METHODS OF TREATMENT WITH COMPOUNDS HAVING RAR alpha RECEPTOR SPECIFIC OR SELECTIVE ACTIVITY

Abstract: Retinoid compounds which act specifically or selectively on RAR alpha receptor subtypes in preference over RAR beta and RAR GAMMA receptor subtypes, possess desirable pharmaceutical properties associated with retinoids, and are particularly suitable for treatment of tumors, such as acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas and head and neck carcinomas, without having one or more undesirable side effects of retinoids, such as inducement of weight loss, mucocutaneous toxicity, skin irritation and teratogenicity.

Description: METHODS OF TREATMENT WITH COMPOUNDS HAVING RAR α 2 RECEPTOR SPECIFIC OR SELECTIVE ACTIVITY 3 BACKGROUND OF THE INVENTION 4 1. Field of the Invention 5 The present invention relates to the use of e compounds which have specific or selective agonist 7 like activity on RAR α retinoid receptors for β treatment of diseases and conditions which respond 9 to treatment by such retinoids. More particularly 10 the present invention is directed to the use of RAR α 11 receptor specific or selective agents for the 12 treatment of tumors. 13 2. Background Art ι Compounds which have retinoid-like activity are is well known in the art, and are described in numerous 16 United States and other patents and in scientific 17 publications. It is generally known and accepted in 18 the art that retinoid-like activity is useful for 19 treating animals of the mammalian species, including 0 humans, for curing or alleviating the symptoms and 1 conditions of numerous diseases and conditions. In 2 other words, it is generally accepted in the art 3 that pharmaceutical compositions having a 4 retinoid-like compound or compounds as the active 5 ingredient are useful as regulators of cell 6 proliferation and differentiation, and particularly 7 as agents for treating skin-related diseases, 8 including, actinic keratoses, arsenic keratoses, 9 inflammatory and non-inflammatory acne, psoriasis, 0 ichthyoses and other keratinization and 1 hyperproliferative disorders of the skin, eczema, 2 atopic dermatitis, Darriers disease, lichen planus, 3 prevention and reversal of glucocorticoid damage 4 (steroid atrophy), as a topical anti-microbial, as 5 skin anti-pigmentation agents and to treat and ι reverse the effects of age and photo damage to the 2 skin. Retinoid compounds are also useful for the 3 prevention and treatment of cancerous and precancerous conditions, including, premalignant and 5 malignant hyperproliferative diseases such as 6 cancers of the breast, skin, prostate, cervix, 7 uterus, colon, bladder, esophagus, stomach, lung, β larynx, oral cavity, blood and lymphatic system, 9 metaplasias, dysplasias, neoplasias, leukoplakias o and papillomas of the mucous membranes and in the 1 treatment of Kaposi's sarcoma. In addition, 2 retinoid compounds can be used as agents to treat 3 diseases of the eye, including, without limitation, 4 proliferative vitreoretinopathy (PVR), retinal 5 detachment, dry eye and other corneopathies, as well 6 as in the treatment and prevention of various 7 cardiovascular diseases, including, without 8 limitation, diseases associated with lipid 9 metabolism such as dyslipidemias, prevention of 0 post-angioplasty restenosis and as an agent to 1 increase the level of circulating tissue plasminogen 2 activator (TPA). Other uses for retinoid compounds 3 include the prevention and treatment of conditions and diseases associated with human papilloma virus 5 (HPV), including warts and genital warts, various 6 inflammatory diseases such as pulmonary fibrosis, 7 ileitis, colitis and Krohn's disease, 8 neurodegenerative diseases such as Alzheimer's 9 disease, Parkinson's disease and stroke, improper pituitary function, including insufficient 1 production of growth hormone, modulation of apoptosis, including both the induction of apoptosis 3 and inhibition of T-cell activated apoptosis, restoration of hair growth, including combination ι therapies with the present compounds and other 2 agents such as Minoxidil R , diseases associated with 3 the immune system, including use of the present compounds as immunosuppressants and 5 immunostimulants, modulation of organ transplant 6 rejection and facilitation of wound healing, 7 including modulation of chelosis. s United States Patent Nos. 4,740,519 (Shroot et 9 al.. , 4,826,969 fMaiσnan et al . ) . 4,326,055 ιo (Loeli er et al.), 5,130,335 (Chandraratna et al.). ιι 5,037,825 (Klaus et al.l. 5,231,113 Chandraratna et 12 al. > . 5,324,840 (Chandraratnaι . 5,344,959 13 fChandraratnai , 5,130,335 (Chandraratna et al.l. 14 Published European Patent Application Nos. 0 170 105 15 (Shudo), 0 176 034 A (Wuest et al... 0 350 846 A 16 (Klaus et al.l. 0 176 032 A (Frickel et al. i . 0 176 17 033 A (Frickel et al. 0 253 302 A (Klaus et al.1. 18 0 303 915 A (Brvce et al. A UK Patent Application GB 19 2190378 A (Klaus et al. ) , German Patent Application 0 Nos. DE 3715955 Al (Klaus et al... DE 3602473 Al 1 (Wuest et al. , and the articles J. Amer. Acad. Derm. 2 1_5 : 756 - 764 (1986) (Sporn et al. ) . Chem. Pharm. 3 Bull. 33: 404-407 (1985) (Shudo et al.) . J. Med 4 Chem. 1988 31, 2182 - 2192 (Kaσechika et al. A 5 Chemistry and Biology of Synthetic Retinoids CRC 6 Press Inc. 1990 p 334 - 335, 354 (Dawson et al. A 7 describe or relate to compounds which include a β tetrahydronaphthyl moiety and have retinoid-like or 9 related biological activity. o United States Patent Nos. 4,980,369, 5,006,550, 1 5,015,658, 5,045,551, 5,089,509, 5,134,159, 2 5,162,546, 5,234,926, 5,248,777, 5,264,578, 3 5,272,156, 5,278,318, 5,324,744, 5,346,895, 4 5,346,915, 5,348,972, 5,348,975, 5,380,877, ι 5,399,561, 5,407,937, (assigned to the same assignee 2 as the present application) and patents and 3 publications cited therein, describe or relate to 4 chroman, thiochroman and 1,2,3,4-tetrahydroquinoline 5 derivatives which have retinoid-like biological 6 activity. 7 United States Patent No. 4,723,028 (Shudo), β Published European Patent Application Nos. 0 170 105 (Shudo), German Patent Application No. DE 3524199 Al o (Shudo), PCT WO 91/16051 (Spada et al. A PCT WO 1 85/04652 (Polusϊ and J. Med Chem. 1988 31, 2182 - 2 2192 (Kagechika et al.), describe or relate to aryl 3 and heteroaryl or diaryl substituted olephines or amides having retinoid-like or related biological s activity. 6 United States Patent Nos. 4,992,468, 5,013,744, 7 5,068,252, 5,175,185, 5,202,471, 5,264,456, s 5,324,840, 5,326,898, 5,349,105, 5,391,753, 9 5,414,007 and 5,434,173 (assigned to the same assignee as the present application) and patents and 1 publications cited therein, describe or relate to compounds which have retinoid-like biological 3 activity and a structure wherein a phenyl and a 4 heteroaryl or a phenyl and a second phenyl group is 5 linked with an olephinic or acetylenic linkage. 6 Still further, several co-pending applications and 7 recently issued patents which are assigned to the 8 assignee of the present application, are directed to 9 further compounds having retinoid-like activity. It is now general knowledge in the art that two 1 main types of retinoid receptors exist in mammals (and other organisms). The two main types or 3 families of receptors are respectively designated 4 RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RAR α , RAR β and RAR r , in RXR the subtypes are: RXR α , RXB β and RXR r . It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. It is also known in the art that the use of retinoid-like compounds for the treatment of various diseases and conditions is not without problems or side effects. The side effects at therapeutic dose levels include headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dislipidemias, skin irritation, headache, hepatotoxicity, etc. These side effects limit the acceptability and utility of retinoids for treating disease. Research is still ongoing in the art to determine which of the RAR or RXR familes and within each family, which of the subtype or subtypes are responsible for mediating certain therapeutic effects, and which type or subtypes are responsible for mediating one or more of the undesired side effects. Accordingly, among compounds capable of binding to retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Such selectivity or specificity is useful as a research tool for discovering the roles of the several receptor types and subtypes in mediating the various effects of retinoids in biological systems, and also as aid for designing retinoid drugs with specific therapeutic effects and/or with reduced side effects ι and toxicity. Along these lines. United States 2 Patent No. 5,324,840 describes a class of compounds 3 in which retinoid-like activity is accompanied by 4 reduced skin toxicity and reduced teratogenic 5 effects. United States Patent No. 5,399,586 ε describes the use of compounds having RXR retinoid 7 receptor agonist activity for the treatment of β mammals afflicted with tumors. United States Patent 9 No. 5,455,265 describes methods of treatment of ιo mammals with compounds having agonist-like activity 11 on RXR receptors. Published PCT application No. 12 W093/11755 is also directed to the use of compounds i3 which are selective RXR receptor agonists. 1 The present invention provides methods of is treatment of tumors with compounds which are 16 specific or selective to RAR α receptors. 17 SUMMARY OF THE INVENTION It has been is discovered in accordance with the present invention 19 that retinoid-like compounds which act selectively, 0 or preferably even specifically on RAR α receptor 1 subtypes in preference over RAR fl and RAR r receptor 2 subtypes, possess desirable pharmaceutical 3 properties associated with retinoids, and are 4 particularly suitable for treatment of tumors, such 5 as acute monocytic leukemia, cervical carcinoma, 6 myeloma, ovarian carcinomas and head and neck 7 carcinomas, without having one or more undesirable 8 side effects of retinoids, such as inducement of 9 weight loss, mucocutaneous toxicity, skin irritation o and teratogenecity. 1 Accordingly, the present invention relates to 2 the use of RAR α specific or selective retinoid 3 compounds for the treatment of diseases and 4 conditions which respond to treatment by such 1 compounds, and particularly to the treatment of 2 tumors, primarily acute monocytic leukemia, cervical 3 carcinoma, myeloma, ovarian carrcinomas and head and 4 neck carcinomas with the RAR α specific or selective 5 retinoid compounds. In accordance with the present 6 invention the RAR α selective compounds are also 7 particularly advantageously used for treatment of β proliferative vitreoretinopathy (PVR) and age 9 related macular degeneration (AMD). o For the purposes of the present description a 1 compound is considered RAR α specific or selective if 2 in a transactivation assay (described below) the 3 compound transactivates the RAR α receptors at a significantly lower concentration than the RAR β and s RAR r receptors. Instead of measuring 6 transactivation, measuring the binding of a compound 7 respectively to the three RAR receptor subtypes is s also feasible. Binding data expressed in Kd numbers 9 obtained in a binding assay (described below) are 0 also indicative of a compound's ability to act 1 specifically or selectively on RAR α receptors in 2 preference over RAR β and RAR r receptors. A compound 3 is considered RAR 0 specific or selective for the 4 purposes of the present invention if the Kd number 5 for its binding to RAR α receptors is approximately 500 times smaller than the Kd for its affinity to 7 RAR β and RAR r receptors. BRIEF DESCRIPTION OF THE DRAWING FIGURES Figure 1 is a graph showing the results of an RPMI 8226 cell culture assay conducted with all trans retinoic acid (ATRA) and two RAR α selective compounds in accordance with the present invention. Figure 2 is another graph showing the results of an AML 193 cell culture assay conducted with two RAR α ι selective compounds in accordance with the present 2 invention, and with two compounds which are not RAR α 3 selective. 4 Figure 3 is still another graph showing results 5 of an AML 193 cell culture assay conducted with 6 three RAR α selective compounds in accordance with the 7 present invention and with all trans retinoic acid β (ATRA) . 9 Figure 4 is a graph showing the proliferation of ιo ovarian tumor cells in a cell culture assay (EDR ιι assay) in the presence of varying concentrations of 12 Compound 2 in accordance with the present invention. 13 Figure 5 is a graph showing the RPE cell 1 proliferation in the presence of all trans retinoic is acid or Compound 42 in the culture medium. i6 Figure 6 is a graph showing the weight of a 17 group of experimental rats which were administered is for 3 days varying doses of an RAR α selective 19 compound in accordance with the present invention. 0 Figure 7 is a bar graph showing the weight of 1 a group of experimental rats at the end of a 4 day 2 period wherein for three days the rats were 3 administered varying doses of Compound 18 in 4 accordance with the invention; 5 Figure 8 is a graph showing the weight of guinea 6 pigs which were treated with varying doses of 7 Compound 42 for 15 days. 8 DETAILED DESCRIPTION OF THE INVENTIONGene al 9 Embodimen sDefinitions regarding the chemical 0 compounds used in the present invention 1 The term alkyl refers to and covers any and all 2 groups which are known as normal alkyl, 3 branched-chain alkyl and cycloalkyl. The term 4 alkenyl refers to and covers normal alkenyl, branch 1 chain alkenyl and cyσloalkenyl groups having one or 2 more sites of unsaturation. Similarly, the term 3 alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more 5 triple bonds. 6 Lower alkyl means the above-defined broad 7 definition of alkyl groups having 1 to 6 carbons in β case of normal lower alkyl, and as applicable 3 to 6 9 carbons for lower branch chained and cycloalkyl ιo groups. Lower alkenyl is defined similarly having 2 ιι to 6 carbons for normal lower alkenyl groups, and 3 12 to 6 carbons for branch chained and cyclo- lower 13 alkenyl groups. Lower alkynyl is also defined 14 similarly, having 2 to 6 carbons for normal lower is alkynyl groups, and 4 to 6 carbons for branch 16 chained lower alkynyl groups. 17 The term "ester" as used here refers to and 18 covers any compound falling within the definition of is that term as classically used in organic chemistry. 0 It includes organic and inorganic esters. Where B 1 in the general formula of the preferred compounds 2 used in the invention is -C00H, this term covers the 3 products derived from treatment of this function 4 with alcohols or thioalcohols preferably with 5 aliphatic alcohols having 1-6 carbons. Where the 6 ester is derived from compounds where B is -CH 2 OH, 7 this term covers compounds derived from organic 8 acids capable of forming esters including 9 phosphorous based and sulfur based acids, or 0 compounds of the formula -CH j OCOR^ where R__ is any i substituted or unsubstituted aliphatic, aromatic, 2 heteroaromatic or aliphatic aromatic group, 3 preferably with 1-6 carbons in the aliphatic 4 portions. ι Unless stated otherwise in this application, 2 preferred esters are derived from the saturated 3 aliphatic alcohols or acids of ten or fewer carbon 4 atoms or the cyclic or saturated aliphatic cyclic 5 alcohols and acids of 5 to 10 carbon atoms. 6 Particularly preferred aliphatic esters are those 7 derived from lower alkyl acids and alcohols. Also 8 preferred are the phenyl or lower alkyl phenyl 9 esters. ιo Amides has the meaning classically accorded that 11 term in organic chemistry. In this instance it 12 includes the unsubstituted amides and all aliphatic 13 and aromatic mono- and di- substituted amides. 1 Unless stated otherwise in this application, is preferred amides are the mono- and di-substituted 16 amides derived from the saturated aliphatic radicals 17 of ten or fewer carbon atoms or the cyclic or 18 saturated aliphatic-cyclic radicals of 5 to 10 i9 carbon atoms. Particularly preferred amides are 20 those derived from substituted and unsubstituted 21 lower alkyl amines. Also preferred are mono- and 2 disubstituted amides derived from the substituted 3 and unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred. 25 Acetals and ketals include the radicals of the 6 formula-CK where K is (-OR) 2 . Here, R is lower 7 alkyl. Also, K may be -ORγO- where R 7 is lower alkyl 8 of 2-5 carbon atoms, straight chain or branched. 9 A pharmaceutically acceptable salt may be 0 prepared for any compound used in this invention 1 having a functionality capable of forming such-salt, 2 for example an acid functionality. A 3 pharmaceutically acceptable salt is any salt which 4 retains the activity of the parent compound and does 1 not impart any deleterious or untoward effect on the 2 subject to which it is administered and in the 3 context in which it is administered. 4 Pharmaceutically acceptable salts may be derived 5 from organic or inorganic bases. The salt may be a e mono or polyvalent ion. Of particular interest are 7 the inorganic ions, sodium, potassium, calcium, and β magnesium. Organic salts may by be made with 9 amines, particularly ammonium salts such as mono-, 10 di- and trialkyl amines or ethanol amines. Salts 11 may also be formed with caffeine, tromethamine and i2 similar molecules. Where there is a nitrogen 13 sufficiently basic as to be capable of forming acid 14 addition salts, such may be formed with any is inorganic or organic acids or alkylating agent such 16 as methyl iodide. Preferred salts are those formed i7 with inorganic acids such as hydrochloric acid, 18 sulfuric acid or phosphoric acid. Any of a number 19 of simple organic acids such as mono-, di- or tri- 20 acid may also be used. 1 Some of the compounds used in the present 2 invention may have trans and cis (E and Z) isomers. 3 In addition, the compounds used in the present invention may contain one or more chiral centers and 5 therefore may exist in enantiomeric and 6 diastereomeric forms. The scope of the present 7 invention is intended to cover the use of all such β isomers per se, as well as mixtures of cis and trans 9 isomers, mixtures of diastereomers and racemic 0 mixtures of enantiomers (optical isomers) as well. 1 Description of the Compounds Preferably Used in the 2 Methods of the Invention 3 The retinoid-like compounds used in the methods of treatment of the present invention are specific or selective for RAR α receptors. That a compound is specific or selective to RAR α receptors can be ascertained in transactivation assays described below where an RAR α specific or selective compound transactivates RAR α receptors at a significantly lower concentrations than RAR β or RAR r receptors. In a binding assay where the ability of the compound to bind to these receptor subtypes is measured, a compound that is considered RAR α specific or selective for the purposes of the present invention binds at least approximately 500 times stronger to RAR α receptors than to the RAR β or RAR r receptors. Alternatively, the compound is considered RAR α specific or selective if in the binding assay its Kd number is approximately in the 10 "1 to 5 X 10 2 nanomolar range and the Kd number for RAR β or RAR r receptors is greater than 1000 nanmolar. The latter is indicated by 0.00 in the below provided Tables where binding data (Kd numbers) for certain exemplary compounds of the present invention are illustrated. Examples for RAR α selective compounds which are preferably used in accordance with the present invention are illustrated by Formula 1 and Formula 2 Formula 1 Formula 2 1 where x is 0 or X_ is [C(R 1 ) 2 ] n where n is an integer 2 between 0 and 2; 3 x is independently H or alkyl of 1 to 6 4 carbons; 5 R 2 is independently hydrogen, or lower alkyl of 6 1 to 6 carbons; 7 R 3 is hydrogen, lower alkyl of 1 to 6 carbons or β F; 9 m is an integer having the value of 0 - 5 ιo o is an integer having the value of 0 - 4 ιι p is an integer having the value of 0 - 2 12 r is an integer having the value 0 - 2; 13 X 2 is N or CH; ι Y is a phenyl or naphthyl group, or heteroaryl 15 selected from a group consisting of pyridyl, 16 thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said 18 phenyl, naphthyl and heteroaryl groups being 19 optionally substituted with one or two R 2 groups; 0 j is a substituent selected independently from 1 the group consisting of F, Br, Cl, I, fluoro 2 substituted C__ 6 alkyl, N0 2 , and OH, with the provisos 3 that: 4 (i) when the compound is in accordance with 5 Formula 1 and Z is 0 then the sum of p and r is at 6 least 1 and Η_ is not a fluoro group in the 3 7 position of a tetrahydronaphthalene ring; 8 (ϋ) when the compound is in accordance with 9 Formula 1 and r is zero and p is 1 and JΛ_ is OH then 0 the OH group is positioned to the L group; 1 W 2 is a substituent selected independently from 2 the group consisting of F, Br, Cl, I, fluoro 3 substituted C__ 6 alkyl, N0 2 , and OH; 4 W 3 is a substituent selected independently from ι the group consisting of F, Br, Cl, I, C 1 _ 6 alkyl, 2 fluoro substituted C__ 6 alkyl, N0 2 , and OH with the 3 proviso that when the compound is in accordance with 4 Formula 2 and X 2 is CH and r is 0 then p is not 0 and 5 at least one W 3 group is not alkyl; 6 L is -(C=Z)-NH- or -NH-(C=Z)- 7 Z is O or S, and β B is COOH or a pharmaceutically acceptable salt 9 thereof , COOR β , CONR 9 R 10 , -CH 2 OH, CH 2 OR ll f CH 2 OCOR xl , 0 CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR,, CR 7 (OR 12 ) 2 , CR-OR^O, 1 where R 7 is an alkyl, cycloalkyl or alkenyl group 2 containing 1 to 5 carbons, R 8 is an alkyl group of 1 3 to 10 carbons or trimethylsilylalkyl where the alkyl 4 group has 1 to 10 carbons, or a cycloalkyl group of s 5 to 10 carbons, or R 8 is phenyl or lower 6 alkylphenyl, R 9 and R 10 independently are hydrogen, 7 an alkyl group of 1 to 10 carbons, or a cycloalkyl 8 group of 5-10 carbons, or phenyl or lower 9 alkylphenyl, R X1 is lower alkyl, phenyl or lower 0 alkylphenyl, R 12 is lower alkyl, and R 13 is divalent 1 alkyl radical of 2-5 carbons. 2 With reference to symbol X_ in Formula 1, 3 compounds are preferred in the methods of the present invention where X_ is [C(R 1 ) 2 ] n and n is 1 5 (tetrahydronaphthalene derivatives) and also where X_ 6 is O (chroman derivatives). With reference to the symbol X 2 in Formula 2, compounds are equally preferred where X 2 is CH or N. When X 2 is CH then 9 the benzene ring is preferably 1, 3, 5 substituted 0 with the L group occupying the 1 position and the W 3 1 and/or R 2 groups occupying the 3 and 5 positions. When the symbol X 2 is N, then the pyridine ring is 3 preferably 2,4,6 substituted with the L group occupying the 4 position and the W 3 and/or R 2 groups occupying the 2 and 6 positions. The R_ groups of Formula 1 are preferably H or CH 3 . The R 3 group of Formula 1 is preferably H. The 4 group B of the preferred compounds of the invention 5 is COOH or a pharamceutically acceptable salt 6 thereof, COOR„ or CONR 9 R 10 , where R 8 , R 9 and R 10 are 7 defined as above. β Referring now to the W x and W 2 groups in Formula 9 1, these groups are, generally speaking, electron 10 withdrawing groups, which are present in the 11 compounds of the invention either in the aromatic i2 portion of the condensed ring system, or as a 13 substituent of the aryl or heteroaryl group Y. 14 Preferably a W 2 group is present in the Y group, and is a x group is also present in the aromatic portion of 16 the condensed ring system. When the Z group is S 17 (thioamides) a f_ or W 2 group does not necessarily 18 have to be present in the compounds of the invention 19 in accordance with Formula 1, although preferably 0 at least one of the JΛ_ or W 2 groups is nevertheless 1 present. In the aryl or heteroaryl Y moiety in the 2 compounds of Formula 1 and Formula 2 as well, the W 2 3 group is preferably located in the position adjacent 4 to the B group; preferably the B group is in para 5 position in the phenyl ring relative to the "amide" 6 moiety, and therefore the W 2 group is preferably in 7 meta position relative to the amide moiety. Where 8 there is a JΛ_ group present in the aromatic portion 9 of the condensed ring system of the compounds of 0 Formula 1, it preferably occupies the 8 position of 1 the chroman nucleus with the Z=C-NH- group occupying 2 the 6 position. In tetrahydronaphthalene compounds 3 of Formula 1, the Z=C-NH- group is preferably in the 4 2-position, and the 2 group is preferably in the 4 position. However, when the W x group is OH in compounds of Formula 1, then the OH is preferably in the 3 position of the tetrahydronaphthalene ring. Preferred W_ and W 2 groups are F, N0 2 , Br, I, CF 3 , C1N 3 , and OH. The presence of one or two fluoro substituents in the Y group (W 2 ) is especially preferred. When the Y group is phenyl, the fluoro substituents preferably are in the ortho and ortho' positions relative to the B group, which is preferably COOH or COOR β . Referring now to the W 3 group in Formula 2, this group is, generally speaking, also an electron withdrawing group or an alkyl group, more specifically preferred W 3 groups are F, N0 2 , Br, I, CF 3 , N 3 , and OH. Alternatively, in the phenyl or pyridyl ring (shown in Formula 2 as substituent "( W 3 /p") W 3 i s n alkyl group, preferably branch-chained alkyl, such as tertiary butyl, and preferably p is 2. With reference to the symbol Y in Formula 1 and in Formula 2 as well, the preferred compounds used in the methods of the invention are those where Y is phenyl, pyridyl, 2-thiazolyl, thienyl, or furyl, more preferably phenyl. As far as substitutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para) substituted by the L and B groups, and where the pyridine ring is 2,5 substituted by the L and B groups. (Substitution in the 2,5 positions in the "pyridine" nomenclature corresponds to substitution in the 6-position in the "nicotinic acid" nomenclature.) In the preferred compounds of the invention there is no optional R x substituent (other than H) on the Y group. The L group of Formula 1 and of Formula 2 is preferably -(C=Z)-NH-, and Z is preferably 0. In other words, those carbamoyl or amide compounds are preferred in accordance with the present invention where the -NH-moiety is attached to the Y group. The compounds which are presently most preferably used in the methods of treatment of the invention are shown below in Table 1 with reference to Formulas 3 and 4 and in Table 2 with reference to Formula 5. Formula 3 Formula 4 3 3 3 4 4 3 3 3 3 3 3 Table 2 Compound # X 2 W 8 W 9 W 10 R * ; 41 N H F H Et 42 N H F H H 43 N H H H Et 44 N H H H H 45 CH H F H Et 46 CH H F H H 47 CH OH F H Et 48 CH OH F H H 49 N H F F Me 50 N H F F H 51 CH H F F Me 52 CH H F F H 53 N H N0 2 H Me 54 N H N0 2 H H Modes of Administration The RAR α specific or selective compounds used in the methods of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need 1 for site-specific treatment, quantity of drug to be 2 administered, and numerous other considerations. 3 In the treatment of dermatoses, it will 4 generally be preferred to administer the drug 5 topically, though in certain cases such as treatment β of severe cystic acne or psoriasis, oral 7 administration may also be used. Any common topical s formulation such as a solution, suspension, gel, 9 ointment, or salve and the like may be used. ιo Preparation of such topical formulations are well 11 described in the art of pharmaceutical formulations 12 as exemplified, for example. Remington's 13 Pharmaceutical Science, Edition 17, Mack Publishing 14 Company, Easton, Pennsylvania. For topical is application, these compounds could also be 16 administered as a powder or spray, particularly in 17 aerosol form. If the drug is to be administered is systemically, it may be confected as a powder, pill, i9 tablet or the like or as a syrup or elixir suitable 0 for oral administration. For intravenous or 1 intraperitoneal administration, the compound will be 2 prepared as a solution or suspension capable of 3 being administered by injection. In certain cases, 4 it may be useful to formulate these compounds by 5 injection. In certain cases, it may be useful to 6 formulate these compounds in suppository form or as 7 extended release formulation for deposit under the 8 skin or intramuscular injection. 9 Other medicaments can be added to such topical o formulation for such secondary purposes as treating 1 skin dryness; providing protection against light; 2 other medications for treating dermatoses; 3 medicaments for preventing infection, reducing 4 irritation, inflammation and the like. ι Treatment of dermatoses or any other indications 2 known or discovered to be susceptible to treatment 3 by retinoic acid-like compounds will be effected by 4 administration of the therapeutically effective dose 5 of one or more compounds of the instant invention. 6 A therapeutic concentration will be that 7 concentration which effects reduction of the 8 particular condition, or retards it expansion. In 9 certain instances, the compound potentially may be ιo used in prophylactic manner to prevent onset of a 11 particular condition. 12 A useful therapeutic or prophylactic i3 concentration will vary from condition to condition 14 and in certain instances may vary with the severity is of the condition being treated and the patient's 16 susceptibility to treatment. Accordingly, no single 17 concentration will be uniformly useful, but will is require modification depending on the 19 particularities of the disease being treated. Such 0 concentrations can be arrived at through routine 1 experimentation. However, it is anticipated that in 2 the treatment of, for example, acne, or similar 3 dermatoses, that a formulation containing between 4 0.01 and 1.0 milligrams per mililiter of formulation 5 will constitute a therapeutically effective 6 concentration for total application. If 7 administered systemically, an amount between 0.01 8 and 5 mg per kg per day of body weight would be 9 expected to effect a therapeutic result in the 0 treatment of many disease for which these compounds 1 are useful. 2 In the treatment of tumors a dose of 3 approximately 0.5 to 5 mg per kg body weight per day 4 is anticipated to constitute the therapeutic dose. ι Alternatively, as is performed frequently in therapy 2 of malignancies, a patient is provided an initial 3 dose of 1 mg per kg body weight per day, and 4 therafter the dose is raised until a maximum 5 tolerated dose is attained. 6 Assay of RAR α receptor selective biological activity 7 and its significance in reduced side effects and β toxicity 9 As it is noted in the introductory section of o this application for patent two main types of 1 retinoic acid receptors (RAR and RXR) exist in 2 mammals (and other organisms). Within each type 3 there are sub-types (RAR C , RAR β , RAR r , RXR α , RXR β and 4 RXR r ) the distribution of which is not uniform in the 5 various tissues and organs of mammalian organisms. 6 Selective binding of only one or two retinoid 7 receptor subtypes within one retinoid receptor s family can give rise to beneficial pharmacological 9 properties because of the varying distribution of 0 the sub-types in the several mammalian tissues or 1 organs. For the above-summarized reasons, binding 2 of any or all of the retinoid receptors, as well as 3 specific or selective activity in a receptor family, 4 or selective or specific activity in any one of the 5 receptor subtypes, are all considered desirable 6 pharmacological properties. 7 In light of the foregoing the prior art has 8 developed assay procedures for testing the agonist 9 like activity of compounds in the RAR α , RAR β , RAR r , 0 RXR α , RXR β and RXR r receptor subtypes. For example, 1 a chimeric receptor transactivation assay which 2 tests for agonist-like activity in the RAR α , RAR β , 3 RAR r , and RXR α receptor subtypes, and which is based 4 on work published by Feigner P. L. and Holm M. 1 (1989) Focus, 11 2 is described in detail in U.S. 2 Patent No. 5,455,265. The specification of United 3 States Patent No. 5,455,265 is expressly 4 incorporated herein by reference. 5 A holoreceptor transactivation assay and a 6 ligand binding assay which measure the ability of 7 compounds to bind to the several retinoid receptor β subtypes, respectively, are described in published 9 PCT Application No. WO W093/11755 (particularly on ιo pages 30 - 33 and 37 - 41) published on June 24, ιι 1993, the specification of which is also 12 incorporated herein by reference. A description of 13 the ligand binding assay is also provided below. 14 BINDING ASSAY is All binding assays were performed in a similar 16 fashion. All six receptor types were derived from 17 the expressed receptor type (RAR α, R , T and RXR α, is β, T) expressed in Baculovirus. Stock solutions of 19 all compounds were prepared as lOmM ethanol 0 solutions and serial dilutions carried out into 1:1 1 DMSO; ethanol. Assay buffers consisted of the 2 following for all six receptor assays: 8% glycerol, 3 120mM KC1, 8mM Tris, 5mM CHAPS 4mM DTT and 0.24mM 4 PMSF, pH - 7.4§ room temperature. 5 All receptor binding assays were performed in 6 the same manner. The final assay volume was 250μl 7 and contained from 10-40μg of extract protein 8 depending on receptor being assayed along with 5 nM 9 of [ 3 H] all-trans retinoic acid or lOnM [ 3 H] 9-cis 0 retinoic acid and varying concentrations of 1 competing ligand at concentrations that ranged from 2 0 - 10 "5 M. The assays were formatted for a 96 well 3 minitube system. Incubations were carried out at 4 4°C until equilibrium was achieved. Non-specific 21 ι binding was defined as that binding remaining in the 2 presence of lOOOnM of the appropriate unlabeled 3 retinoic acid isomer. At the end of the incubation 4 period, 50μl of 6.25% hydroxyapitite was added in 5 the appropriate wash buffer. The wash buffer 6 consisted of lOOmM KC1, lOmM Tris and either 5mM 7 CHAPS (RXR α, β, T ) or 0.5% Triton X-100 (RAR α, β, 8 T). The mixture was vortexed and incubated for 10 e minutes at 4°C, centrifuged and the supernatant o removed. The hydroxyapitite was washed three more 1 times with the appropriate wash buffer. The 2 receptor-ligand complex was adsorbed by the 3 hydroxyapitite. The amount of receptor-ligand 4 complex was determined by liquid scintillation s counting of hydroxyapitite pellet. 6 After correcting for non-specific binding, IC 50 7 values were determined. The IC 50 value is defined as s the concentration of competing ligand needed to 9 reduce specific binding by 50%. The IC 50 value was 0 determined graphically from a loglogit plot of the 1 data. The K d values were determined by application 2 of the Cheng-Prussof equation to the IC 50 values, the 3 labeled ligand concentration and the K d of the 4 labeled ligand. 5 The results of ligand binding assay are expressed 6 in K d numbers. (See Cheng et al. Biochemical 7 Pharmacology Vol. 22 pp 3099-3108, expressly 8 incorporated herein by reference.) 9 Table 3 shows the results of the ligand binding 0 assay for certain exemplary compounds of the 1 invention. TABLE 3 Ligand Binding Assay Compound # K d (nanomolar) RARα RARβ RARΓ RXRα RXRβ RXRΓ 2 1.90 480.0 0.00 0.00 0.00 0.00 4 1.3 0.00 0.00 0.00 0.00 0.00 6 3.00 0.00 0.00 0.00 0.00 0.00 10 24.0 0.00 0.00 0.00 0 00 0.00 12 14 ,0 0.00 0.00 0.00 0 00 0.00 14 52 0 0.00 0.00 0.00 0 00 0.00 16 51 0 0.00 0.00 0.00 0 00 0.00 18 16 0 0.00 0.00 0.00 0, 00 0.00 20 57 0 0.00 0.00 0.00 0.00 0.00 22 15 0.00 0.00 0.00 0.00 0.00 24 7.5 0.00 0.00 0 00 0 .00 0.00 26 245.0 0.00 0.00 0 00 0.00 0.00 28 162.0 0.00 0.00 0 00 0.00 0.00 30 <3.00 0.00 0.00 0 00 0.00 0.00 32 2.30 0.00 0.00 0 00 0 ,00 0.00 34 9.00 0.00 0.00 0, 00 0 00 0.00 42 14.00 0.00 0.00 0.00 0.00 0.00 44 19.00 0.00 0.00 0.00 0.00 0.00 46 26.0 0.00 0.00 0.00 0.00 0.00 48 77.0 0.00 0.00 0.00 0.00 0.00 50 62.0 0.00 0.00 0.00 0.00 0.00 52 87.0 0.00 0.00 0.00 0.00 0.00 54 94.0 0.00 0.00 0.00 0.00 0.00 TTNPB 1 72 36 0.00 indicates value greater than lOOOnM (nanomolar) ι TTNPB is a well known prior art retinoid (4-(E)-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2- yl)propen-l-yl)benzoic acid, that is not RAR α selective. ι As it can be seen from the foregoing data, the 2 compounds used in accordance with the present 3 invention specifically or selectively bind to RAR α 4 retinoid receptors. It has been discovered in 5 accordance with the present invention that this 6 unique type of selectivity allows the compounds to 7 retain beneficial retinoid-like properties while β reduces certain side effects and toxicity. More β specifically, certain in vitro cell culture assays ιo are described below, in which the ability of the RAR α ιι specific or selective compounds to significantly 12 inhibit the growth of cancer cells is demonstrated. 13 CANCER CELL LINE ASSAYS 14 MATERIALS AND METHODS is Hormones 16 All trans-retinoic acid (t-RA) (Sigma Chemicals 17 Co., St. Louis, MO) was stored at -70°C. Prior to 18 each experiment the compound was dissolved in 100% 19 ethanol at 1 mM and diluted in culture medium 0 immediately before use. All experiments were 1 performed in subdued light. Controls were assayed 2 using the same concentration of ethanol as present 3 in the experimental plates and this concentration of 4 diluent had no effect in either assay. 25 Cells and Cell Culture 6 The cell lines, RPMI 8226, ME-180 and AML-193 27 were obtained from the American Type Culture 28 Collection (ATCC, Rockville, MD). RPMI 8226 is a 29 human hematopoietic cell line obtained from the 30 peripheral blood of a patient with multiple myeloma. 31 The cells resemble the lymphoblastoid cells of other 2 human lymphocyte cell lines and secrete α-type light 3 chains of immunoglobulin. RPMI-8226 cells are grown 34 in RPMI medium (Gibco) supplemented with 10% fetal 1 bovine serum, glutamine and antibiotics. The cells 2 were maintained as suspension cultures grown at 37°C 3 in a humidified atmosphere of 5% C0 2 in air. The 4 cells were diluted to a concentration of 1 x lOVml 5 twice a week. 6 ME-180 is a human epidermoid carcinoma cell line derived from the cervix. The tumor was a highly β invasive squamous cell carcinoma with irregular cell 9 clusters and no significant keratinization. ME-180 ιo cells were grown and maintained in McCoy's 5a medium 11 (Gibco) supplemented with 10% fetal bovine serum, 12 glutamine and antibiotics. The cells were 13 maintained as monolayer cultures grown at 37°C in a i4 humidified atmosphere of 5% C0 2 in air. The cells is were diluted to a concentration of 1 x lOVml twice a 16 week. 17 AML-193 was established from the blast cells 18 classified as M5 Acute Monocyte Leukemia. The i9 growth factor, granulocyte colony-stimulation factor 20 (GM-CSF) was required to establish this cell line 21 and growth factors are necessary for its continuous 2 proliferation in chemically defined medium. AML-193 3 cells were grown and maintained in Iscove's modified 4 Dulbecco's medium supplemented with 10% fetal bovine 5 serum, glutamine and antibiotics with 5μg/ml insulin 6 (Sigma Chemical Co.) and 2 ng/ml rh GM-CSF (R and D 7 Systems). The cells were diluted to a concentration 8 of 3 x lOVml twice a week. 9 Incorporation of 3 H-Thymidine 0 The method used for determination of the 1 incorporation of radiolabeled thymidine was adapted 2 from the procedure described by Shrivastav et al. 3 RPMI-8226 cells were plated in a 96 well round 4 bottom microtiter plate (Costar) at a density of 1 1,000 cells/well. To appropriate wells, retinoid 2 test compounds were added at the final 3 concentrations indicated for a final volume of 150 4 μl/well. The plates were incubated for 96 hours at 5 37°C in a humidified atmosphere of 5% C0 2 in air. 6 Subsequently, 1 μCi of [5'- 3 H]-thymidine (Amersham, 7 U.K. 43 Ci/mmol specific activity) in 25 μl culture β medium was added to each well and the cells were 9 incubated or an additional 6 hours. The cultures ιo were further processed as described below. 11 ME-180 wells, harvested by trypsinization were 12 plated in a 96 well flat bottom microtiter plate 13 (Costar) at a density of 2,000 cells/well. The i4 cultures were treated as described above for RPMI is 8226 with the following exceptions. After 16 incubation with thymidine the supernatant was 17 carefully removed, and the cells were washed with a 18 0.5 mM solution of thymidine in phosphate buffered 19 saline. ME180 cells were briefly treated with 50μl 20 of 2.5% trypsin to dislodge the cells from the 1 plate. 22 AML-193 cells were plated in a 96 well round 23 bottom microtiter plate (Costar) at a density of 24 1,000 cells/well. To appropriate wells, retinoid 5 test compounds were added at the final 6 concentrations indicated for a final volume of 150 7 μl/well. The plates were incubated for 96 hours at 8 37°C in a humidified atmosphere of 5% C0 2 in air. 9 Subsequently, 1 μCi of [5 , - 3 H]-thymidine (Amersham, 0 U.K., 43 Ci/mmol specific activity) in 25 μl culture 1 medium was added to each well and the cells were 2 incubated for an additional 6 hours. 3 The cell lines were then processed as follows: 4 the cellular DNA was precipitated with 10% ι trichloroacetic acid onto glass fiber filter mats 2 using a SKATRON multi-well cell harvester (Skatron 3 Instruments, Sterling VA) . Radioactivity 4 incorporated into DNA, as a direct measurement of 5 cell growth, was measured by liquid scintillation 6 counting. The numbers represent the mean 7 disintegrations per minute of incorporated thymidine β from triplicate wells ± SEM. 9 The graph of Figure 1 of the appended drawings o shows that in the above described RPMI 8226 cell 1 (malignant myeloma) culture assay Compounds 4 and 12 2 (two exemplary compounds used in accordance with 3 this invention) inhibited the growth of these 4 malignant cells, substantially as well as a 5 comparison compound, all trans retinoic acid (ATRA) . 6 The graph of Figure 1 also demonstrates that whereas 7 in a low concentration range (10 ~12 to approximately 8 10" 9 ) all trans retinoic acid (ATRA) actually 9 facilitates growth of these cells, the RAR a selective 0 Compounds 4 and 12 of the present invention do not 1 stimulate but rather already in this low concentrations inhibit the growth of these malignant cells. The graph of Figure 2 shows that in the above described AML 193 (acute monocytic leukemia) cell culture assay Compounds 22 and 42 in accordance with this invention inhibited the growth of these malignant cells. Two other compounds for which data are also shown in this graph are designated AGN 193090 and AGN 193459. (An AGN number is an arbitrary designation number used by the corporate assignee of the present invention.) The compounds AGN 193090 and AGN 193459 are not RAR α selective. These compounds respectively are ι 4-[ (8-cyano-5,6-dihydro-5,5-dimethylnaphth-2-yl)ethy 2 nyl]benzoic acid, and 3 4-[ (5,6-dihydro-5,5-dimethylnaphth-7(6H)-8-(1-2,2-di methylpropylidene)naphth-2-yl)ethynyl]benzoic acid, 5 and their Kd values for RAR α , RAR β and RAR r receptors 6 are 109, 34, 77 and 6, 2, 7, respectively. The 7 graph of Figure 2 demonstrates that the RAR α e selective or specific compounds inhibit the 9 malignant cell growth at low concentrations where o the pan agonist AGN 193090 and AGN 193459 compounds 1 do not inhibit but rather at these low 2 concentrations even stimulate such cell growth. 3 Figure 3 is another graph showing the results of 4 an AML-193 cell culture assay, where Compounds 4, 12 s and 18 in accordance with the present invention, and 6 all trans retinoic acid (ATRA) were tested. The 7 data show that the RAR α selective compounds reduce s cell proliferation at low concentrations whereas 9 ATRA at the same low concentration actually promotes cell proliferation. 1 In another line of assays the effect of the retinoid compounds is tested against cells obtained 3 from solid tumors of patients. This EDR assay is 4 described below as follows: 5 Freshly resected solid tumor biopsies were received within 24 hours of surgery. Species were processed for assay after retaining a portion of the tumor for paraffin embedding and histopathologic 9 confirmation of specimen viability and tissue diagnosis. The remaining specimen was dissociated 1 into small fragments using sterile scissors. The small tissue fragments were then exposed to collagenase and DNAase for 2 hours with mixing a C0 2 incubator in order to release the tumor cells from the connective tissue stroma. The resulting cell suspension was washed, and cell counts determined from a cytospin preparation. Tumor cells were resuspended at 40,000 cells per ml in 0.3% agarose in RMPI 1640 supplemented with 15% FCS, glutamine and antibiotics, and 0.5 ml were plated into each well of a 24 well plate over 0.5 ml layer of 0.5% agarose. These culture conditions prevent cell adherence, thereby allowing only transformed cells to proliferate. Additionally, the cells grow into three dimensional spheroids, recapitulating their in vivo morphology. Retinoid drugs were added 24 hours after plating to insure specimen reequilibration to a growth environment after the rigors of transport and processing. Cells were grown for four days in the presence of drug, with 3 H-thymidine (5 uCi/ml) added 48 hours prior to harvest to insure adequate labeling of proliferating cells. After the agarose-cell suspension was liquefied at 90°C, cells were harvested onto glass fiber filters, which were counted in 5 ml scintillation fluid using a Beckman 6500 liquid scintillation counter. Results are reported as fraction of untreated control cell proliferation. Treatment groups were performed in duplicate or triplicate, while the controls were performed in quadruplicate. The graph of Figure 4 shows the effect of Compound 2 on ovarian tumors obtained from 4 patients, and demonstrates that the compound inhibits this tumor cell proliferation in a concentration dependent manner. It will be understood by those skilled in the art, that the ability of the RAR α selective compounds ι to significantly inhibit growth of malignant cells 2 in the above described assays is an indication that 3 these compounds can be administered with beneficial effect to tumor bearing mammals (including humans) 5 for the treatment of tumors, particularly acute 6 monocytic leukemia, cervical carcinoma, myeloma, 7 ovarian carcinomas and head and neck carcinomas. 8 It has also been discovered in accordance with 9 the present invention that the proliferation of ιo retinal pigment epithelium cells is inhibited by RAR α ιι selective compounds. By way of background it is 12 noted that after retinal detachment the retinal 13 pigment epithelium (RPE) becomes dedifferentiated, 14 proliferates and migrates into the subretinal space is (Campochiaro et al., Invest. Opthal & Vis. Sci. 16 32:65-72 (1991)). Such processes therefore have an 17 impact upon the success of retinal reattachment 18 procedures. RAR agonists such as all-trans-retinoic 19 acid (ATRA) exhibit an antiproliferative effect upon 0 the growth rate of primary human RPE cultures 1 (Campochiaro et al., ibid) and have been shown to 2 decrease the incidence of retinal detachment after 3 retinal reattachment surgery in human studies 4 (Fekrat et al. , Opthamology 102:412-418 (1994)). 5 The graph of Figure 5 shows the concentration 6 dependent inhibitory effect of all trans retinoic 7 acid (ATRA) and of Compound 42 on RPE proliferation β in an assay procedure which is described below. 9 Analysis of primary RPE cultures 0 Primary cultures of human retinal pigment 1 epithelium (RPE) were established from eyes as 2 previously described, (Campochiaro et al.. Invest. 3 Opthal & Vis. Sci. 32:65-72 (1991)). 5 X 10 4 Cells 4 were plated in 16-mm wells of 24-well multiwell 1 plates in Dulbecco's modified Eagle's medium (DMEM 2 Gibco) containing 10% fetal bovine serum (FBS). 3 Cells were treated with ethanol alone (control), ATRA (10 ~10 to 10 "6 M) in ethanol, and Compound 42 s (10 ~10 to 10" 6 M) in ethanol. Cells were fed with 6 fresh media containing the appropriate 7 concentrations of these compounds every two days for β a total of six days treatment. Cells were removed 9 from the plates via treatment with trypsin and the ιo number of cells were counted with an electronic cell 11 counter. As it can be seen in Figure 5 treatment of 12 primary RPE cells with ATRA and with Compound 42 13 both led to a dose dependent decrease in RPE cell 14 proliferation. is The effect of topically administering to 16 experimental hairless mice RAR α selective retinoid i7 compounds in accordance with the present invention 18 was also evaluated in a topical skin irritation i9 assay, using the RAR α selective Compound 18 of the 0 invention. More particularly, skin irritation was i measured on a semi-quantitative scale by the daily 2 subjective evaluation of skin flaking and abrasions. 3 A single number, the topical irritation score, 4 summarizes the skin irritation induced in an animal 5 during the course of an experiment. The topical 6 irritation score is calculated as follows. The 7 topical irritation score is the algebraic sum of a 8 composite flaking score and a composite abrasion 9 score. The composite scores range from 0-9 and 0-8 0 for flaking and abrasions, respectively, and take 1 into account the maximum severity, the time of 2 onset, and the average severity of the flaking and 3 abrasions observed. 4 The severity of flaking is scored on a 5-point ι scale and the severity of abrasions is scored on a 2 4-point scale, with higher scores reflecting greater 3 severity. The maximum severity component of the 4 composite scores would be the highest daily severity 5 score assigned to a given animal during the course 6 of observation. 7 For the time of onset component of the composite β score, a score ranging from 0 to 4 is assigned as 9 follows: 10 ιι Time to Appearance of 12 Flaking or Abrasions of 13 Severity 2 or greater 14 (days) Time of Onset Score 15 16 8 0 7 6-7 1 18 5 2 19 3-4 3 0 1-2 4 1 2 The average severity component of the composite 3 score is the sum of the daily flaking or abrasion 4 scores divided by the number of observation days. 5 The first day of treatment is not counted, since the 6 drug compound has not had an opportunity to take 7 effect at the time of first treatment. β To calculate the composite flaking and abrasion 9 scores, the average severity and time of onset 0 scores are summed and divided by 2. The result is i added to the maximal severity score. The composite 2 flaking and abrasion scores are then summed to give 3 the overall topical irritation score. Each animal 4 receives a topical irritation score, and the values are expressed as the mean + SD of the individual scores of a group of animals. Values are rounded to the nearest integer. Thus, female hairless mice [Crl:SKHl-hrBR] (8-12 weeks old, n=4) were treated topically for 5 consecutive days with Compound 18 in doses expresed in nanomol/25 g, which is particularly given in Table 4. Treatments are applied to the dorsal skin in a total volume of 4 ml/kg (-0.1 ml). Mice were observed daily and scored for flaking and abrasions up to and including 3 days after the last treatment, i.e., day 8. Table 4 Eight Day Topical Assay in Hairless Mice of Compound 18 Dose Mortality Body Weight Flaking Abrasion Composite (out of 4 ) % gain or Score Score Score (loss) 100 0 8 ± 7 0 1 1 + 1 1000 0 4 ± 1 1 1 2 ± 0 of TTNPB 0.9 0 5 ± 2 5 3 8 ± 2 2.7 0 (4 ± 3) 6 3 9 ± 2 9 0 (11 ± 3) 7 5 11 ± 2 These data show that the RAR α selective compound causes virtually no skin irritation and no weight 1 loss up to 1000 nmol/25g in the test model. For 2 comparison it should be noted that the well known 3 prior art retinoid compound 4-(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnapht 5 halen-2-yl)propen-l-yl)benzoic acid (TTNPB), which 6 is not RAR α selective, causes much more serious skin 7 irritation in the above-noted test, as is shown in β the foregoing table. Another important advantage of administering o RAR α selective retinoid compounds to a mammal lies in the significantly reduced teratogenic potency of the 2 RAR σ selective compounds compared to many other 3 retinoids, as measured by a chondrogenesis 4 suppression bioassay. This assay is performed as s follows: 6 High-density "spot" cultures of limb bud 7 mesenchymal cells are used to compare the ability of 8 various concentrations of test drugs to suppress 9 chondrogenic differentiation as a bioassay. 0 Forelimb buds of mouse embryos on day 12 of 1 gestation (54 ± 2 somites) are dissociated in a 2 trypsin-EDTA solution, and the resultant single-cell 3 suspension is plated as 20-μl spots (200,000 4 cells/spot) on plastic culture dishes. Retinoid 5 concentrations ranging from 0.3 ng/ml to 3 μg/ml (1 6 nM-10 μM) are added to the culture medium (Eagle's 7 MEM + 10% fetal bovine serum, GIBCO) 24 hours after β initial plating. Control cultures receive only the 9 vehicle (ethanol, concentration ≤ 1% by vol); 0 Retinoic acid is used as a positive control in 1 another set of cultures. 2 The cultures are terminated 96 hours after 3 plating, at which time the medium is removed and the 4 cells are fixed for 1 hour in 10% formalin ι containing 0.5% cetylpyridinium chloride. The 2 cultures are rinsed in acetic acid and stained for 1 3 hour in 0.5% Alcian blue solution at pH 1.0, 4 differentiated in 3% acetic acid, and then 5 dehydrated in ethanol and scored for chondrogenesis 6 under the microscope. An absence or reduction in 7 the number of cartilage nodules in stained cultures β as compared with control cultures is taken as a 9 measure of suppression of chondrogenesis. The ιo number of cartilage nodules stained in the whole ιι spot, mean number of nodules, and standard 12 deviations are calculated for four replicate 13 cultures per treatment. The median concentration 14 causing a 50% inhibition of chondrogenesis compared is with controls (IC 50 ) is calculated by logarithmic 16 curve fitting of the dose-response data. The IC 50 17 values are expressed in nanogram per mililiter is (ng/ml) units. An IC 50 value of greater 19 concentration in this assay signifies lesser 0 teratogenecity. Table 5 indicates the results 1 obtained in this assay for Compounds 10, 18, and 42 2 in accordance with the present invention, as well as 3 for comparison with all trans retinoic acid (ATRA) 4 and 4-(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra- 5 methylnaphtha-len-2-yl ) propen-l -yl ) benzoic acid 6 ( TTNPB ) . 7 β Table 5 9 Compound IC 50 ( ng/ml ) o 10 250 1 18 220 2 42 65 3 ATRA 55 4 TTNPB 0.01 1 As it can be seen the compounds used in 2 accordance with the present invention are less 3 teratogenic than all trans retinoic acid and 4 significantly (of the 10 4 order of magnitude) less 5 teratogenic than the prior art TTNPB compound. 6 Weight loss or gain that experimental animals 7 experience upon administration of retinoid compounds β is another test of the drug's toxicity, with 9 significant weight loss at relatively low doses ιo indicating a significant toxic side effect of the ιι retinoid. In one experiment, groups of 5 rats were 12 treated with varying doses (administered in corn 13 oil) of a test retinoid for 3 days. The rats were 14 euthanized 24 hours after the last dose. The graph is of Figure 6 shows the average weight of each group 16 of rats treated with a daily dose of 10, 30, and 90 17 μmol/kg/day of Compound 42, as well as the average 18 weight of a group of control rats which were not 19 given the retinoid. As it can be seen, the RAR α 0 selective Compound 42 caused virtually no weight 1 loss, as compared to the control, except in a very 2 high dose (90 μmol/kg/day). The graph of Figure 7 3 shows the weight of the rats on the fourth day (24 4 hours after last administration of retinoid) in a 5 similar test with varying doses of Compound 18, with 6 a zero dose indicating the control. As it can be 7 seen, this RAR α selective retinoid caused virtually 8 no weight loss even in the high dose of 90 9 μmol/kg/day. It is noteworthy that in similar tests 0 TTNPB, which binds to all three RAR receptor 1 subtypes (see Table 3) causes very significant 2 weight loss. In this experiment involving the rats 3 treated with Compound 42, significant mucocutaneous 4 toxicity was not observed. 1 In another experiment three-week old male 2 Hartley guinea pigs were implanted intraperitonially 3 with osmotic pumps containing 20 % DMSO/80 4 polyethylene glycol (vehicle) or Compound 42 at 5 concentrations of 4.4, 13.3 or 40 mg/ml in vehicle. 6 Based on the initial body weights and known pumping 7 rate, approximate doses of 0, 2, 6, and 18 mg/kg/day β doses of Compound 42 are estimated. Body weights 9 and clinical observations were recorded at least 10 every other day for 14 days post-implantation. The ιι guinea pigs were euthanized after 14 days, and the 12 pumps were examined for possible failure. The graph 13 of Figure 8 shows the weight of the animals involved 14 in this experiment over the course of 15 days. As is it can be seen from the graph, the lower and middle 16 doses of the RAR α selective retinoid compound 17 (Compound 42) caused no, or only statistically is insignificant depression of weight gain, relative to 19 the control animals. Significant depression of 0 weight gain was observed only in the high dose 1 (18mg/kg/day) of Compound 42. Importantly, no signs 2 of mucocutaneous toxicity were observed at any dose 3 of Compound 42 in this experiment. The foregoing, 4 markedly reduced mucocutaneous toxicity observed 5 when animals are treated with RAR α selective 6 compounds in accordance with the present invention, 7 is a significant advantage, because mucocutaneous 8 toxicity is the major and most irksome retinoid side 9 effect or toxicity in human patients. 0 Synthetic Methods for Preparing the Preferred 1 Examples of RAR„ Selective Compounds of the Invention 2 General structure of the compounds which are 3 preferably used in the methods of treatment of the 4 present invention are shown above in Formula 1 and ι Formula 2. These compounds can be made by the 2 synthetic chemical pathways illustrated here. The 3 synthetic chemist will readily appreciate that the 4 conditions set out here are specific embodiments 5 which can be generalized to any and all of the 6 compounds represented by these formulas. 7 Generally speaking the process of preparing 8 compounds preferably used in the methods of the 9 invention in accordance with Formula 1 involves the ιo formation of an amide by the reaction of a compound ιι of the general Formula 6 with a compound of general 12 Formula 7, or by the reaction of a compound of 13 general Formula 6a with a compound of general 14 Formula 7a. Similarly, the process of preparing is compounds in accordance with Formula 2 involves the 16 formation of an amide by the reaction of a compound 17 of the general Formula 8 with a compound of general 18 Formula 7, or by the reaction of a compound of 19 general Formula 8a with a compound of general 0 Formula 7a. 1 A compound of Formula 6 is an acid or an 2 "activated form" of a carboxylic acid attached to 3 the aromatic portion of a tetrahydronaphthalene, (X x 4 = [C(R 1 ) 2 ] n and n is 1), dihydroindene ([C(R 1 ) 2 ] n where 5 n is 0) or chroman (X x is 0) nucleus. The carboxylic 6 acid, or its "activated form" is attached to the 2 7 or 3 position of the tetrahydronaphthalene, and to 8 the 6 or 7 position of the chroman moieties. In the 9 compounds preferably used in accordance with the 0 invention the attachment is to the 2 position of 1 tetrahydronaphthalene and to the 6 position of 2 chroman. 3 The term "activated form" of the carboxylic acid 4 should be understood in this regard as such ι derivative of the carboxylic acid which is capable 2 of forming an amide when reacted with a primary 3 amine of Formula 7. In case of the "reverse amides" 4 the activated form of a carboxylic acid is a 5 derivative (Formula 7a) that is capable of forming 6 an amide when reacted with a primary amine of 7 Formula 6a. This, generally speaking, means such β derivatives of a carboxylic acid which are normally 9 known and used in the art to form amide linkages ιo with an amine. Examples of suitable forms or 11 derivatives for this purpose are acid chlorides, 12 acid bromides, and esters of the carboxylic acid, 13 particularly active esters, where the alcohol moiety 14 of the ester forms a good leaving group. Presently is most preferred as reagents in accordance with 16 Formula 6 (or Formula 7a) are acid chlorides (X 3 is 17 Cl). The acid chlorides of Formula 6 (or of Formula is 7a) can be prepared by traditional methods from the i9 corresponding esters (X 3 is for example ethyl) by 0 hydrolysis and treatment with thionyl chloride 1 (S0 2 C1). The acid chlorides of Formula 6 (or of 22 Formula 7a) can also be prepared by direct treatment 3 of the carboxylic acids with thionyl chloride, where 4 the carboxylic acid, rather than an ester thereof is 5 available commercially or by a known synthetic 6 procedure. The acid chlorides of Formula 6 (or of 7 Formula 7a) are typically reacted with the amine of 8 Formula 7 (or amine of Formula 6a) in an inert 9 solvent, such as methylene chloride, in the presence 0 of an acid acceptor, such as pyridine. 1 The carboxylic acids themselves in accordance 2 with Formula 6 (or Formula 7a) are also suitable for 3 amide formation when reacted with an amine, a 4 catalyst (4-dimethylaminopyridine) in the presence ι of a dehydrating agent, such as 2 dicyclohexylcarbodiimide (DCC) or more preferably 3 l-(3-dimethylaminopropyl)-3-ethylcarbodiimide 4 hydrochloride (EDC). 5 The carboxylic acids or the corresponding esters 6 of Formula 6, are generally speaking, prepared as 7 described in the chemical scientific or patent β literature and the literature procedures for their 9 preparation may be modified, if necessary, by such o chemical reactions or processes which per se are 1 known in the art. For example, generally speaking, 2 2,2, 4,4 and/or 2,2,4,4-substituted chroman 3 6-carboxylic acids and chroman 7-carboxylic acids 4 are available in accordance with the teachings of s United States Patent Nos. 5,006,550, 5,314,159, 6 5,324,744, and 5,348,975, the specifications of 7 which are expressly incorporated herein by 8 reference. 5,6,7,8-Tetrahydronaphthalene-2- 9 carboxylic acids are, generally speaking, available 0 in accordance with the teachings of United States 1 Patent No. 5,130,335, the specifications of which is 2 expressly incorporated herein by reference. 3 The foregoing general description of the 4 reactions which lead to formation of the amides of 5 Formula 1 is also, generally speaking, applicable to 6 the formation of the amides of Formula 2. The 7 reagents which are used in accordance with the β general principles mentioned above for the formation 9 of amide compounds of Formua 2 are: activated forms o of a carboxylic acids shown in Formula 8 and in 1 Formula 7a, and the amines of Formula 7 and of 2 Formula 8a. 3 4 Formula 6 Formula 7 Formula 6a Formula 7a Formula 8 Formula 8a The carboxylic acids or the corresponding esters of Formula 8, are generally speaking, prepared as described in the chemical scientific or patent literature and the literature procedures for their preparation may be modified, if necessary, by such chemical reactions or processes which per se are known in the ar . u HNθ3HtSOa T1CI3/HCI HOAC/H2CWTHF Compound Λ Compoαn B Compound C Compound G Reaction Scheme 1 Comrx> and J Krar-se, J. G. Compo md I Syruheiis 1972, pl40 Compound H Compound K Compound Reaction Scheme 2 Compound P Compound O Compound T Compound V Reaction Scheme 2 (continued) ι Reaction Schemes 1 and 2 provide examples for 2 the synthesis of derivatives of 5,6,7,8-tetrahydro- 3 5,5,8,8-tetramethyl-naphthalene-2-carboxylic acid, 4 which are within the scope of Formula 6 and which 5 are reacted with an amine of Formula 7 to provide 6 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene- 7 2-yl)carbamoyl derivatives within the scope of β Formula 1. Thus, as is shown in Reaction Scheme 1, 9 ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- ιo naphthalene-2-carboxylate (Compound A) is nitrated 11 to provide the corresponding 3-nitro compound 12 (Compound B) . The nitro group of Compound B is 13 reduced to provide the corresponding 3-amino 1 compound (Compound C) which is described in the is publication Lehmann et al. Cancer Research, 1991, 16 51, 4804. Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra- i7 methyl-3-amino-naphthalene-2-carboxylate (Compound 18 C) is brominated to yield the corresponding 4-bromo 19 derivative (Compound D) , which is converted by 0 treatment with isoamylnitrite and reduction with 1 H 3 P0 2 , to ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra- 2 methyl- 4-bromonaphthalene-2-carboxylate (Compound 3 E). Saponification of Compound E yields 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth 5 alene-2-carboxylic acid (Compound F) which is used 6 as a reagent in accordance with Formula 6. Ethyl 7 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth 8 alene-2-carboxylate (Compound C) is also diazotized and reacted with HBF 4 to provide ethyl 0 5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-3-fluoronaph 1 thalene-2-carboxylate (Compound G) which serves 2 either per se or after saponification as a reagent 3 in accordance with Formula 6. 4 5 , 6 , 7 , 8 -Tetrahydro-5 , 5 , 8 , 8 -tetramethyl-2 - hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMC1) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymet- hoxy-2-bromonaphthalene (Compound J) . Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetra- methyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahy- dro-5,5,8,8-tetramethyl-l-bromo-2-hydroxynaphthalene -3-carboxylic acid (Compound M) . Compound L and Compound M serve as reagents in accordance with Formula 6. The hydroxy group of Compound M is protected for further transformations with methoxymethyl chloride (M0MC1) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-l-bromo-2-methoxymethoxynaphthalene-3-ca rboxylie acid (Compound N) . 1 2 3 4 5 6 7 8 9 16 17 Compound O Compound X 23 24 25 26 27 28 29 30 31 32 33 34 Reaction Scheme 3 Several Steps Compound Y Compound Al Compound Z Reaction Scheme 4 Shxoot, B. U. S. Patent 5,059,621 Reaction Scheme 5 1 Reaction Schemes 3, 4 and 5 provide examples for 2 the synthesis of derivatives of 2,2,4,4 and 3 4,4-substituted chroman-6-carboxylic acids which can 4 serve as reagents in accordance with Formula 6 for 5 the synthesis of the carbamoyl (amide) compounds 6 within the scope of the present invention. Thus, 7 referring now to Reaction Scheme 3, β 2,2,4,4-tetramethylchroman-6-carboxylic acid 9 (Compound O, see U. S. Patent No. 5,006,550) is ιo brominated with bromine in acetic acid to yield the ιι corresponding 8-bromo derivative (Compound P) . 12 Compound P is converted to the acid chloride by 13 treatment with thionyl chloride, and the resulting 14 acid chloride is suitable for reaction with an amine 15 of Formula 3 to provide the carbamoyl (amide) 16 compounds of the invention. The acid chloride is 17 also reacted with an alcohol (methanol) in the 18 presence of base to yield the corresponding ester, 19 methyl 2,2,4,4-tetramethyl-8-bromochroman-6- 0 carboxylate (Compound R) . The bromo function of 1 Compound R is converted to a trifluoromethyl 2 function by treatment with sodium trifluoroacetate 3 in the presence of cuprous iodide catalyst and 4 l-methyl-2-pyrrolidinone (NMP), and the carboxylate 5 ester group is saponified to yield 6 2,2,4,4-tetramethyl-8-trifluoromethylchroman-6-carbo 7 xylic acid (Compound S) . Compound S is within the β scope of Formula 6 and is suitable per se or as the 9 acid chloride or in other "activated" form to react 0 with the amines of Formula 7 to yield the carbamoyl 1 (amide) compounds of the invention. 2 2,2,4,4-Tetramethylchroman-6-carboxylic acid 3 (Compound O) is also converted to the methyl ester 4 (Compound T) which is then nitrated to yield ι 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylic acid 2 (Compound V), still another reagent within the scope 3 of Formula 6. Moreover, in the example further 4 shown in Reaction Scheme 3, 5 2,2,4,4-tetramethylchroman- 6-carboxylic acid 6 (Compound 0) is converted to the ethyl ester and 7 nitrated thereafter to yield ethyl β 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylate (Compound W) . Still further. Compound 0 is reacted ιo with IC1 to yield 2,2,4,4-tetramethyl8-iodochroman- 11 6-carboxylic acid (Compound X) . 12 In accordance with the example shown in Reaction 13 Scheme 4, 2-methylphenol is subjected to a series of i4 reactions in accordance with the teachings of United is States Patent No. 5,045,551 (incorporated herein by 16 reference) to yield 2,2,4,4,8-pentamethylchroman 17 (Compound Y) . Compound Y is brominated with bromine 18 in acetic acid to give 2,2,4,4,8-pentamethyl-6- 19 bromochroman (Compound Z) which is reacted with 0 t-butyl lithium and thereafter with carbon dioxide 1 to give 2,2,4,4,8-pentamethylchroman-6-carboxylic 2 acid (Compound A x ) . 3 Reaction Scheme 5 illustrates the synthesis of 4 4,4-dimethyl-8-bromochroman-6-carboxylic acid 5 (Compound B 1 ) by bromination of 6 4,4,-dimethyl-chroman-6-carboxylic acid which is 7 available in accordance with the teachings of United β States Patent No. 5,059,621, the specification of 9 which is incorporated herein by reference. 0 2,2,4,4,8-Pentamethylchroman-6-carboxylic acid 1 (Compound A x ) and 4,4,-dimethyl-8-bromochroman- 32 6-carboxylic acid (Compound B_ ) serve as reagents, 33 either per se, or as the corresponding acid 34 chlorides (or other "activated form), in accordance ι with Formula 6 for the synthesis of the carbamoyl 2 (amide) compounds of the present invention. 3 Referring back now to the reaction between the 4 reagent of Formula 6 with an amine compound of 5 Formula 7 it is noted that the amine compounds are, 6 generally speaking, available in accordance with the 7 state-of-the-art. as described in the scientific and 8 patent literature. More specifically, the amine 9 compounds of Formula 7 can be prepared as described ιo in the scientific and patent literature, or from ιι known compounds of the literature, by such chemical 12 reactions or transformations which are within the 13 skill of the practicing organic chemist. Reaction 14 Scheme 6 illustrates examples for the preparation of is amine compounds of Formula 7 (where Y is phenyl) 16 from commercially available starting materials 17 (Aldrich Chemical Company, or Research Plus, Inc.). is The illustrated compounds of Formula 7 are used for 19 the synthesis of several preferred compounds used in 0 the methods of the invention. 1 2 3 4 5 6 7 8 9 0 1 2 3 4 Compound Cl Compound FI Reaction Scheme 6 CompoundHI 1 Thus, in accordance with Reaction Scheme 6, 2 3-nitro-6-methyl-fluorobenzene (Aldrich) is 3 subjected to oxidation, conversion of the resulting 4 carboxylic acid to an acid chloride and thereafter 5 to an ethyl ester, followed by reduction of the 6 nitro group, to yield ethyl 7 2-fluoro-4-amino-benzoate (Compound C t ) . 8 3-Nitro-6-methyl-bromobenzene (Aldrich) and 9 3-nitro-6-methyl-chlorobenzene (Aldrich) are ιo subjected to essentially to the same series of ιι reactions to yield ethyl 2-bromo-4-amino-benzoate 12 (Compound O_ ) and ethyl 2-chloro-4-amino-benzoate i3 (Compound E_ ) , respectively. 2-Nitro-4-aminobenzoic 14 acid (Research Plus) is converted to its methyl 15 ester (Compound F x ) through the corresponding acid 16 chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid 17 (Aldrich) is esterified by treatment with ethanol in is the presence of l-(3-dimethylaminopropyl)-3- 19 ethylcarbodiimide hydrochloride (EDC) and 0 4-dimethylaminopyridine in CH 2 C1 2 to give ethyl 1 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G_ ) . 2 2,4,6-Trifluorobenzoic acid (Aldrich) is converted 3 to the methyl ester through the acid chloride, and the 4-fluoro atom is displaced by reaction with 5 sodium azide, followed by hydrogenation, to yield 6 methyl 2,6-difluoro-4-amino benzoate (Compound E_ ) . 7 Compounds C x , D_ , E_ , F l f G_ and E_ serve as amine 8 reagents in accordance with Formula 7. Further 9 examples of reagents in accordance with Formula 7 0 are nitro, fluoro, chloro, bromo and trifluoromethyl 1 derivatives of a ino substituted heteroaryl 2 carboxylic acids, or their lower alkyl esters, such 3 as ethyl 2-amino-4-chloropyridine 2-carboxylate, 4 ethyl 5-amino-3-chloropyridine 5-carboxylate, and ι 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The 2 latter examples qcan be prepared by respective 3 chlorination or bromination of 4 2-aminopyridine-5-carboxylic acid or of its ester, 5 3-aminopyridine-6-carboxylic acid or of its ester e (described in WO 93/06086) and of 7 2-aminothiophene-5-carboxylic acid (described in 8 PCT/US92/06485) . 9 The reactions between the compounds of Formula 6 ιo and Formula 7 or between compounds of Formula 6a and ιι 7a, described above, comprise the actual syntheses 12 of the carbamoyl (amide) compounds of the invention. 13 Numerous examples of this reaction are described in 14 detail in the experimental section below. The is carbamoyl (amide) compounds of the invention can be 16 converted into thiocarbamoyl (thioamide) compounds 17 of the invention where with reference to Formula 1 Z is is S, by reacting the carbamoyl (amide) compound 19 with 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- 0 diphosphetane-2,4-disulfide (Lawesson's reagent). 1 This reaction is illustrated in Reaction Scheme 7 2 for two specific examples for the compounds used in 3 the methods of the invention. 4 5 6 7 8 9 0 1 2 3 4 Compound II Compound 21 Compound 1 Compound 23 Reaction Scheme 7 In Reaction Scheme 7 one starting material ethyl 4-[5' ,6 ' ,7 ' , 8 '-tetrahydro-5 ' ,5' ,8 ' ,8 '-tetramethyl- naphthalen-2-yl)carbamoyl]benzoate (Compound 1_ ) is obtained in accordance with the teachings of Kagechika et al. J. Med Chem. 1988 31, 2182 - 2192. The other starting material, ethyl 2-fluoro-4-[5 ' ,6 ' ,7 ' , 8 '-tetrahydro-5 ' , 5 ' , 8 ' , 8 '-tetra methylnaphthalen-2-y1)carbamoyl]benzoate (Compound 1) is obtained in accordance with the present invention. Compound K. Compound 5 Reaction Scheme 8 Compound 32 Reaction Scheme 9 Compound 13 Reaction Scheme 10 Reaction Schemes 8, 9 and 10 disclose examples for the preparation of carbamoyl (amide) compounds of the invention, first by a coupling reaction of a compound of Formula 6 with a compound of Formula 7, followed by one or more reactions performed on the carbamoyl (amide) compound that has been first obtained directly in the coupling reaction. Thus, as is shown in Reaction Scheme 8, 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-methoxymethoxynaphthalene-2-carboxylic acid (Compound K) is coupled with ethyl 4-amino-2-fluorobenzoate (Compound C x ) in CH 2 C1 2 in the presence of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) and dimerhylaminopyridine (DMAP) to give ethyl 1 2-fluoro-4-[5' ,6' ,7' ,8'-tetrahydro-5',5',8',8'-tetra 2 methyl-2'-methoxymethoxy-naphthalen- 3 3'-yl)carbamoyl]benzoate (Compound Kj) . The methoxymethyl protecting group is removed from 5 Compound K_ by treatment with thiophenol and e borontrifluoride ethereate resulting in ethyl 7 2-fluoro-4-[5' ,6' ,7' ,8'-tetrahydro-5' ,5 ' ,8' ,8'-tetra β methyl-2'-hydroxy-naphthalen-3'-yl)carbamoyl]- 9 benzoate (Compound 5). The hydroxy function of ιo Compound 5 is converted into an n-hexyl ether by ιι treatment with hexyl iodide in the presence of mild 12 base. 13 In accordance with Reaction Scheme 9 14 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-bromo-2-met is hoxymethoxynaphthalene-3-carboxylic acid (Compound 16 N) is coupled with methyl 4-amino-2,6-difluoro- 17 benzoate (Compound H x ) in CH 2 C1 2 solvent in the 18 presence of ethylcarbodiimide hydrochloride (EDC) 19 and DMAP to provide methyl 0 2,6-difluoro-4-[ (5',6',7',8'-tetrahydro-5' ,5' ,8' ,8'- 1 tetramethyl-1'-bromo-2'-methoxymethoxy-naphthalen-3' 2 -yl)carbamoyl]benzoate (Compound VL_ ) , from which the 3 esterifying methyl group and the methoxymethyl 4 protecting group are removed by treatment with base 5 and acid, respectively to yield 6 2,6-difluoro-4-[ (5',6',7',8'-tetrahydro-5' ,5' ,8' ,8'- 7 tetramethyl-1'-bromo-2'-hydroxy-naphthalen-3'-yl)car 8 bamoyl]benzoic acid (Compound 32). 9 Reaction Scheme 10 discloses the example of 0 converting 2,2,4,4-tetramethyl-8-nitrochroman-6- 1 carboxylic acid (Compound V) into the corresponding 2 acid chloride by treatment with thionyl chloride, 3 followed by coupling with ethyl 4 4-amino-2-fluorobenzoate (Compound C_ ) and hydrogenation to yield ethyl 2-fluoro-4-[ (2',2',4' ,4'-tetramethyl-8'-amino-6'-chr omanyl)carbamoyl]benzoate (Compound N x ) . Compound N x is converted to the corresponding 8-azido compound, ethyl 2-fluoro-4-[(2',2' f 4',4'-tetramethyl-8'-azido- 6 '-chromanyl)carbamoyl]benzoate (Compound 13) by treatment with isoamyl nitrate and NaN 3 . Formula 6 Reaction Scheme 11 1 Reaction Scheme 11 illustrates the synthesis of 2 the primary amine compounds of Formula 6a from the 3 acid chlorides (X 3 = Cl) or other form of activated A acids of Formula 6 where the primary amine of 5 Formula 6a is not available by a published 6 literature procedure. Thus, substantially in 7 accordance with the step of a Curtius rearrangement, 8 the acid chloride of Formula 6 is reacted with 9 sodium azide in acetone to yield the azide compound 0 of Formula 9. The azide of Formula 9 is heated in a 1 polar high boiling solvent, such as t-butanol, to 2 provide the intermediate isocyanate of Formula 10, 3 which is hydrolyzed to yield a compound of Formula 4 6a. Michael Rciπn n t al J. MaL Chem. Compourxl V. 1995, 38, 2531-2540 1 Reaction Scheme 12 1 Reaction Scheme 12 illustrates examples for 2 preparing compounds of Formula 7a where such 3 compounds are not available commercially or by a published literature procedure. Thus, by way of 5 example 2,5-difluoro-4-bromobenzoic acid (available 6 by the literature procedure of Suσawara et al. Kogyo 7 Kaguku Zasshi 1970. 73, 972-979) is first esterified β by treatment with ethyl alcohol and acid to yield 9 the corresponding ester, and thereafter is reacted ιo with butyl lithium followed by carbon dioxide to ιι give the monoester of 2,5-difluoro terephthalic acid 12 (Compound T_ ) . A similar sequence of reactions 13 performed on 2,3,5,6-difluoro-4-bromobenzoic acid 14 (available by the literature procedure of Reuman et is al. J. Med. Chem. 1995, 38, 2531-2540) yields the 16 monoester of 2,3,5,6-tetrafluoroterephthalic acid 17 (Compound V x ) . The just illustrated sequence of 18 reaction can be, generally speaking, utilized for 19 the synthesis of all compounds of Formula 7a with 0 such modification which will become readily apparent 1 to those skilled in the art, where such compounds 2 are not available by a known literature procedure. 3 Reaction Scheme 13 provides an example for the 4 preparation of 2,6-di-tert-butylisonicotinic acid 5 (Compound C 3 ) which is a reagent in accordance with 6 Formula 8 for the preparation of several preferred 7 compounds of the present invention. Thus, 8 2,6-di-tert-butyl-4-methylpyridine (available 9 commercially from Aldrich Chemical Co.) is reacted 0 with N-bromosuccinimide and benzoyl peroxide to 1 provide 4-bromomethyl-2,6-di-tert-butylpyridine 2 (Compound A 3 ) . Compound A 3 is reacted with base 3 (sodium hydroxyde) to yield the coresponding 4 hydroxy ethyl compound (Compound B 3 ), which is thereafter oxidized in a Jones oxidation reaction to give 2,6-di-tert-butylisonicotinic acid (Compound C,). Compound A - Compound B Jσne's acsione Compound C 3 Compound D Compound E, lBuLi/CO, Compound F 0 Reaction Scheme 13 ι A further example of a compound which serves as 2 a reagent for preparing the carbamoyl (or amide) 3 compounds of the present invention is provided in 4 Reaction Scheme 13. 2,4-Di-tert-butylphenol 5 (Aldrich) is brominated in glacial acetic acid to 6 yield 2-bromo-4,6-di-tert-butylphenol (Compound D 3 ) 7 which is thereafter reacted with methoxymethyl β chloride (MOMCl)to give 9 -methoxymethyl-2-bromo-4,6-di-tert-butylphenol o (Compound E 3 ) . Compound E 3 is treated with t-butyl 1 lithium followed by carbon dioxide to yield 2 O-methoxymethyl-3,5-di-tert-butylsalicylic acid 3 (Compound F 3 ) . Compound F 3 is a reagent which 4 differs from the compounds generally encompassed by s Formula 8 only in that the hydroxyl funtion of this 6 compound is protected by the methoxymethyl (MOM) 7 group. However, the methoxymethyl protecting group 8 is removed after formation of the carbamoyl (amide) 9 linkage, as exemplified in Reaction Scheme 14. 0 Reaction of an aromatic bromo compound (such as 1 Compound D 3 ) with t-butyl lithium followed by carbon dioxide is a preferred method for preparing several 3 aromatic carboxylic acids in accordance with Formula 4 8 and Formula 7a, described in the present 5 application. 6 The primary amine compounds of Formula 8a which 7 are not available commercially or by a published literature procedure can be made from the acid 9 chlorides (X 3 = Cl) or other form of activated acids of Formula 8 substantially in accordance with the 1 steps of a Curtius rearrangement, in analogy to the reaction steps described above in connection with Reaction Scheme 11. Compound C. Compound C- Compound .5 Reaction Scheme 14 Reaction Scheme 14 (continued) ι Reaction Scheme 14 illustrates examples for the 2 formation of the carbamoyl (amide) compounds in 3 accordance with Formula 2, by reaction of a reagent 4 of Formula 8 with a reagent of Formula 7. Thus, 5 2,6-di-tert-butylisonicotinic acid (Compound C 3 ) is β reacted with thionyl chloride (S0C1 2 ) to provide the 7 intermediate acid chloride, which is then reacted 8 with ethyl 2-fluoro-4-amino-benzoate (Compound C x ) in 9 the presence of an acid acceptor (pyridine) to yield ιo ethyl 2-fluoro-4-[ (2'6 '-di-tert-butylpyrid-4'- ιι yl)carbamoyl]benzoate (Compound 41 ) . As another 12 example, 3,5-di-tert-butylbenzoic acid (available by is the literature procedure of Ka echika et al.. J. 14 Med. Chem. 1988, 31, 2182, incorporated herein by is reference) is reacted with thionyl chloride, 16 followed by ethyl 2-fluoro-4-amino-benzoate 17 (Compound C_ ) to yield ethyl 2-fluoro-4-[ (3' ,5'-di- i8 tert-butylphenyl)carbamoyl]benzoate (Compound 45). 19 As still another example, 0-methoxymethyl-3,5-di- 0 tert-butylsalicylic acid (Compound F 3 )is reacted with 1 ethyl 2-fluoro-4-amino-benzoate (Compound C_ ) in the 2 presence of 4-dimethylaminopyridine (DMAP) catalyst 3 and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide 4 hydrochloride (EDC) to give ethyl 2-fluoro-4-[ (2'- 5 methoxymethy1-3' ,5'-di-tert-butylphenyl)car- 6 bamoyl]benzoate (Compound G 3 ) . The methoxymethyl protecting group is removed from Compound G 3 by 8 treatment with borontrifluoride ethereate and 9 thiophenol to yield ethyl 2-fluoro-4-[ (2'-hydroxy- 0 3' ,5'-di-tert-butylphenyl)carbamoyl]benzoate 1 (Compound 47) . 2 In yet another example shown in Reaction Scheme 3 14, 2,6-di-tert-butylisonicotinic acid (Compound C 3 ) 4 is reacted with thionyl chloride (S0C1 2 ), the ι resulting intermediate acid chloride is reacted with 2 methyl 2,6-difluoro-4-amino benzoate (Compound H x ), 3 followed by saponification of the ester group, to 4 yield 2,6-difluoro-4-[ (2' ,6'-di-tert-butylpyrid- 5 4'yl)carbamoyl]benzoic acid (Compound 50). 6 3,5-Di-tert-butylbenzoic acid is subjected to the 7 same sequence of reactions to provide β 2,6-difluoro-4- [ (3 ' ,5'-di-tert-butylphenyl)car- 9 bamoyl]benzoic acid (Compound 52). ιo As yet another example, shown in Reaction Scheme 11 14, 2,6-di-tert-butylisonicotinic acid (Compound C 3 ) 12 is reacted with thionyl chloride (S0C1 2 ), followed by i3 methyl 2-nitro-4-aminobenzoate (Compound F_ ) and 14 saponification of the ester function to give 15 2-nitro-4-[ (2 ' ,6 '-di-tert-butylpyrid-4'-yl)carbamoyl 16 jbenzoic acid (Compound 54) . i7 Numerous other reactions suitable for preparing 18 compounds of the invention, and for converting 19 compounds of Formula 1 and/or of Formula 2 into 0 still further compounds which can be used in the 21 methods of treatment of the present invention, and 2 also for preparing the reagents of Formula 6, 3 Formula 7, Formula 8, Formula 6a, Formula 7a and 4 Formula 8a will become readily apparent to those 5 skilled in the art in light of the present 6 disclosure. In this regard the following general 7 synthetic methodology, applicable for conversion of 8 the compounds of Formula 1 and/or of Formula 2 into 9 further homologs and/or derivatives, and also for 0 preparing the reagents of Formula 6, Formula 7, and 31 8, (as well as 6a, 7a and 8a) is noted. 32 Carboxylic acids are typically esterified by 33 refluxing the acid in a solution of the appropriate 34 alcohol in the presence of an acid catalyst such as 1 hydrogen chloride or thionyl chloride. 2 Alternatively, the carboxylic acid can be condensed 3 with the appropriate alcohol in the presence of 4 dicyclohexylcarbodiimide and dimethylaminopyridine. 5 The ester is recovered and purified by conventional 6 means. Acetals and ketals are readily made by the 7 method described in March, "Advanced Organic β Chemistry," 2nd Edition, McGraw-Hill Book Company, p 9 810). Alcohols, aldehydes and ketones all may be ιo protected by forming respectively, ethers and ιι esters, acetals or ketals by known methods such as 12 those described in McOmie, Plenum Publishing Press, 13 1973 and Protecting Groups. Ed. Greene, John Wiley & 1 Sons, 1981. is The acids and salts derived from compounds of 16 Formula 1 and Formula 2 are readily obtainable from 7 the corresponding esters. Basic saponification with 18 an alkali metal base will provide the acid. For 9 example, an ester may be dissolved in a polar 0 solvent such as an alkanol, preferably under an 1 inert atmosphere at room temperature, with about a 2 three molar excess of base, for example, potassium 3 or lithium hydroxide. The solution is stirred for 4 an extended period of time, between 15 and 20 hours, 5 cooled, acidified and the hydrolysate recovered by 6 conventional means. 7 The amide (in Formula 1 or 2 B is CONR β R 10 ) may 8 be formed by any appropriate amidation means known 9 in the art from the corresponding esters or 0 carboxylic acids. One way to prepare such compounds 1 is to convert an acid to an acid chloride and then 2 treat that compound with ammonium hydroxide or an 3 appropriate amine. 4 Alcohols are made by converting the 1 corresponding acids to the acid chloride with 2 thionyl chloride or other means (J. March, "Advanced 3 Organic Chemistry", 2nd Edition, McGraw-Hill Book 4 Company), then reducing the acid chloride with 5 sodium borohydride (March, Ibid, pg. 1124), which 6 gives the corresponding alcohols. Alternatively, 7 esters may be reduced with lithium aluminum hydride β at reduced temperatures. Alkylating these alcohols 9 with appropriate alky halides under Williamson ιo reaction conditions (March, Ibid, pg. 357) gives the 11 corresponding ethers. These alcohols can be 12 converted to esters by reacting them with 13 appropriate acids in the presence of acid catalysts i4 or dicyclohexylcarbodiimide and is dimethylaminopyridine. 16 Aldehydes can be prepared from the corresponding 17 primary alcohols using mild oxidizing agents such as 18 pyridinium dichromate in methylene chloride (Corey, 19 E. J., Schmidt, G. , Tet. Lett.. 399, 1979) . or 0 dimethyl sulfoxide/oxalyl chloride in methylene 1 chloride (Omura, K., Swern, D., Tetrahedron. 1978. 2 34., 1651). 3 Ketones can be prepared from an appropriate 4 aldehyde by treating the aldehyde with an alkyl 5 Grignard reagent or similar reagent followed by 6 oxidation. 7 Acetals or ketals can be prepared from the β corresponding aldehyde or ketone by the method 9 described in March, Ibid, p 810. 30 31 ι Specific Examples 2 Ethyl 4-Amino-2-fluorobenzoate (Compound C_ ) 3 To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 4 6.4 mmol, Aldrich) and Na 2 Cr 2 0 7 (2.74 g, 8.4 mmol) in 5 13.7 ml of HOAc was added slowly 6.83 ml of H 2 S0 4 . 6 This mixture was slowly heated to 90 °C for 1 h to 7 give a greenish heterogeneous solution. The mixture β was cooled to room temperature and diluted with 9 ethyl acetate. The PH of the solution was adjusted ιo to 4 with NaOH (aq.). The mixture was extracted ιι with more ethyl acetate. The organic layer was 12 washed with NaHC0 3 (sat.), then brine and dried over 13 Na 2 S0 4 . After filtration, the solution was 14 concentrated to dryness which then was dissolved in 15 6 ml of S0C1 2 , and heated at 80 °C for 1 h. The 16 excess of S0C1 2 was removed under reduced pressure 17 and the residue was dissolved in 5 ml of CH 2 C1 2 , 2 ml 18 of EtOH and 2 ml of pyridine. The mixture was 9 stirred at room temperature for 2 h and concentrated 0 to dryness. Ethyl 2-fluoro-4-nitrobenzoate was 1 obtained as a white solid after column 2 chromatography of the residue with ethyl 3 acetate/hexane (1/9). This solid was then dissolved 4 in 10 ml of ethyl acetate, and Pd/C (50 mg) was 5 added. Hydrogenation with a hydrogen balloon 6 converted ethyl 2-fluoro-4-nitrobenzoate into the 7 title compound. β *H NMR δ 7.77 (t, J = 8.4 Hz, 1H), 6.41 (dd, J_ = 9 8.6, J 2 = 2.2 Hz, 1H), 6.33 (dd, J_ = 13.0, J 2 = 2.2 o Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.3 (b, 2H), 1.37 1 (t, J = 7.1 Hz, 3H) . 2 Methyl 4-Amino-2.6-difluorobenzoate (Compound _ ) 3 A solution of trifluorobenzoic acid (150 mg, 4 0.85 mmol, Aldrich) in 0.5 ml of S0C1 2 was heated ι under reflux for 2h. The reaction mixture was 2 cooled to room temperature, and excess of S0C1 2 was 3 removed under reduced pressure. The residue was 4 dissolved in 1 ml of pyridine and 0.2 ml of 5 methanol. After stirring at room temperature for 30 β min, solvent was removed and the residue was 7 purified by column chromatography (ethyl β acetate/hexane 1/10) to give methyl trifluoro- 9 benzoate as a colorless oil. This oil was then o dissolved in 1 ml of CH 3 CN, then a solution of NaN 3 1 (100 mg, 1.54 mmol) in 0.5 ml of water was added. 2 The reaction mixture was refluxed for two days. 3 Salt was filtered and the remaining solution was 4 concentrated to an oil. This oil was then dissolved s in 1 ml of methanol, followed by a catalytic amount 6 of Pd/C (10%, w/w) . The reaction mixture was 7 hydrogenated under a hydrogen balloon for 12 h. 8 Catalyst was removed and the solution was 9 concentrated to an oil. After column chromatography 0 (ethyl acetate/hexane 1/3), the title product was 1 obtained as colorless crystals. 2 Ή NMR δ 6.17 (d, J = 10.44 Hz, 2H), 4.2 (b, 2H), 3 3.87 (s, 3H). 4 8-Bromo-2.2.4.4-tetramethyl-6-chromanoic acid 5 (Compound P) 6 To a solution of 2,2,4,4-tetramethyl-6-chro- manoic acid (200 mg, 0.85 mmol) in 0.5 ml of AcOH 8 was added Br 2 (0.07 ml, 1.28 mmol). The resulting 9 dark-orange solution was stirred at room temperature 0 for overnight. The excess bromine was removed under 1 reduced pressure. Then the solution was poured into 2 5 ml of water and extracted with ethyl acetate 3 (3x3ml). The combined ethyl acetate layers were 4 further washed with NaHC0 3 (sat.), brine and dried ι over MgS0 4 . After concentration, the residue was 2 purified by column chromatography (silica gel, ethyl 3 acetate/hexane 1/3) to yield the desired product 4 (170 mg, as white solids. s X H NMR δ 8.11 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 2.2 6 Hz, 1H), 1.90 (s, 2H), 1.43 (s, 6H), 1.39 (s, 6H) . 7 8-Iodo-2.2.4.4-tetramethyl-6-chromanoic Acid β (Compound X) g To a solution of 2,2,4,4-tetramethyl-6-chro- ιo manoic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH was 11 added IC1 (0.07 ml, 1.4 mmol). The resulting 12 colored solution was stirred at room temperature for 13 overnight. Following the same procedure as for the 14 synthesis of 8-bromo-2,2,4,4-tetramethyl-6- 15 chromanoic acid (Compound P), the reaction gave the 16 title compound (107 mg) as white solids. 17 -E NMR δ 8.35 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 2.2 ιβ Hz, 1H), 1.87 (s, 2H), 1.43 (s, 6H), 1.38 (s, 6H). 19 2.2,4,4-Tetramethyl-8-trifluoromethylchroman-6-oic 0 acid (Compound S) 1 A solution of 8-bromo-2,2,4,4-tetramethyl-6- 2 chromanoic acid (Compound R, 150 mg, 0.48 mmol) in 1 3 ml of S0C1 2 was refluxed for 2 h. After cooling to 4 room temperature, the excess of S0C1 2 was removed 5 under reduced pressure and the residue was dissolved 6 in 1 ml of pyridine and 0.2 ml of methanol. The 7 mixture was stirred at room temperature for 30 min. 8 Solvent was removed and the residue was passed 9 through a column (silica gel, ethyl acetate/hexane 0 1/10) to give the methyl 8-bromo-2,2,4,4-tetra- 1 methylchromanoate (158 mg) as a colorless oil. To a 2 solution of this methyl ester in 3 ml of 3 N-methylpyrrolidone (NMP) was added NaC0 2 CF 3 (502 mg, 3.7 mmol) and Cul (350 mg, 1.84 mmol). The resulting mixture was heated to 175 °C (bath temp) for 2 h. The resulting mixture was cooled to room temperature and poured into ice-water. The product was extracted into ethyl acetate (3x3ml). The combined organic layers were dried and concentrated to dryness. The crude material was purified by column chromatography (ethyl acetate/chloroform 1/10) to give the title compound as a colorless oil (120 mg) . This was hydrolyzed under standard conditions to give the title compound. -n NMR δ 8.21 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 1.92 (s, 2H), 1.41 (s, 12H) . Ethyl 8-Nitro-2.2.4.4-tetramethyl-6-chromanoate (Compound W) Ethyl 2,2,4,4-tetramethyl-6-chromanoate (150 mg, 0.57 mmol) was slowly added to 0.3 ml of cone. H 2 S0 4 at 0 °C. To this mixture was added very slowly 0.03 ml of HN0 3 . The reaction mixture was stirred at 0 °C for 30 min and poured into ice-water. The product was extracted into 5 ml of ethyl acetate, washed with NaHC0 3 (sat.), brine and dried over MgS0 4 . After concentration, the product was purified by column chromatography (ethyl acetate/hexane 1/10) to yield 74 mg of light-yellow oil. -U NMR δ 8.24 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.95 (s, 2H), 1.43 (s, 6H), 1.42 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H). 2-0XO-4.4.8-trimethylchroman (Compound P x ) In a 500 ml of round bottom flask, NaH (1.66 g, 60% suspension in oil, 0.046 mol) was washed with dry hexane. Then, dry THF (22 ml) was added followed by o-cresol (5 g, 0.046 mol) in 10 ml of dry THF. The reaction mixture was stirred at 0 °C 1 for 30 min followed by addition of 3,3-dimethyl 2 acryloyl chloride in 10 ml of THF. The resulting 3 white slurry was stirred at room temperature for 12 h, then slowly quenched with water. The mixture was 5 then extracted with ethyl acetate. The organic 6 layer was washed with brine, water and dried over 7 MgS0 4 . After filtration and removal of the solvent, β a yellow oil was obtained (10.44 g) . This oil was 9 then dissolved in 50 ml of dry CH 2 C1 2 , and was 10 canulated into a solution of A1C1 3 (10.8 g, 0.069 ιι mmol) in 10 ml of CH 2 C1 2 . The reaction mixture was 12 stirred at room temperature for 12 h. Then 13 ice-water was carefully added and the organic layer 1 was separated, and washed with NaHC0 3 (sat), brine, is water and finally dried over MgS0 4 . After removal of 16 the drying agent and solvent, the residue was 17 purified by column chromatography (silica gel, ethyl 18 acetate/hexane 1/9) to yield the title compound (4.408 g) as an oil. 0 -E NMR δ 7.1 (m, 3H) , 2.62 (s, 2H) , 2.33 (s, 3H) , 1 1.36 (s, 6H). 2 2.4-Dimethyl-4- ( 2 '-hydroxy-3 '-methylphenyl)pentan-2- 3 ol (Compound R_ ) 4 To a solution of 2-oxo-4,4,8-trimethylchroman 5 (Compound P ιr 2.20 g, 11.5 mmol) in 40 ml of dry 6 ethyl ether was added methyl magnesium bromide 7 (12.67 ml, 38 mmol, 3 M solution in THF). The 8 reaction mixture was stirred at room temperature for 9 12 h, then quenched with NH 4 C1 (sat.) until all 0 precipitate dissolved. The mixture was extracted 1 with diethyl ether and the combined organic layers 2 were separated and washed with brine, water and 3 dried over MgS0 4 . After filtration and removal of 4 the solvent, the title compound was obtained as a ι tan solid (2.215 g) . 2 *H NMR δ 7.16 (d, J = 7.88 Hz, 1H), 7.00 (d, J = 6.72 3 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 5.89 (b, 1H), 4 2.21 (s, 3H), 2.17 (s, 2H), 1.48 (s, 6H), 1.10 (s, s 6H) . 6 2, 2, 4, 4, 8-Pentamethyl-6-bromochroman (Compound 7 Z) A solution of 2,4-dimethyl-4-(2'-hydroxy-3'- 8 methylphenyl)pentan-2-ol (Compound R x , 2.215 g, 9.98 9 mmol) in 30 ml of 15% of H 2 S0 4 was heated to 110 °C. ιo After cooling to room temperature, the reaction ιι mixture was extracted with diethyl ether. The 12 organic layer was washed with NaHC0 3 (sat.), brine 13 and water. After filtration and removal of solvent, 14 the residue was passed through a column (silica gel, is pure hexane) to give the title compound as a clear 16 oil (1.636 g) . This oil was then dissolved in 1.5 17 ml of HOAc, then Br 2 (0.4113 ml, 7.98 mmol) was 18 added. The reaction mixture was stirred at room 19 temperature for 12 h. Solvent was removed under 0 reduced pressure and to the residue was added ethyl 1 acetate, and the resulting mixture was washed with 2 NaHC0 3 (sat.), brine, water and dried over MgS0 4 . 3 After filtration and removal of solvent, the residue 4 was passed through a column (silica gel, pure 5 hexane) to give the title compound as a white solid 6 (2.227 g) . 7 *H NMR δ 7.21 (s, 1H), 7.06 (s, 1H), 2.14 (s, 3H), 8 1.79 (s, 2H), 1.32 (s, 6H), 1.31 (s, 6H) . 9 2.2.4.4.8-Pentamethyl-6-chromanoic Acid (Compound A x ) 0 To a solution of 2,2,4,4, 8-pentamethyl-6-bromo- 1 chroman (Compound Z) (1.2 g, 4.24 mmol) in 18 ml of 2 dry THF at -78 °C under argon gas was added slowly 3 5.48 ml of t-BuLi (1.7 M in hexane, 9.33 mmol). The 4 reaction mixture was stirred at -78 °C for 1 h. Then 1 C0 2 was bubbled through the solution for 1 h. After 2 removal of C0 2 stream, the reaction mixture was 3 stirred for an additional hour at -78 °C. Then 10% of HC1 was added. After warming up to room 5 temperature, the reaction mixture was extracted with 6 ethyl acetate. The organic layer was further washed 7 with brine and dried over Na 2 S0 4 . After 8 concentration, the residue was purified by column g chromatography (ethyl acetate/hexane 5/95) to yield ιo the title compound as a white solid (774 mg) . 11 *H NMR δ 7.96 (s, 1H) , 7.75 (s, 1H), 2.23 (s, 3H), 12 1.88 (s, 2H), 1.39 (s, 6H). 13 8-Bromo-4.4-dimethyl-6-chromanoic Acid (Compound B x ) i Using the same procedure as for the synthesis of is 8-bromo-2,2,4,4-tetramethylchromanoic acid (Compound 16 P) but using 4,4-dimethylchromanoic acid (100 mg, 17 0.49 mmol), the title compound was obtained as a is white solid. 19 4J NMR δ 8.10 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 0 Hz, 1H), 4.39 (t, J = 5.44 Hz, 2H), 1.89 (t, J = 5.4 1 Hz, 1H), 1.38 (s, 6H). 2 Ethyl 2-Amino-l-bromo-5.5,8.8-tetrahydro-5.5.8.8- 3 tetramethylnaphthalene-3-carboxylate (Compound D) 4 To a solution of ethyl 5,6,7,8-tetrahydro- 5 5,5,8, 8-tetramethyl-3-aminonaphthalene-2-carboxylate 6 (Compound C, 58 mg, 0.21 mmol) in 2 ml of HOAc was 7 added Br 2 (0.02 ml, 0.42 mmol). The orange solution 8 was stirred at room temperature for 2 days. The 9 excess Br 2 and HOAc were removed under reduced 0 pressure and the residue was passed through a column 1 (silica gel, ethyl acetate/hexane 1/10) to yield the 2 title compound as a light-orange oil (59 mg, 79.5%). 3 -H NMR δ 7.90 (s, 1H), 6.41 (b, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.70 (m, 4H), 1.58 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H) . Ethyl 5.6.7.8-tetrahydro-5.5.8.8-tetramethyl -4-bromonaphthalene-2-carboxylate (Compound E) Ethyl 2-Amino-l-bromo-5,5,8,8-tetrahydro- 5,5,8,8-tetramethylnaphthalene-3-carboxylate (Compound D, 59 mg, 0.17 mmol) was dissolved in 2 ml of EtOH at 0°C. To this solution was added 1ml of trifluoroacetic acid and 1 ml of isoamylnitrite. The reaction mixture was stirred at 0°C for 30 min then H 3 P0 2 (0.325 ml, 3.14 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. NaHC0 3 (sat.) was added and the reaction mixture was extracted with ethyl acetate, dried over MgS0 4 , filtered and concentrated to give an oil. The product was purified by column chromatography (silica gel, ethyl acetate/hexane 1/10) to give the title compound as a colorless oil. X H NMR δ 8.02 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.71 (m, 4H), 1.56 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.31 (s, 6H) . Ethyl 5.6.7.8-tetrahydro-5.5.8.8-tetramethyl-3-fluoro- naphthalen-2-yl-carboxylate (Compound G) In an ice bath, ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth alene-2-carboxylate (Compound C, 150 mg, 0.55 mmol) was added 0.24 ml of HBF 4 (48% solution in water), followed by a solution of NaN0 2 (81 mg, 1.16 mmol) in 1 ml of water. The slurry was left in a refrigerator for 3 days. The reaction mixture was washed successively with ethyl acetate until TLC showed no UV visible spot at the baseline. The ι ethyl acetate layer was dried with MgS0 4 and the 2 solution was concentrated to an oil. The oil was 3 further dissolved in 1 ml of toluene and the mixture was heated under reflux for 2 h. After the reaction 5 cooled to room temperature, solvent was evaporated 6 and the residue was passed through a column (silica 7 gel, ethyl acetate/hexane 1/10) to give the title β compound as an oil. 9 -H NMR δ 7.85 (d, J - 7.8 Hz, 1H) , 7.04 (d, J = 12.3 ιo Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.69 (s, 4H), ιι 1.38 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 12 6H). 13 2-Bromo-3-hydroxy-5.5.8.8-tetrahydro-5.5.8.8-tetrame 14 thylnaphthalene (Compound I) is Using the same procedure as for the synthesis of 16 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid 17 (Compound P) but using 2-hydroxy-5,5,8,8-tetrahydro- 18 5,5,8,8-tetramethyltetralin (700 mg, 3.43 mmol) and 19 Br 2 (0.177 ml, 3.43 mmol) in 1.5 ml of HOAc, the 0 title compound was obtained as a white solid (747 1 mg) . 2 NMR δ 7.36 (s, 1H), 6.96 (s, 2H), 5.32 (b, 1H) , 3 1.66 (s, 4H), 1.25 (s, 12H) . 4 5.6.7.8-Tetrahydro-5.5.8,8-tetramethyl-3-methoxymet- 5 hoxy-2-bromonaphthalene (Compound J) 6 To a solution of 2-bromo-3-hydroxy-5,5,8,8-tet- 7 rahydro-5,5,8,8-tetramethylnaphthalene (Compound I, 8 600 mg, 2.12 mmol) and catalytic amount of Bu 4 NBr in 9 20 ml of dry CH 2 C1 2 at 0 °C was added 0 diisoproylethylamine (1.138 ml, 12.75 mmol), 1 followed by methoxymethyl chloride (0.484 ml, 6.39 2 mmol). The reaction mixture was heated at 45 °C for 3 12 h. The reaction mixture was washed with 10% of 4 citric acid, then NaHC0 3 (sat.), brine and dried over MgS0 4 . After filtration and removal of the solvent, the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the title compound (722 mg) as a white solid. *H NMR δ 7.43 (s, 1H), 7.06 (s, 1H), 5.21 (s, 2H) , 3.54 (s, 3H), 1.66 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H) . 3-Methoxymethoxy-5.5.8.8-tetramethyl-5.6.7.8-tetrah ydronaphthalen-2-yl carboxylic acid (Compound K) Using the same procedure as for the synthesis of 2,2,4,4,8-pentamethy1-6-chromanoic acid (Compound A_ ) but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 3-methoxymethoxy-2-bromonaphthalene (Compound J, 722 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7 M solution in hexane), the title compound was obtained as a white solid (143 mg) . -K NMR δ 8.12 (s, 1H), 7.19 (s, 1H), 5.40 (s, 2H), 3.58 (s, 3H), 1.70 (s, 4H) , 1.30 (s, 12H) . Ethyl 2-Fluoro-4-r (5'.6'.7A8 f -tetrahvdro- 5',5',8',8'-tetramethylnaphthalen-2 '-yl)carbamoyl]be nzoate (Compound 1) To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- 2-naphthoic acid (46 mg, 0.2 mmol) was added 1 ml thionyl chloride. This mixture was refluxed for 2 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in 2 ml of CH 2 C1 2 . To this solution was added ethyl 4-amino-2-fluorobenzoate ((Compound C_ , 37 mg, 0.2 mmol) followed by 0.5 ml of pyridine. The reaction mixture was stirred at room temperature for 4 h and was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane 1/10) to give the title compound as white solids. *H NMR δ 8.06 (b, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.78 (dd, J x = 2.0 Hz, J 2 = 12.9 Hz, 1H), 7.55 (dd, J_ = 2.0 Hz, J 2 = 8.2 Hz, 1H) , 7.40 (d, J = 8.3 Hz, 1H), 7.32 (dd, J_ = 2.02 Hz, J 2 = 8.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J = 7.2 Hz), 1.32 (s, 6H), 1.30 (s, 6H) . Ethyl 2-Fluoro-4-f (5' .6'.7'.8'-tetrahvdro-4 ' - bromo-5 ' ,5 ' .8' .8 '-tetramethylnaphthalen-2'-yl )carbarn oyl]benzoate (Compound 3) Using the same procedure as for the synthesis of ethyl 2-fluoro-4-[-5' ,6' ,7' ,8'-tetrahydro- 5' ,5' ,8' ,8'-tetramethylnaphthalen-2'-y1)carbamoyl]be nzoate (Compound 1), but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth alene-2-carboxylic acid (Compound F), the title compound was obtained as a white solid. *H NMR δ 8.30 (b, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.74 (dd, J : = 2.1 Hz, J 2 = 12.8 Hz, 1H), 7.35 (dd, J x = 2.0 Hz, J 2 = 8.4 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.67 (m, 4H), 1.55 (s, 6H) , 1.39 (t, J = 7.2 Hz, 3H), 1.31 (s, 6H) . Ethyl 2-Fluoro-4-r (3'-methoxymethoxy-5 ' .6 ' .1 ' .8 '-tet- rahydro-5 ' . 5',8 f ,8'-tetramethylnaphthalen-2 '-yl)car- bamoy1 benzoate (Compound K_) Using the same procedure as for the synthesis of ethyl 2-fluoro-4-[ (3'-methoxymethoxy-4'-bromo- 5' ,6' ,7' ,8'-tetrahydro-5' ,5' ,8' ,8'-tetramethylnaphth alen-2'-yl)carbamoyl]benzoate (Compound S_) , but using 3-methoxymethoxy-5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl carboxylic acid (Compound K, 143 mg, 0.49 mmol) and 4-amino-2-fluorobenzoate (Compound C l t 98.5 mg, 0.54 mmol), the title compound was obtained as a white solid. - NMR δ 10.1 (b, 1H), 8.20 (s, 1H), 7.93 (t, J = 8.8 Hz, 1H), 7.83 (d, J = 13.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.41 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.59 (S, 3H), 1.70 (s, 4H), 1.31 (s, 12H), 1.26 (t, J = 7.1 Hz, 3H) . Ethyl 2-Fluoro-4-f (3 '-hvdroxy-5' .6 ' .7 ' ,8 '- tetrahvdro-5',5',8', 8 '-tetramethyl-2- naphthalenyl )carbamoyl]benzoate (Compound 5) A solution of ethyl 2-fluoro-4-[ (3 '-methoxymet- hoxy-5' ,6 ' ,7 ' ,8'-tetrahydro-5' , 5' ,8' ,8 '-tetramethylnaphthalen-2'-y1)carbamoyl] benzoate (Compound K lf 50.7 mg, 0.11 mmol) in 2 ml of CH 2 C1 2 was added thiophenol (0.061 ml, 0.55 mmol). The reaction mixture was stirred at 0 °C for 5 min, then BF 3 .Et 2 0 (0.027 ml, 0.22 mmol) was added. The reaction mixtrue was stirred at 0 °C for 2 h, then NaHC0 3 (sat.) was added. The organic layer was separated, and washed with brine, water and dried over MgS0 4 . After filtration and removal of solvent, the residue was passed through a column (silica gel, ethyl acetate/hexane 1/3) to give the title compound as white solid (44.2 mg) . X H NMR δ 8.61 (b, 1H), 7.94 (t, J = 8.42 Hz, 1H), 7.71 (dd, J = 10.8, 2.0 Hz, 1H), 7.53 (s, 1H), 7.35 (dd, J = 6.4, 2.0 Hz, 1H), 6.96 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.69 (s, 4H), 1.40 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H), 1.27 (s, 6H) . Ethyl 2-Fluoro-4-r (4 ' .4 '-dimethyl-8 '-bromochroman- 6 '-yl)carbamoyl]benzoate (Compound 7) In a 10 ml of round bottom flask. 4,4-dimethyl-8-bromo-6-chromanoic acid (Compound B lf 139 mg, 0.485 mmol) was added S0C1 2 (1 ml, large excess). The resulting solution was heated at 90 °C for 2 h and allowed to cool to room temperature. The excess of S0C1 2 was evaporated under reduced pressure. The residue was dissolved in CH 2 C1 2 (3 ml) . Ethyl 4-amino-2-fluorobenzoate (Compound C lf 90 mg, 0.49 mmol) was added followed by pyridine (0.5 ml, large excess). The reaction mixture was stirred for overnight and then concentrated to dryness. The residue was purified by column chromatography with ethyl acetate/hexane (1/5) to yield the title compound as a white solid (190 mg) . X H NMR δ 7.95 (t, J = 8.31 Hz, 1H), 7.88 (b, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 12.89, 2.0 Hz, 1H), 7.30 (dd, J = 8.55, 2.0 Hz, 1H), 4.37 (m, 5H), 1.89 (t, J = 5.49 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.39 (s, 6H). Ethyl 2-Fluoro-4-r(2'.2'.4',4'-tetramethyl-8'-bro o- chroman-6'-yl )carbamoyl]benzoate (Compound 9) Using the same procedure as for ethyl 2-fluoro-4-[ (4' ,4'-dimethyl-8'-bromochroman-6'-yl)ca rbamoyl]benzoate (Compound 7), but using 2,2,4,4-tetramethyl-8-bromo-6-chromanoic acid (Compound P, 70 mg, 0.22 mmol) and ethyl 4-amino-2-fluorobenzoate (Compound C lf 38 mg, 0.22 mmol), the title compound was obtained as a white solid (80 mg, 76%). *H NMR δ 8.25 (b, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.83 (s, 2H), 7.74 (dd, J_ = 2.0, J 2 = 13.0 Hz, 1H), 7.34 (dd, J x = 2.0, J 2 = 8.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.88 (S, 2H), 1.41 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H), 1.37 (s, 6H) . Ethyl ι 2-Fluoro-4-r f2' .2' .4' .4'-tetramethyl-8'-trifluoromet 2 hylchroman-6'-yl)carbamoyl] benzoate (Compound 11) 3 Using the same procedure as for ethyl 4 2-fluoro-4-[ (4' ,4'-dimethyl-8'-bromochroman-6'-yl)ca 5 rbamoyl]benzoate (Compound 7), but using 6 2,2,4,4-tetramethyl-8-trifluoromethyl-6-chromanoic 7 acid (Compound S, 57 mg, 0.19 mmol) and ethyl e 4-amino-2-fluorobenzoate (Compound C lf 35 mg, 0.19 9 mmol), the title compound was obtained as white o solids. 1 l E NMR δ 8.06 (d, J = 2.2 Hz, 1H), 7.99 (b, 1H), 7.95 2 (t, J = 8.55 Hz, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.76 3 (dd, J = 12.8, 2.1 Hz, 1H), 7.33 (dd, J = 8.55, 1.9 4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.93 (s, 2H), 5 1.41 (s, 12H), 1.40 (t, J = 7.2 Hz, 3H) . Ethyl 6 2-Fluoro-4-r (2 ' .2' .4' .4'-tetramethyl-8'-amino- 7 chroman-6'-yl )carbamoyl1benzoate (Compound N x ) s Using 8-nitro-2, 2, 4, 9 4-tetramethylchroman-6-carboxylic acid (Compound V) 0 and following the same procedure as for the 1 synthesis of ethyl 2-fluoro-4-[ (4' ,4'-dimethyl- 2 8'-bromochroman-6'-yl)carbamoyl]benzoate (Compound 3 7), ethyl 2-fluoro-4-[2' ,2' ,4' ,4'-tetramethyl- 4 8'-nitrochroman-6'-yl) ]carbamoylbenzoate was 5 obtained as a white solid. This compound (50 mg, 6 0.12 mmol) was dissolved in 2 ml of methanol. A 7 catalytic amount of Pd/C was added to the solution 8 and the solution was maintained under H 2 atmosphere 9 (hydrogen balloon) for overnight. The catalyst was 0 removed by filtration and the solvent was evaporated 1 to give the title compound as a white solid. 2 -E NMR δ 7.93 (t, J = 8.43 Hz, 1H), 7.90 (b, 1H), 3 7.73 (dd, J = 12.9, 2.0 Hz, 1H), 7.29 (dd, J = 8.43, 1.96 Hz, 1H), 7.23 (d, J = 2.14 Hz, 1H), 7.01 (d, J ι = 2.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.88 (s, 2 2H), 1.39 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.37 3 (S, 6H). 4 Ethyl 2-Fluoro-4- (2' , ' .4' .4'-tetramethyl-8'- 5 azidochroman-6'-yl)carbamoy11benzoate (Compound 13) e To a solution of ethyl 7 2-fluoro-4-[ (2',2',4',4'-tetramethyl-8'-aminochroman β -6'-yl)carbamoyl]benzoate (Compound N lf 32 mg, 0.077 9 mmol) in 3 ml of EtOH was added 0.5 ml of o trifluoroacetic acid (TFA) and 0.5 ml of 1 isoamylnitrite at 0°C. The reaction was stirred for 2 2 h when a solution of NaN 3 (5 mg, ) in 0.2 ml of 3 water was added. The reaction mixture was allowed 4 to warm to room temperature and stirred for s overnight. The solvent was removed and the residue 6 was purified by column chromatography ( silica gel, 7 ethyl acetate/ hexane 1/10) to give the title 8 compound as a colorless oil. 9 : H NMR δ 8.0 (b, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 12.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, J = 1 8.5, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.90 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.45 (s, 6H), 1.40 (s, 6H) . Methyl 2.6-Difluoro-4-IP2'.2'.4',4'-tetramethyl-8'-trifluor omethylchroman-6'-yl)carbamoyl]benzoate (Compound 15) Using the same procedure as for ethyl 2-fluoro-4-[ (4' ,4'-dimethyl-8'-bromochroman-6'-yl)ca rbamoyl]benzoate (Compound 7), but using 2,2,4,4-tetramethyl-8-trifluoromethylchromanoic acid (Compound S, 11.2 mg, 0.037 mmol) and methyl 4-amino-2,6-difluorobenzoate (Compound R_, 6.6 mg, 0.035 mmol), the title compound was obtained as ι white crystals. 2 l E NMR δ 8.21 (b, 1H), 8.05 (s, 1H), 7.82 (s, 1H) , 3 7.36 (d, J = 10.20 Hz, 1H), 3.93 (s, 3H) , 1.92 (s, 4 2H), 1.40 (s, 12H). s Ethyl 2-Fluoro-4-r (2' . 2'. 4'. 6 4 '-tetramethyl-8 '-iodochroman-6'-yDcarbamoyllbenzoa 7 te (Compound 17) β Using the same procedure as for ethyl 9 2-fluoro-4-[ (4 ' ,4 '-dimethyl-8'-bromochroman-6 '-yl)ca ιo rbamoyl]benzoate (Compound 7), but using ιι 2,2,4,4-tetramethyl-8-iodochromanoic acid (Compound 12 X, 81 mg, 0.25 mmol) and ethyl 4-amino-2- 13 fluorobenzoate ((Compound C_, 55 mg, 0.30 mmol), the 1 title compound was obtained as a white solid. 15 X H NMR δ 8.05 (b, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.94 16 (t, J = 8.4 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.75 17 (dd, J = 12.88, 2.1 Hz, 1H), 7.33 (dd, J = 8.8, 2.1 18 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.89 (s, 2H), 1 1.42 (s, 6H), 1.38 (s, 6H). Ethyl 0 2-Fluoro-4-f (2'.2' .4' ,4' .8 '-pentamethylchroman- 1 6'-y1)carbamoyl]benzoate (Compound 19) 2 Using the same procedure as for ethyl 3 2-fluoro-4-[ (4 ' ,4 '-dimethyl-8'-bromochroman-6'-yl)ca 4 rbamoyl]benzoate (Compound 9), but using 5 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound 6 A x , 92 mg, 0.37 mmol) and ethyl 7 4-amino-2-fluorobenzoate (Compound C lf 75 mg, 0.41 8 mmol), the title compound was obtained as a white 9 solid ( 100 mg) . o -E NMR δ 8.31 (b, 1H), 7.90 (t, J = 8.24 Hz, 1H), 1 7.76 (dd, J = 14.29, 1.7 Hz, 1H), 7.74 (s, 1H), 7.43 2 (s, 1H), 7.35 (dd, J = 8.67, 1.7 Hz, 1H), 4.32 (q, J 3 = 7.1 Hz, 2H), 2.18 (s, 3H), 1.84 (s, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H), 1.34 (s, 6H) . 1 Ethyl 2 4-f f5' .6' ,7' .8'-tetrahvdro-5' ,5' ,8' ,8'-tetramethyl-2 3 -naphthalenyl)thiocarbamoy11benzoate (Compound 21) 4 To a solution of ethyl 5 4-[(5',6',7',8'-tetrahydro-5' ,5' ,8' , 6 8 '-tetramethylnaphthalen-2-yl)carbamoyl]benzoate (Compound 1_ , 61 mg, 0.16 mmol) in 2 ml of anhydrous β benzene was added Lawesson's reagent (45 mg, 0.112 9 mmol). The resulting yellow solution was refluxed ιo under N 2 for 2 h. The solvent was removed and the ιι residue was purified by column chromatography 12 (silica gel, ethyl acetate/hexane 1/5) to give the 13 title compound as a yellow solid (55 mg, 87%). 14 X H NMR δ 9.04 (b, 1H), 8.11 (d, J = 8.70 Hz, 2H), 15 7.85 (b, 2H), 7.75 (b, 1H), 7.55 (dd, J = 8.2, 1.9 16 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 4.38 (q, J = 7.1 1 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J = 7.1 Hz, 3H), is 1.30 (s, 12H). is Ethyl 2-Fluoro-4-r (5'.6'.7'.8'-tetrahvdro- 0 5' .5' .8' .8'-tetramethylnaphthalen-2'-yl)thiocarbamoy 1 11benzoate (Compound 23) 2 Using the same procedure as for the synthesis of 3 ethyl 4-[(5',6',7',8'-tetrahydro-5' ,5' ,8' ,8'- 4 tetramethy1-2-naphthalenyl)thiocarbamoyl]benzoate 5 (Compound 21) but using ethyl 6 2-fluoro-4-[ (5' ,6' ,7' ,8 '-tetrahydro-5' ,5' ,8',8'-tetr amethylnaphthalen-2'-yl)carbamoyl]benzoate (Compound 8 1, 167 mg, 0.42 mmol) in 8 ml of benzene and 9 Lawensson's reagent (220 mg, 0.544 mmol), the title 0 compound was obtained as a bright yellow solid 1 (127.5 mg) . 2 l E NMR δ 9.30 (b, 1H), 8.05 (b, 1H), 7.95 (t, J = 3 8.37 Hz, 1H), 7.77 (d, J = 1.89 Hz, 1H), 7.53 (dd, J 4 = 8.24, 2.1 Hz, 1H), 7.49 (b, 1H), 7.35 (d, J = 8.24 1 Hz , 1H ) , 4 . 33 ( q, J = 7 . 1 Hz , 1H ) , 1 . 71 . ( s , 4H ) , 2 1 . 32 ( s , 6H ) , 1 . 30 ( s , 6H ) . 3 3-Hydroxy-5.5.8.8-tetramethyl-5.6.7.8-tetrahydronap hthalen-2-yl carboxylic acid (Compound ) 5 To a solution of 2-bromo-3-methoxymethoxy- 6 5,5,8,8-tetrahydro-5,5,8,8-tetramethylnaphthalene 7 (Compound J, 722 mg, 2.2 mmol) in 10 ml of dry THF β at -78°C under argon was added slowly 2.86 ml of Θ t-BuLi (1.7 M in hexane, 4.8 mmol). The reaction o mixture was stirred at -78°C for 1 h. Then C0 2 was 1 bubbled through the solution for 1 h. After removal 2 of C0 2 stream, the reaction mixture was stirred for 3 an additional hour at -78°C. Then 10% of HC1 was 4 added. After warming up to room temperature, the s reaction mixture was left overnight then extracted 6 with ethyl acetate. The organic layer was washed 7 with brine and dried over Na 2 S0 4 . After s concentration, the residue was purified by column 9 chromatography (ethyl acetate/hexane 1/3) to yield 0 the title compound as a white solid. 1 -E NMR d 7.85 (s, 1H), 6.93 (s, 1H), 1.68 (s, 4H), 2 1.28 (s, 12H). 3 4-Bromo-3-hydroxy-5.5.8.8-tetramethyl-5.6.7.8-tetrah 4 ydronaphthalen-2-yl carboxylic acid (Compound M) 5 3-Hydroxy-5,5,8,8-tetramethy1-5,6,7,8-tetrahydro- 6 naphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) was dissolved in 1 ml of HOAc. To this solution was β added Br 2 (0.033 ml, 0.62 mmol). The reaction 9 mixture was left at room temperature for over night, o A stream of air was passed through the reaction 1 mixture to remove the unreacted Br 2 . The remaining 2 solid was dissolved in small amount of THF and 3 purified by column chromatography (ethyl 4 acetate/hexane 1/1) to yield the desired product as ι a cream colored solid. 2 X E NMR d 7.91 (s, 1H), 1.75 (m, 2H), 1.64 (m, 2H), 3 1,62 (s, 6H), 1.30 (s, 6H) . 4 4-Bromo-3-methoxymethoxy-5.5.8.8-tetramethyl-5.6.7.8 5 -tetrahydronaphthalen-2-yl carboxylic acid (Compound 6 N) 7 To a solution of 4-bromo-3-hydroxy-5,5,8,8- β tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid 9 (Compound M) , 233 mg, 0.71 mmol) in 6 ml of CH 2 C1 2 ιo was added chloromethyl methyl ether (0.162 ml, 2.1 11 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) 12 and a catalytic amount of tetrabutylammouimn 13 bromide. The reaction mixture was heated to 45 °C 14 for 2 h. The reaction mixture was concentrated and is the residue was purified by column chromatography 16 (ethyl acetate/hexane 1/9) to yield the i7 methoxymethyl ester of the title compound as a white 18 solid (200 mg). This white solid was further 19 dissolved in 20 ml of EtOH. An aqueous solution of 0 NaOH (0.5 ml, 1M) was added. The reaction mixture 1 was stirred at room temperature for over night. The 2 EtOH was removed and the residue was added 2 ml of 3 ethyl acetate and 3 ml of water. This mixture was 4 very slowly acidified with 10% HC1 to PH = 7. The 5 ethyl acetate layer was separated and washed with 6 brine, dried over Na 2 S0 4 . After filtration of the 7 drying agent and removal of solvent, the reaction 8 yielded the title compound as a white solid (155 9 mg). l E NMR d 7.99 (s, 1H), 5.20 (s, 2H) , 3.66 (s, o 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 1 (s, 6H) . 2 Ethyl 2-fluoro-4-f (3'-methoxymethoxy-4'-bromo- 3 5' .6' .7' .8'-tetrahvdro-5' .5' .8 ' .8'-tetramethylnaphth 4 alen-2'-y1)carbamoyl1benzoate (Compound S_ ) ι To a solution of 4-bromo-3-methoxymethoxy- 2 5,5,8,8-tetramethy1-5,6,7,8-tetrahydronaphthalen-2-y 3 1 acid (Compound N, 80 mg, 0.22 mmol) in 4 ml of 4 CH 2 C1 2 was added DMAP (60 mg, 0.26 mmol), ethyl 5 2-fluoro-4-aminobenzoate (Compound C_, 43 mg, 0.24 6 mmol) and EDC (50 mg, 0.26 mmol). The reaction 7 mixture was stirred at room temperature for β overnight and then concentrated to dryness. The residue was purified by column chromatography (ethyl o acetate/hexane 1/3) to yield the title compound as a 1 clear oil (45 mg). 2 E NMR d 9.92 (b, 1H), 8.10 (s, 1H), 7.94 (t, J = 8.4 3 Hz, 1H), 7.81 (dd, J = 12.9; 1.9 Hz, 1H), 7.35 (dd, 4 J = 8.5; 1.8 Hz, 1H), 5.20 (s, 2H) , 4.39 (q, J = s 7.1 Hz, 2H), 3.61 (s, 3H), 1.74 (m, 2H), 1.64 (m, 6 2H), 1.60 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 7 (s, 6H). 8 Methyl 9 2.6-Difluoro-4-f (3'-methoxymethoxy-4'-bromo-5' .6' .7' 0 ,8'-tetrahydro-5' ,5' ,8' ,8'-tetramethylnaphtha- 1 len-2'-y1 )carbamoyl]benzoate (Compound M x ) 2 Using the same procedure as for the synthesis of 3 compound ethyl 2-fluoro-4-[ (3'-methoxymethoxy- '- 4 bromo-5' ,6' ,7' ,8'-tetrahydro-5' ,5' ,8' ,8'-tetramethyl 5 naphthalen-2'-yl)carbamoyl]benzoate (Compound S x ) but 6 using 4-bromo-3-methoxymethoxy-5,5,8,8-tetramethyl- 7 5,6,7,8- tetrahydronaphthalen-2-yl acid (Compound N, β 80 mg, 0.22 mmol), DMAP (60 mg, 0.26 mmol), methyl 9 2,6-difluoro-4-aminobenzoate (Compound H 17 52 mg, 0 0.24 mmol) and EDC (50 mg, 0.26 mmol), the title 1 compound was obtained as a clear oil. 2 l E NMR d 10.01 (b, 1H), 8.11 (s, 1H), 7.42 (d, J = 3 10.0 Hz, 2H), 5.2 (s, 2H), 3.95 (s, 3H), 3.63 (s, 4 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.35 1 ( s , 6H ) . 2 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A 3 ) 3 To a mixture of 2,6-di-t-butyl-4-methylpyridine 4 (Aldrich, 2.0 g, 9.73 mmol) in 25 ml of dry CC1 4 was 5 added benzoyl peroxide (24 mg, 0.097 mmol) and NBS 6 (1.9 g, 10.7 mmol). The reaction mixture was 7 refluxed for 16 hours. After it cooled to room β temperature, the solvent was removed in vacuo and 9 the residue was purified by column chromatography o (silica gel, hexane) to give an oil (1.957 g) which 1 contained 82% of the desired product and 18% of the 2 starting material. X H NMR δ 7.09 (s, 2H), 4.39 (s, 3 2H), 1.35 (s, 18H). 4 4-Hydroxymethyl-2,6-di-t-butylpyridine (Compound B 3 ) s A heterogeneous solution of 6 4-bromomethyl-2,6-di-t-butylpyridine (Compound A 3 , 7 1.743 g, 82% purity) in 20 ml of 12% NaOH in water 8 and 10 ml of 1,4-dioxane was refluxed for 12 hours. 9 The solution spontaneously separated into two layers 0 as it cooled to room temperature. The upper layer 1 was separated and ethyl acetate was added. This 2 organic layer was then washed with brine, water and 3 dried over MgS0 4 . The desired product was purified by column chromatography (ethyl acetate/hexane 1/9) 5 to give a white solid. H NMR δ 7.09 (s, 2H), 4.67 6 (d, J = 4.4 Hz, 2H), 2.3 (b, 1H), 1.36 (s, 18H) . 7 2,6-Di-t-butylisonicotinic acid (Compound C 3 ) β Jone's reagent was added dropwise to a solution of 9 4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B 3 , o 302 mg, 1.37 mmol) in 5 ml of acetone until the 1 solution changed color from light yellow to orange 2 (55 drops of Jone's reagent were consumed). After 5 3 minutes 2 ml of isopropanol were added to the reaction mixture, and a green precipitate of Cr 3+ 1 salt was formed. The precipitate was removed by 2 filtration and the solution was diluted with ethyl 3 acetate, then washed with brine, water and dried over MgS0 4 . After filtration, the solvent was 5 removed to give the desired product as a white solid 6 (227 mg). *H NMR δ 7.71 (s, 2H), 1.34 (s, 18H) . 7 2-Bromo-4.6-di-t-butylphenol (Compound D 3 ) β To a solution of 2,4-di-t-butylphenol (Aldrich, 9 2.0 g, 9.7 mmol) in 2 ml of HOAc was added Br 2 (0.5 ιo ml, 9.7 mmol). The reaction mixture was stirred at 11 room temperature for 12 hours. Solvent was removed 12 under reduced pressure and the residue was purified 13 by column chromatography (ethyl acetate/hexane 1/20) 14 to yield the desired product (2.54 g) as a white 15 solid. H NMR δ 7.33 (d, J = 2.3 Hz, 1H), 7.24 (d, J 16 = 2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H). 17 0-Methoxymethyl-2-bromo-4.6-di-t-butylphenol ιβ (Compound E 3 ) 19 To a solution of 2-bromo-4,6-di-t-butylphenol 20 (Compound D 3 2.54 g, 8.88 mmol) and catalytic amount 21 of Bu 4 NI in 20 ml of dry CH 2 C1 2 at 0°C was added 22 diisopropylethylamine (9.51 ml, 53 mmol), followed 23 by methoxymethyl chloride (2.02 ml, 26.6 mmol). The 24 reaction mixture was heated to 45°C for 12 hours. 5 The reaction mixture was then washed with 10% citric 6 acid, then NaHC0 3 (sat.), brine, and dried over 27 MgS0 4 . After filtration and removal of the solvent 8 under reduced pressure, the residue was purified by 9 column chromatography (pure hexane) to yield the 30 title compound (2.79 g) as a colorless oil. X H NMR δ 31 7.40 (d, J = 2.44 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H) , 2 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 33 9H). 34 O-Methoxymethyl-3' .5'-di-t-butylsalicylic acid ι (Compound F 3 ) 2 To a solution of 0-methoxymethyl-2-bromo-4,6- 3 di-t-butylphenol (Compound E 3 , 2.79 g, 8.5 mmol) in 4 30 ml of dry THF at -78°C under Ar was added 11 ml 5 of t-BuLi (1.7 M in hexane, 18.7 mmol). This 6 mixture was stirred at -78°C for 1 hour. Then C0 2 7 (g) was bubbled into the solution at -78°C for 1 β hour. After removal of the C0 2 stream, the reaction 9 mixture was stirred for an additional hour at -78°C. ιo Then 10% of HC1 was added and the mixture was ιι allowed to warm to room temperature and extracted 12 with ethyl acetate. The organic layer was washed i3 with brine and dried over Na 2 S0 4 . After 14 concentration, the residue was purified by column is chromatography (ethyl acetate/hexane 1/1) to yield 16 the title compound as a white solid (492 mg) . X H NMR 17 δ 7.75 (d, J = 2.81 Hz, IH), 7.60 (d, J = 2.8 Hz, 18 IH), 5.07 (s, 2H), 3.62 (s, 3H), 1.33 (s, 9H), 1.26 19 (s, 9H). 0 Ethyl 2-fluoro-4-r 2'6'-di-t-butylPyrid-4'- 1 y1 )carbamoyl]benzoate (Compound 41) 2 A solution of 2,6-di-t-butylisonicotinic acid 3 (Compound C 3 , 47.3 mg, 0.20 mmol) in 2 ml of S0C1 2 4 was heated under reflux for 2 hours. Excess S0C1 2 5 was removed in vacuo and the residue was dissolved 6 in 2 ml of dry CH 2 C1 2 , and ethyl 7 2-fluoro-4-aminobenzoate (Compound C l t 40.2 mg, 0.22 8 mmol) and pyridine (0.0835 ml, 0.69 mmol) were 9 added. The reaction mixture was stirred at room 0 temperature for 12 hours. Solvent was removed and the residue was purified by column chromatography 2 (ethyl acetate/hexane 1/9) to yield the title 3 compound (71.2 mg) as white crystals. X H NMR δ 8.56 4 (b, IH), 7.91 (t, J = 8.36 Hz, IH), 7.53 (dd, J = 1 12.82, 2.0 Hz, IH), 7.39 (dd, J = 8.7, 2.0 Hz, IH), 2 4.33 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 3 1.35 (s, 18H). 4 Ethyl 4- r ( 2 ' , 6 ' -di-t-butylpyrid-4 ' -yl ) car- 5 bamoyl1benzoate (Compound 43) e Using the same procedure as for the synthesis of 7 ethyl 2-fluoro-4-[ (2 '6'-di-t-butylpyrid-4 '- β yl)carbamoyl]benzoate (Compound 41) but using s 2,6-di-t.-butylisonicotinic acid (Compound C 3 , 101 mg, o 0.43 mmol) and ethyl 4-aminobenzoate (78 mg, 0.47 1 mmol), the title compound was obtained as a white 2 solid (135 mg) . *H NMR δ 8.43 (b, IH),, 8.02 (d, J = 3 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.48 (s, 2H), 4 4.33 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 5 1.35 (s, 18H). 6 Ethyl 7 2-Fluoro-4-r (3' .5'-di-t-butylphenyl )carbamoyl1benzoa s te (Compound 45) 9 Using the same procedure as for the synthesis of 0 ethyl 2-fluoro-4-[ (2 '6'-di-t-butylpyrid-4 '- 1 yl)carbamoyl]benzoate (Compound 41) but using 2 3,5-di-t-butylbenzoic acid (60 mg, 0.26 mmol, 3 available by literature procedure, see Kagechika et 4 al. J. Med Chem. 1988 31, 2182 - 2192) and ethyl 5 2-fluoro-4-aminobenzoate (Compound C lf 51.5 mg, 0.28 6 mmol), the title compound was obtained as a white 7 solid (66 mg). l E NMR δ 8.21 (b, IH), 7.93 (t, J = β 8.3 Hz, IH), 7.79 (dd, J = 12.8, 2.0 Hz, IH), 7.67 9 (d, J = 1.8 Hz, 2H), 7.65 (t, J = 1.7 Hz, IH), 7.35 o (dd, J = 8.7, 2.1 Hz, IH), 4.36 (q, J = 7.2 Hz, 2H), 1 1.39 (t, J = 7.2 Hz, 3H), 1.36 (s, 18H) . 2 Ethyl 3 2-Fluoro-4-f ( 2'-methoxymethyl-3 ' .5'-di-t-butylphenyl 4 )carbamoyl1benzoate (Compound G 3 ) 1 To a mixture of 0-methoxymethyl-3' ,5'-di-t- 2 butylsalicylic acid (Compound F 3 , 150 mg, 0.51 mmol), 3 4-dimethylaminopyridine (142 mg, 0.61 mmol) and ethyl 2-fluoro-4-aminobenzoate (Compound C lt 102 mg, 5 0.56 mmol) in 5 ml of dry CH 2 C1 2 was added l-(3-di- 6 methylaminopropyl)-3-ethylcarbodiimide hydrochloride 7 (117 mg, 0.61 mmol). The reaction mixture was β stirred at room temperature for 12 hours. Solvent 9 was evaporated in vacuo and the residue was o dissolved in ethyl acetate, then washed with brine, 1 water and dried over MgS0 4 . After filtration, 2 solvent was removed and the residue was purified by 3 column chromatography (ethyl acetate/hexane 1/3) to 4 give the title compound (58 mg) . X H NMR δ 8.97 (b, 5 IH), 7.94 (t, J = 8.37 Hz, IH), 7.78 (d, J = 2.7 Hz, 6 IH), 7.61 (d, J = 13.0 Hz, IH), 7.56 (d, J = 2.6 Hz, 7 IH), 7.35 (d, J = 8.7 Hz, IH), 5.00 (s, 2H), 3.53 s (s, 3H), 4.38 (q, J = 7.1 Hz, 2H), 1.47 (s, 9H), 9 1.39 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H) . 0 Ethyl i 2-Fluoro-4-r (2'-hydroxy-3' .5'-di-t-butylphenyl )carba moyllbenzoate (Compound 47) To a solution of ethyl 2-fluoro-4-[ (2'- 4 methoxymethy1-3 ' ,5 '-di-t-butylphenyl)carbamoyl]benzo 5 ate (Compound G 3 , 34 mg, 0.07 mmol) in 1 ml of THF were added 10 drops of HOAc. The reaction mixture was heated to reflux for 12 hours. Solvent was removed and ethyl acetate was added. The solution was washed with NaCH0 3 (sat.), brine, water and dried over MgS0 4 . Solvent was removed in vacuo to give an 1 oil. The oil was allowed to be exposed to the atmosphere for 12 hours during which time crystals formed. The crystals were collected and washed several times with hexane to afford the title 1 compound as a white solid (13.5 mg) . H NMR δ 10.73 2 (s, IH), 7.98 (d, J = 2.56 Hz, IH) , 7.88 (b, IH), 3 7.75 (t, J = 8.26 Hz, IH), 7.60 (d, J = 2.44 Hz, 4 IH), 7.32 (dd, J = 12.3, 2.0 Hz, IH), 7.02 (dd, J = 5 8.6, 2.0 Hz, IH), 4.35 (q, J = 7.2 Hz, 2H) , 1.39 (s, 6 9H), 1.37 (t, J « 7.2 Hz, 3H), 1.5 (s, 9H). 7 2.6-Difluoro-4-r (2' ,6'-di-t-butylpyrid-4'yl )carbamov β l]benzoic Acid (Compound 50) 9 To 2,6-di-t-butylisonicotinic acid (Compound C 3 , ιo 20 mg, 0.085 mmol) was added 1 ml of S0C1 2 . The 11 mixture was heated under reflux for 2 hours. After 12 cooling to room temperature, excess S0C1 2 was removed 13 and the residue was dissolved in 2 ml of CH 2 C1 2 . To 4 this solution was added methyl 2,6-difluoro-4-amino- 15 benzoate (Compound R_, 16 mg, 0.085 mmol) and 16 triethylamine (0.015 ml, 0.1 mmol). The reaction 17 mixture was kept at room temperature for 2 hours and 18 then concentrated to dryness. The residue was i9 purified by column chromatography with ethyl 20 acetate/hexane (1/10) to yield the methyl ester of 1 the title compound. This was saponified according 22 to the general procedure (see below) to give the 23 title compound as a colorless solid. H NMR δ 7.44 24 (s, 2H), 7.40 (d, J = 11.8 Hz, 2H) 1.37 (s, 18H). 25 2.6-Difluoro-4-f (3' .5'-di-t-butylphenyl)car-bamoyl]b 26 enzoic Acid (Compound 52) 7 Using the same procedure as for the preparation 8 of 2,6-difluoro-4-[ (2' ,6'-di-t-butylpyrid- 9 4'yl)carbamoyl]benzoic acid (Compound 50) but using so 3,5-di-t-butylbenzoic acid (37 mg, 0.16 mmol) and 31 methyl 2,6-difluoro-4-aminobenzoate (Compound H lf 29 32 mg, 0.16 mmol), the title compound was obtained as 33 colorless crystals. l E NMR δ 7.92 (b, IH) 7.60 (m, 34 3H), 7.42 (d, J = 10.0 Hz, 2H), 1.38 (s, 18H) . 1 2-Nitro-4-r ( 2 ' .6'-di-t-butylpyrid-4'-yl \carbamoyl1be 2 nzoic Acid (Compound 54) 3 Using the same procedure as for the preparation 4 of 2,6-difluoro-4-[ (2' ,6'-di-t-butylpyrid- 5 4'yl)carbamoylJbenzoic acid (Compound 50) but using 6 2,6-di-t-butylisonicotinic acid (40 mg, 0.17 mmol) 7 and methyl 2-nitro-4-aminobenzoate (Compound F lf 33 β mg, 0.17 mmol), the title compound was obtained as a 9 light yellow oil. X H NMR δ (acetone-d 6 ) 10.25 (b, o IH), 8.32 (s, IH), 7.97 (d, J = 8.1 Hz, IH), 7.93 1 (b, IH), 7.70 (s, 2H), 1.36 (s, 18H) . 2 Methyl 2-nitro-4-r (4 '-bromo-5' .6' .7' .8'-tetrahydro- 3 5' ,5' ,8' .8'-tetramethylnaphthalen-2'-yl)carbamoyl]be 4 nzoate (Compound 25) s Using the same procedure as for the synthesis of 6 Compound 1, but using Compound F and Compound F_ , the 7 desired product was obtained as a white solid. 8 *H NMR δ 9.24 (b, IH), 9.23 (d, J = 1.8 Hz, IH), 7.92 9 (dd, J = 8.4, 2.4, Hz, IH), 7.87 (d, J = 2.1 Hz, 0 IH), 7.84 (d, 3 = 2.1 Hz, IH), 7.80 (d, J = 8.7 Hz, 1 IH), 3.91 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.58 2 (s, 3H), 1.33 (s, 3H). 3 General procedure for the syntheses of benzoic 4 acid derivatives by hydrolyzing the corresponding 5 methyl or ethyl esters. 6 To a solution of ester (3.0 mmol) in 20 ml of 7 EtOH was added 5 ml of 1 N NaOH in water. The β reaction mixture was stirred at room temperature for 9 overnight and neutralized with 10% HC1 to PH=5. The 0 alcohol was removed by evaporation and the aqueous 1 layer was extracted with ethyl acetate (3x10ml). 2 The combined ethyl acetate layers were washed with 3 NaHC0 3 (sat.), brine and dried over MgS0 4 . After concentration, the desired acid was obtained which ι could be recrystallized in ethyl acetate or in 2 acetonitrile. 3 2-Fluoro-4-r(5'.6',7'.8'-tetrahydro-5' ,5' ,8' ,8'-tetr 4 amethylnaphthalen-2'-yl)carbamoyl]benzoic Acid 5 (Compound 2) e *H NMR δ (acetone-D 6 ) 9.86 (b, IH), 7.95 (m, 3H), 7 7.75 (dd, J = 7.9, 2.2 Hz, IH), 7.62 (dd, J = 8.5, s 1.6 Hz, IH), 7.50 (d, J = 8.3 Hz, IH), 1.73 (s, 4H), 9 1.32 (s, 6H), 1.30 (s, 6H) . o 2-Fluoro-4-π4'-bromo-5' .6' .7' .8'-tetrahvdro-5' .5' .8 1 ' ,8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic 2 Acid (Compound 4) 3 *H NMR δ (acetone-D 6 ) 9.97 (b, IH), 8.04 (d, J = 1.89 4 Hz, IH), 8.01 (d, J = 1.90 Hz, IH) , 7.95 (t, J = 5 8.55 Hz, IH), 7.90 (dd, J = 12.28, 2.0 Hz, IH), 7.59 6 (dd, J = 8.67, 1.50 Hz, IH), 1.76 (m, 4H), 1.58 (s, 7 6H), 1.35 (s, 6H). 8 2-Fluoro-4-r (3'-hydroxy-5' .6' .7' .8'-tetrahydro-5' .5' 9 .8' .8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic 0 Acid (Compound 6) i X H NMR (acetone-D 6 ) δ 11.3 (b, IH) , 10.2 (b, IH), 2 7.94 (m. 2H), 7.85 (dd, J = 11.4, 1.95 Hz, IH), 7.53 3 (dd, J = 6.59, 2.08 Hz, IH), 6.94 (s, IH), 2.85 (b, 4 IH), 1.70 (s, 4H), 1.29 (S, 6H), 1.28 (s, 12H). 5 2-Fluoro-4-r (8'-bromo-4' .4'-dimethylchroman-6'-y1)ca 6 rbamoyl]benzoic Acid (Compound 8) 7 X H NMR (acetone-d 6 ) δ 9.87 (b, IH), 8.04 (d, J = 2.1 8 Hz, IH), 8.03 (d, J = 2.1 Hz, IH), 7.94 (t, J = 8.66 9 Hz, IH), 7.91 (dd, J = 13.8, 2.0 Hz, IH), 7.57 (dd, o J = 8.6, 2.0 Hz, IH), 4.37 (t, J = 5.44 Hz, 2H), 1 1.92 (t, J = 5.44 Hz, 2H), 1.40 (s, 6H). 2 2-Fluoro-4-r(2'.2'.4'.4'-tetramethyl-8 '-bromochroman 3 - 6'-yl)carbamoyl1benzoic Acid (Compound 10) 4 -E NMR δ (acetone-d 6 ) 9.87 (b, IH), 8.06 (d, J = 2.2 ι Hz, IH), 8.04 (d, J = 2.1 Hz, IH), 7.94 (t, J = 8.54 2 Hz, IH), 7.91 (dd, J = 14.0, 2.0 Hz, IH) , 7.59 (dd, 3 J = 8.5, 2.3 Hz, IH), 1.96 (s, 2H), 1.42 (s, 6H), 4 1.41 (s, 6H). 5 2-Fluoro-4-IP2'.2'.4'.4'-tetramethyl-8'-trifluoro- 6 methylchroman-6'-yl)carbamoyl] benzoic Acid 7 (Compound 12) β X H NMR (acetone-d 6 ) δ 10.02 (b, IH), 8.31 (s, IH), 9 8.09 (s, IH), 7.92 (m, 2H) , 7.56 (d, J = 7.69 Hz, 0 IH), 2.00 (s, 2H), 1.44 (S, 6H), 1.41 (s, 6H). 1 2-Fluoro-4-r(2',2'.4',4'-tetramethyl-8 '-azidochroman 2 - 6'-yl)carbamoyl1benzoic Acid (Compound 14) 3 -E NMR δ 8.03 (t, J = 8.4 Hz, IH), 7.87 (b, IH), 7.79 4 (dd, J = 13, 2.0 Hz, IH), 7.64 (d, J = 2.2 Hz, IH), s 7.32 (dd, J = 8.66, 1.9 Hz, IH), 7.22 (d, J = 2.1 6 Hz, IH), 1.91 (s, 2H), 1.45 (s, 6H), 1.41 (s, 6H) . 7 2. 6-Difluoro-4-r(2'.2'.4'.4'-tetramethyl-8'- 8 trifluoromethylchroman-6'-yl)carbamoyl]benzoic acid 9 (Compound 16) 0 *H NMR (acetone-d 6 ) δ 8.30 (d, J = 2.3 Hz, IH), 8.06 1 (d, J = 2.2 Hz, IH), 7.59 (d, J = 10.32 Hz, 2H), 2 1.954 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H) . 3 2-Fluoro-4-f 2',2',4'.4'-tetramethyl-8'-iodochroman- 4 6 '-yl)carbamoyl1benzoic Acid (Compound 18) 5 l E NMR δ (acetone-d 6 ) 10.0 (b, IH), 8.24 (s, IH), 6 8.07 (s, IH), 7.94 (m, 2H), 7.57 (d, J = 8.67 Hz, 7 IH), 1.95 (s, 2H), 1.41 (s, 12H) . 2-Fluoro-4-T (2' .2'.4'.4'.8'-pentamethylchroman-6 '-yl 9 )carbamoyl1benzoic Acid (Compound 20) λ H NMR δ 0 (acetone-d 6 ) 9.77 (b, IH), 7.90 (m, 3H), 7.65 (d, J = i 2.0 Hz, IH), 7.56 (dd, J = 8.61, 2.0 Hz, IH), 2.19 (s, 3H), 1.90 (s, 2H), 1.38 (s, 6H), 1.37 (s, 6H) . 4-ι r ι / 5'.6'.7'.8'-tetrahvdro-5' .5' .8 ' .8'-tetramethylna phthalen-2'-yl)thiocarbamoyl1benzoic Acid (Compound 1 22) 2 X H NMR δ 9.08 (b, IH), 8.17 (d, J = 8.61, 2H), 7.95 3 (b, 2H), 7.77 (b, IH), 7.57 (dd, J = 8.1, 2.1 Hz, 4 IH), 7.37 (d, J = 8.2 Hz, IH), 1.72 (s, 4H), 1.32 s (s, 6H), 1.31 (s, 6H). e 2-Fluoro-4-r(5'.6'.7',8'-tetrahydro-5' .5' .8' .8'-tetr 7 amethylnaphthalen-2'-yl)thiocarbamoyl1benzoic Acid β (Compound 24) 9 X H NMR δ (acetone-d 6 ) 11.1 (b, IH), 8.27 (b, J = 13.2 o Hz, IH), 8.02 (t, J = 8.3 Hz, IH), 7.89 (s, IH), 1 7.86 (d, J = 10.0 Hz, IH), 7.62 (d, J - 8.3 Hz, IH), 2 7.41 (d, J - 8.37 Hz, IH), 1.72 (s, 4H), 1.30 (s, 3 12H). 4 2-Fluoro-4-r (3'-hydroxy-4'-bromo-5' .6' .7' .8 '-tetrahy s dro-5' .5' . 8' .8 - -tetramethylnaphthalen-2'- 6 yl)carbamoyl]benzoic Acid (Compound 30) 7 A solution of ethyl 2-fluoro-4-[ (3'- 8 methoxymet-hoxy-4'-bromo-5' ,6' ,7' ,8'-tetrahydro-5' ,5 9 ' ,8' ,8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoa 0 te (Compound S lf 45 mg, 0.084 mmol) in 1 ml of EtOH was added 1 ml of aqueous solution of NaOH (1M). 2 The reaction mixture was stirred at room temperature 3 for overnight and acidified to PH = 1 with 10% HC1. 4 EtOH was removed and ethyl acetate and more water 5 were added to the solution. The organic layer was 6 separated and washed with NaHC0 3 , brine and dried 7 over MgS0 4 . After filtration and concentration, the β reaction yielded 2-fluoro-4-[ (3 '-methoxymethoxy- 9 4'-bromo-5' ,6' ,7' ,8'-tetrahydro-5' ,5' ,8' ,8'-tetramet 0 hylnaphthalen-2'-yl)carbamoyl]benzoic acid as a i white solid. The methoxymethyl group was removed by 2 dissolving the white solid in 2 ml of MeOH and 3 3 drops of HC1 (con.). After stirring for overnight, 4 the reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate 2 and water. The organic layer was separated, washed 3 with NaHC0 3 , brine and dried over MgS0 4 . After 4 filtration and concentration, the residual solid was 5 purified in a mini (pipette) column with ethyl 6 acetate /hexane (1/1) to give the title compound as 7 a white solid (5.0 mg) . β X H NMR d (acetone-d 6 ) 10.19 (b, IH), 8.01 (s, IH), 9 7.96 (t, J = 8.6 Hz, IH), 7.76 (dd, J = 11.2; 2.0 ιo Hz, IH), 7.54 (dd, J = 8.8; 2.0 Hz, IH), 1.75 (m, 11 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.32 (s, 6H). 12 2.6-Difluoro-4-r (3'-hydroxγ-4'-bromo-5' .6' .7' .8'-tet 13 rahydro-5' , 5' ,8' ,8'-tetramethylnaphthalen-2 ' - i4 yl)carbamoyl1benzoic Acid (Compound 32) 15 Using the same procedure as for the synthesis of 16 2-fluoro-4-[ (3 '-hydroxy-4'-bromo-5' ,6' ,7' ,8 '-tetrahy 17 -dro-5' ,5' ,8' ,8'-tetramethylnaphthalen-2'-yl)carbamo is yl]benzoic acid (Compound 30) the title compound was 19 obtained as a white solid. 0 X H NMR d(acetone-d 6 ) 10.23 (b, IH), 8.01 (s, IH), i 7.52 (d, J = 10.2 Hz, 2H), 4.8 (b, IH), 1.75 (m, 2 2H), 1.65 (m, 2H), 1.60 (s, 6H), 1.31 (s, 6H) . 3 2.6-Difluoro-4- \ (5'.6'.7'.8'-tetrahydro-5' .5' .8' .8'- 4 tetramethylnaphthalen-2'-yl)carbamoyl]benzoic Acid 5 (Compound 34) 6 To 5,5,8,8-tetramethy1-5,6,7,8-tetrahydro- 7 2-naphthoic acid (43 mg, 0.19 mmol) was added 1 ml 8 of thionyl chloride. This mixture was refluxed for 9 2 h. Excess thionyl chloride was removed under o reduced pressure and the residue was dissolved in 2 1 ml of CH 2 C1 2 . To this solution was added methyl 2 4-amino-2,6-difluorobenzoate (Compound H lf 7 mg, 0.2 3 mmol) followed by 0.5 ml of pyridine. The reaction 4 mixture was stirred at room temperature for 4 h and ι was concentrated under reduced pressure. The 2 residue was purified by column chromatography (ethyl 3 acetate/hexane 1/5) to give the methyl ester of the 4 desired product as a colorless oil. 5 X H NMR d 8.11 (d, J = 1.9 Hz, IH), 8.05 (b, IH), 7.86 6 (dd, J = 6.2, 2.2 Hz, IH), 7.41 (m, 3H), 3.93 (s, 7 3H), 1.69 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H) . This β colorless oil was hydrolyzed to the desired product 9 with NaOH/H 2 0/EtOH according to the general o procedure. 1 -E NMR d (acetone-d 6 ) 9.74 (b, IH), 7.95 (s, IH), 2 7.70 (d, J = 6.8 Hz, IH), 7.43 (d, J = 8.4 Hz, 3H), 3 1.71 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H) . 4 2-Nitro-4-r 4'-bromo-5' .6' .7' .8'-tetrahydro-5' .5' .8' s ,8' ,-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic 6 acid (Compound 26) 7 l E NMR δ (acetone-d 6 ): 10.16 (b, IH), 8.42 (d, J = 8 2.0 Hz, IH), 8.09 (dd, J = 8.6; 2.1 Hz, IH), 8.06 9 (d, J = 2.2 Hz, IH), 8.04 (d, J = 2.2 Hz, IH), 7.93 0 (d, J - 8.6 Hz, IH), 1.75 (m, 2H), 1.65 (m, 2H), 1 1.57 (s, 3H), 1.34 (s, 3H) . 2-Fluoro-4-f ( 2 ' ,6'-di-t-butylpyrid-4'-yl)carbamoyl]b 3 enzoic Acid (Compound 42) 4 *H NMR δ (CD 3 0D) 7.92 (t, J = 8.36 Hz, IH), 7.82 5 (dd, J = 12.82, 2.0 Hz, IH), 7.63 (s, 2H), 7.55 (dd, 6 J = 8.7, 2.1 Hz, IH), 1.39 (s, 18H). 4-f (2' .6'-Di-t-butylpyrid-4'-y1)carbamoyl1benzoic 8 acid (Compound 44) 9 -E NMR δ (CD 3 OD) 8.02 (d, J = 8.85 Hz, 2H), 7.85 (d, J = 8.85 Hz, 2H), 7.63 (s, 2H), 1.40 (s, 18H) . 2-Fluoro-4-r (3' .5'-di-t-butyl)phenylcarbamoyl]benzoi c acid (Compound 46) 3 X H NMR δ (CD 3 OD) 7.92 (t, J = 8.3 Hz, IH), 7.80 (dd, J = 12.8, 2.0 Hz, IH), 7.79 (d, J = 1.8 Hz, 1 2H), 7.69 (t, J = 1.7 Hz, IH), 7.57 (dd, J = 8.7, 2 2.1 Hz, IH), 1.37 (s, 18H) . 3 2-Fluoro-4-r (2 '-hydroxγ-3 ' ,5 '-di-t-buty Dphenylcarba 4 moyl] benzoic acid (Compound 48) s X H NMR δ (acetone-d 6 ) 12.3 (b, IH), 10.07 (b, 6 IH), 7.98 (t, J = 8.48 Hz, IH), 7.80 (m, 2H), 7.58 7 (d, J = 2.3 Hz, IH), 7.56 (dd, J - 8.8, 2.0 Hz, IH), β 1.44 (s, 9H), 1.31 (s, 9H) .

Claims: 1 WHAT IS CLAIMED IS: 2 1. A process of administering to a mammal a 3 retinoid campound which binds specifically or 4 selectively to a RAR α retinoid receptors in 5 preference over RAR β and RAR r retinoid receptors, for 6 the purpose of treating or preventing a disease or 7 condition which is responsive to treatment by RAR α 8 specific or selective retinoid agonists. 2. A process in accordance with Claim 1 where ιo the RAR α specific or selective retinoid compound ιι binds approximately 500 times stronger to RAR α 12 retinoid receptors than to RAR β and RAR r retinoid 13 receptors. 14 3. A process in accordance with Claim 1 where is the RAR α specific or selective retinoid compound is 16 administered to a mammal for the treatment or i7 prevention of the disease or condition selected from 18 acute monocytic leukemia, cervical carcinoma, 19 myeloma, ovarian carcinomas, head and neck 20 carcinomas, proliferative vitreoretinopathy (PVR) 21 and age related macular degeneration (AMD) . 22 4. A process in accordance with Claim 3 where 23 the RAR α specific or selective retinoid compound is 24 administered in a dose of approximately 0.5 to 5 mg 25 per kg body weight per day. 26 5. A process in accordance with Claim 1 where 27 the RAR α specific or selective retinoid compound is 28 administered to a mammal for the treatment or 29 prevention of the disease or condition selected from 30 actinic keratoses, arsenic keratoses, inflammatory 31 and non-inflammatory acne, psoriasis, ichthyoses, 32 eczema, atopic dermatitis, Darriers disease, lichen 33 planus, glucocorticoid damage, topical microbial 34 infection, skin pigmentation, age and photo damage to the skin, premalignant and malignant hyperproliferative diseases, Kaposi's sarcoma, diseases of the eye, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, cardiovascular diseases, dyslipidemias, prevention of post-angioplasty restenosis, diseases associated with human papilloma virus (HPV) , inflammatory diseases, neurodegenerative diseases, improper pituitary function, insufficient hair growth, diseases associated with the immune system, and wound healing. 6. A process in accordance with Claim 1 where the RAR α specific or selective retnoid compound has the formula (i) or the formula (ii) formula (i) formula (ii) where X_ is 0 or X_ is [C(R 1 ) 2 ] n where n is an integer between 0 and 2; R_ is independently H or alkyl of 1 to 6 carbons; R 2 is independently hydrogen, or lower alkyl 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 - 5; o is an integer having the value of 0 - 4 p is an integer having the value of 0 - 2 r is an integer having the value 0 - 2; X 2 is N or CH; 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, naphthyl and heteroaryl groups being optionally substituted with one or two R 2 groups; Yξ_ is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C 1-6 alkyl, N0 2 , and OH, with the provisos that: (i) when the compound is in accordance with formula (i) and Z is 0 then the sum of p and r is at least 1 and Η_ is not a fluoro group in the 3 position of a tetrahydronaphthalene ring; (ϋ) when the compound is in accordance with formula (i) and r is zero and p is 1 and W x is OH then the OH group is positioned α to the L group; W 2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C 1-6 alkyl, N0 2 , and OH; 3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C^alkyl, fluoro substituted C__ 6 alkyl, N0 2 , and OH with the proviso that when the compound is in accordance with Formula 2 and X 2 is CH and r is 0 then p is not 0 and at least one W 3 group is not alkyl; L is - ( C=Z ) -NH- or -NH- ( C=Z ) - Z is 0 or S , and B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , -CH 2 OH, CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR,, CR 7 (OR 12 ) 2 , C γO ^O, 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__ is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons. 7. A process in accordance with Claim 6 where the RAR α specific or selective retinoid compound is in accordance with formula (i). 8. A process in accordance with Claim 7 where in the formula of the RAR α specific or selective retinoid compound X x is [C(R 1 ) 2 ] n and n is 1. 9. A process in accordance with Claim 8 where in the formula of the RAR α specific or selective retinoid compound Y is phenyl. 10. A process in accordance with Claim 6 where the RAR α specific or selective retinoid compound is in accordance with formula (ii) . 11. A process in accordance with Claim 10 where in the formula of the RAR α specific or selective retinoid compound Y is phenyl. 12. A process of administering to a mammal a retinoid compound which binds specifically or selectively to a RAR α retinoid receptors in 1 preference over RAR β and RAR r retinoid receptors, for 2 the purpose of treating or preventing a disease or s condition which is responsive to treatment by RAR α 4 specific or selective retinoid agonists, the 5 retinoid compound being specific or selective for 6 RAR α retinoid receptors in preference over RAR β and 7 RAR r retinoid receptors when in a binding assay the e K d value of binding to RAR α receptors is 9 approximately 500 times smaller than the κ d value for 0 binding to RAR β and RAR r retinoid receptors. 1 13. A process in accordance with Claim 12 where 2 the RAR α specific or selective retinoid compound is 3 administered to a mammal for the treatment or 4 prevention of the disease or condition selected from s actinic keratoses, arsenic keratoses, inflammatory 6 and non-inflammatory acne, psoriasis, ichthyoses, 7 eczema, atopic dermatitis, Darriers disease, lichen 8 planus, glucocorticoid damage, topical microbial 9 infection, skin pigmentation, age and photo damage 0 to the skin, premalignant and malignant i hyperproliferative diseases, Kaposi's sarcoma, 2 diseases of the eye, proliferative vitreoretinopathy 3 (PVR), retinal detachment, dry eye and other 4 corneopathies, cardiovascular diseases, 5 dyslipidemias, prevention of post-angioplasty 6 restenosis, diseases associated with human papilloma 7 virus (HPV), inflammatory diseases, 8 neurodegenerative diseases, improper pituitary 9 function, insufficient hair growth, diseases 0 associated with the immune system, and wound 1 healing. 2 14. A process in accordance with Claim 13 where 3 the RAR α specific or selective retinoid compound is administered to a mammal for the treatment or ι prevention of the disease or condition selected from 2 acute monocytic leukemia, cervical carcinoma, 3 myeloma, ovarian carcinomas, head and neck 4 carcinomas, proliferative vitreoretinopathy (PVR) 5 and age related macular degeneration (AMD). 6 15. A process in accordance with Claim 13 where 7 the RAR α specific or selective retinoid compound has s the formula (i) or the formula (ii) 9 0 1 7 8 9 1 formula (i) formula (ii) where X x is 0 or X_ is [C(R 1 ) 2 ] n where n is an integer between 0 and 2; R_ is independently H or alkyl of 1 to 6 carbons; R 2 is independently hydrogen, or lower alkyl 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 - 5; o is an integer having the value of 0 - 4; p is an integer having the value of 0 - 2; r is an integer having the value 0 - 2; X 2 is N or CH; ι Y is a phenyl or naphthyl group, or heteroaryl 2 selected from a group consisting of pyridyl, 3 thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 4 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said 5 phenyl, naphthyl and heteroaryl groups being 6 optionally substituted with one or two R 2 groups; 7 lrJ_ is a substituent selected independently from e the group consisting of F, Br, Cl, I, fluoro 9 substituted C__ 6 alkyl, N0 2 , and OH, with the provisos o that: i (i) when the compound is in accordance with 2 formula (i) and Z is O then the sum of p and r is at 3 least 1 and W x is not a fluoro group in the 3 4 position of a tetrahydronaphthalene ring; s (ϋ) when the compound is in accordance with 6 formula (i) and r is zero and p is 1 and W x is OH 7 then the OH group is positioned α to the L group; 8 W 2 is a substituent selected independently from 9 the group consisting of F, Br, Cl, I, fluoro 0 substituted alkyl, N0 2 , and OH; 1 W 3 is a substituent selected independently from 2 the group consisting of F, Br, Cl, I, C h alky1, 3 fluoro substituted C x _ 6 alkyl, N0 2 , and OH with the 4 proviso that when the compound is in accordance with 5 Formula 2 and X 2 is CH and r is 0 then p is not 0 and 6 at least one W 3 group is not alkyl; 7 L is -(C=Z)-NH- or -NH-(C=Z)- 8 Z is O or S, and 9 B is COOH or a pharmaceutically acceptable salt 0 thereof, C00R 8 , CONR 9 R 10 , -CH 2 0H, CH 2 0R lιr CH^COR^, 1 CHO, CH(0R 12 ) 2 , CH0R 13 0, -C0R 7 , CR 7 (0R 12 ) 2 , CR 7 0R 13 0, 2 where R 7 is an alkyl, cycloalkyl or alkenyl group 3 containing 1 to 5 carbons, R 8 is an alkyl group of 1 4 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„ 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 u is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons. 16. A process in accordance with Claim 15 where the RAR α specific or selective retinoid compound is in accordance with formula (i) . 17. A process in accordance with Claim 15 where the formula the RAR α specific or selective retinoid compound is in accordance with formula (ii) . 18. A process of administering to a mammal a retinoid compound which binds specifically or selectively to a RAR α retinoid receptors in preference over RAR β and RAR r retinoid receptors, for the purpose of treating or preventing the disease or condition selected from acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas, head and neck carcinomas, proliferative vitreoretinopathy (PVR) and age related macular degeneration (AMD) the retinoid compound being specific or selective for RAR α retinoid receptors in preference over RAR β and RAR r retinoid receptors when in a binding assay the K d value of binding to RAR α receptors is approximately 500 times smaller than the K d value for binding to RAR β and RAR r retinoid receptors, the retinoid compound having the formula (i) or the formula (ii) formula (i) formula (ii) where X_ is 0 or X x is [C(R 1 ) 2 ] n where n is an integer between 0 and 2; R_ is independently H or alkyl of 1 to 6 carbons; R 2 is independently hydrogen, or lower alkyl 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 - 5, o is an integer having the value of 0 - 4 p is an integer having the value of 0 - 2 r is an integer having the value 0 - 2; X 2 is N or CH; 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, naphthyl and heteroaryl groups being optionally substituted with one or two R 2 groups; W x is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C__ e alkyl, N0 2 , and OH, with the provisos that : (i) when the compound is in accordance with ι formula (i) and Z is 0 then the sum of p and r is at 2 least 1 and W 2 is not a fluoro group in the 3 3 position of a tetrahydronaphthalene ring; (ϋ) when the compound is in accordance with 5 formula (ii) and r is zero and p is 1 and W 1 is OH 6 then the OH group is positioned α to the L group; 7 W 2 is a substituent selected independently from β the group consisting of F, Br, Cl, I, fluoro 9 substituted C__ 6 alkyl, N0 2 , and OH; ιo W 3 is a substituent selected independently from 11 the group consisting of F, Br, Cl, I, C^alkyl, 12 fluoro substituted C x _ 6 alkyl, N0 2 , and OH with the 13 proviso that when the compound is in accordance with 14 Formula 2 and X 2 is CH and r is 0 then p is not 0 and 15 at least one 3 group is not alkyl; 16 L is -(C=Z)-NH- or -NH-(C=Z)- 17 Z is O or S, and i8 B is COOH or a pharmaceutically acceptable salt 19 thereof , COOR 8 , CONR 9 R 10 , -CH 2 0H , C^OR^ , CH 2 OCOR ll f 0 CHO , CH ( 0R 12 ) 2 , CH0R 13 0 , -COR, , CR 7 ( OR 12 ) 2 , , 1 where R 7 is an alkyl, cycloalkyl or alkenyl group 2 containing 1 to 5 carbons, R 8 is an alkyl group of 1 3 to 10 carbons or trimethylsilylalkyl where the alkyl 4 group has 1 to 10 carbons, or a cycloalkyl group of 5 5 to 10 carbons, or R 8 is phenyl or lower 6 alkylphenyl, R 9 and R 10 independently are hydrogen, 7 an alkyl group of 1 to 10 carbons, or a cycloalkyl 8 group of 5-10 carbons, or phenyl or lower 9 alkylphenyl, R 1X is lower alkyl, phenyl or lower 0 alkylphenyl, R 12 is lower alkyl, and R 13 is divalent 1 alkyl radical of 2-5 carbons. 2 19. A process in accordance with Claim 18 where 3 the RAR α specific or selective retinoid compound is 4 in accordance with formula (i), and Y is phenyl. ι 20. A process in accordance with Claim 19 where the 2 RAR α specific or selective retinoid compound is 3 selected from the group consisting of: 4 ethyl 2-fluoro-4-[ (5' ,6' ,7' ,8'-tetrahydro- 5 5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be 6 nzoate; 7 2-fluoro-4-[(5',6',7',8'-tetrahydro- β 5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be nzoic acid; o ethyl 2-fluoro-4-[ (5' ,6' ,7' ,8'-tetrahydro-4'- i bromo-5' ,5' ,8' ,8'-tetramethylnaphthalen-2'-yl)carbam 2 oyl]benzoate; 3 2-fluoro-4-[ (4'-bromo-5' ,6' ,7' ,8'-tetrahydro- 4 5' ,5' ,8' ,8'-tetramethylnaphthalen-2'-y1)carbamoyl]be 5 nzoic acid; 6 ethyl 7 2-fluoro-4-[ (2' ,2' ,4' ,4'-tetramethyl-8'-bromochroman s -6'-yl)carbamoyl]benzoate; 9 0 2-fluoro-4-[ (2',2',4',4'-tetramethyl-8'-bromochroman 1 - 6'-yl)carbamoyl]benzoic acid; 2 ethyl 2-fluoro-4-[ (2' ,2' ,4' ,4'-tetramethyl-8'- 3 trifluoromethylchroman-6'-yl)carbamoyl] benzoate; 4 2-fluoro-4-[(2' ,2' ,4' ,4'-tetramethyl-8'- 5 trifluoro-methylchroman-6'-yl)carbamoyl] benzoic 6 acid; 7 ethyl 2-fluoro-4-[ (2' ,2' ,4' ,4'-tetramethyl-8'- β azidochroman-6'-yl)carbamoyl]benzoate; 9 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'- 0 azidochroman- 6'-yl)carbamoyl]benzoic acid; 1 ethyl 2-fluoro-4-[ (2' , 2', 4', 4'-tetramethyl- 2 8'-iodochroman-6'-yl)carbamoyl]benzoate; 3 2-fluoro-4-[ (2' ,2' ,4' ,4'-tetramethyl-8'- 4 iodochroman-6'-yl)carbamoyl]benzoic acid; 1 ethyl 4- [ ( 5 ' , 6 ' , 7 ' , 8 ' -tetrahydro-5 ' , 5 ' , 8 ' , 8 ' - 2 tetramethyl-2-naphthalenyl)thiocarbamoy1]benzoate, 3 and 4 4-[(5',6',7',8'-tetrahydro-5' ,5' ,8' ,8'- 5 tetramethylnaphthalen-2'-yl)thiocarbamoyl]benzoic 6 acid. 7 21. A process in accordance with Claim 18 where β the RAR α specific or selective retinoid compound is 9 in accordance with formula (ii), and Y is phenyl. ιo 22. A process in accordance with Claim 19 where ii the RAR α specific or selective retinoid compound 12 is : i3 ethyl 2-fluoro-4-[ (2'6'-di-tert-butylpyrid-4'- 1 yl)carbamoyl]benzoate, or is 2-fluoro-4-[ (2' ,6'-di-t-butylpyrid-4'- 16 yl)carbamoyl]benzoic acid.

Inventors: CHANDRARATNA ROSHANTHA A, DUONG TIEN T, TENG MIN, CHANDRARATNA, ROSHANTHA, A., DUONG, TIEN, T., TENG, MIN
Applicants: ALLERGAN INC, ALLERGAN
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P3, A61P5, A61P9, A61P17, A61P25, A61P27, A61P29, A61P31, A61P35, A61P37