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. ##STR2##
U.S. Pat. No. 5,648,514 describes a series of substituted (5,6)-dihydronaphthalene derivatives having retinoid-like biological activity of the formula ##STR3##
wherein
R.sub.1 is hydrogen or alkyl of 1 to 10 carbons; PA1 R.sub.2 and R.sub.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; PA1 m is an integer having the value of 0-3; PA1 o is an integer having the value 0-3; PA1 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.sub.2 groups; PA1 A is (CH.sub.2).sub.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; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, CH.sub.2 OH, CH.sub.2 OR.sub.11, CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or trilower alkylsilyl, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.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.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.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.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons; and PA1 R.sub.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.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl, C.sub.1 -C.sub.10 alkyl, naphthyl-C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 -alkenylphenyl having 1 to 3 double bonds, C.sub.1 -C.sub.10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C.sub.1 -C.sub.10 alkenyl having 1 to 3 double bonds, phenyl-C.sub.1 -C.sub.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.sub.14, CN, CON(R.sub.1).sub.2, (CH.sub.2).sub.p CO.sub.2 R.sub.8 where p is an integer between 0 to 10, or R.sub.22 is aminoalkyl or thioalkyl of 1 to 10carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C.sub.1 to C.sub.10 alkyl group and having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R.sub.22 is represented by (CH.sub.2).sub.p XR.sub.1 or by (CH.sub.2).sub.p NR.sub.1 R.sub.2 ; where X is O or S, the R.sub.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.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl-C.sub.1 -C.sub.10 alkyl, or naphthyl-C.sub.1 -C.sub.10 alkyl. PA1 X.sub.1 is [C(R.sub.1).sub.2 ].sub.n where R.sub.1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2; ##STR5## PA1 R.sub.2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; PA1 R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F; PA1 m is an integer having the value of 0 to 3; PA1 o is an integer having the value of 0 to 3; PA1 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.sub.2 groups, or PA1 when Z is --(CR.sub.1.dbd.CR.sub.1).sub.n' -- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR.sub.2.dbd.CR.sub.2).sub.n' group and B; PA1 A is (CH.sub.2).sub.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; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, CH.sub.2 OH, CH.sub.2 OR.sub.11, CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or Si(C.sub.1-6 alkyl).sub.3, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.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.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.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.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons; and PA1 R.sub.14 is (R.sub.15).sub.r -substituted alkyl of 1-6 carbons, (R.sub.15).sub.r -substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R.sub.15).sub.r -substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R.sub.15).sub.r -phenyl, (R.sub.15).sub.r -naphthyl, or (R.sub.15).sub.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 PA1 R.sub.15 is independently H, F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8, NR.sub.8 CON(R.sub.8).sub.2, OH, OCOR.sub.8, OR.sub.8, CN, COOH, COOR.sub.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, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons.
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.sup.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 ##STR4##
wherein
Two of the agents included within the scope of WO 97/48672 are the compounds having the structural formula I and II ##STR6##
These compounds show very potent activity against dermatological diseases. Unexpectedly, the present inventors have discovered that these compounds show also a substantially reduced irritancy profile. While WO 97/48672 generally discloses these compounds as having retinoid-like activity as agents for treating skin-related diseases, there is no specific disclosure of compounds I and II or their unexpectedly low-irritation profile, which are the subject of the present invention.
In another aspect, the present inventors have also found that compounds I and II are effective tumor inhibiting agents, and thus are useful in human and/or veterinary medicine. WO 97/48672 generally discloses these compounds having retinoid-like activity and as agents for preventing or treating cancerous and precancerous conditions. The assay supporting this statement is a measure of the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA) induction of ornithine decarboxylase (ODC) in mouse epidermis by certain compounds disclosed in application. TPA-induced ODC activity is known to occur at pre-malignant stages. Although the correlation of this assay with cellular anti-proliferation is well established, there is no evidence in the WO 97/48672 patent application of in vivo inhibition of fully established tumor growth by the disclosed compounds. The present inventors have found that the anti-proliferation activity of the compounds of this invention is translated to a potent inhibition of established tumor growth, equivalent to the most potent antitumor agents such as doxorubicin.