkyl radical of 2-5 carbons; and
R
22
is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C
1
-C
10
-alkylphenyl, naphthyl, C
1
-C
10
-alkylnaphthyl, phenyl, C
1
-C
10
alkyl, naphthyl-C
1
-C
10
alkyl, C
1
-C
10
-alkenylphenyl having 1 to 3 double bonds, C
1
-C
10
-alkynylphenyl having 1 to 3 triple bonds, phenyl-C
1
-C
10
alkenyl having 1 to 3 double bonds, phenyl-C
1
-C
10
alkynyl having 1 to 3 triple bonds, hydroxyalkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where the acyl group is represented by COR
14
, CN, CON(R
1
)
2
, (CH
2
)
p
CO
2
R
8
where p is an integer between 0 to 10, or R
22
is aminoalkyl or thioalkyl of 1 to 10carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C
1
to C
10
alkyl group and having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R
22
is represented by (CH
2
)
p
XR
1
or by (CH
2
)
p
NR
1
R
2
; where X is O or S, the R
14
group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C
1
-C
10
-alkylphenyl, naphthyl, C
1
-C
10
-alkylnaphthyl, phenyl-C
1
-C
10
alkyl, or naphthyl-C
1
-C
10
alkyl.
That disclosure is specifically limited to the ethynyl linker. The two compounds disclosed in the present invention have the ethenyl linker. The substituent in position 8 (R
22
) is defined as being, among others, an alkenyl group of 2 to 10 carbons and having 1 to 3 double bonds or an alkynyl group having 2 to 10 carbons and 1 to 3 triple bonds. This general definition does not specify the direct attachment to the dihydronaphthalene nucleus at position 8.
Published PCT patent application WO 97/48672 discloses a series of 5,6-dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like activity of the formula
wherein
X
1
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 to 3;
o is an integer having the value of 0 to 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, 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
2
═CR
2
)
n′
group and B;
A is (CH
2
)
q
where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, 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 Si(C
1-6
alkyl)
3
, where R
7
is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R
8
is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl 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 divalent alkyl radical of 2-5 carbons; and
R
14
is (R
15
)
r
-substituted alkyl of 1-6 carbons, (R
15
)
r
-substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R
15
)
r
-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (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 an integer having the values of 0-5, 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, COOH, COOR
8
and alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, a

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