Compounds having retinoid-like activity

Details Compounds having retinoid-like activity Compounds having retinoid-like activity

2002-02-13

2004-11-30

Richter, Johann (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S569000, C560S056000, C562S466000

Reexamination Certificate

active

06825233

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compounds having retinoid-like activity. More specifically, the compounds of the present invention are useful for preventing and/or treating various skin disorders, such as, but not limited to, acne, psoriasis and damage from irradiation. Further, they have antitumor and antiarthritic activities.
BACKGROUND
Retinoic acid and its natural and synthetic analogues (retinoids) 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. See, for example, Roberts, A. B. and Sporn, M. B. in “The Retinoids,” Sporn, et al. eds, 1984, 2, pp. 209-286, Academic Press, New York; Lippman, et al.,
Cancer Treat. Rep.,
1987, 71, p. 391; ibid., p. 493; Hong et al.,
N. Engl. J. Med.,
1990, 323, p. 795; Huang, M. et al.,
Blood,
1988, 72, p. 567.
Retinoids have also been shown to be useful in treating rheumatic diseases. See, e.g. Coffey et al.,
Retinoids as Potential Antirheumatic Agents, Chemistry and Biology of Synthetic Retinoids
, pp 520-537, CRC Press Inc., M. I. Dawson and W. H. Okamura Ed.(1990).
A few retinoids are already in clinical use in the treatment of dermatological diseases such as acne and psoriasis. For example, isotretinoin is used clinically for oral therapy of severe acne, and etretinate is particularly useful in the treatment of psoriasis. See, e.g., Orfanos et al., Drugs, 1987, 34, pp.459-503.
Other examples of retinoid compounds include arotinoid (formula II) and retinobenzoic acid (formula III), wherein Q equals —NHCO—, —CONH—, —COCH═CH—, —CH═CHCO—, —COCH
2
—, and the like. See, e.g. Loeliger, et al.
Eur. J. Med. Chem.
1980, 15, pp. 9-15; Kagechika, H. et al., J. Med. Chem., 1988, 31, No. 11, pp. 2182-2192.
Other compounds that have been reported include:
1. European 708,100 (Apr. 24, 1996), to C.I.R.D., covering the following structure:
wherein R, R′ and R″ are as defined therein.
2. European 709,382 (May 1, 1996), to C.I.R.D, covering the following structure:
wherein R is as defined therein.
The compounds of the instant invention are distinguished from those above by the presence of a 2-atom “linker” joining the two phenyl rings, in contrast to the 1-atom or 3-atom linkers shown, and by the difference in the tricyclic rings. The compounds of the instant invention contain a tricyclic fused ring system with two optionally substituted aromatic rings, rather than the tetracyclic tetrahydro-methanodibenzofuran fused ring system in the compounds shown above.
SUMMARY OF THE INVENTION
The present invention is directed to a compound having formula I:
or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, wherein
R
a
and R
b
are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, substituted amino, mercapto, polyfluoroalkyl, C
1-6
alkyl, substituted C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, formyl, carboxyl, aryl or heteroaryl;
Linker is selected from the group consisting of C
2
alkyl, C
2
alkenyl, C
2
alkynyl, —C(═O)—NH—, —NH—C(═O)—, —CH
2
O—, —O—C(═O)—, —C(═S)—NH—, —C(═O)—O—, —C(═O)—S—, —S—C(═O)—, —S—CH
2
—, —CH
2
—NH—, —C(═O)—CH
2
—, —NH—C(═S)—, —CH
2
S—, —OCH
2
—, —NHCH
2
;
X is O, S, —C(R
1
)
2
—, C═O, —C(R
1
)
2
Y— or —YC(R
1
)
2
—, wherein Y is selected from the group consisting of O, S and C(R
2
)
2
,wherein R
1
and R
2
are, independently, hydrogen or methyl; and
Z is hydrogen or C
1-6
alkyl.
In some embodiments, R
a
and R
b
are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, mercapto, CF
3
, C
1-6
alkyl, halosubstituted C
1-6
alkyl, hydroxy-substituted C
1-6
alkyl, aminosubstituted C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, formyl, carboxyl, mono- or di-C
1-6
alkyl-substituted amino, aryl or heteroaryl;
Linker is selected from the group consisting of —CH═CH—, —C≡C—, —C(═O)—NH—, —NH—C(═O)—, —CH
2
O—, —O—C(═O)—, —C(═S)—NH—, —C(═O)—O—, —C(═O)—S—, —S—C(═O)—, —S—CH
2
—, —CH
2
—CH
2
—, —CH
2
—NH—, —C(═O)—CH
2
—,—NH—C(═S)—, —CH
2
S—, —OCH
2
—, —NHCH
2
or —CRc═CRd-, wherein Rc and Rd are independently hydrogen or C
1-6
alkyl;
X is O, S, —C(R
1
)
2
—, C═O, —C(R
1
)
2
Y— or —YC(R
1
)
2
—, wherein Y is selected from the group consisting of O, S and C(R
2
)
2
and R
1
and R
2
are, independently hydrogen or methyl; and Z is hydrogen or C
1-6
alkyl.
In some embodiments, X is —C(R
1
)
2
Y— or —YC(R
1
)
2
—, wherein Y is selected from the group consisting of O, S and C(R
2
)
2
and R
1
and R
2
are, independently, hydrogen or methyl; and Z is hydrogen or C
1-6
alkyl.
In some embodiments, X is represented by O, S, C(R
1
)
2
, or C═O, wherein R
1
is hydrogen or methyl, resulting in a five-membered ring.
In some embodiments, the present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula I and a pharmaceutically acceptable carrier therefor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds represented by formula I
or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, wherein
R
a
and R
b
are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, mercapto, CF
3
, C
1-6
alkyl, halosubstituted C
1-6
alkyl, hydroxy-substituted C
1-6
alkyl, aminosubstituted C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, formyl, carboxyl, mono- or di-C
1-6
alkyl-substituted amino, aryl or heteroaryl;
Linker is selected from the group consisting of —CH═CH—, —C≡C—, —C(═O)—NH—, —NH—C(═O)—, —CH
2
O—, —O—C(═O)—, —C(═S)—NH—, —C(═O)—O—, —C(═O)—S—, —S—C(═O)—, —S—CH
2
—, —CH
2
—CH
2
—, —CH
2
—NH—, —C(═O)—CH
2
—, —NH—C(═S)—, —CH
2
S—, —OCH
2
—, —NHCH
2
— or CRc═CRd-, where Rc and Rd are independently hydrogen or C
1-6
alkyl;
X is —C(R)
2
Y— or —YC(R)
2
—, where Y is selected from the group consisting of O, S and C(R)
2
; or
X is selected from the group consisting of O, S, C(R)
2
, and C═O (5-membered ring), wherein R is hydrogen or methyl; and
Z is hydrogen or C
1-6
alkyl.
Definitions
As used herein, the term “alkyl” includes cyclic, branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, cyclopropylmethyl, octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclododecyl, adamantyl, and the like. Alkyl groups may be substituted with substituents, such as, halo, amino, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO
2
NH
2
, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH
2
, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term “polyfluoroalkyl” means that at least one hydrogen atom in an alkyl side-chain is replaced by a fluorine atom.
The term “amino”, herein alone or as part of another group refers to —NH
2
. An “a

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