APOPTOSIS INDUCING ADAMANTYL DERIVATIVES AND THEIR USAGE AS ANTI-CANCER AGENTS

TECHNICAL FIELD OF THE INVENTION

The invention relates to the discovery that specif¬ ic adamantyl or adamantyl group derivative containing retinoid related compounds induce apoptosis of cancer cells and therefore may be used for the treatment of cancer, including advanced cancers. Also, the present invention relates to novel adamantyl or adamantyl group derivative containing retinoid related compounds and their use for the treatment and/or prevention of cancer, keratinization disorders, dermatological conditions and other therapies.

BACKGROUND OF THE INVENTION

Solid tumors are the leading cause of death attrib¬ utable to cancers worldwide. Conventional methods of treating cancer include surgical treatments, the admin- lstration of chemotherapeutic agents, and recently im¬ mune based treatments which typically involve the admin¬ istration of an antibody or antibody fragment which may be conjugated to a therapeutic moiety such as a radio- nuclide. However, to date, such treatments have been of limited success.

Surgical treatments are generally only successful if the cancer is detected at an early stage, i.e., be¬ fore the cancer has infiltrated major organs and surgery becomes non-feasible. Chemotherapeutic treatments

available today are also of limited usefulness because of their non-selective killing and/or toxicity to most cell types. Also, many tumor cells eventually become resistant against the chemotherapeutic agent, thus mak- ing treatment of solid tumors and other tumors non-fea¬ sible. For example, persons treated with cisplatin often develop tumors which are cisplatin resistant. Immune based treatments are also subject to numerous problems including difficulty in targeting antibodies to desired sites, e.g., solid tumors, and host immune reac¬ tions to the administered antibody, attributable to the fact that to date most therapeutic antibodies have been of murine origin.

The usage of retinoids for the prevention of cancer has also been reported. In contrast to most convention¬ al chemotherapeutic agents, retinoids function via spe¬ cific signal transduction pathways, activating defined receptors in the cell nucleus. These receptors, the RARs, and the RXRs bind to specific DNA sequences, reti- noic acid response elements, or RAREs. In addition, retinoids interact with other transcription factors, in particular the activator protein-1 {AP-1) .

It is believed that the selective action of certain synthetic retinoids is based on the ability of these molecules to selectively activate subclasses of RARs and/or RXRs in the context of specific DNA sequences and/or proteins. Because of this specificity, not all retinoids possess the same activities. Indeed, thou¬ sands of different retinoids have been synthesized with the object being the identification of retinoids having optimal therapeutic activity.

To date, most retinoids have been found to inhibit tumor progression or cell proliferation of certain can¬ cers, but do not directly eliminate cancer cells. Con- sequently, retinoids have been considered predominantly

for the prevention of cancer but not for direct treat¬ ment .

One special class of retinoids or retinoid related compounds comprises adamantyl retinoid derivatives. These compounds are aromatic heterocyclic retinoids which contain an adamantyl group or an adamantyl group derivative. In contrast to normal retinoids such as retinoic acid (all -trans, 9-cis or 13-cis) and their synthetic analogs and derivatives, the adamantyl reti- noid derivatives exhibit enhanced activity against spe¬ cific tumor cells both in vit o and in vivo .

Retinoids also comprise known usage in the treat¬ ment of keratinization disorders and other dermatologi¬ cal diseases. For example, the use of retinoic acid, vitamin D or analogues thereof for the topical treatment of various dermatological diseases and in the cosmetic field is well known.

However, notwithstanding the large number of reti¬ noids which have been reported, the identification of retinoids or retinoid related compounds having enhanced properties, in particular enhanced therapeutic activity, constitutes a significant need in the art.

BRIEF DESCRIPTION AND OBJECTS OF THE INVENTION It is an object of the invention to identify spe¬ cific retinoid or retinoid related compounds having enhanced properties, in particular anti-cancer activity.

It is a more specific object of the invention to identify specific classes of adamantyl or adamantyl derivative containing retinoid related compounds having anti-cancer activity, preferably characterized by the ability to induce apoptosis of cancer cells.

It is an even more specific object of the invention to use adamantyl retinoid related compounds of the fol¬ lowing formulae for the treatment of cancer:

with the proviso that such compound is not an RAR-γ receptor-specific agonist ligand (defined infra.) and, in which is independently -CH ₂ -O- -S- -Ξ0- or -SO,

X is a radical selected from among those of the following formulae (i) - (iii) :

wherein

Y is a radical -CO-V- ^■ CH=CH-, -CH ₃ C=CH-

-CH=CCH ₃ -, or

V is an oxygen atom (-0-) , an aza radical (-NH-) , a radical -CH=CH- or -C=C-;

Z is a radical -CH- and Z' is an oxygen atom, or

Z is a nitrogen atom (N) and Z' is an aza radical (-NH-) ;

R ₁ is a hydrogen atom, a halogen, or a lower alkyl radical ;

R' _x is a hydrogen atom, a halogen, or a lower alkyl radical ; R ₂ is a hydroxyl radical, a halogen, an alkyl radi¬ cal, optionally substituted by one or more hydroxyl or acyl groups, an- alkoxyl radical, optionally substituted

by one or more hydroxyl, alkoxyl or aminocarbonyl groups, and/or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen; j is a hydrogen atom, a halogen, an hydroxyl radi¬ cal, an alkyl radical, or an alkoxyl radical;

R ₂ and R ₃ can form together a radical -0-CH ₂ -0-;

R ₄ is a hydrogen atom, an alkyl radical, an alkoxyl radical or a halogen; R ₅ is a radical -CO-R ₁₀ , an alkyl radical, optional¬ ly substituted by one or more hydroxyl groups, or a halogen;

R ₆ is a hydrogen atom, a halogen atom, an alkoxyl radical, or hydroxyl group; R ₇ is a hydrogen atom or a halogen;

R ₈ is a hydrogen atom, a halogen atom or an alkyl radical;

R ₉ is a hydrogen atom, a hydroxyl radical or a halogen atom; R ₁₀ is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r", wherein r' and r" represent a hydrogen atom, an optionally substituted ammoalkyl radical, a mono- or polyhydroxyalkyl radical, an option¬ ally substituted aryl radical or an amino acid or sugar residue or alternatively, taken together, form a hetero- cycle; or a compound having generic formula (III) :

wherein R' _lf R _l R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and W are as defined for compounds of formula (I) ; or a compound having generic formula:

wherein R' _lf R ₁₇ R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and W are as de¬ fined for compounds of formula (I) . For compounds hav¬ ing formula IV, R ₆ is preferably not hydrogen.

It is a further object of the invention to provide novel classes of adamantyl and adamantyl derivative containing retinoids having desirable pharmacological and/or cosmetic properties.

It is a more specific object of the invention to provide novel classes of adamantyl and adamantyl deriva¬ tive containing retinoids having desirable pharmacologi-

cal and/or cosmetic properties having the formula set forth below:

wherein is independently -CH ₂ -, -O- , -S-, -SO- or -S0 ₂ -

X is a radical selected from among those of the following formulae (i)-(iii)

wherein

Y is a radical -CO-V-, -CH=CH-, -CH ₃ =CH-,

V is an oxygen atom (-0-) , an aza radical (-NH-) , a radical -CH=CH- or -C≡C- ;

Z is a radical -CH- and Z' is an oxygen atom, or

Z is a nitrogen atom (N) and Z' is an aza radical (-NH-) ; R _j is a hydrogen atom, a halogen, or a lower alkyl radical;

R'j is a hydrogen atom, a halogen, or a lower alkyl radical;

R ₂ is a hydroxyl radical, a halogen atom, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substi¬ tuted by one or more hydroxyl, alkoxyl or aminocarbonyl groups, and/or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen;

R ₃ is a hydrogen atom, a halogen, an hydroxyl radi¬ cal, an alkyl radical, or an alkoxyl radical;

R ₂ and R ₃ can form together a radical -0-CH ₂ -0-;

R ₄ is a hydrogen atom, an alkyl radical, an alkoxyl radical or a halogen;

R^ is a radical -CO-R ₁₀ , an alkyl radical, optional¬ ly substituted by one or more hydroxyl groups, or a halogen;

R ₆ is a hydrogen atom, a halogen atom or an alkoxyl radical, or hydroxyl group;

R ₇ is a hydrogen atom or a halogen; R ₈ is a hydrogen atom, a halogen atom or an alkyl radical ;

R ₉ is a hydrogen atom, a hydroxyl radical or a halogen atom;

R ₁₀ is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r", wherein r' and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono- or polyhydroxyalkyl radical, an option¬ ally substituted aryl radical, or an amino acid or sugar residue, or alternatively, taken together, form a het- erocycle, their pharmaceutically acceptable salts, their optical and/or geometrical isomers thereof; with the proviso that at least two of R ₂ , R ₃ and R ₄ cannot be hydrogen and the further proviso that R ₂ and R ₃ cannot together form -0-CH ₂ -0-, or is a compound of general formula (I) ;

wherein V, , R-' , R _1# R ₂ , R ₃ , R ₄ , R,, R ₆ , R ₇ , R _B , R ₉ , R ₁₀ , X, Y, Z' , Z are as defined supra , with the proviso that at least one of is -0-, -S-, -SO-, or -S0 ₂ -, and/or at least one of R _λ and R _x ' is halogen or a lower alkyl radical, and more preferably at least one is -O- and/- or R _j is a lower alkyl radical and/or R ₁ ' is a lower alkyl radical; or is a compound of generic formula (I) ;

herein V, , R.' . R., R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , Y, Z and Z' are as defined supra , with the proviso that R _s is -CO-R ₁₀ and R ₁₀ is a radical of formula -Nr'r", wherein one of r' and r" is hydrogen, and the other is an optionally substituted aminoalkyl radical or alterna¬ tively r' and r" , together, form a heterocycle, prefera¬ bly a piperazmo or a homolog thereof; where preferably X has formula (n) and/or R ₈ is preferably hydrogen and/or R ₉ is preferably hydrogen. or is a compound of formula (III) :

wherein R' _lf R , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and W are as defined for compounds of formula (I) .

It is another object of the invention to provide therapeutic and/or cosmetic compositions containing such novel retinoid compounds.

It is a further object of the invention to provide therapeutic/prophylactic/cosmetic methods involving the administration of a novel adamantyl or adamantyl deriva¬ tive compound according to the invention. Such methods will include known usages of retinoid compounds, m particular, usage for treatment/prophylaxis of kerato- lytic associated disorders associated with differentia¬ tion and/or proliferation and other dermal related dis¬ orders .

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 compares the activity of selected adaman¬ tyl retinoids according to the invention and all-trans- retinoic acid against human cancer cell lines. Figure 2 compares the activity of selected adaman¬ tyl retinoids according to the invention and all-trans- retinoic acid against a human non-small lung carcinoma cell line.

Figure 3 compares the activity of selected adaman- tyl retinoids according to the invention and all-trans- retinoic acid against human prostate adenocarcinoma, human metastatic prostate adenocarcinoma, and human prostate carcinoma cell lines.

Figure 4 compares the activity of selected adaman- tyl retinoids according to the invention and all-trans- retinoic acid against a human liver cancer cell line. Figure 5 shows the effect of 6- [3- (1-adamantyl) - 4 , 5-methylenedioxyphenyl] -2-naphthoic acid in a human pancreatic cancer BxP-3 animal model.

DETAILED DESCRIPTION OF THE INVENTION

Toward that end, the present inventors, quite sur¬ prisingly, have discovered that specific adamantyl reti¬ noid derivatives induce apoptosis of cancer cells. This is highly unexpected as in contrast to most conventional chemotherapeutic agents, retinoids and also most known adamantyl retinoids, function via specific signal trans- duction pathways, activating defined receptors in the cell nucleus. By contrast, it has been unexpectedly discovered that the specific adamantyl retinoid deriva- tives which are disclosed infra induce cancer cell apoptosis and therefore may be used to eradicate cancer cells. Consequently, these retinoids may be used for

the direct treatment of cancers, including advanced cancers.

More specifically, the present invention relates to the use of adamantyl retinoid derivatives having the following formula (I) for inducing apoptosis:

wherein is independently -CH ₂ - -0- ^• S- ^■ SO- or •SO,

X is a radical selected from among those of the following formulae (i)-(iii)

wherein

Y is a radical -CO-V-, -CH=CH-, -CH ₃ C=CH-,

;

V is an oxygen atom (-0-) , an aza radical (-NH-) , a radical -CH=CH- or -CaC-;

Z is a radical -CH- and Z' is an oxygen atom, or

Z is a nitrogen atom (N) and Z' is an aza radical (-NH-) ; _x is a hydrogen atom, halogen atom or a lower alkyl radical;

R' _x is a hydrogen atom, halogen atom or a lower alkyl radical; R ₂ is a hydroxyl radical, halogen atom, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, -an alkoxyl radical, optionally substi-

tuted by one or more hydroxyl, alkoxyl or aminocarbonyl groups, and/or optionally interrupted by one or more oxygen atoms, an acyl radical or an aminocarbonyl radi¬ cal, or a halogen; R ₃ is a hydrogen atom, halogen atom, a hydroxyl radical, an alkyl radical, or an alkoxyl radical;

R ₂ and R ₃ can form together a radical -0-CH ₂ -0-;

R ₄ is a hydrogen atom, halogen atom, an alkyl radi¬ cal, or an alkoxyl radical; R ₅ is a radical -C0-R ₁₀ or an alkyl radical, option¬ ally substituted by one or more hydroxyl groups,

R ₆ is a hydrogen atom, a halogen atom, preferably fluorine, an alkoxyl radical, or a hydroxyl group;

R ₇ is a hydrogen atom or a halogen atom, preferably a fluorine atom;

R ₈ is a hydrogen atom, a halogen atom or an alkyl radical ;

R ₉ is a hydrogen atom, a halogen atom or a hydroxyl radical; R ₁₀ is a hydroxyl radical, an alkoxy radical, a formula -Nr'r", wherein r' and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substi¬ tuted aryl radical, or an amino acid or sugar residue, or alternatively, taken together, form a heterocycle, their pharmaceutically acceptable salts, or their opti¬ cal and/or geometrical isomers thereof, with the proviso that such compounds do not include RAR-γ receptor- specific agonist ligands. By RAR-γ receptor-specific agonist ligands in the subject application, it is intended ligands which pos¬ sess a dissociation constant for ligands of the type RAR-α which is at least 10 times greater than the disso¬ ciation constant of these ligands for receptors of the

type RAR-γ, and wherein such ligands further induce the differentiation of F9 cells.

All trans-retmoic acid and certain analogs thereof are known to be capable of inducing the differentiation of embryonic tetracarc oma F9 cells cultured m the presence of agonists of RARs receptors. Also, the se¬ cretion of plasmmogen activator is known to accompany this differentiation and is an indicator of the biologi¬ cal response of these cells to retinoids. (See Skin Pharmacol . , 3:256-267 (1994) .)

Methods for measuring these dissociation constants are known in the art. For example, suitable methods are disclosed in the following references which are incorpo¬ rated by reference herein. "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptors Subtypes", in Reti¬ noids, Progress Research and Clinical Applications, Chapter 19 (pp 261-267) , Marcel Dekker Inc., edited by Maria A. Livrea and Lester Packer; "Synthetic Retinoids: Receptor Selectivity and Biological Activity" , in Pharmacol . Skin, Basal, Karger, 1993, Vol. 5:117-127;

"Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors", in Skin Pharmacol . , Vol. 5:57-65 (1992) ; "Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-γ", in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pp 977-983; and "Selective High Affinity RAR-cv or RAR-β Retinoic Acid Receptor Ligands", in Molecular Pharmacology, Vol. 40:556-562. See, also WO 97/13505, which discloses methods for lden- tification of RAR-γ agonist ligands.

More preferably, the apoptosis inducing derivatives of formula (I) will have the formula (II) :

in which W, and R- are defined above, and wherein such compounds do not include RAR-γ receptor-specific agonist ligands.

In one preferred embodiment, at least two of the radicals W are -CH ₂ - . Still more preferably, all of the W radicals are -CH ₂ - . In another preferred embodiment, at least one of R _λ and R-' is a hydrogen atom. Still, more preferably, R _j and R _: ' are both hydrogen atoms.

According to the invention, lower alkyl radical refers to a radical having from 1 to 6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and hexyl radicals.

Alkyl radical refers to a radical having 1 to 20 carbon atoms, straight chain or branched, especially methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octa- decyl radicals.

Acyl radical refers to a radical having 1 to 20 carbon atoms, straight chain or branched, containing a CO group, such as acetyl or benzoyl . Alkoxy radical refers to a radical having 1 to 20 carbon atoms, straight chain or branched, containing an alkoxy group.

Sugar residue refers to a residue derived in par¬ ticular from glucose, galactose or mannose or alterna¬ tively from glucuronic acid.

Monohydroxyalkyl radical refers to a radical having 1 to 6 carbon atoms, especially a hydroxy ethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4- hydroxybutyl , 5-hydroxypentyl or 6-hydroxyhexyl radical.

Polyhydroxyalkyl radical refers to a radical having 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, espe- cially a 2,3 dihydroxypropyl, 2 , 3 ,4-trihydroxybutyl or 2,3 , 4, 5-tetrahydroxypentyl radical or the pentaerythri- tol residue.

Aryl radical refers to a phenyl radical optionally substituted by at least one halogen, a hydroxyl or a nitro functional group.

Aminoalkyl radical optionally substituted refers to an alkyl radical substituted by an amino residue, the amino residue may also be substituted by at least one alkyl radical, such as aminoethyl , methylaminoethyl, or dimethylaminoethyl radical.

Amino acid residue refers to a residue derived from any amino acid, such as lysine, glycine or aspartic acid.

Heterocycle preferably refers to a piperidino, morpholino, pyrrolidino, piperazine or homologs thereof, optionally substituted at the 4-position by a C _j -Cg alkyl radical or a mono- or polyhydroxyalkyl radical as de¬ fined above.

Some compounds having the above generic formulae and their preparation have been disclosed in the follow¬ ing patent and patent applications incorporated herein by reference in their entirety: U.S. 4,740,519; U.S. 4,920,140; U.S. 5,059,621; U.S. 5,260,295; U.S. 5,428,052; U.S. 4,717,720; U.S. 4,940,696; U.S. 5,183,889; U.S. 5,212,303; U.S. Re 34440; U.S.

4,927,928; U.S. 5,200,550; U.S. 5,332,856; U.S. 5,468,897; U.S. Patent No. 5,547,983; 1992; U.S. 5,476,860; U.S. 5,015,758; U.S. 5,183,889; FR 91 05394; French patent application No. 95 14260, filed on Decem¬ ber 1, 1995; and French patent application No. 95 14261, filed on December 1, 1995.

Also, the present invention provides specific novel classes of adamantyl retinoid derivatives having the generic formulae set forth below, or their pharmaceuti¬ cally acceptable salts, or optical and/or geometrical isomers thereof which induce apoptosis and/or which further comprise other desirable pharmacological proper¬ ties :

wherein R ' ^ R _{l t} R ₂ R, R. X and W are as defined supra , with the proviso that at least two of R ₂ , R ₃ and R ₄ are other than hydrogen; and with the further proviso that R ₂ and R ₃ cannot together form -0-CH ₂ -0-, or compounds of generic formula I, set forth below:

(I)

fined supra , except with the proviso that at least one of W is -O- , -S-, -SO- or -S0 ₂ and/or at least one of R ₁ and R ₁ ' is halogen or a lower alkyl radical, preferably, wherein at least one of W is

-O- and/or Rj is a lower alkyl radical and/or R _x ' is a lower alkyl radical, and/or also preferably wherein X comprises formula (ii) , and/or R _s is preferably hydrogen and/or R ₉ is hydrogen and/or R ₅ is -CO-R ₁₀ ; or compounds of generic formula I, set forth below:

wherein W, X, R _x ' , R _ι; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R _e , R ₉ , R ₁₀ , Y, V are as defined supra , except with the proviso that R _s is -CO-R ₁₀ , and R ₁₀ is a radical of formula Nr'r", wherein at least one of r' and r" is hydrogen and the

other is an optionally substituted aminoalkyl radical, or alternatively r' and r", taken together, form a het- erocycle, preferably a piperazino or a homolog thereof, preferably wherein X comprises formula (ii) and/or more preferably R ₈ is hydrogen and/or R ₉ is hydrogen. Also, preferred are compounds of formula (I) wherein R ₂ is an alkoxy radical or hydroxyl group and/or R ₃ is hydrogen and/or R ₄ is hydrogen and/or R ₂ and R ₃ together form -0-CH ₂ -0- _; or compounds of formula (III) :

wherein R'j, R _x , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ and W are as defined supra ;

A more specific subclass of compounds of formula (I) comprises compounds of formula (II) below:

wherein R , R _{l r} R ₂ , R ₃ , R ₄ , X and W are as defined above and at least two of R ₂ , R ₃ and R ₄ are not hydrogen, and wherein R ₂ and R ₃ cannot together form -0-CH ₂ -0; or com¬ pounds of formula (II) wherein R _b is -C-O-R ₁₀ , R ₁₀ is a radical of formula -Nr'r", wherein one of r' and r" is hydrogen and the other is an optionally substituted aminoalkyl radical, or alternatively r' and r" taken together form a heterocycle, preferably piperazino or a homolog thereof, and wherein preferably R _a is hydrogen and/or R ₉ is hydrogen; or compounds of formula (II) where at least one of W is -O- , -S-, -SO- or -S0 ₂ and/or at least one of R _x and R is halogen or a lower alkyl radical, wherein X preferably has formula (ii) , and more ^■ preferably R ₈ is hydrogen and/or R ₉ is preferably hydro- gen and/or R _s is -CO-R ₁₀ .

Also preferred are compounds of formula (II) where¬ in R ₂ is an alkoxy radical or hydroxyl group and/or R ₃ is hydrogen and/or R ₄ is hydrogen and/or R ₂ and R ₃ together form -0-CH ₂ -0. An even more specific subclass of novel retinoid related compounds of formula (II) comprises adamantyl retinoid related compounds having the generic formula set forth below.

R ₂ , R ₃ ,

R R ₇ , R ₈ , R ₉ and W are as defined supra , with the provi so that at least two of R, R ₃ and R ₄ are other than hydrogen, and with the further proviso that R ₂ and R ₃ cannot together form -0-CH ₂ -0-.

Preferred compounds of formula (V) comprise reti- noid related compounds wherein R _s is a hydroxycarbonyl radical, preferably -CO-R ₁₀ , and/or compounds wherein R ₂ is a hydroxyl radical, an alkoxyl radical, and/or R _β is hydrogen, and/or R ₉ is hydrogen and/or R ₃ is a hydroxyl radical or alkoxyl radical, and/or R ₄ is hydrogen or an alkyl radical .

Other preferred compounds of formula (V) include compounds wherein at least one of W is -O- , -S-, -SO- or -S0 ₂ - and/or at least one of R _α and R is halogen or a lower alkyl radical . The novel retinoid derivatives of the present in¬ vention can be synthesized by known methods for synthe¬ sizing retinoids such as are disclosed in the patents and applications incorporated by reference herein. Further, specific methods for the synthesis of the reti- noids of formula (V) are described below.

SCHEME I

According to synthetic Scheme I a halobenzene de¬ rivative (1) (see schematic of Scheme I infra) is cou¬ pled to a naphthyl halide or 2-naphthyl trifluorome- thanesulfonate (2) to form (3), e.g., through treatment of (1) in dry THF with butyl lithium at -78°C followed by zinc chloride, followed by (2) in the presence of nickel bis (diphenylphosphino) ethane dichloride. A ter¬ tiary ester or halide derived from an oxaadamantyl, adamantyl, thiaadamantyl or related molecule of formula (4) is then reacted with (3) in the presence of 0.1 to 1.3 molar equivalents of an appropriate acid (e.g., sulfuric acid or trifluoromethylsulfonic acid if X3 is acetoxy or mesyloxy) in a mixed solvent, preferably containing cyclohexane and either heptane, dichlorome- thane, or 1, 2-dichloroethane at a temperature between 25°C and 90°C.

Esters obtained in accordance with the above meth¬ ods wherein R ₅ is an ester group may be converted, ac- cording to known procedures, into various analogs which are the objects of meanings for the radical R ₅ . For example, such esters include saponified acids which can be transformed into acid chlorides which are easily converted into amides. Alternatively, such amides can be obtained by the direct action of amines on the esters obtained as described above. Moreover, the reduction of the esters, aldehydes or amides by an appropriate reduc¬ ing agent (for example lithium aluminohydride) further permits the production of the corresponding alcohols and amines.

The subject synthetic method is especially preferred if R ₂ is an alkoxy or hydroxy group and R ₅ , R ₈ and R ₉ are not strongly electron-donating groups such as alkoxy, hydroxy or alkamino, and all of the functionali- ties other than R' _ι; R _x , and W are compatible with butyl

lithium or can be used in a protected form that is com¬ patible with butyl lithium.

SCHEME I

SCHEME II

A second method (Scheme II) for synthesizing the novel adamantyl retinoids of formula (V) is shown Scheme II. This method comprises reacting a tertiary ester or halide derived from an oxaadamantyl, adamantyl, thiaada antyl or related molecule of formula (3) with a halobenzene derivative (1) the presence of 0.1 to 1.3 molar equivalents of an appropriate acid (sulfuπc acid or trifluoromethylsulfonic acid if X ₃ is acetoxy, hydroxy or mesyloxy) m a mixed solvent containing cyclohexane and either heptane, dichloromethane, or 1,2-dιchlor- oethane at a temperature between 25 and 90°C. The re¬ sulting adduct (6) is then coupled to the 2-naphthyl halide or 2-naphthyl trifluoromethanesulfonate (2) to form (5) , e.g, through treatment of (6) in dry THF with butyl lithium at -78°C followed by zinc chloride, fol¬ lowed by (2) in the presence of nickel bis (diphenylphos- phino)ethane dichloride.

Esters obtained m accordance with the methods described above wherein R ₅ is an ester group may be converted, according to known procedures, into various analogs which are provided for based on the definition of the R ₅ radical in generic formula (V) . For example, such esters include saponified acids which can be trans- formed into acid chlorides which turn are easily converted into amides. Alternatively, such amides can be obtained by the direct action of amines on the esters obtained earlier. The reduction of the esters, alde¬ hydes or amides by an appropriate reducing agent (for example, lithium aluminohydnde) further permits produc¬ tion of the corresponding alcohols and amines.

This synthetic scheme is preferred if R ₅ , R ₈ and/or R ₉ are strongly electron-donating groups such as alkoxy, hydroxy or alkammo, and all of the functionalities are

compatible with butyl lithium or can be used in a pro¬ tected form that is compatible with butyl lithium.

SCHEME π

The subject adamantyl retinoid derivatives identi¬ fied supra which induce apoptosis may be used for the treatment of many different cancers. Specific examples

of cancers treatable with the subject retinoid deriva¬ tives include by way of example bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung can¬ cers such as small cell lung cancer and non-small cell lung cancer, myeloma, neuroblastoma/glioblastoma, ovari¬ an cancer, pancreatic cancer, prostate cancer, skin can¬ cer, liver cancer, melanoma, colon cancer, cervical carcinoma, breast cancer, and leukemias . Moreover, because of their apoptosis inducing activity, the sub- ject adamantyl retinoid derivatives are especially well suited for treatment of solid tumors and advanced can¬ cers which cannot be treated by most conventional cancer therapies.

In treating cancer, the adamantyl or adamantyl derivative compounds of the present invention may be administered by any pharmaceutically acceptable means, e.g., systemically, enterally, parenterally or topical¬ ly. An effective therapeutic dosage will comprise a dosage sufficient to induce apoptosis of cancer cells. This dosage will vary dependent upon factors such as the condition of the patient treated, the specific compound, whether it is used alone or in combination with other therapies, among other factors. In general, an effec¬ tive dosage will vary from 0.01 mg/kg to 100 mg/kg of body weight, and more preferably 1 mg to 50 mg of body weight, typically administered at the rate of 1 to 3 dosages per diem.

As discussed, the adamantyl retinoid derivatives according to the invention which induce apoptosis are useful for treating many different types of cancers.

Specific adamantyl retinoid compounds according to the invention which have been demonstrated to exhibit such activity are set forth below. The specific types of cancers that these compounds have been shown to be ac- tive against are also identified.

LIST OF ACTIVE COMPOUNDS

Compound Name Types of Cancers Active Against

6- [3- (1-adamantyl) -4-methoxyphenyl] brain, cervical, 2-naphthoic acid head and neck, leu¬ kemia, lymphoma, prostate, skin

2- [3- (1-adamantyl) -4-methoxyphenyl] brain, colon, leuke¬ 5-benzimida2ole carboxylic acid mia, lung, lymphoma, myeloma, ovarian, pancreatic, pros¬ tate, skin, liver

6- [3- (1-adamantyl) -4-hydroxymethyl- bladder, brain, phenyl] -2-naphthoic acid breast, cervical, colon, head and neck, leukemia, kid¬ ney, lung, myeloma, ovarian, pancreatic, prostate, skin, liv¬ er

6- [3- (1-adamantyl) -4-hydroxy-5- brain, breast, kid¬ methoxyphenyl] -2-naphthoic acid ney, lung, leukemia, 1 mphoma, mye1oma, ovarian, pancreatic, prostate, skin, liv¬ er

6- [3- (1-adamantyl) -4-acetoxymethyl- head and neck, leu¬ phenyl] -2-naphthoic acid kemia, lung, lympho¬ ma, myeloma, pancre¬ atic, skin

6- [3- (1-adamantyl) -4, 5-methylenedi- brain, breast, head oxyphenyl] -2-naphthoic acid and neck, kidney, leukemia, lung, lym¬ phoma, mye1oma, ovarian, prostate, skin, liver

N-{6- [3- (1-adamantyl) -4-methoxy- brain, breast, head phenyl] -2-naphthalenecarboxoyl)- and neck, myeloma, piperizide prostate, skin

4-{3-OXO-3- [3- (1-adamantyl) -4- brain, breast, leu¬ methoxyphenyl] -l-propynyl}benzoic kemia, lung, lympho¬ acid ma, skin, liver

4- [N- (3- (1-adamantyl) -4-methoxyben- head and neck, kid¬ zoyl) amido] 2-methoxybenzoic acid ney, ovarian, skin

2- [3- (1-adamantyl) -4-methoxyphenyl] - 1eukemia, lymphoma, 5-methylbenzimidazole myeloma

6- [3- ( -adamantyl) -4- (1,2-dihydroxy- brain, breast, leu¬ ethyDphenyl] -2-naphthoic acid kemia, pancreatic, skin

Compound Name Types of Cancers Active Against

12 6- [3- (1-adamantyl) -4-hydroxy-6- head and neck, leu¬ methylphenyl] -2-naphthoic acid kemia, pancreatic

13 6- [3- (1-adamantyl) -4-methoxy-6- brain, head and methylphenyl] -2-naphthoic acid neck, leukemia, pan¬ creatic

14 6- [3- (1-adamantyl) -4-hydroxyphenyl] - bladder, kidney, 2-hydroxymethylnaphthalene skin

15 4- [3- (1-adamantyl) -4-methoxybenzyl- breast, leukemia, oxyjbenzoic acid prostate 16 2- [3- (1-adamantyl) - -methoxyphenyl] - brain, breast, pros¬ 5-benzofurancarboxylic acid tate

17 6- [3- (1-adamantyl) -4- ydroxypheny1] - leukemia 2-naphthoic acid methyl ester

18 1-methyl-4-hydroxy-6- [3- (1- lymphoma, liver adamantyl) - -methoxyphenyl] -2- naphthoic acid methyl ester

19 N-{4- [N- (3- (1-adamantyl) -4-methoxy- kidney, myeloma, benzoyl) amido]benzoyl}morpholide prostate, skin

20 4- [3- (1-adamantyl) -4-methoxybenzoyl- lymphoma, skin oxy] -2-fluorobenzoic acid 21 4-hydroxycarbonyl-2-fluorophenyl leukemia ester of 3- (1-adamantyl) -4-methoxy- benzoic acid

22 6- [3- (1-adamantyl) -4-ethylphenyl] -2- breast, leukemia, naphthoic acid myeloma

23 6- [3- (1-adamantyl) -4- (3-hydroxy- breast, leukemia, propoxy)phenyl] -2-naphthoic acid lymphoma

24 6- [3- (1-adamantyl) -4-aminocarbonyl- leukemia, lymphoma phenyl] - -naphthoic acid

25 N- (4-carboxyphenyl) -3- (1-adamantyl) - lymphoma 3-oxopropionamide 26 2-hydroxy-4-{2- [3- (1-adamantyl) -4- lymphoma methoxyphenyl] - -hydroxyethoxy}ben- zoic acid

27 (S) -6- [3- (1-adamantyl) -4- (2S,3- leukemia dihydrσxypropoxy) henyl] -2-naphthoic acid

28 (E) 4-{3-oxo-3- [3-methoxy-4- (1- leukemia adamantyl)phenyl]prop-1-enyl}benzoic acid

29 (E) 4-{3-oxo-3- [4- (2-methoxyethoxy- brain, leukemia, methoxγ) -3- (1-adamantyl)phenyl]prop- lung, lymphoma, l-enyl)benzoic acid prostate

Compound Name Types of Cancers Active Against

30 (E) 4-{2- [4- (6-aminocarbonylpentyl- lymphoma, myeloma oxy) -3- (1-adamantyl)phenyl]ethenyl}- benzoic acid

31 3- (1-adamantyl) -4-methoxy-N- (4- leukemia carboxyphenyl)benzamidine

32 4"-Erythromycin A ester of 6~[3-{l- leukemia, 1ymphoma adamantyl) -4-methoxyphenyl] 2- naphthoic acid

33 4-carboxyphenyl ester of 3-(l- leukemia, skin adamantyl) -4- (2, 3-dihydroxypro- proxy)benzoic acid

34 6- [3- (1-adamantyl) -4- (2, 3-dihydroxy- leukemia, skin propoxy) henyl] -2-naphthoic acid

35 N-4-carboxyphenyl 3- (1-adamantyl) -4- leukemia, lymphoma, (methoxycarbonyl)benzamide myeloma

36 6- [3- (1-adamantyl) - , 5-dihydroxy- brain, head and phenyl] -2-naphthoic acid neck, leukemia, lym¬ phoma, mye1oma, pan- creatic

37 6- [3- (3-methyl-1-adamantyl) -4,5- kidney, leukemia, methylenedioxyphenyl] -2-naphthoic lung, lymphoma, skin acid

38 6- [3- (2-oxa-1-adamantyl) -4, 5- leukemia, skin methylenedioxyphenyl] -2-naphthoic acid

39 6-_[3- (2-oxa-1-adamantyl) -4-methoxy¬ kidney, lymphoma, phenyl] -2-naphthoic acid skin, liver

40 6- [3- (2-oxa-3-methyl-1-adamantyl) -4- bladder, breast, methoxyphenyl] -2-naphthoic acid kidney, leukemia, lung, lymphom , ovarian, prostate, skin

41 6- [3- ( -methyl-1-adamantyl) -4- skin methoxyphenyl] -2-naphthoic acid

42 6- [3- (3, 5-dimethyl-1-adamantyl) -4- skin methoxyphenyl] -2-naphthoic acid

43 6- [3- (3, 5-dimethyl-1-adamantyl) -4,5- prostate, breast, methylenedioxyphenyl] -2-naphthoic neuroblastoma acid

44 N-{6- [3- (1-adamantyl) -4-methoxy¬ bladder, kidney, phenyl] -2-naphthalenecarboxoyl}homo- epidermal, leukemia piperazide lung, neuroblastoma, hepatoma, cervix, skin

Compound Name Types of Cancers Active Against

45 N- (2-ammoethyl) -{6- [3- (1-adaman¬ bladder, kidney, tyl) -4-methoxyphenyl] -2-naphthalene- prostate, leukemia, carboxamxde] breast, lung, neuro¬ blastoma, hepatoma, , cervix skin

46 N- {6- [3- ( 1 - adamantyl ) -4, 5-methylene- prostate, neuroblas- dioxy] - -naphthalenecarboxoyl} piper- toma, hepatoma azide

47 N- {6- [3- (1-adamantyl) -4, 5-methylene bladder, neuroblas¬ dαoxy] -2 -naphthalenecarboxoyl }homo- toma, cervix, skin piperazide

48 N- (2-ammoethyl) - {6- [3- (1-adaman- breast, hepatoma, tyl) -4, 5-methylenedιoxyphenyl] -2- skin naphthalenecarboxamide }

49 breast, neuroblasto¬ ma, leukemia lic acid

As can be seen from the above, the subject adamantyl retinoids exhibit a broad range of activity against numerous different types of cancers.

Moreover, the present invention also relates to the usage of the specific novel classes of adamantyl reti¬ noid compounds identified supra for other therapeutic as well as cosmetic usages.

Depending on the nature of the radicals used, the sub ect adamantyl or adamantyl derivative containing retinoid compounds should exhibit either an agonist activity in the test for differentiation of embryonic teratocarcmoma cells (F9) in mice (Cancer Research, 43 , p. 5268 (1983)) and/or in the test for inhibition of ornith e decarboxylase after induction by TPA mice (Cancer Research, 2B, p. 793-801 (1978)) or, contrast, an antagonist activity with respect to the expression of one or more biological markers in the test for differentiation of embryonic teratocarcmoma cells (F9) mice (Sk n Pharmacol., 3, pp. 256-267 (1990)) and/or for the in vitro differentiation of human kera- t ocytes (Anal. Biochem. , 192, pp. 232-236 (1991)) .

Based on these properties, the novel adamantyl or adamantyl derivative containing retinoid compounds ac¬ cording to the invention are well suited in the follow¬ ing fields of therapy: (1) for treating dermatological conditions associ¬ ated with a keratinization disorder related to differen¬ tiation and proliferation, in particular for treating acne vulgaris, comedonic or polymorphic acne, acne rosa- cea, nodulocystic acne, acne conglobate, senile acne and secondary acnes such as solar, drug or occupational acne;

(2) for treating other types of keratinization disorders, in particular ichthyoses, ichthyosiform con¬ ditions, Darier's disease, palmoplantar keratoderma, leukoplakia and leucoplakiform conditions or cutaneous or mucosal (oral) lichen;

(3) for treating other dermatological conditions associated with a keratinization disorder manifesting an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous or skin atopy, such as eczema, or respiratory atopy or alternatively gingival hypertro¬ phy; the compounds can also be used in certain inflamma- tory conditions not exhibiting keratinization disorder;

(4) for treating all dermal or epidermal prolifer¬ ations, whether benign or malignant, whether or not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, florid oral papilloma- toses and the proliferations which can be induced by ultraviolet radiation, in particular in the case of basal cell and prickle cell epithelioma;

(5) for treating other dermatological disorders, such as bullous dermatoses and collagen diseases;

(6) for treating certain ophthalmological disor¬ ders, in particular corneopathies;

(7) for repairing or controlling aging of the skin, whether photoinduced or chronologic, or for reduc- ing actinic keratoses and pigmentations, or any patholo¬ gy associated with chronologic or actinic aging;

(8) for preventing or treating the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;

(9) for preventing or treating disorders of heal¬ ing, or for preventing or for repairing stretch marks;

(10) for controlling disorders of the sebaceous function, such as hyperseborrhoea of acne or simple seborrhoea;

(11) for the prevention of cancerous or precancer- ous conditions;

(12) for the treatment of inflammatory conditions such as arthritis; (13) for the treatment of any condition of viral origin at the cutaneous or general level;

(14) for the prevention or treatment of alopecia,-

(15) for the treatment of dermatological or general conditions including an im unological component; (16) for the treatment of ailments of the cardio¬ vascular system, such as arteriosclerosis, and myocardi- al infarction; and

(17) for the treatment or prevention of osteoporo¬ sis . For the aforesaid therapeutic or pharmaceutical applications, the novel compounds according to the in¬ vention can advantageously be used in combination with other compounds displaying a retinoid-type activity, with vitamins D or derivatives thereof, with corticoste- roids, with compounds which control free radicals, α-

hydroxy or α-keto acids or derivatives thereof, or al¬ ternatively with ion channel blockers.

By "vitamins D or derivatives thereof" are intend¬ ed, for example, derivatives of vitamin D ₂ or D ₃ and in particular 1,25-dihydroxyvitamin D ₃ . By "compounds which control free radicals" are intended, for example, a- tocopherol , superoxide dismutase, ubiquinol or certain metal chelating agents.

By "cv-hydroxy or α-keto acids or derivatives there- of" are intended, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts, amides or esters thereof.

By "ion channel blockers" are intended, for exam¬ ple, Minoxidil (2, 4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.

The present invention thus also features medicinal compositions containing at least one of the above-iden¬ tified novel adamantyl retinoid compounds, one of its chiral or geometric isomers, or one of its pharmaceuti- cally acceptable salts, or other derivatives thereof.

The pharmaceutical/therapeutic compositions of the present invention, intended especially for treating the aforesaid disease states comprise a pharmaceutically acceptable vehicle, carrier or diluent which is compati- ble with the mode or regime of administration selected for the given composition and at least one novel adaman¬ tyl compound according to the invention or one of its chiral or geometric isomers, or a pharmaceutically ac¬ ceptable salt thereof. The administration of the compounds according to the invention can be carried out by any suitable means of administration, e.g., systemically, enterally, paren- terally, topically or ocularly.

For enteral administration, the medicinal/pharma- ceutical compositions may be in the form of tablets,

hard gelatin capsules, dragees, syrups, suspensions, solutions, elixirs, powders, granules, emulsions or polymeric or lipid microspheres or nanospheres or vesi¬ cles which permit a controlled release. For parenteral administration, the compositions may be in the form of solutions or suspensions for perfusion or for injection.

Effective dosage of a novel retinoid compound ac¬ cording to the invention in the above-identified thera¬ pies may be determined by well known methods. In gener- al, the compounds according to the invention are admin¬ istered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg by body weight, and at the rate or regime of 1 to 3 doses per diem.

For topical administration, the pharmaceutical compositions based on novel compounds according to the invention are more particularly intended for treating the skin and the mucosal membranes and can then be pro¬ vided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which permit controlled release. These compositions for topical administration can, moreover, be provided either in anhydrous form or in an aqueous form, according to the particular clinical indication.

For ocular administration, they are principally eye washes .

These compositions for a topical or ocular applica- tion contain at least one novel adamantyl retinoid ac¬ cording to the invention, or one of its optical or geo¬ metric isomers or, alternatively one of its salts, at a concentration preferably ranging from 0.001% to 5% by weight relative to the total weight of the composition.

As discussed, the novel adamantyl compounds accord¬ ing to the invention also find application in the cosme¬ tics field, in particular for body and hair care/hygiene, and especially for the treatment of skins tending to develop acne, for hair regrowth and combating hair loss, for combating the greasy appearance of the skin or the hair, for protecting against the deleterious effects of sunlight or in the treatment of physiologi¬ cally dry skin, and for preventing and/or for control- ling photoinduced or chronologic aging.

For cosmetic applications, the novel compounds according to the invention can, moreover, be advanta¬ geously be used in combination with other compounds displaying a retinoid-type activity, with vitamin D or derivatives thereof, with corticosteroids, with com¬ pounds which control free radicals, with α-hydroxy or a- keto acids or derivatives thereof, or alternatively with ion channel blockers, all of these various active agents being as defined above. The present invention therefore also features cos¬ metic compositions comprising a cosmetically acceptable vehicle, carrier or diluent which is suitable for topi¬ cal application, at least one of the novel adamantyl retinoid compounds identified supra or one of its chiral or geometric isomers, or one of its salts, etc. Such cosmetic compositions are advantageously in the form of a cream, milk, lotion, ointment, gel, polymeric or lipid vesicles or nanospheres or microspheres, soap or sham¬ poo. The concentration of the retinoid compound in the cosmetic compositions according to the invention advan¬ tageously ranges from 0.001% and 3% by weight relative to the total weight of the composition.

The medicinal and cosmetic compositions according to the invention can, in addition, contain inert or even

pharmacodynamically or cosmetically active additives or combinations of these additives, and, especially: wet¬ ting agents; depigmenting agents such as hydroqui one, azelaic acid, caffeic acid or kojic acid; emollients; hydrating or moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alterna¬ tively urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives thereof, or benzoyl peroxide; anti- biotics such as erythromycin and esters thereof, neomy- cin, clindamycin and esters thereof, or tetracyclines; anti-fungal agents such as ketoconazole or 4,5-ρoly- methylene-3-isothiazolidones; agents promoting hair regrowth, such as Minoxidil (2 ,4-diamino-6-piperidino- pyrimidine 3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-l, 2,4-benzothiadiazine 1, 1-dioxide) and phenytoin (5, 5-diphenylimidazolidine-2,4-dione) ; non-steroidal anti-inflammatory agents; carotenoids and especially β-carotene; anti-psoriatic agents such as anthralin and its derivatives; and, lastly, eicosa-

5, 8, 11, 14-tetraynoic and eicosa-5, 8, 11-triynoic acids, and esters and amides thereof.

The compositions according to the invention can also contain flavor-enhancing agents, preservatives such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and antioxidants such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.

In order to further illustrate the present inven¬ tion and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.

EXAMPLES

The following examples relate to synthesis of spe¬ cific adamantyl retinoid related compounds. All start¬ ing materials were obtained from Aldπch Chemical Compa- ny except for the methyl ester of 6- (4-methoxyphenyl) - naphthoic acid (which was synthesized according to U.S. patent 5,015,758) and 3-methyl-2-oxa-l-adamantanol (which was synthesized according to Stetter, Chemi sche Beπchte, .99, p. 1435 (1966)) .

EXAMPLE 1

Synthesis 2-oxa-l-adamantanol

386.6 mg (2.54 mmoles) of bicyclo [3.3.1] nonane-3 , 7- dione is dissolved in 5 mL of methanol and treated with sodium borohydπde (100 mg, 2.64 mmoles) at 0°C for 2 hours. The solution is treated with 5 mL of saturated aqueous sodium bicarbonate for 1 hour at 25°C and ex¬ tracted with 3 x 10 L portions of chloroform. The combined chloroform extracts are combined, dried over sodium sulfate, stripped of solvent m vacuo, and puri- fied by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate) yielding 343 mg (88%) of the desired product. ¹ HNMR (CDC1 ₃ , 500 Mhz) : d 1.563 (d, 2H) , 1.70-1.76 (m, 1H) , 1.788 (d, 2H, J=ll.l Hz) , 1.839 (d, 2H, J=13.1 Hz) , 1.925 (d, 2H, J=13.0 Hz) , 2.310 (s, 2H) , 2.690 (s, 1H) , 4.283 (s, 1H) .

EXAMPLE 2 Synthesis of 3-methyl-1-adamantyl acetate

121 mg (0.728 mmoles) of 3-methyl-1-adamantanol are dissolved in 0.2 mL n-heptane and 0.2 mL cyclohexane A mixture of 0.2 L (2.25 mmoles) of acetic anhydride and 2 microliters (0.036 mmoles) of concentrated sulfuπc acid is added, and the mixture is stirred at ambient temperature for 20.5 hours. The solution is dissolved

in 10L of ether and extracted with 10 mL of water. The aqueous layer is extracted with 10 mL ether. The ether layers are combined, extracted with 2 x mL of water followed by 40 mL of aqueous sodium bicarbonate (10 g/liter) , dried over magnesium sulfate, and stripped of solvent in vacuo. The product is a colorless oil with Rf 0.55 (silica: eluant hexane 75%, ethyl acetate 25%) .

EXAMPLE 3 Synthesis of 3, 5-dimethyl-l-adama tyl acetate 2.486 (10.2 mmoles) of 3 , 5-dimethyl-1-bromoadaman- tane is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 mL of acetic acid. The solu¬ tion is poured over 100 grams of ice, allowed to melt, and extracted with 3 x 10 mL of diethyl ether. The com- bined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, yielding 1.521 (67%) of the desired product, a colorless oil. TLC: Rf=0.68 (silica plate: eluant hexane 90%, ethyl acetate 10%) . ΗNMR (CDC1 ₃ , 500 Mhz) : 0.858 (s, 6H) , 1.115 (d, 2H, J=12.4 Hz) , 1.177 (d, 2H, J=12.4 Hz) , 1.260 (d, 2H, J=12.3 Hz) , 1.367 (d, 2H, J=12.3 Hz) , 1.714 (d, 2H, J=11.6 Hz) , 1.766 (d, 2H, J=11.6 Hz), 1.939 (s, 2H) , 1.976 (s, 3H) , 2.191 (m, 1H) .

EXAMPLE 4 Synthesis of 2-oxa-1-adamantyl esylate

340 mg (2.21 mmoles) of 2-oxa-l-adamantanol (see Example 1) and 20 mg (0.163 mmoles) of 4-dimethylamino- pyridine are dissolved in 5 mL of dry pyridine under argon at -40°C. A suspension of 565 mg (3.25 mmoles) of methanesulfonic anhydride in 8 mL of dry pyridine is added at -40°C. The rest of solid methanesulfonic anhy-

dride was added into the reaction flask. The mixture is stirred at 0°C, and allowed to warm to 25°C over 18 hours. After removing the solvent in vacuo, the residue was dissolved in 20 mL dichloromethane, washed with 10 mL of water, and dried to yield 512 mg (100%) of the desired product. Rf= .50 (50% ethyl acetate in hex¬ anes) . ¹ HNMR (CDC1 ₃ , 500 Mhz) : d 1.594 (d, 2H, J=13.0 Hz) , 1.76-1.86 (m, 2H) , 2.010 (d, 4H, J=12.5 Hz) , 2.330 (d, 2H, J=11.9 Hz) , 2.380 (s, 2H) , 3148 (a, 3H) , 4.439 (s, 1H) .

EXAMPLE 5 Synthesis of 3-methyl-2-oxa-1-adamantyl mesylate

A mixture of 230 mg (1.37 mmoles) of 3-methyl-2- oxa-1-adamantanol, 20 mg (0.163 mmoles) of 4-dimethyl- aminopyridine, and 350 mg (2.0 mmoles) of methanesul- fonic anhydride is treated with 10 mL of dry pyridine under argon at -40°C. The reaction mixture is warmed to 0°C and allowed to gradually warm to 25°C over 13 hours. The solvent is removed in vacuo, and the residue dis- solved in 20 mL dichloromethane, washed with 10 mL of water, dried over sodium sulfate, and stripped of sol¬ vent in vacuo, yielding 341 mg of crude (approximately 95% pure) product. TLC: Rf=0.75 (Silica: 50% hexanes, 50% ethyl acetate) .

EXAMPLE 6

Synthesis of methyl ester of 6- (3,4-methylenedioxy- phenyl) -2-naphthoic acid

Magnesium turnings (1.48 g, 61 mmoles) were placed in a 250 mL three-neck flask attached to a reflux con- denser. The flask was evacuated under vacuum with heat- gun. Argon and dry THF (100 mL) were introduced. 5-

Bromo-1, 3-benzodioxole (6.0 mL, 10.0 g, 49.8 mmoles) was added and the mixture was heated at 80°C oil bath. A

few minutes later the reaction was initiated and the mixture was refluxed for 3 hr. A portion of such Grignard solution (50 mL, 24.9 mmole) was added into a solution of anhydrous zinc chloride (3.46 g, 24.9 mmole) in dry THF (40 mL) and the resulting mixture was stirred for 30 minutes at room temperature. The organozinc solution was transferred into a flask containing 1,- bis (diphenylphosphono) ethane dichloronickel (II) (400 mg) and methyl 6-bromo-2-naphthoate (5.23 g, 19.9 mmole) in dry THF (40 mL) . The reaction solution was stirred at room temperature for 18 hours. Water (150 mL) was added and the whole was extracted with ethyl acetate (200 mL) . After drying over anhydrous sodium sulfate, concentra¬ tion and recrystallization (heptane and dichloromethane) gave the desired product (3.25 g, 53%) . M.p. 147-149°C.

EXAMPLE 7

Synthesis of methyl ester of 6- [3- (3, 5-dimethyl-l- adama tyl) -4-methoxyphenyl] -2-naphthoic acid

121 mg ((0.54 mmoles) of the ester obtained in Example 3 and 147.5 mg (0.505 mmoles) of the methyl ester of 6- (4-methoxyphenyl) naphthoic acid were dissolved in a mixture of 0.4 mL cyclohexane and 1 mL of 1, 2-dichloroethane. While stirring vigorously, concen¬ trated sulfuric acid (15 microliters, 0.27 mmoles) was added. The mixture was heated to 75°C for 5 hours while stirring and stirred at 25°C for 28 days. The solvent was removed in vacuo, and the material purified by col¬ umn chromatography on silica using toluene as an eluant, yielding 157 mg (68%) of the desired product. M.p. =143- 147°C.

EXAMPLE 8

Synthesis of methyl ester of 6- [3- (3-methyl-l- adamantyl) -4-methoxyphenyl] -2-naphthoic acid

36.4 mg (0.175 mmoles) of the ester obtained Example 2 and 51 mg (0.175 mmoles) of the methyl ester of 6- (4-methoxyphenyl)naphthoic acid are dissolved a mixture of 0.14 mL cyclohexane and 0.35 mL of 1,2- dichloroethane. While stirring vigorously, concentrated sulfuric acid (5 microliters, 0.09 mmoles) is added. The mixture is stirred at 90°C for 14 hours and at 25°C for 24 hours. The solvent is removed vacuo, and the material is purified by column chromatography on silica using toluene as an eluant, yielding 15.8 mg (20.5%) of the desired product. M.p. =146-147°C.

EXAMPLE 9

Synthesis of methyl ester of 6- [3- (2-oxa-1-adamantyl) -4- methoxyphenyl] -2-naphthoic acid

142 mg (0.61 moles) of 2-oxa-1-adamantyl mesylate (from Example 4) and 137.5 mg (0.47 mmoles) of the meth- yl ester of 6- (4-methoxyphenyl) naphthoic acid are dis¬ solved 2 mL of dichloromethane and 0.2 mL of cyclohexane 80 microliters (0.9 mmoles) of concentrat¬ ed trifluorosulfonic acid are added. The mixture is stirred for 90 hours, dissolved in 25 mL dichloromethane, filtered, and adsorbed onto 2 grams of silica. The compound is purified by column chromatogra¬ phy on silica using toluene as an eluant, yielding 32.3 mg (16%) of the desired product. TLC: Rf=0.12 (silica plate: eluant = toluene) . 1HNMR (CDC1 ₃ , 500 MHz) :

1.709 (d, 2H J=12.3 Hz) 1.817 (d, 2H J=12.3 Hz) 1.92652 (d, 1H J=12.7 Hz) 1.996 (d, 1H J=12.5 Hz) 2.099 (d, 2H J=12.2 Hz)

Synthesis of methyl ester of 6- [3- (2-oxa-3-methyl-l- adamantyl) 4-methoxyphenyl] -2-naphthoic acid

76.2 mg (0.26 mmoles) of the methyl ester of 6- (4- methoxyphenyl) naphthoic acid and 61.3 mg (0.25 mmoles) of the me-sylate obtained in Example 5 are suspended in a mixture of 0.85 mL 1, 2-dichloroethane and 80 microliters of cyclohexane. 30 microliters of concentrated trifluorosulfonic acid (0.339 mmoles) is added, and the suspension is stirred at 25°C for 5 days. The product is purified using preparative TLC on silica places with toluene as the eluant, yielding 4.5 mg (4%) of the de¬ sired product. TLC: Rf=0.38 (silica plate: eluant=toluene) . ¹ H MR (DMSO-d6, 500 Mhz) 1.763 (s, 4H) , 2.074 (s, 3H) , 2.140 (s, 5H) , 2.539 (s, 3H) , 3.872 (s, 3H) , 3.924( s, 3H) , 7,128 (d, 1H, J=3.5 Hz) , 7.584 (d, 1H, J=1.8 Hz) , 7.664 (dd, 1H, Jl=1.7 Hz) , J2=8.7 Hz) , 7.914 (dd, 1H, Jl=1.5 Hz, J2=7.3 Hz) , 7.988 (d, 1H, J=9.1Hz) , 8.108 (d, 1H, J=9.1 Hz) , 8.185 (d, 1H, J=3.6 Hz) , 3.238 (s, 1Η) , 8.637 (s, 1H) . MS 454 (M ⁺ ) .

EXAMPLE 11

Synthesis of methyl ester of 6- [3- (3, 5-dimethyl-l- ada antyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid

To a mixture of methyl ester of 6- (3, 4-methylenedi- oxyphenyl) -2-naphthoic acid (see Example 6, 70 mg, 0.23 mmole) , 3, 5-dimethyl-1-adamantyl acetate (see Example 3,

63.4 mg, 0.285 mmole) in dichloroethane (1.2 mL) were added two drops of cyclohexane followed by addition of trifluoromethanesulfonic acid (0.030 mL, 0.34 mmole) . The reaction mixture was stirred at room temperature for four days. Preparative TLC purification (10% ethyl acetate in hexanes) gave the desired product (44 mg, 40%.) . Rf: 0.24 (10% ethyl acetate/hexane) . ^l mMR (CDC1 ₃ , 500 Mhz) 0.899 (s, 6H) , 1.233 (s, 2H) , 1.395 (d, 2H, J=13.3 Hz), 1.463 (d, 2H, J=12.2 Hz), 1.681 (d, 2H, J=12.2 Hz) , 1.741 (d, 2H, J=12.1 Hz) , 1.929 (d, 2H, J=1.4 Hz) , 2.18-2.20 (m, 1H) , 3.990 (s, 3H) , 6.012 (s, 2H) , 7.078 (d, 1H, J=l .7 Hz) , 7.099 (s, 1H) , 7.743 (dd, 1H, Jl=1.7 Hz, J2=3.5 Hz) , 7.919 (d, 1H, J=8.7 Hz), 7.974 (s, 1H) , 7.983 (d, 1H, J=9.2 Hz) , 8.072 (d, 1H, J=7.8 Hz) ^" , 8.610 (s, 1H) . MS 468 (M ⁺ )

EXAMPLE 12

Synthesis of methyl ester of 6- [3- (3-methyl-l- adamantyl) -4, 5-methylenedioxyphenyl] -2-naphthoic acid To a mixture of methyl ester of 6- (3, 4-methylenedi- oxyphenyl) -2-naphthoic acid (see Example 6, 48.9 mg, 0.16 mmole) , 3-methyl-1-adamantyl acetate (see Example 2, 40.2 mg, 0.193 mmole) in dichloroethane (1.2 L) were added two drops of cyclohexane followed by the addition of trifluoromethanesulfonic acid (0.020 mL, 0.227 mmole) . The reaction mixture was stirred at room tem¬ perature for four days. Preparative TLC purification (10% ethyl acetate in hexanes) gave the desired product (35 mg, 48%) . R.f=0.27 (10% ethyl acetate in hexanes) . ¹ HNMR (CDC1 ₃ , 500 Mhz) , 0.87 (s. 3H) , 1.520 (s, 4H) ,

1.661 (d, 1H, J=12.5 Hz) , 1.737 (d, 1H, J=12.4 Hz) , 1.787 (s, 2H) , 1.984 (d, 2H, J=11.7 Hz), 2.049 (d, 2H, J=12.1 Hz) , 2.154 (s, 2H) . 3.990 (s, 3H) , 6.012 (s, 2H) , 7.084 (s, 1H) , 7.105 (s, 1H) , 7.745 (d, 1H, J=8.3 Hz), 7.914 (d, 1H, J=8.6 Hz), 7.974 (s, 1H) , 7.982 (d, 1H, J=8.4 Hz) , 8.071 (d, 1H, J=3.6 Hz) , 8.610 (s, 1H) . MS 454 (M ⁺ )

EXAMPLE 13

Synthesis of methyl ester of 6- [3- [ (2-oxa-1-adamantyl) - 4,5-methylenedioxyphenyl] -2-naphthoic acid

To a mixture of methyl ester of 6- (3 , 4-methylenedi- oxyphenyl) -2-naphthoic acid (see Example 6, 22.6 mg,

0.074 mmole) , 2-oxa-1-adamantyl mesylate (see Example 4,

50 mg, 0.22 mmole) in dichloroethane (1.2 mL) were added two drops of cyclohexane followed by the addition of trifluoromethanesulfonic acid (0.020 L, 0.227 mmole) . The reaction mixture was stirred at room temperature for two days. Preparative TLC purification (10% ethyl ace¬ tate in hexanes) gave the desired product (5 mg, 15%) . Rf=0.15 (silica 10% ethyl acetate, 90% hexanes) . MS: 443 (M+H ⁺ ) .

EXAMPLE 14

Synthesis of 6- [3- (3-methyl-1-adamantyl) -4- methoxyphenyl] -2-naphthoic acid 10 mg (0.0226 mmoles) of the ester from Example 8 are dissolved in 0.5 mL of n-butanol and treated with 0.1 mL of 1 molar potassium hydroxide in n-BuOH (0.1 mmoles of potassium hydroxide) . The solution is heated at 105°C for 110 minutes and cooled to 25°C. The reac- tion mixture is treated with 2.5 L of water and 0.5 mL of acetic acid, and the volatiles are removed under vacuum. Washing with water to remove potassium acetate and drying under, vacuum yields 6.6 mg (68.5%) of the desired product. ¹ HNMR (DMS0-d6, 500 Mhz) 0.873 (s, 3H) ,

1.203 (s, 2H) , 1.363 (d, 2H, J=ll .9 Hz) , 1.434 (d, 2H, J=11.3 Hz) , 1.723 (d, 2H, J=12.0 Hz) , 1.783 (d, 2H, J=11.9 Hz) , 1.968 (s, 2H) , 2.154 (s, 2H) , 3.862 (s, 3H) , 7.124 (d, IH, J=3.7 Hz) , 7.566 (d, IH, J=2.2 Hz) , 7.653 (dd, IH, Jl=1.8 Hz, J2=8.0 Hz) , 7.88 (d, IH, Jl=1.4 Hz,

J2=8.7 Hz) , 7.987 (dd, IH, Jl=l .5 Hz, J2=8.8 Hz) , 8.078 (d, IH, J=8.6 Hz) , 8.162 (d, IH, 1=8.6 Hz) , 8.199 (s, IH) , 8.599 (s, IH) .

EXAMPLE 15 Synthesis of 6- [3- (3,5-dimethyl-l-adama tyl) -4-methoxy¬ phenyl] -2-naphthoic acid

The ester from example 7 is hydrolyzed as described in Example 14, yielding 35% of the desired product.

M.p. 258-263°C.

EXAMPLE 16

Synthesis of 6- [3- (2-oxa-1-adamantyl) -4-methoxyphenyl] - 2-naphthoic acid

The ester from Example 9 is hydrolyzed as described in Example 14, yielding 70% of the desired product. NMR (DMSO-d6, 500 MHz) , 1.632 (s, 2H) , 1.696 (s, 2H, J=11.8 Hz) , 1.910 (s, 2H) , 1.969 (d, 2H, J=11.6 Hz) , 2.167 (s, 2H) , 2.686 (s, 2H) , 3.856 (s, 3H) , 4.330 (s, IH) , 7.130 (d, IH, J=8.6 Hz) , 7.678 (dd, IH, Jl=7.3 Hz, J2=2.0 Hz) , 7.827 (d, IH, J=8.7 Hz) , 7.975 (d, IH, J=2.4 Hz) , 7.984 (s, IH) , 8.0686 (d, IH, J=8.5 Hz) , 8.138 (d, IH, J=8.7 Hz) , 8.147 (s, IH) , 8.562 (s, IH) .

EXAMPLE 17

Synthesis of 6- [3- (2-oxa-3-methyl-1-adamantyl) -4- methoxyphenyl] -2-naphthoic acid The ester from Example 10 is hydrolyzed as described in Example 14, yielding the desired product.

^J HNMR (DMSO-d6, 500 MHz) , 1.763 (s, 4H) , 2.073 (s, 3H) ,

2.141 (s, 5H) , 2.539 (s, 3H) , 3.871 (s, 3H) , 7.126 (d,

1H, J=7.6 Hz), 7.580 (d, IH, J=1.8 Hz), 7.659 (dd, IH, Jl=8.1 Hz, J2=1.7 Hz) , 7.895 (d, IH, J=9.3 Hz) , 7.974 (dd, IH, Jl=8.8, J2=1.4) , 8.077 (d, IH, J=8.7 Hz) , 3.156 (d, IH, J=8.6 Hz), 8.223 (s, IH) , 8.587 (s, IH) .

EXAMPLE 18

Synthesis of 6- [3- (3,5-dimethyl-1-adamantyl) -4, 5-methyl- enedioxyphenyl] -2-naphthoic acid

The ester from Example 11 is hydrolyzed as described in Example 14, yielding 78% of the desired product. Rf : 0.23 (50% ethyl acetate in hexanes) . ^J HNMR (DMSO-d6, 500 Mhz) , 0.875 (s, 6H) , 1.208 (s, 2H) , 1.368 (d, 2H, J=11.5 Hz), 1.432 (d, 2H, J=12.0 Hz) , 1.674 (d, 2H, J=12.0 Hz), 1.717 (d, 2H, J=12.0 Hz) , 1.905 (s, 2H) , 2.16-2.18 (m, IH) , 6.063 (s, 2H) , 7.143 (s, IH) , 7.284 (s, IH) , 7.843 (d, IH, J=8.5 Hz) , 7.990 (d, IH, J=9.0 Hz) , 8.024 (d, IH, J=9.0 Hz) , 8.120 (d, IH, J=8.5 Hz) , 8.186 (s, IH) , 8.561 (s, IH) . MS 454 (M ¹ ) .

EXAMPLE 19

Synthesis of 6- [3- (3-methyl-1-adamantyl) -4,5-methylene- dioxyphenyl] -2-naphthoic acid

The ester from Example 12 is hydrolyzed as described in Example 14, yielding 59% of the desired product. Rf: 0.22 (50% ethyl acetate in hexanes) . ^X HNMR

(DMSO-d6, 500 Mhz) : 0.861 (s, 3H) , 1.485 (s, 4H) , 1.622 (d, IH, J=12.4 Hz) , 1.692 (d, IH, J=12.3 Hz) , 1.766 (s, 2H) , 1.962 (d, 2H, J=11.5 Hz) , 2.009 (d, 2H, J=12.3 Hz) , 2.117 (s, 2H) , 6.065 (s, 2H) , 7.156 (s, IH) , 7.297 (s, IH) , 7.877 (d, IH, J=8.3 Hz) , 7.981 (d, IH, J=8.2 Hz), 8.060 (d, IH, J=8.6 Hz) , 8.147 (d, IH, J=3.6 Hz) , 8.221 (s, IH) , 8.601 (s, IH) . MS: 440 (M ⁺ ) .

EXAMPLE 20

Synthesis of 6- [3- [ (2-oxa-1-adamantyl) -4, 5-methylenedi- oxyphenyl] -2-naphthoic acid

The ester from Example 13 is hydrolyzed as described in Example 14, yielding 65% of the desired product. Rf : 0.16 (50% ethyl acetate in hexanes) .

EXAMPLE 21

Preparation of the methyl ester of 6- [3- (3-methyl-l- adamantyl) -4-hydroxyphenyl] -2-naphthalenecarboxylic acid.

To a solution of the ester obtained in Example 8

(129 mg, 0.29 mmol) in anhydrous methylene chloride (5 mL) was added to 2M boron tribromide solution (2.1 mL,

2.1 mmol) slowly under argon at 0°C. The solution was stirred at 0°C for 90 minutes before adding methanol (20 mL) . After 16 hours, the reaction solution was poured into aqueous solution of sodium hydrogen sulfate (0.48 g) and potassium carbonate (0.8 g) . The mixture was extracted with ether (2 x 100 mL) . The ether layer was dried over sodium sulfate and evaporated. Column chro¬ matography with silica gel gave the desired product (83 mg, 65.6%) , MR (CDCL ₃ 500 MHz) ; 0.891 (s, 3H) , 1.528 (s, 4H) , 1.665 (d, IH, J=12.4) , 1.754 (d, IH, J=12.0) , 1.892 (s, 2H) , 2.087 (d, 2H, J=11.2 Hz) , 2.155 (d, 2H, J=ll.l Hz) , 2.167 (s, 2H) , 3.99 (s, 3H) , 6.780 (d, IH, J=8.2) , 7.430( dd, IH, J=2.0, 8.2) , 7.585 (d, IH, J=2.0) , 7.774 (dd, IH, J=1.4, 8.4) , 7.918 (d, IH, J=8.6) , 7.988 (d, IH, J=8.2) , 7.996(s, IH) , 8,069(dd, IH, J=1.6, 8.4) , 8.612(s,lH) .

EXAMPLE 22

Preparation of 6- [3- (3-methyl-1-adamantyl) -4-hydroxy- phenyl] -2-naphthalenecarboxylic acid.

A solution of the ester from Example 24 (75 mg.

0.172 mmol) in 0.25 M potassium hydroxide in n-butanol

(10 mL) was refluxed under argon for 4 hours. A slight¬ ly excess of acetic acid was added and the whole was ex¬ tracted with methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and evapo- rated. Column chromatography with silica gel (1:15 methanol/methylene chloride) gave the desired product in almost quantitative yield. 'NMR (DMS0-d ₆ , 500 MHz) : .843 (s, 3H) , 1.464 (s, 4H) , 1.6109 (d, III) , 1.668 (d, IH) , 1.844 (s, 2H) , 2.06 ( , 6H) , 6.91 (d, IH, T=8.0 Hz) , 7.49 (dd, IH, J=2.5, 10.4) , 7.85 (dd, IH, J=1.5, 8.8) ,

7.96 (dd, IH, J=0.6-7.6) , 8.05 (d, IH, J=8.7) , 8.124 (d, IH, J=8.7) , 8.147 (s, IH) , 8.571 (s, IH) .

EXAMPLE 23

Preparation of N- (2-aminoethyl) -{6- [3- (1-adamantyl) -4- methoxyphenyl] -2-naphthalenecarboxamide}.

To a suspension of 6- [3- (1-adamantyl) -4-methoxy¬ phenyl] -2-naphthalenecarboxylic acid (3 g, 7.27 mmoles) in dry toluene (20 mL) was added thionyl chloride (0.6 mL, 8.22 mmoles) and DMF (0.04 mL) under argon. The reaction mixture was heated to 100°C for ten minutes and another 0.04 mL of DMF was added. After 30 minutes, more thionyl chloride (0.1 mL, 1.37 mmoles) was added and the reaction mixture was heated to 110°C for 60 minutes . The solvent and excess thionyl chloride were removed in vacuo. The resulting solid was stirred with 100 mL dry methylene chloride under argon. This was added to a mixture of ethylene diamine (5.25 mL, 70 mmoles) in dry methylene chloride under argon at 0°C while stirring rapidly. The solution was allowed to warm to ambient temperature while stirring rapidly dur¬ ing one hour. The reaction mixture was poured carefully into 350 L of IN aqueous HC1 while stirring, and the methylene chloride was removed in vacuo. The resulting precipitate (hydrochloride salt of the product) was

washed with IN HC1, water, THF, and methylene chloride. Yield of hydrochloride salt: 2.76 g, 77%. The free base was generated by neutralizing with aqueous sodium bicarbonate and extracting the product into tetrahydro- furan, drying the organic layer over sodium sulfate, and removing the solvent. MS 455 (M+H ⁺ ) .

EXAMPLE 24

Preparation of N-{6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthalenecarboxoyl}homopiperazide. This amide was prepared from 6- [3- (1-adamantyl) -4- methoxyphenyl] -2-naphthalenecarboxylic acid and homo¬ piperazine using a procedure analogous to the one in Example 24. MS: 495 (M+H ⁺ ) .

EXAMPLE 25 Preparation of N-{6- [3- (1-adamantyl) -4, 5-methylenedi- oxy] -2-naphthalenecarboxoyl}piperazide.

This amide was prepared from 6- [3- (1-adamantyl) -

4 , 5-methylenedioxy] -2-naphthalenecarboxylic acid and piperazine using a procedure analogous to the one in Example 24. MS: 495 (M+H ⁺ )

EXAMPLE 26

N-{6- [3- (1-adamantyl) -4,5-methylenedioxy] -2-naphthalene- carboxoyl}homopiperazide.

This amide was prepared from 6- [3- (1-adamantyl) - 4 , 5-methylenedioxy] -2-naphthalenecarboxylic acid and homopiperazine using a procedure analogous to the one in

Example 24. MS: 509 (M+H ⁺ ) .

EXAMPLE 27

N- (2-aminoethyl) -{6- [3- (1-adamantyl) -4,5-methylenedioxy- phenyl] -2-naphthalenecarboxamide}.

This amide was prepared from 6- [3- (1-adamantyl) -

4, 5-methylenedioxy] -2-naphthalenecarboxylic acid and

ethylenediam e using a procedure analogous to the one m Example 24. MS: 469 (M+H ⁺ )

EXAMPLE 28

N- (2-dimethylaminoethyl) -{6- [3- (1- damantyl) -4,5-methy- lenedioxypehnyl] -2-naphthalenecarboxamide}.

This amide was prepared from 6- [3- (1-adamantyl) -

4, 5-methylenedιoxy] -2-naphthalenecarboxylιc acid and 2- dimethylaminoethylamine using a procedure analogous to the one in Example 24. MS: 495 (M-H )

EXAMPLE 29

The anti-cancer activity of various adamantyl reti¬ noid compounds according to the invention was compared to all-trans-ret oic acid using cell-based high throughput screening assays. Specifically, the follow- g compounds were tested in such assays: all-trans- retinoic acid, 6 [3 (1-adamantyl) -4-methoxyphenyl] -2-naph¬ thoic acid, 2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benz- lmidazole carboxylic acid, 6- [3- (1-adamantyl) -4-hydroxy- 5-methoxyphenyl] -2-naphthoic acid, 6- [3- (1-adamantyl) -4- acetoxymethylphenyl] -2-naphthoic acid and 6-[3-(l- adamantyl) -4, 5-methylenedιoxyphenyl] -2-naphthoιc acid.

These compounds were tested against a panel of human tumor cell lines having a variety of tissue ori¬ gins, and having distinct tumor characteristics. The tumor cell cultures were exposed to the above retinoid compounds for a specific duration. After such exposure, the percentage of surviving cells was then measured using standard assays. These results were then compared for different compounds, with an active compound being defined as one which results a percentage survival of less than 80.

These results are contained in Figure 1. Based on these results, it can be seen that compounds according

to the invention were active against a number of dis¬ tinct human cancers. By contrast, all-trans-retmoic acid did not give comparable results.

EXAMPLE 30 Based on the previous results, various active com¬ pounds according to the invention, in particular 2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benzιmιdazole carboxyl¬ ic acid, 6- [3- (1-adamantyl) -4-hydroxymethylphenyl] -2- naphthoic acid; 6- [3- (1-adamantyl) -4-hydroxy-5-methoxy- phenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) - , 5-methyl- enedioxyphenyl] -2-naphthoic acid, as well as all-trans- retmoic acid, were tested against various human cancer cell lines at retmoid concentrations ranging from 10 ⁹ M to 10 ^s M. These results are contained m Figures 2-4, and show that adamantyl compounds according to the in¬ vention exhibit significant anti-cancer activity. By contrast, all-trans-retmoic acid did not exhibit simi¬ lar activity.

EXAMPLE 31 The anti cancer activity of a compound according to the invention, 6- [3- (1-adamantyl) -4 , 5-methylenedιoxy- phenyl] -2-naphthoic acid was also evaluated m a human xenograft mouse animal model containing human pancreatic cancer BxPC-3 tumor cells. Starting twenty-eight days after inoculation of tumor cells, said xenograft con¬ taining mice were administered the ret oid compound mtraperitoneally at a dosage of 80 mg/kg body weight . Also, a control group of said mice was inoculated under similar conditions with the pharmaceutical vehicle used for formulation (but lacking the retinoid compound) . These results are contained in Figure 5 and show that the retmoid compound according to the invention, 6- [3- (1-adamantyl) -4, 5-methylenedioxyphenyl] -2-naphthoιc

acid resulted in substantial reduction in tumor size compared to the control group which were not adminis¬ tered this retinoid compound. Therefore, based on these results, it is apparent that the anti-cancer activity of adamantyl compounds according to the invention, which is apparently attributable to apoptosis inducing activity, is observed both in vi tro and in vivo .

STRUCTURES OF ACTIVE COMPOUNDS

(1 -adamantyl)

7.

20.

^■ 58-

-60-