CA2241758A1 - Methods of treatment with compounds having rar.alpha. receptor specific or selective activity - Google Patents

Methods of treatment with compounds having rar.alpha. receptor specific or selective activity Download PDF

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CA2241758A1
CA2241758A1 CA002241758A CA2241758A CA2241758A1 CA 2241758 A1 CA2241758 A1 CA 2241758A1 CA 002241758 A CA002241758 A CA 002241758A CA 2241758 A CA2241758 A CA 2241758A CA 2241758 A1 CA2241758 A1 CA 2241758A1
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rar
compound
group
carbons
alkyl
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Inventor
Min Teng
Tien T. Duong
Roshantha A. Chandraratna
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Allergan Inc
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P27/00—Drugs for disorders of the senses
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/06—Antihyperlipidemics
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    • A61P35/00—Antineoplastic agents
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    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • G01N25/48—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation
    • G01N25/4846—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample
    • G01N25/4866—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity on solution, sorption, or a chemical reaction not involving combustion or catalytic oxidation for a motionless, e.g. solid sample by using a differential method

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

W O 97/24116 PCT~US96/20511 1 METHODS OF TREATMENT WI~H COM1 OUNV~ EL~VING RL~R~
2 RECEPTOR SPECIFIC OR SE~E~-~v~ A~ lVl Y
3 R~r~nOUND OF THE ~v~h~lON
4 1. Field of the Invention The present invention relates to the use of 6 compounds which have specific or selective agonist 7 like activity on RARa retinoid receptors for 8 treatment of diseases and conditions which respond to treatment by such retinoids. More particularly o the present invention is directed to the use of RARa receptor specific or selective agents for the ~2 treatment of tumors.
13 2. Background Art 14 Compounds which have retinoid-like activity are t5 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 1~ treating Anim~ls of the m~mm~lian specie~, including humans, for curing or alleviating the symptoms and 21 conditions of numerous diseases and conditions. In 22 other words, it is generally accepted in the art 23 that pharmaceutical compositions having a 24 retinoid-like compound or compounds as the active ingredient are use~ul as regulators of cell 26 proliferation and differentiation, and particularly n as agents for treating skin-related diseases, 28 including, actinic keratoses, arsenic keratoses, 29 inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and 31 hyperproliferative disorders of the skin, eczema, 32 atopic dermatitis, Darriers disease, lichen planus, ~3 prevention and reversal of glucocorticoid damage 34 (steroid atrophy~ r as a topical anti-microbial, as 3~ skin anti-pigmentation agents and to treat and CA 0224l7~8 l998-06-26 W O 97/24116 PCTAUS96/20Sll 1 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 4 precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as 6 cancers of the breast, skin, prostate, cervix, 7 uterus, colon, bladder, esophagus, stomach, lung, 8 larynx, oral cavity, blood and lymphatic system, g metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the 11 treatment of Kaposi's sarcoma. In addition, 12 retinoid compounds can be used as agents to treat 3 diseases of the eye, including, without limitation, 14 proliferative vitreoretinopathy ~PVR), retinal detachment, dry eye and other corneopathies, as well 16 as in the treatment and prevention of various ~7 cardiovascular diseases, including, without 8 limitation, diseases associated with lipid 1~ metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to 21 increase the level of circulating tissue plasminogen 22 activator (TPA). Other uses for retinoid compounds 23 include the prevention and treatment of conditions 24 and diseases associated with human papilloma virus ~HPV), including warts and genital warts, various 26 inflammatory diseases such as pulmonary fibrosis, 27 ileitis, colitis and Rrohn's disease, 28 neurodegenerative diseases such as Alzheimer's 2~ disease, Parkinson's disease and stroke, improper pituitary function, including insufficient 31 production of growth hormone, modulation of 32 apoptosis, including both the induction of apoptosis 33 and inhibition of T-cell activated apoptosis, 34 restoration of hair growth, including combination W O 97/24116 PCT~US96120511 1 therapies with the present compounds and other 2 agents such as MinoxidilR, diseases associated with - 3 the immllne system, including use of the present 4 compounds as immllnosuppressants and immllnostimulants~ modulation of organ transplant 6 rejection and facilitation of wound healing, 7 including modulation of chelosis.
8 United States Patent Nos. 4,740,519 (Shroot et ~ al.), 4,826,969 (Maignan et al.), 4,326,055 (Loeliger et al.~, 5,130,335 (Chandraratna et al.), 5,037,825 (Klaus et al.), 5,231,113 ~Chandraratna et 2 al.), 5,324,840 (Chandraratna), 5,344,959 3 (Chandraratna), 5,130,335 (Chandraratna et al.), 4 Published European Patent Application Nos. 0 170 105 (Shudo), 0 176 034 A (Wuest et al.), 0 350 846 A
16 (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176 17 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 8 0 303 915 A ~Bryce et al.), UK Patent Application GB
1~ 2190378 A (Klaus et al.), German Patent Application Nos. DE 3715955 A1 (Klaus et al.), DE 3602473 A1 2t (Wuest et al., and the articles J. Amer. Acad. Derm.
22 15: 756 - 764 (1986) (Sporn et al.), Chem. Pharm.
23 Bull. 33: 404-407 (1985) (Shudo et al.), J. Med 24 Chem. 1988 31, 2182 - 2192 (Kagechika et al.), Chemistry and Biology of Synthetic Retinoids CRC
26 Press Inc. 1990 p 334 - 335, 354 (Dawson et al.), 27 describe or relate to compounds which include a 28 tetrahydronaphthyl moiety and have retinoid-like or 2~ related biological activity.
United States Patent Nos. 4,980,369, 5,006,550, 31 5,015,658, 5,045,551, 5fO89,509, 5,134,159, 32 5,162,546, 5,234,926, 5,248,777, 5,264,578, 33 5,272,156, 5,278,318, 5,324,744, 5,346,895, 34 5,346,915, 5,348,972, 5,348,975, 5,380,877, W O 97/24116 PCT~US96/20511 1 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 derivatives which have retinoid-like biological 6 activity.
~ United States Patent No. 4,723,028 (Shudo), 8 Published European Patent Application Nos. 0 170 105 9 (Shudo), German Patent Application No. DE 3524199 A1 (Shudo), PCT WO 91/16051 (Spada et al.), PCT WO
85/04652 (Polus) and J. Med Chem. 1988 31, 2182 -2192 (Kagechika et al.), describe or relate to aryl and heteroaryl or diaryl substituted olephines or amides having retinoid-like or related biological activity.
6 United States Patent Nos. 4,992,468, 5,013,744, 17 5,068,252, 5,175,185, 5,202,471, 5,264,456, 18 5,324,840, 5,326,898, ~,349,105, 5,391,753, 1~ ~,414,Q07 and 5,434,173 (assigned to the same assignee as the present application) and patents and 21 publications cited therein, describe or relate to ~ compounds which have retinoid-like biological 23 activity and a structure wherein a phenyl and a 24 heteroaryl or a phenyl and a second phenyl group is linked with an olephinic or acetylenic linkage.
26 Still further, several co-pending applications and 27 recently issued patents which are assigned to the 28 assignee of the present appLication, are directed to 2~ further compounds having retinoid-like activity.
It is now general knowledge in the art that two 31 main types of retinoid receptors exist in m~mm~ls ~ ( and other organisms). The two main types or 33 families of receptors are respectively designated 34 RARs and RXRs. Within each type there are subtypes;

in the RAR family the subtypes are designated RARa~
2 RARB and RARr~ in RXR the subtypes are: RXRa~ ~XB,3 and 3 RXRr. It has also been estab~ished in the art that 4 the distribution of the two main retinoid receptor ~ 5 types, and of the ~everal sub-types is not uniform 6 in the various tissues and organs of m~mm~lian 7 organisms.
8 It is also known in the art that the use of retinoid-like compounds for the treatment of various 0 diseases and conditions is not without problems or 11 side effects. The side effects at therapeutic dose 12 levels include headache~ teratogenesis, 13 mucocutaneous toxicity, musculoskeletal toxicity, 14 dislipidemias, skin irritation, headache, 16 hepatotoxicity, etc. These side effects limit the 16 acceptability and utility of retinoids for treating 17 disease. Research is still ongoing in the art to 18 determine which of the RAR or RXR familes and within 19 each family, which of the subtype or subtypes are 20 responsible for mediating certain therapeutic 21 effects, and which type or subtypes are responsible 22 for mediating one or more of the undesired side 23 effects. Accordingly, among compounds capable of 24 binding to retinoid receptors, specificity or 25 selectivity for one of the main types or families, 26 and even specificity or selectivity for one or more 27 subtypes within a family of receptors, is considered 28 a desirable pharmacological property. Such 29 selectivity or specificity is useful as a research 30 tool for disaovering the roles of the several , ~ 31 receptor types and subtypes in mediating the various 32 e~fects of retinoids in ~iological systems, and also 33 as aid for designing retinoid drugs with specific 34 therapeutic effects and/or with reduced side effects W O 97/24116 PCTrUS96/20511 1 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 effects. United States Patent ~lo. 5,399,586 6 describes the use of compounds having RXR retinoid 7 receptor agonist activity for the treatment of 8 mAmmals afElicted with tumors. United States Patent 9 No. 5,455,265 describes methods of treatment o~
o m~mmAls with compounds having agonist-like activity on RXR receptors. Published PCT application No.
2 WO93/11755 is also directed to the use of compounds 3 which are selective RXR receptor agonists.
14 The present invention provides methods of treatment of tumors with compounds which are 16 specific or selective to RARa receptors.
7 SUMMARY OF THE lNVI!;~. lON It has been 8 discovered in accordance with the present invention 19 that retinoid-like compounds which act selectively, 20 or preferably even specifically on RARa receptor 21 subtypes in preference over RARB and RARr receptor 22 subtypes~ possess desirable pharmaceutical 23 properties associated with retinoids, and are 24 particularly suitable for treatment of tumors, such 25 as acute monocytic leukemia, cervical carcinoma, 26 myeloma, ovarian carcinomas and head and neck 27 carcinomas, without having one or more undesirable 28 side effects of retinoids, such as inducement of 29 weight loss, mucocutaneous toxicity, skin irritation 30 and teratogenecity.
31 Accordingly, the present invention relates to 32 the use of RAR~ specific or selective retinoid 33 compounds for the treatment of diseases and 34 conditions which respond to treatment by such W O 97/24116 PCT~US96/20511 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 RARa specific or selective retinoid compounds. In accordance with the present 6 invention the RARa selective compounds are also 7 particularly advantageously used for treatment of 8 proliferative vitreoretinopathy (PVR) and age 9 related macular degeneration (AMD).
For the purposes of the present description a 11 compound is considered RAR~ specific or selective if 12 in a transactivation assay (described below) the 13 compound transactivates the RARa receptors at a 14 significantly lower concentration than the RARB and 15 RARr receptors. Instead of measuring 16 tran~activation, measuring the binding of a compound 17 respectively to the three RAR receptor subtypes is 18 a~so feasible. Binding data expressed in Kd numbers 19 obtained in a binding assay (described below) are 20 also indicative of a compound's ability to act 21 specifically or selectively on RARa receptors in 22 preference over RARB and RARr receptors. A compound 23 iS considered RARa specific or selective for the 24 purposes of the present invention if the Xd number 25 for its binding to RARa receptors is approximately 26 500 times smaller than the Kd for its affinity to 27 RARB and RA~r receptors.

29 Figure 1 is a graph showing the results of an RPM~
30 8226 cell culture assay conducted with all trans 31 retinoic acid (A~RA) and two RARa selective compounds 32 in accordance with the present invention.
33 Figure 2 is another graph showing the results of 34 an AML 193 cell culture assay conducted with two RAR~

1 selective compounds in accordance with the present 2 invention, and with two compounds which are not RARa 3 selective.
4 Figure 3 is still another graph showing results ~ of an AML 193 cell culture assay conducted with r 6 three RARa selective compounds in accordance with the 7 present invention and with all trans retinoic acid 3 (ATRA)-9 Figure 4 is a graph showing the proliferation of 10 ovarian tumor cells in a cell culture assay (EDR
assay) in the presence of varying concentrations of Compound 2 in accordance with the present invention.
Figure 5 is a graph showing the RPE cell proliferation in the presence of all trans retinoic acid or Compound 42 in the culture medium.
Figure 6 is a graph showing the weight of a 17 group of experimental rats which were a~lmin; stered 18 for 3 days varying doses of an RARa selective 19 compound in accordance with the present invention.
Figure 7 is a bar graph showing the weight of 21 a group of experimental rats at the end of a 4 day 22 period wherein for three days the rats were 23 a~mini stered varying doses of Compound 18 in 24 accordance with the invention;
Fig~re 8 is a graph showing the weight of guinea 26 pigs which were treated with varying doses of 27 Compound 42 for 15 days.
28 DE~TT~n DESCRIPTION OF ~E lNv~:N~IONGeneral 2~ ~O~; mentsDefinitions regarding the chemical 30 compounds used in the present invention 31 The term alkyl refers to and covers any and all 32 groups which are known as normal alkyl, 33 branched-chain alkyl and cycloalkyl. The term 34 alkenyl refers to and covers normal alkenyl, branch CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 chain alkenyl and cycloalkenyl groups having one or 2 more sites of unsaturation. Similarly, the term - 3 alkynyl refers to and covers normal alkynyl, and 4 branch chain alkynyl groups having one or more triple bonds.
6 Lower alkyl means the above-defined broad 7 definition of alkyl groups having 1 to 6 carbons in 8 case of normal lower alkyl, and as applicable 3 to 6 9 carbons for lower branch chained and cycloalkyl 0 groups. Lower alkenyl is defined similarly having 2 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 4 similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch 6 chained lower alkynyl gronps.
7 The term "ester" as used here refers to and 8 covers any compound falling within the definition of 1~ that term as classically used in organic chemistry.
It includes organic and inorganic esters. Where B
21 in the general formula of the preferred compounds 22 used in the invention is -COOH, this term covers the 23 products derived from treatment of this function 24 with alcohols or thioalcohols preferably with aliphatic alcohols having 1-6 carbons. Where the 26 ester is derived from compounds where B is -CH20H, 27 this term covers compounds derived from organic 28 acids capable of forming esters including 2~ phosphorous based and sulfur based acids, or compounds of the formula -CH20CORll where Rll is any 31 substituted or unsubstituted aliphatic, aromatic, 32 heteroaromatic or aliphatic aromatic group, 33 preferably with 1-6 carbons in the aliphatic 34 portions.

W O 97t24116 PCT~US96/20SlI

1 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 atom~ or the cyclic or ~aturated aliphatic cyclic 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 ~ esters.
Amides has the m~n; ~g classically accorded that term in organic chemistry. In this instance it 2 includes the unsubstituted amides and all aliphatic 3 and aromatic mono- and di- substituted amides.
4 Unless stated otherwise in this application, preferred amides are the mono- and di-substituted 6 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 1~ carbon atoms. Particularly preferred amides are those derived from substituted and unsubst~tuted 21 lower alkyl amines. Also preferred are mono- and ~ disubstituted amides derived from the substituted 23 and un~ub~tituted phenyl or lower alkylphenyl 24 amine~;. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of the 26 formula-CK where K is (-OR) 2. Here, R is lower 27 alkyl. Also, X may be -OR70- where R7 is lower alkyl 28 of 2-5 carbon atoms, straight chain or branched.
29 A pharmaceutically acceptable salt may be 30 prepared for any compound used in this invention 31 having a functionality capable of forming such-salt, ~ for example an acid functionality. A
33 pharmaceutically accepta3~le salt is any salt which 34 retains the activity of the parent compound and does W O 97/24116 PCTrUS96/20511 1 not impart any deleterious or untoward effect on the 2 subject to which it is a-lministered and in the 3 context in which it is a~i n; stered.
4 phArlnRceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a 6 mono or polyvalent ion. Of particular interest are 7 the inorganic ions, sodium, potassium, calcium, and 8 magnesium. Organic salts may by be made with ~ amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts 11 may also be formed with caffeine, trometh~m;ne and 12 similar molecules. Where there is a nitrogen 3 sufficiently basic as to be capable of forming acid 4 addition salts, such may be formed with any inorganic or organic acids or alkylating agent such 16 as methyl iodide. Pre~erred salts are those formed 7 with inorganic acids such as hydrochloric acid, 8 sulfuric acid or phosphoric acid. Any of a number 19 of simple organic acids such as mono-, di- or tri-acid may also be used.
21 Some of the compounds used in the present ~ invention may have trans and cis (E and Z) isomers.
23 In ~ddition, the compounds used in the present 24 invention may contain one or more chiral centers and 25 therefore may exist in enantiomeric and 26 diastereomeric forms. The scope of the present 27 invention is intended to cover the use of all such 28 isomers per se, as well as mixtures of cis and trans 2~ isomers, mixtures of diastereomers and racemic 30 mixtures of enantiomers (optical isomers) as well.
31 Description of the Compounds Preferably Used in the 32 Methods of the Invention 33 The retinoid-like compounds used in the methods of treatment of the present invention are specific CA 0224l758 l998-06-26 or selective for RARa receptors. That a compound is 2 specific or selective to RARa receptors can be 3 ascertained in transactivation assays described 4 below where an RARa specif~ic or selective compound transactivates RARa receptors at a significantly 6 lower concentrations than RAR,~ or ~ARr receptors. In a binding assay where the a~i7ity of the compound to 8 bind to these receptor subtypes is measured, a compound that is considered ~ARa specific or o selective for the purposes of the present invention 11 binds at least approximately 500 times stronger to 12 RARa receptors than to the RARB or RARr receptors.
13 Alternatively, the compound is considered RARa 14 specific or selective if in the binding assay its Kd 15 number is approximately in the 10~1 to 5 X 102 16 nanomolar range and the Kd number for RAR~ or RARr 17 receptors is greater than 1000 nanmolar. The latter 8 is indicated by 0.00 in the below provided Tables 1~ where binding data (Kd numbers) for certain 20 exemplary compounds of the present invention are 21 illustrated.
22 Examples ~or RARa selective compounds which are 23 preferably used in accordance with the present 24 invention are il~ustrated }~y Formula 1 and Formula 2 27 R 1 R1 (R2)m (R2)m ~3)O _ ~ - L - Y(Wz)r~ r L - Y(W2)r---~

31 (W1)p (W3)p ~Formula 1 Formula 2 where Xl is O or Xl is tC(Rl) 2]n where n is an integer 2 between 0 and 2;
- 3 Rl iS independently H or alkyl of l to 6 4 carbons;
R2 iS independently hydrogen, or lower alkyl of 6 1 to 6 carbons;
~ R3 is hydrogen, lower al~yl of l to 6 carbons or 8 F;
9 m is an integer having the value of 0 - 5;
o is an integer having the value o~ 0 - 4;
p is an integer having the value of 0 - 2;
2 r is an integer having the value 0 - 2;
13 X2 is N or CH;
t4 Y iS a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, 16 thienyl, ~uryl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said 18 phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Wl iS a substituent selected independently from 21 the group consisting o~ F, Br, Cl, I, ~luoro 22 substituted Cl_6 alkyl, NO2, and OH, with the pro~isos 23 that:
24 (i) when the compound is in accordance with Formula l and Z is O then the sum of p and r is at 26 least l and Wl is not a fluoro group in the 3 27 position of a tetrahydronaphthalene ring;
28 (ii) when the compound is in accordance with 2~ Formula l and r is zero and p is l and Wl is OH then the OH group is positioned cx to the L group;
31 W2 iS a substituent selected independently from 32 the group consisting of F, Br, Cl, I, fluoro 33 substituted Cl_6 alkyl, NO2, and OH;
34 W3 iS a substituent selected independently from CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 the group consisting of F, Br, Cl, I, C16alkyl, 2 fluoro substituted C16 alkyl, NO2, and OH with the 3 proviso that when the compound is in accordance with 4 Formula 2 and X2 is CH and r is O then p is not O and 6 at least one W3 group is not alkyl;
6 ~ iS - ( C=Z ) -NH- or -NH-(C=Z)-7 Z iS O or S, and 8 B is COOH or a pharmaceutically acceptable salt thereof, COOR~, CON~9Rlo, -CH20H, CH20Rll, CH20CORll, 0 CHO, CH(ORl2) 2 ~ CHOR}30, --COR~,CR7(0R~2) 2 ~ CR,ORl30, where R, is an alkyl, cycloalkyl or alkenyl group 2 containing 1 to 5 carbons, R8 is an alkyl group of 13 to 10 carbons or trimethylsilylalkyl where the alkyl 14 group has 1 to 10 carbons, or a cycloalkyl group of 5 5 to 10 carbons, or R8 is phenyl or lower 6 alkylphenyl, Rg and Rlo independently are hydrogen, 7 an alkyl group of 1 to 10 carbons, or a cycloal3~yl 18 group of 5--10carbons, or phenyl or lower 19 alkylphenyl, R1l is lower alkyl, phenyl or lower alkylphenyl, Rl2 is lower alkyl, and Rl3 is divalent 21 alkyl radical of 2-5 carbons.
22 With re:Eerence to symbol Xl in For~nula 1, 23 compounds are preferred in the methods of the 24 present invention where X1 is tC(Rl) 2~n and n is (tetrahydronaphthalene derivatives) and also where X
26 iS O ~ chroman derivatives~. With reference to the 27 symbol X2 in Formula 2/ compounds are equally 28 preferred where X2 is CH or N. When X2 is CH then 2~ the benzene ring is preferably 1, 3, 5 substituted with the L group occupying the 1 position and the W3 31 and/or R2 groups occupying the 3 and 5 positions.
32 When the symbol X2 is N, then the pyridine ring is 33 preferably 2,4,6 substituted with the L group 34 occupying the 4 position and the W3 and/or R2 groups CA 0224l758 l998-06-26 WO97/24116 PCT~S96/20511 1 occupying the 2 and 6 positions.
2 The Rl groups of Fo~nnula 1 are preferably H or 3 CH3. q~he R3 group of Formula 1 is preferably H. The 4 group B of the preferred compounds of the invention ~ is COOH or a pharamceutically acceptable salt 6 thereof, COOR8 or CONRgRlo, where R", Rg and Rlo are 7 defined as above.
8 Referring now to the W1 and W2 groups in Formula 9 1, these groups are, generally ~3peaking, electron withdrawing groups, which are present in the compounds of the invention either in the aromatic 12 portion of the condensed ring system, or as a 13 substituent of the aryl or heteroaryl group Y.
14 Preferably a W2 group is present in the Y group, and a W1 group is also present in the aromatic portion of 16 the condensed ring system. When the Z group is S
17 ( thioamides) a Wl or W2 group does not necessarily 8 have to be present in the compounds of the invention 19 in accordance with Formula l, although preferably at least one of the w1 or W2 groups is nevertheless 21 present. In the aryl or heteroaryl Y moiety in the z compounds of Formula 1 and Formula 2 as well, the W2 23 group is preferably located in the position adjacent 24 to the B group; preferably the B group is in para position in the phenyl ring relative to the "amide"
26 moiety, and therefore the W2 group is preferably in 27 meta position relative to the amide moiety. Where 28 there is a W1 group present in the aromatic portion 29 of the condensed ring system of the compounds of Formula l, it preferably occupies the 8 position of 3t the chroman nucleus with the Z=C-NH- group occupying ~ the 6 position. In tetrahydronaphthalene compounds 33 of Formula 1, the Z=C-NH- group is prefera3~ly in the 34 2-position, and the W1 group is prefer~bly in the 4 CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 1 position. However, when the Wl group is OH in 2 compounds of Formula 1, then the OH is preferably in 3 the 3 position of the tetrahydronaphthalene ring.
4 Preferred Wl and W2 groups are F, NO2, Br, I, CF3, ClN3, and OH. The presence of one or two ~ fluoro substituents in the Y group (W2) is especially 7 preferred. When the Y group is phenyl, the fluoro 8 substituents preferably are in the ortho and ortho' 9 positions relative to the B gxoup, which is preferably COOH or COOR8.
11 Referring now to the W3 group in Formula 2, this 12 group is, generally speaking, also an electron 13 withdrawing group or an alkyl group, more 14 specifically preferred W3 groups are F, NO2, Br, I, 15 CF3, N3, and OH. Alternatively, in the phenyl or 16 pyridyl ring (shown in Formula 2 as substituent 17 " (W3)p" ) W3 iS an alkyl group, preferably 18 branch-chained alkyl, such as tertiary butyl, and 19 preferably p is 2.
With reference to the symbol Y in Formu~a 1 and 21 in Formula 2 as well, the preferred compounds used 22 in the methods of the invention are those where Y is 23 phenyl, pyridyl, 2-thiazolyl, thienyl, or furyl, 24 more preferably phenyl. As far as substitutions on 25 the ~ (phenyl) and Y (pyridyl) groups are concerned, 26 compounds are preferred where the phenyl group is 27 1~ 4 (para) substituted by the L and B groups, and 28 where the pyridine ring is 2,5 substituted by the L
29 and B groups. (Substitution in the 2,5 positions in 30 the "pyridine" nomenclature corresponds to 31 substitution in the 6-position in the "nicotinic 32 acid" nomenclature.) In the preferred compounds of s3 the invention there is no optional Rl substituent 34 ( other than H) on the Y group.

W O 97/24116 PCT~US96/20511 1 The L group of Formula 1 and of Fonmula 2 is 2 preferably -(C--Z)-NH-, and Z is preferably 0. In 3 other words~ those carbamoyl or amide compounds are 4 preferred in accordance with the present invention s where the -NH-moiety is attached to the Y group.
6 The compounds which are presently most 7 preferably used in the methods of treatment of the 8 invention are shown below in Table 1 with re~erence 9 to Formulas 3 and 4 and in Table 2 with re~erence to to Formula 5.

Ws 22 Formula 3 26 N ~--C02RB-2~ R, H W7 R ~ 'f \W4 31 Ws 34 Formula 4 CA 0224l758 l998-06-26 W O 97t24116 PCT~US96/20511 8 Formula S
~RT.
Compound No. Formula Rl W4 W5 Z W6 W7 R8 12 l 3 -- H H O F H Et 14 3 3 -- H Br O F H Et 4 3 -- H Br O F H H
6 5 3 -- OH H O F H Et 18 7 4 H H Br O F H Et 19 8 4 H H Br O F H H
9 4 CH3 H Br O F H Et 21 lO 4 CH3 H Br O F H H
22 11 4 CH3 H CF3 0 F H Et 24 13 4 CH3 H N3 0 F H Et 27 l6 4 CH3 H CF3 0 F F H
28 17 4 CH3 H I O F H Et 29 l8 4 CH3 H I O F H H
19 4 CH3 H CH3 0 F H Et 32 21 3 -- H H S H H Et 34 23 3 -- H H S F H Et CA 022417~8 1998-06-26 W O 97/24116 PCT~US96/20511 2 2~ 3 -- H Br O NOz H CH3 3 26 3 -- H Br O NO2 H H
4 27 4 CH3 H H O F H Et 6 29 3 ---- OH Br O F H Et 7 30 3 ---- OH Br O F H H
8 31 3 -- OH Br O F F Me 9 32 3 -- OH Br O F F H
~O 33 3 -- H H O F F Me 13 ~!able 2 Compound ~ X2 W8 W9 W10 R 8 t5 41 N H F H Et 17 43 N H H H Et 19 45 CH H F H Et 21 47 CH OH F H Et 23 49 N H F F Me 51 CH H F F Me 27 53 N H NO2 H Me 2~
Modes of Administration 31 The RARa specific or selective compounds used in ~ the methods of this in~ention may be a~min;stered 33 systemically or topically, depending on such 34 considerations as the condition to be treated, need CA 0224l7~8 l998-06-26 1 for site-specific treatment, quantity of drug to be 2 a~mi n; stered, and numerous other considerations.
3 In the treatment of dermatoses, it will 4 generally be preferred to a~mi n i ster the drug 5 topically, though in certain cases such as treatment 6 of severe cystic acne or psoriasis, oral 7 a~m; n; stration may also be used. Any common topical 8 formulation such as a solution, suspension, gel, 9 ointment, or salve and the like may be used.
10 Preparation of such topical formulations are well described in the art of pha~rmaceutical formulations ~2 as exemplified, for example, Remington's 13 Pharmaceutical Science, Edition 17, Mack Publishing 14 Company, Easton, Pennsylvania. ~or topical 15 application, these compounds could also be 16 a~m i n i stered as a powder or spray, particularly in 17 aerosol form. If the drug is to be a~m; n; stered 18 systemically, it may be confected as a powder, pill, 19 tablet or the like or as a syrup or elixir suitable 20 for oral a~m; n; stration. For intravenous or 21 intraperitoneal administration, the compound will be 22 prepared as a solution or suspension capable of 23 being a~mi~lstered by injection. In certain cases, 24 it may be useful to formulate these compounds by 25 in3ection. In certain cases, it may be useful to 26 formulate these compounds in suppository form or as 27 extended release formulation for deposit under the 28 skin or intramuscular injection.
29 Other medicaments can be added to such topical 30 formulation for such secondary purposes as treating 31 skin dryness; providing protection against light;
32 other medications for treating dermatoses;
33 medicaments for preventing infection, reducing 34 irritation, inflammation and the like.

CA 022417~8 1998-06-26 W O 97/24116 PCT~US96/20S11 1 Treatment of dermatoses or any other indications 2 known or discovered to be ~usceptible to treatment 3 ]:~y retinoic acid-like compounds will be effected by 4 a~m;nistration of the therapeutically effective dose ~ 6 of one or more compounds of the instant invention.
6 A therapeutic concentration will be that 7 concentration which ef~ects reduction of the 8 particular condition, or retards it expansion. In 9 certain instances, the compound potentially may be 0 used in prophylactic manner to prevent onset of a 11 particular condition.
12 A useful therapeutic or prophylactic 3 concentration will vary from condition to condition 4 and in certain instances may vary with the severity of the condition being treated and the patient~s 16 susceptibility to treatment. Accordingly, no single 17 concentration will be uniformly useful, but will 18 re~uire modification depending on the 1~ particularities of the disease being treated. Such concentrations can be arrived at through routine 21 experimentation. However, it is anticipated that in ~ the treatment of, for ex~mrle, acne, or similar 23 dermatoses, that a formulation containing between 24 0.01 and 1.0 milligrams per mililiter of formulation will constitute a therapeutically effective 26 concentration for total application. If 27 a~lm;nistered systemically, an amount between O.01 28 and 5 mg per kg per day of body weight would be 29 expected to effect a therapeutic result in the treatment of many disease for which these compounds 31 are useful.
32 In the treatment of tumors a dose of 33 approximately 0.5 to 5 mg per kg body weight per day 34 is anticipated to constitute the therapeutic dose.

CA 0224l758 l998-06-26 1 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 ~x;
5 tolerated dose i5 attained.
6 Assay of RARa receptor selective biological activity 7 and its significance in reduced side effects and 8 toxicity As it is noted in the introductory section of o this application for patent two main types of 11 retinoic acid receptors (RAR and RXR) exist in 12 mAmm~ lS ( and other organisms). Within each type 13 there are sub-types (RARal RARB ~ RAR~, RXRa, RXRB and 14 RXRr) the distribution of which is not uniform in the 15 various tissues and organs of m~mm~ lian organisms.
16 Selective binding of only one or two retinoid 17 receptor subtypes within one retinoid receptor 18 family can give rise to beneficial pharmacological 19 properties because of the varying distribution of 20 the sub-types in the several mAmm~lian tissues or 2t organs. For the above-sllmm~rized reasons, binding 22 of any or all of the retinoid receptors, as well as 23 specific or selective activity in a receptor family, 24 or selective or specific activity in any one of the 25 receptor subtypesl are all considered desirable 26 pharmacological properties.
27 In light of the foregoing the prior art has 28 developed assay procedures for testing the agonist 29 like activity of compounds in the RARa, RARB, RARr, 30 RXRa, RXRB and RXRr receptor subtypes. For example, 31 a chimeric receptor transactivation assay which 32 tests for agonist-like activity in the RARa, RARB, 33 RARr, and RXRa receptor subtypes, and which is based 34 on work published by Feigner P. L. and Holm M.

W O 97/24116 PCT~US96/20511 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.
A holorecepto~ transactivation assay and a 6 ligand bin~;ng assay which measure the ability of 7 compounds to bind to the several retinoid receptor 8 subtypes, respectively, are described in published g PCT Application No. WO WO93/11755 (particularly on pages 30 - 33 and 37 - 41) published on June 24, 11 1993, the specification of which is also 12 incorporated herein by reference. A description of 13 the ligand binding assay is also provided below.

All binding assays were performed in a similar 16 fashion. All six receptor types were derived from 17 the expressed receptor type (RAR a, B, r and RXR ~, 18 J3, r ) expressed ~n Baculovirus. Stock solutions of lo all compounds were prepared as lOmM ethanol so}utions and serial dilutions carried out into 1:1 21 DMSO; ethanol. Assay buffers consisted of the ~ following for all six receptor assays: 8% glycerol, 23 120mM KCl, 8mM Tris, 5m~ CHAPS 4mM DTT and 0.24mM
24 PMSF, pH - 7.4@ room temperature.
All receptor binding assays were performed in 26 the same manner. The final assay volume was 250~1 27 and contained from 10-40~g of extract protein 28 depending on receptor being assayed along with ~ nM
2~ of [3H] all-trans retinoic acid or lOnM [3H] 9-cis retinoic acid and varying concentrations of 31 competing ligand at concentrations that ranged from ~ 0 - 10-5 M. The assays were formatted for a 96 well 33 minitube system. Incubations were carried out at 34 4~C until equilibrium was achieved. Non-specific W O 97/24116 PCT~US96/20511 binding was defined as that binding r~m~i ni ng in the 2 presence of lOOOnM of the appropriate unlabeled 3 retinoic acid isomer. At the end of the incubation 4 period, 50}11 of 6.2596 hydroxyapitite was added in the appropriate wash buffer. The wash buffer 6 consisted of lOOmM KCl, lOmM Tris and either 5mM
7 CHAPS (RXR a, B, r) or 0.5% Triton X-100 (RAR a, J3, 8 r ) . The mixture was vortexed and incubated for 10 9 minutes at 4~C, centrifuged and the supernatant removed. The hydroxyapitite was washed three more times with the appropriate wash buffer. The 2 receptor-ligand complex was adsorbed by the 3 hydroxyapitite. The amount of receptor-ligand 14 complex was determined by liquid scintillation counting of hydroxyapitite pellet.
16 After correcting for non-specific binding, IC50 values were determined. The IC50 value is defined as 8 the concentration of competing ligand needed to 1~ reduce specific binding by 50%. The IC50 value was determined graphically from a loglogit plot of the 21 data. The Kd values were det~rm-ned by application 22 of the Cheng-Prussof equation to the IC50 values, the 23 labeled ligand concentration and the Kd of the 24 labeled ligand.
26 The results of ligand bindi~g assay are expressed 26 in Kd numbers. (See Cheng et al. Biochemical 27 Pharmacology Vol. 22 pp 3099-3108, expressly 28 incorporated herein by reference.) 29 Table 3 shows the results of the ligand binding assay for certain exemplary compounds of the 31 invention.

CA 022417~8 1998-06-26 W O 97/24116 PCT~US96/20511 1 ~RT.~ 3 2 Ligand R; n~; n~ Assay 3 Compound #Kd (nanomolar) 4 RA~a RAR~ RARr RXR~ RXR~
5 RXRr 6 2 1 . 90 480.0 0.00 0.00 0.00 0,00 7 4 1.3 0.00 0.00 0.00 0.00 0.00 8 6 3.00 0.00 0.00 0.00 0.00 0,00 9 10 24.0 0.00 0.00 0.00 0.00 0.00 10 12 14.0 0.00 0.00 0.00 o.oo o.oo 11 14 52.0 0.00 0.00 0.00 o.oo o.oo 12 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 14 20 57.0 0.00 0.00 0.00 0.00 ~-~~
1~ 22 15 0 . 00 0 . 00 0 . 00 0 . 00 0 . 00 16 24 7.5 0.00 0.00 0.00 0.00 0,00 17 26 245.0 0.00 0.00 0.00 0.00 0.00 18 28 162.0 0.00 0.00 0.00 0.00 0.00 19 30 <3.00 0.00 0.00 0.00 0.00 0.00 20 32 2.30 0.00 0.00 0.00 0.00 0.00 21 34 9.00 ~-~~ ~-~~ ~-~~ ~-~~ ~-~~
22 42 14 . 00 0 . 00 0 . 00 0 . 00 0 . 00 0 . 00 23 44 19 . 00 0 . 00 0 . 00 0 . 00 0 . 00 0 . 00 24 46 26.0 0.00 0.00 0.00 0.00 o.oo 25 48 77.0 0.00 0.00 0.00 0.00 0.00 26 50 62.0 0.00 0.00 0.00 0.00 0.00 27 52 87.0 0.00 0.00 0,00 o,oo 0.00 28 54 94.0 0.00 0.00 0.00 0.00 0.00 29 ~ Nr~l 72 5 36 30 0.00 indicates value greater than lOOOnM (nanomolar) 31 1 'l"l'N~ iS a well known prior art retinoid (4-(E~-2-32 ( 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-3~ yl)propen-1-yl)benzoic acid, that is not RARa 34 selective.

W O 97/24116 PCT~US96/20511 1 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 RA~a 4 retinoid receptors. It has been discovered in 6 accordance with the present invention that this 6 unique type of selectivity allows the compounds to 7 retain beneficial retinoid-like properties while 8 reduces certain side effects and toxicity. More 9 specifically, certain in vitro cell culture assays are described below, in which the ability of the RARa 11 specific or selective compounds to significantly 12 inh; hit the growth of cancer cells is demonstrated.
13 C~UNCER CELL LINE ~.e,e~YS

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 20 immediately before use. All experiments were 21 performed in subdued light. Controls were assayed 22 using the same concentration of ethanol as present 23 in the experimental plates and this concentration of 24 diluent had no effect in either assay.
25 Cells and Cell Culture 26 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 32 human lymphocyte cell lines and secrete a-type light 33 chains of immunoglobulin. RPMI-8226 cells are grown 34 in RPMI medium ~Gibco~ supplemented with 10% fetal W O 97/24116 PCTrUS96/20511 1 bovine serum, glutAm;ne and antibiotics. The cell~
2 were maintained as suspension cultures grown at 37~C
3 in a humidified atmosphere of 5% C02 in air. The 4 cells were diluted to a concentration of 1 x 105/ml 5 twice a week.
6 ME-180 is a human epidermoid carcinoma cell line 7 derived from the cervix. ~he tumor was a highly 8 invasi~re squamous cell carcinoma with irregular cell ~ clusters and no significant keratinization. ME-180 cells were grown and maintained in McCoy's 5a medium 11 (Gibco) supplemented with 10% fetal bovine serum, 12 glut~mi ne and antibiotics. The cells were 13 maintained as monolayer cultures grown at 37~C in a 14 humidi~ied atmosphere of 5% CO2 in air. The cells ~6 were diluted to a concentration of 1 x 105/ml twice a 16 week.
17 AML-193 was established from the blast cells 18 classified as M5 Acute Monocyte Leukemia. The t~ growth ~actor, granulocyte colony-stimulation factor 20 ~ GM-CSF) was required to establish this cell line 21 and growth factors are necessary for its continuous 22 proliferation in chemically defined medium. AML-193 23 cells were grown and maintained in Iscove's modified 24 Dulbecco's medium ~upplemented with 10% fetal bovine 25 serum, glu~Amine and antibiotics with 5~g/ml insulin 26 (Sigma Chemical Co.) and 2 ng/ml rh GM-CSF (R and D
27 Systems). The cells were diluted to a concentration 28 of 3 x 1 o5 /ml twice a week.
29 Incorporation of 3H-Thymidine The method used for determination of the 31 incorporation of radiolabeled thymidine was adapted 32 from the procedure described by Shrivastav et al.
33 RP~I-8226 cells were plated in a 96 well round 34 bottom microtiter plate (Costar) at a density of W O 97/24116 PCT~US96/20511 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 yl/well. The plates were incubated for 96 hours at 6 37~C in a humidified atmo~phere of 5% CO2 in air.
6 Subsequently, 1 ~Ci of [5'-3H]-thymidine (Amersham, 7 U.K. 43 Ci/mmol specific activity) in 25 ~1 culture 8 medium was added to each well and the cells were o incubated for an additional 6 hours. The cultures 0 were further processed as described below.
ME-180 wells, harvested by trypsinization were 2 plated in a 96 well flat bottom microtiter plate ~3 (Costar) at a density of 2,000 cells/well. The 14 cultures were treated as described above for RPMI
8226 with the following exceptions. After 16 incubation with thymidine the supernatant was 17 carefully removed, and the cells were washed with a 8 O. 5 mM solution of thymidine in phosphate buffered 1~ saline. ME180 cells were briefly treated with 50~1 20 of 2.5% trypsin to dislodge the cells from the 21 plate.
22 AMI.-193 cells were plated in a 96 well round 23 bottom microtiter plate (Costar~ at a density of 24 l,OOO cells/well. To appropriate wells, retinoid 26 test compounds were added at the final 26 concentrations indicated for a ~inal volume of 150 27 ~l/well. The pla~es were incubated for 96 hours at 28 37~C in a humidified atmosphere of 5% C02 in air.
29 Subsequently, 1 71Ci of [5'-3H]-thymidine (Amersham, 30 U.K., 43 Ci/mmol specific activity) in 25 yl culture 31 medium was added to each well and the cells were 32 incubated for an additional 6 hours.
33 The cell lines were then processed as follows:
34 the cellular DNA was precipitated with 10%

CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 1 trichloroacetic acid onto glass ~iber filter mats 2 using a SKATRON multi-well cell harvester ~Skatron 3 Instruments, Sterling V~). Radioactivity 4 incorporated into DNA, as a direct measurement of cell growth, was measured by li~uid scintillation 6 counting. The numJ~ers represent the mean 7 disintegrations per minute of incorporated thymidine 8 from triplicate wells + SEM.
The graph of Figure 1 of the appended drawings 0 shows that in the above described RPMI 8226 cell (malignant myeloma) culture assay ~ompounds 4 and 12 12 ( two exemplary compounds used in accordance with 13 this invention) inhibited the growth of these 14 malignant cells, substantially as well as a 15 comparison compound, all trans retinoic acid (AT~A).
6 The graph of Figure 1 al~3o demonstrates that whereas 7 in a low concentration range ~10-l2 to approximately 8 lO-9) all trans retinoic acid (ATRA) actually 1~ facilitates growth of~ these cells, the RARa selective 20 Compounds 4 and 12 of the present invention do not 21 stimulate but rather already in this low 22 concentrations ; nh; hit the growth of these malignant 23 cells.
24 The graph of Figure 2 shows that in the above 25 described AML ~93 (acute monocytic leukemia) cell 26 culture assay Cc~ r~unds 22 and 42 in accordance with 27 this invention i nh; hited the growth of these 28 malignant cells. Two other compounds for which data 2~ are also shown in this graph are designated AGN
30 193090 and AGN 193459. (An AGN number is an 31 arbitrary designation number used by the corporate 32 assignee of the present invention.) The compounds 33 AGN 19309Q and AGN 193459 are not RARa selective.
34 These compounds respectively are 1 4-[(8-cyano-5,6-dihydro-5,5-dimethylnaphth-2-yl)ethy 2 nyl]benzoic acid, and 3 4-t(5,6-dihydro-5,5-dimethylnaphth-7(6H)-8-(1-2,2-di 4 methylpropylidene)naphth-2-yl)ethynyl]benzoic acid, 5 and their Kd values for RAR~, RAR~ and RARr receptors 6 are lQ9, 34, 77 and 6, 2, 7, respectively. The 7 graph of F~gure 2 demonstrates that the RARa 8 selective or specific compounds ; nh i hit the ~ malignant cell growth at low concentrations where the pan agonist AGN 193090 and AGN 193459 compounds 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 and 18 in accordance with the present invention, and 6 all trans retinoic acid ~ATRA) were tested. The 7 data show that the RARa selective compounds reduce 8 cell proliferation at low concentrations whereas 19 ATRA at the same low concentration actually promotes cell proliferation.
21 In another line of assays the effect of the 22 retinoid compounds is tested against cells obtained 23 from solid tumors of patient This EDR assay is 24 described below as follows:
Freshly resected solid tumor biopsies were 26 received within 24 hours of surgery. Species were 27 processed for assay after retaining a portion o~ the 28 tumor for paraffin embedding and histopathologic 29 confirmation of specimen viability and tissue diagnosis. The remaining specimen was dissociated 31 into small fragments using sterile scissors. The 32 small tissue fragments were then exposed to 33 collagenase and DNAase for 2 hours with mixing a C02 34 incubator in order to release the tumor cells from W O 97/24116 PCT~US96/20511 1 the connective tissue stroma. The resulting cell 2 suspension was washed, and cell counts determined ~ 3 from a cytospin preparation. Tumor cells were 4 resuspended at 40,000 cells per ml in 0.3% agarose in RMPI 1640 supplemented with 15% FCS, glutamine 6 and antibiotics, and 0.5 ml were plated into each 7 well of a 24 well plate over 0.5 ml layer of 0.5%
8 agarose. These culture conditions prevent cell 9 adherence, thereby allowing only transformed cells to proliferate. Additionally, the cells grow into three dimensiona~ spheroids, recapitulating their in 2 vivo morphology.
3 Retinoid drugs were added 24 hours after plating 4 to insure specimen reequilibration to a growth environment after the rigors of transport and 6 processing. Cells were grown for four days in the 7 presence of drug, with 3H-thymidine (5 uCi/ml) added 18 48 hours prior to harvest to insure adequate labeling of proliferating cells. After the 20 agarose-cell suspension was liquefied at 90~C, cells 21 were harvested onto glass fiber filters, which were 22 counted in 5 ml scintillation fluid using a Beckman 23 6500 liquid scintillation counter.
24 Results are reported as fraction of untreated 25 control cell proliferation. Treatment groups were 2~ performed in duplicate or triplicate, while the 27 controls were performed in quadruplicate.
28 The graph of Figure 4 shows the effect of 29 Compound 2 on ovarian tumors obtained from 4 30 patients, and demonstrates that the compound 31 i nh ihitS this tumor cell proliferation in a ~ concentration dependent manner.
33 It will be understood by those skilled in the 34 art, that the ability of the RARa selective compounds W O 97124116 PCT~US96/20511 to significantly i nhihit growth of malignant cells 2 in the above described assays is an indication that~
3 these compounds can be a~ministered with beneficial 4 effect to tumor bearing m~mm~ls (including hllm~ns) 6 for the treatment of tumors, particularly acu~e 6 monocytic leukemia, cervical carcinoma~ myeloma, 7 ovarian carcinomas and head and neck carcinomas.
8 It has also been discovered in accordance with ~ the present invention that the proliferation of retinal pigment epithelium cells is i nhi hited by RARa 11 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 15 (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 1~ acid (ATRA) e~hibit an antiproliferative effect upon the growth rate of primary human RPE cultures 21 (Campochiaro et al., ibid) and have been shown to 22 decrease the incidence of retinal detachment after 23 retinal reattachment surgery in human studies 24 (Fekrat et al., Opthamology 102:412-418 (1994)).
26 The graph of Figure 5 shows the concentration 26 dependent inhibitory effect of all trans retinoic 27 acid (ATRA) and of Compound 42 on RPE proliferation 28 in an assay procedure which is described below.
29 Analysis o~ primary RPE cultures Primary cultures of human retinal pigment 31 epithelium (RPE) were established from eyes as 32 previously described, (Campochiaro et al., Invest.
33 Opthal & Vis. Sci. 32:65-72 (1991)). 5 X 104 Cells 34 were plated in 16-mm wells of 24-well multiwell W O 97/24116 PCTrUS96/20511 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), 4 ATRA (10-1~ to 10-6 M) in ethanol, and Compound 42 6 (10-l~ 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 8 a total of six days treatment. Cells were removed 9 from the plates via treatment with trypsin and the 0 number of cells were counted with an electronic cell 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 ~PE cell 4 proliferation.
The effect of topically a~m;nistering to 6 experimental hairless mice RAR~ selective retinoid 7 compounds in accordance with the present invention 8 was also evaluated in a topical skin irritation 1~ assay, using the RAR~ selective Compound 18 of the 20 invention. More particularly, skin irritation was 21 mea~ured on a semi-quantitative scale by the daily 22 subjective evaluation of skin flaking and abrasions.
23 A single number, the topical irritation score, 24 s-lmm~rizes the skin irritation induced in an An;m~l 25 during the course of an experiment. The topical 26 irritation score is calculated as follows. The 27 topical irritation score is the algebraic sum of a 28 composite flaking score and a composite abrasion 29 score. The composite scores range from 0-9 and 0-8 30 for flaking and abrasionsr respectively, and take 31 into account the maximum severity, the time of 32 onset, and the average severity of the flaking and 33 abrasions observed.
34 The severity of flaking is scored on a 5-point CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 ~ 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 score assigned to a given An;m~l during the course 6 of observation.
7 For the time of onset component of the composite 8 8core~ a score ranging from 0 to 4 is assigned as ~ follows:

Time to Appearance of 2 Flaking or Abrasions of 3 Severity 2 or greater 14 ( days) Time of Onset Score 22 The average severity component of the composite 23 score is the sum of the daily flaking or abrasion 24 scores divided by the number of observation days.
25 The first day of treatment is not counted, since the 26 drug compound has not had an opportunity to take 27 effect at the time of first treatment.
28 To calculate the composite flaking and abrasion 29 scores, the average severity and time of onset 30 scores are summed and divided by 2. The result is 31 added to the maximal severity score. The composite 32 flaking and abrasion scores are then summed to give 33 the overall topical irritation score. Each ~nim~l 34 receives a topical irritation score, and the values W O 97/24116 PCT~US96/20511 1 are expressed as the mean + SD of the individual 2 scores of a group of animals. Values are rounded to 3 the nearest integer.
4 Thus, female hairless mice tCrl:SKH1-hrBR] (8-12 weeks old, n=4) were treated topically for 5 6 consecutive days with Co~round 18 in doses expresed 7 in nanomol/25 g, which is particularly g~ven in 8 Table 4. Treatments are applied to the dorsal skin in a total volume of 4 ml/kg ( 0.1 ml). Mice were o observed daily and scored for flaking and abrasions up to and including 3 days after the last treatment, 2 i. e., day 8.
13 Ta3~le 4 4 Eight Day Topical Assay in Hairless Mice of Compound 18 6 Dose Mortality Body Weight Flaking Abrasion 17 Composite 8 ( out of 4)% gain or Score Score Score 19 (loss) 21 100 0 8 i 7 0 1 1 i 1 23 1000 0 4 + 1 1 1 2 + O

of ~TNPB

27 O.9 O 5 + 2 5 3 8 + 2 29 2.7 0 (4 + 3) 6 3 9 + 2 31 9 0 (ll i 3) 7 5 11 i 2 33 These data show that the RARa selective compound 34 causes virtually no skin irritation and no weight 1 loss up to lO00 nmol/2~g in the test model. For 2 comparison it should be noted that the well known 3 prior art retinoid compound 4 4-(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnapht halen-2-yl)propen-l-yl)benzoic acid (TTNPB), which 6 iS not RARa selective, causes much more serious skin ~ irritation in the above-noted test, as is shown in 8 the foregoing ta~le.
~ Another important advantage of administering RARa selective retinoid compounds to a m~mm~ 1 lies in the significantly reduced teratogenic potency of the 2 RARa selective compounds compared to many other 3 retinoids, as measured by a chondrogenesis 14 suppression bioassay. This assay is performed as 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 1~ chondrogenic differentiation as a bioassay.
20 Forelimb buds of mouse embryos on day 12 of 21 gestation (54 + 2 somites~ are dissociated in a 22 trypsin-EDTA solution, and the resultant single-cell 23 suspension is plated as 20-1ul spots (200rOOO
24 cells/spot) on plastic culture dishes. Retinoid 25 concentrations ranging from 0.3 ng/ml to 3 yg/ml (l 26 nM-lO ~M) are added to the culture medium (Eagle's 27 MEM + 10% fetal bovine serum, GIBC0) 24 hours after 28 initial plating. Control cultures receive only the 29 vehicle (ethanol, concentration ~ 1% by vol);
30 Retinoic acid is used as a positive control in 31 another set of cultures.
32 The cultures are terminated 96 hours after 33 plating, at which time the medium is removed and the 34 cells are fixed for l hour in 10% formalin CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96120511 1 containing 0.5% cetylpyridinium chloride. The 2 cultures are rinsed in acetic acid and stained for 3 hour in 0.596 Alcian blue solution at pH 1.O, 4 differentiated in 3% acetic acid, and then 6 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 8 as compared with control cultures is taken as a g measure of suppression of chondrogenesis. The number of cartilage nodules stained in the whole 11 spot, mean number of nodules, and standard 12 deviations are calculated for four replicate 13 cultures per treatment. The median concentration 14 causing a 5096 inhibition of chondrogenesis compared with controls (IC50) is calculated by logarithmic 16 curve Eitting of the do~e-response data. The ICso 17 values are expressed in nanogram per mililiter 18 ( ng/ml) units. An IC50 value of greater 1~ concentration in this assay signifies lesser teratogenecity. Table 5 indicates the results 21 obtained in this assay for Compounds 10, 18, and 42 22 in accordance with the present invention, as well as 23 for comparison with all trans retinoic acid (ATRA) 24 and 4-(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-2s methylnaphtha-len-2-yl)propen-1-yl)benzoic acid 26 (TTNPB).

28 Table 5 2~ Compound IC50 (ng/ml) 34 TTNPB 0.01 W O 97/24116 PCTrUS96/20~11 1 As it can be ~een the compounds used in 2 accordance with the present invention are less 3 teratogenic than all trans retinoic acid and 4 significantly (of the 104 order of magnitude) less teratogenic than the prior art TTNPB compound.
6 Weight loss or gain that experimental Fln;m~ls 7 experience upon a~m; n i stration of retinoid compounds 8 iS another test of the drug's toxicity, with significant weight loss at relatively low doses 0 indicating a significant toxic side effect of the 11 retinoid. In one experiment, groups of 5 rats were 12 treated with varying doses ( a~m; n i stered in corn 13 oil) of a test retinoid for 3 days. The rats were 14 euthanized 24 hours after the last dose. The graph 15 of Figure 6 shows the average weight of each group 16 of rats treated with a daily dose of 10, 30, and 90 17 ~mol/kg/day of Compoun~ 42 r 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 RA~a selective Compound 42 caused virtually no weight 21 loss, as compared to the control r except in a very 22 high dose (90 ymol/kg/day). The graph of Figure 7 23 shows the weight of the rats on the fourth day (24 24 hours after last allmin;stration of retinoid) in a similar test with varying doses of Compound 18, with 26 a zero dose indicating the control. As it can be 27 seen~ this RARa selective retinoid caused virtually 28 no weight loss even in the high dose of 90 29 ~mol/kg/day. It is noteworthy that in similar tests TTNPB, which binds to all three RAR receptor 31 subtypes (see Table 3) causes very significant 32 weight loss. In this experiment involving the rats 33 treated with Co~npound 42, significant mucocutaneous 34 toxicity was not observed.

W O 97/24116 PCT~US96/20511 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 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 8 doses oE Compound 42 are estimated. Body weights g and clinical observations were recorded at least every other day for 14 days post-implantation. The 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 An;m~ls involved 4 in this experiment over the course of 15 days. As it can be seen from the graph, the lower and middle doses of the RARa selective retinoid compound 7 (Compound 42) caused no, or only statistically 8 insignificant depression of weight gain~ relative to 1~ the control animals. Significant depression of 20 weight gain was observed only in the high do~e 21 ( 18mg/kg/day) of Compound 42. Importantly, no signs ~ of mucocutsneous toxicity were observed at any dose 23 of Compound 42 in this experiment. The foregoing, 24 markedly reduced mucocutaneous toxicity observed 25 when ~n; m~ ls are treated with RARa selective 26 compounds in accordance with the present invention, 27 is a significant advantage, because mucocutaneous 28 toxicity is the major and most irksome retinoid side 2~ effect or toxicity in human patients.
30 Synthetic Methods for Preparing the Preferred 31 Examples of RARC~ Selective Compounds of the Invention 32 General structure of the compounds which are 33 preferably used in the methods of treatment of the 34 present invention are shown above in Formula 1 and CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 1 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 speciEic embodiments 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 g invention in accordance with Formula 1 involves the formation o~ an amide by the reaction of a compound 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 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 Formula 7a.
21 A compound of Formula 6 is an acid or an 22 " activated form" of a carboxylic acid attached to 23 the aromatic portion of a tetrahydronaphthalene, (Xl 24 = rC(Rl)2]n and n is 1), dihydroindene ([C(Rl)2]l, where n is 0) or chroman ~Xl is O) nucleus. The carboxylic 26 acid, or its "activated form" is attached to the 2 27 or 3 position of the tetrahydronaphthalene, and to 28 the 6 or 7 position of the chroman moieties. In the 2~ compounds pre~erably used in accordance with the invention the attachment is to the 2 position of 31 tetrahydronaphthalene and to the 6 position of ~ chroman.
33 The term "activated form" of the carboxylic acid 34 should be understood in this regard as such W O 97/24116 PCTrUS96/20511 1 derivative of the carboxylic acid which is capable 2 of i~orming 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 ~ derivative (Formula 7a) that is capable of forming 6 an amide when reacted with a primary amine of 7 Formu}a 6a. This, generally speaking, means such 8 derivatives of a carboxylic acid which are normally ~ known and used in the art to form amide linkages 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 most preferred as reagents in accordance with 16 Formula 6 lor Formula 7a) are acid chlorides ( X3 iS
17 Cl). The acid chlorides of Fon~ula 6 (or of Formula 18 7a) can be prepared by traditional methods from the 1~ corresponding esters (X3 iS for example ethyl) by hydrolysis and treatment with thionyl chloride 21 (SO2Cl). The acid chlorides of Formula 6 (or of 22 Formula 7a) can also be prepared by direct treatment 23 of the carboxylic acid~ with thionyl chloride, where 24 the carboxylic acid, rather than an ester thereof is available commercially or by a known synthetic 26 procedure. The acid chlorides of Formula 6 (or of 27 Formula 7a) are typically reacted with the amine of 28 Formula 7 (or amine of Formula 6a) in an inert 29 solvent, such as methylene chloride r in the presence of an acid acceptor, such as pyridine.
31 The carboxylic acids themselves in accordance 32 with Formula 6 (or Formula 7a) are also suitable for 33 amide formation when reacted with an amine, a 34 catalyst (4-dimethylaminopyridine) in the presence W O 97/24116 PCT~US96/20511 1 of a dehydrating agent, such as 2 dicyclohexylcarbodiimide (DCC) or more preferably 3 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide 4 hydrochloride (EDC).
s The carboxylic acids or the corresponding esters ~ of Formula 6, are generally speaking, prepared as 7 described in the chemical scientific or patent 8 literature and the literature procedures for their g preparation may be modified, if necessary, by such chemical reactions or processes which per se are 11 known in the art. For example, generally speaking, 12 2,2, 4,4 and/or 2,2,4,4-substituted chroman ~3 6-carboxylic acids and chroman 7-carboxylic acids 14 are available in accordance with the teachings of 15 United States Patent Nos. 5,0û6,550, 5,314,159, 16 5,324,744, and 5,348,975, the specifications of 17 which are expressly incorporated herein by 18 reference. 5,6,7,8-Tetrahydronaphthalene-2-1~ carboxylic acids are, generally speaking, available 20 in accordance with the teachings of United States 21 Patent No. ~,130,335, the specifications of which is 22 expressly incorporated herein by reference.
23 The foregoing general description of the 24 reactions which lead to formation of the amides of 25 Formula 1 is also, generally speaking, applicable to 26 the formation of the amides of Formula 2. The 27 reagents which are used in accordance with the 28 general principles mentioned above for the formation 29 of amide compounds of Formua 2 are: activated forms 30 of a car~oxylic acids shown in Formula 8 and in 31 Formula 7a, and the amines of Formula 7 and of ~ Formula 8a.

CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 R, ~R, ~R2)m 3 ~
(R3)o ll l COX3 6 ~ X, ~ \ H~N Y(W2)r - B
(W1)p 9~ormula 6 Formula 7 12R1 ~R1 (R2)m (W~)P x3c~y(wz)r--B

18Formula 6a Formu~a 7a 21(~2)m (R2)m 22 (W3)p ~ ~--COX (W3)p ~--NH

27 Formula 8 Formula 8a 28 The carboxylic acids or the corresponding esters 2~ of Formula 8, are generally speaking, prepared as 30 described in the chemical scientific or patent 31 literature and the literature procedures for their 32 preparation may be modified, if necessary, by such 33 chemical reactions or processes which per se are 34 known in the art.

PCT~US96/20511 4 ~ ENO~K2SO~ ~ T~CI~Cl 6 ~ ~ NO2 7 C~mrn~ B
CnmrnnnAA

9 E ~ EOA- ~ 2) EI3~0 r~m~n~c ~nm~n~D

~6 ~ ELO~ OF ~ ~

Br Br 21 Com~und E rnmr-t-nr~ F

2.l ~ ~F[6F.~ ~ Tohe: ~ I~ CO~EI

28 Compou~d G
29 (~', C

34 Reaction Scheme 1 CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20~11 I><f ~ Br3 EIOAC, ~CX3OCH~.Cl ~ ~OMOM
10 X~ X~E~r C~LC~ Am.

12 K~ . G. rnmr mr~ I ~
1 3 Sy~r 1972, pl40 rnmr~ltn~ ~

~OMOM >~CO2H
16 78 ~C ~ Ll J~Br~,/HOAc 17 2) CO~ (g) X~~ CO2H X OH
18 Cnmr~n~ g Comp~Qnri L

21 X ~CO2H OEI3OCH.Cl j~ r,CO2H

24 X OH (i-Pr)2EtN X OMOM
Br 26 Cor~pound M Cnmrf~ N

2~

34 Reaction Scheme 2 W O 97/24116 PCTnJS96/20511 7 ~ i3r3,~OA~ ~ 1)50clz ~ ~ O ~ O ~ C~C.17 Cn~r--n~O E ~r 11 rnmro~nr~ p 12 ~ ~/ 1) F3CCO2N- ~Co2H

~ C~13,NMP.180~C
t5 1 ¦ 2)NaOH~tOH / ~
16 8r ~F3 17 t~nmr~unrt R
rnmrl-n~l S

21 ~ ~ ~ 1)50CI3 ~ I)HNO3 H25 ~ 2)NaOEJEtOH

23 Crm~undO rnm~l~n~T

28 ~ ~ CO2H

rnm~ ~rl V

34 Reaction Scheme 2 ( continued ) CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 Reaction Schemes l 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 are reacted with an amine of Formula 7 to provide 6 (~, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-7 2-yl)carbamoyl derivatives within the scope oi~
8 Formula 1. Thus, as is shown in Reaction Scheme 1, g ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-carboxylate ~Compouna A) is nitrated 11 to provide the corresponding 3-nitro compound 12 ( rom~ound B ) . The nitro group of Compound B is 13 reduced to provide the corresponding 3-amino 14 compound (Compound C) which is described in the 15 publication Lehm~nn et al. Cancer Research, 1991, 16 51, 4804. Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra-17 methyl-3-amino-naphthalene-2-carboxylate (Compound 18 C) iS brominated to yield the corresponding 4-bromo 1~ derivative (Compound D), which is converted by treatment with isoamylnitrite and reduction with 21 H3P02, to ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra-~ methyl- 4-bromonaphthalene-2-carboxylate (Compound 23 E). Saponification of Compound E yields 24 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth 25 alene-2-carboxylic acid (Compound F) which is used 26 as a reagent in accordance with Formula 6. Ethyl 27 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth 28 alene-2-carboxylate (Compound C) is also diazotized 29 and reacted with HBF4 to provide ethyl 30 5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-3-fluoronaph 31 thalene-2-carboxylate (Compound G) which serves 32 either per se or after saponii~ication as a reagent 33 in accordance with Formula 6.
34 5,6,7,8-Tetrahydro-5,5j8,8-tetramethyl-2-CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 hydroxynaphthalene (Compound ~, available in 2 accordance with the publication Krause Synthesis 3 1972 140), is the starting material in the ex~mple 4 shown in Reaction Scheme 2. Compound X is brominated to provide the corresponding 3-bromo 6 compound (Compound I) which is thereafter protected 7 in the hydroxyl function by treatment with 8 methoxymethyl chloride (MOMCl) to yield ~ 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymet-hoxy-2-bromonaphthalene (romr~und J). Comr~und ~ is 11 reacted with _-butyllithium and carbon dioxide to 12 provide the corresponding carboxylic acid (Compound 13 K) from which the methoxymethyl protecting group is ~4 removed by acid to give 15 5,6,7,8-tetrahydro-5,5,8,8-tetra-16 methyl-2-hydroxynaphthalene-3-carboxylic acid 17 (Compound L). Compound I. is brominated to yield 18 5,6,7,8-tetrahy-1~ dro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene 20 -3-carboxylic acid (CoInpound M). Compou~d I, and 21 Compound M serve as reagents in accordance with 22 Formu7a 6. The hydroxy group of Compound M is 23 protected for further transformations with 24 methoxymethyl chloride (MOMCl) in the presence of 25 base, yielding 5,6,7,8-tetr~hydro-5,5,8,8-26 tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-ca 27 rboxylic acid (Compound N~.

0 C02~ 1) soaz X~ C~E2H5 12 ~1~J~ 3) HNO31~I2SO~

~~nmr~nnr~ O f'nmr~lnrl W

i I ~I lCI ~ ~ J

23 ~~nmI~qn~ O Cnmr~n~ X

34 Reaction Scheme 3 W O 97124116 PCT~US96/20511 6 ~ Se~ 5~ps 8 Cnmro~Y

11 , ~ l)tBuL~rEF/-78~C ~ CO2H
12 Br21E~OA~ 2~CfJ~

fnmr~nn~ Al tS fnm~--n-l Z

1~
Reaction Scheme 4 24 Br.AaOAc ~ ~ CO~H

28 ~r Shmat,B.
29 U.S.~1~3t 5,059,621 fnm~- n~ Bl 34 Reaction Scheme 5 W O 97/24116 PCT~US96/20511 1 Reaction Schemes 3, 4 and 5 provide ex~m~les for 2 the synthesis oi~ 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 6 the synthesis of the carbamoyl (amide) compounds 6 within the scope of the present invention. Thus, 7 referring now to Reactioxl Scheme 3, 8 2,2,4,4-tetramethylchroman-6-carboxylic acid 9 (compound O, see U. S. Patent No. 5,006,550~ is o brominated with bromine in acetic acid to yield the corresponding 8-bromo derivative (Compound P).
12 Compound P is converted to the acid chloride by 13 treatment with thionyl chloride, and the resulting 4 acid chloride is suitable for reaction with an amine of Formula 3 to provide the carbamoyl (amide) 6 compounds of the invention. The acid chloride is 7 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-carboxylate (Compound R). The bromo function o:f~
21 Compound R is converted to a trifluoromethyl 22 function by treatment with sodium trifluoroacetate 23 in the presence of cuprous iodide catalyst and 24 1-methyl-2-pyrrolidinone (NMP), and the carboxylate ester group is saponifie<:l to yield 26 2,2,4,4-tetramethyl-8-trifluoromethylchroman-6-carbo 27 xylic acid (Compound S). ~'omround S is within the 28 scope of Formula 6 and is suitable per se or as the 29 acid chloride or in other "activated" form to react 30 with the amines of Formula 7 to yield the carbamoyl 31 ( amide~ compounds of the invention.
32 2,2,4,4-Tetramethylchroman-6-carboxylic acid 33 ( Compound o) is also converted to the methyl ester 34 ( Compound T) which is then nitrated to yield W O 97124116 PCT~US96/20511 1 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylic acid 2 (Compound V), ~till another reagent within the scope 3 of Formula 6. Moreover, in the example further 4 shown in Reaction Scheme 3, 2,2,4,4-tetramethylchroman- 6-carboxylic acid 6 ( Compound O) is converted to the ethyl ester and 7 nitrated thereafter to yield ethyl 8 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylate 9 ( Compound W). Still further, Compound O is reacted 0 with ICl to yield 2,2,4,4-tetramethyl8-iodochroman-11 6-carboxylic acid (Compound X).
12 In accordance with the example shown in Reaction 3 Scheme 4, 2-methylphenol is subjected to a series of 4 reactions in accordance with the teachings of United States Patent No. 5,045,551 (incorporated herein by 16 reference) to yield 2,2,4,4,8-pentamethylchroman 7 (Compound ~'). Compound Y is bromin~ted with bromine 8 in acetic acid to give 2,2,4,4,8-pentamethyl-6-1~ bromochroman (Compound Z) which is reacted with t-butyl lithium and thereafter with carbon dioxide 21 to give 2,2,4,4,8-pentamethylchroman-6-carboxylic 22 acid (Compound A1).
23 Reaction Scheme 5 illus~rates the synthesis of 24 4,4-dimethyl-8-bromochroman-6-carboxylic acid (Compound Bl) by bromination of 26 4,4,-dimethyl-chroman-6-carboxylic acid which is 27 available in accordance with the teachings of United 28 States Patent No. 5,059,621, the specification of 29 which is incorporated herein by reference.
so 2,2,4,4,8-Pentamethylchroman-6-carboxylic acid 31 ( Compound A1) and 4,4,-dimethyl-8-bromochroman-32 6-carboxylic acid (Compound Bl) serve as reagents, 33 either per se, or as the corresponding acid 34 chlorides (or other "activated form), in accordance W O 97/24116 PCT~US96/20511 1 with Formula 6 for the synthesis of the carbamoyl 2 ( amide) compounds of the present invention.
3 Referring ~ack now to the reaction between the 4 reagent of Formula 6 with an amine compound of Formula 7 it i5 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 compounds of Formula 7 can be prepared as described 0 in the scientific and patent literature, or from 11 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 amine compounds of Formula 7 (where Y is phenyl) 16 from commercially available starting materials 17 (Aldrich ~hemical Company, or Research Plus, Inc.).
18 The illustrated compounds of Formu~a 7 are used for 1~ the ~ynthesis of several preferred compounds used in the methods of the invention.

2~

CA 0224l758 l998-06-26 PCT~US96/20511 1 ~ l)N 2Cr2C~OAc,H2SO4,~C ~ CD~C~I$
2N02 F 4) ~~ P~C' CH~C17 H2N F
4 C~mr~on~~ Cl 6 ~ I)Na2Cs2C7,HOAc,E~SO4,9 , ~ CO2C~H~

8 N02 Br 4) ~ ' ClI2C12 HzN Rr Cn~po~n~l Dl 12 I)Na_Cr.O1.HOAc.H-S04.90 ~ ~ CO2C2H~

No2 Cl 3)EtOH~, CH7CI7 H2N Cl t~nmr~nrl Pl 17 ~ 2) MeOEitlEA/ CH?CI7 ~"~ CO2CH3 21 rnmllolln~T Fl 27 F~ ~CO2H EtOE~ ~ cc2C2Hs Com~ ~dGl 2~ ~ F

~ F~co2H 3 ~NaN3/cE 3cN H2N~CO2CH3 34 Reaction Scheme 6 ~rn~.ln~HI

W O 97/24116 PCTrUS96/20511 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 to an ethyl ester, followed by reduction of the 6 nitro group, to yield ethyl 7 2-fluoro-4-amino-benzoate (Compound Cl).
8 3-Nitro-6-methyl-bromobenzene (Aldrich) and 9 3-nitro-6-methyl-chlorobenzene (Aldrich) are o subjected to essentially to the same series of reactions to yield ethyl 2-bromo-4-amino-benzoate 12 (Compound Dl) and ethyl 2-chloro-4-amino-benzoate 13 (Compound El), respectively. 2-Nitro-4-aminobenzoic 14 acid (Research Plus) is converted to its methyl ester (Compound Fl) through the corresponding acid 16 chloride. 2,3,5,6-Tetrafluoro-4-amino-}~enzoic acid 17 ( Aldrich) is esterified by treatment with ethanol in 18 the presence of 1-(3-dimethylaminopropyl)-3-19 ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH2Cl2 to give ethyl 21 2,3,5 r 6-tetrafluoro-4-amino-benzoate (Compound Gl).
22 2,4,6-Trifluorobenzoic acid (Aldrich) is converted 23 to the methyl ester through the acid chloride, and 24 the 4-fluoro atom is displaced by reaction with 26 sodium azide, followed by hydrogenation, to yield 26 methyl 2,6-difluoro-4-amino benzoate (C~ompound Hl).
27 Compounds Cl, Dl, El, Fl, Gl and Hl serve as amine 28 reagents in accordance with Formula 7. Further 2~ examples of reagents in accordance with Formula 7 are nitro, fluoro, chloro, bromo and trifluoromethyl 31 derivatives of amino substituted heteroaryl 32 carboxylic acids, or their lower alkyl esters, such 33 as ethyl 2-amino-4-chloropyridine 2-carboxylate, 34 ethyl 5-amino-3-chloropyridine 5-carboxylate, and W O 97/24116 PCTrUS96/20511 1 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 6 (described in WO 93/06086) and of 7 2-aminothiophene-5-carboxylic acid (described in 8 PCT/US92/06485).
The reactions between the compounds of Formula 6 0 and Formula 7 or between compounds of Formula 6a and 7a, described above, comprise the actual syntheses 2 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 carbamoyl (amide) compounds of the invention can be 6 converted into thiocarbamoyl (thioamide) compounds 7 of the invention where with reference to Formula 1 Z
18 is S, by reacting the carbamoyl (amide) compound 19 with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent).
21 This reaction is illustrated in Reaction Scheme 7 22 for two specific examples for the compounds used in 23 the methods of the invention.

2~

~

W O 97/24116 PCT~US96/20511 6 N~ ~ wensson X N~3'~
D ~J1H b~ 8~C

rn~r ~Il 21 ~2 16 ~ /~N~ C02E~ H~ Co~Et 7 k~J H b ~J

19 ~nm~l~ I Compound 23 24 Reaction Scheme 7 In Reaction Scheme 7 one starting material ethyl 26 4-[5~,6~,7~,8'-tetrahydro-5',5',8',8~-tetramethyl-27 naphthalen-2-yl)carbamoyl~benzoate (Compound I1) is 28 obtained in accordance with the teachings of 2~ Kaqechika et al. J. Med Chem. 1988 31, 2182 - 2192.
30 The other starting material, ethyl 31 2-fluoro-4-[5',6',7',8'-tetrahydro-5',5',8',8~-tetra 32 methylnaphthalen-2-yl)carbamoyl]benzoate ~Compound 33 1) is obtained in accordance with the present ~ invention.

CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 6 EDC. DMAP , ~N~CO2~2H'~
9 ~ f~ ~ Ethyl 1 ~ n-2-f~ s~ l ~ ~ ~OMOM X~ ~OMOM
11 Compound Cl ~nmro--~
12 ~'n~ nr7 E
13 o ~ CO2CzHs lhinrh nn 16 8F3 O(C-H5~ X~OH

18 rnmr~n~ 5 0 l~CO2c2Hs 22 ~N~F
23 ~ oC,H,s ~-~ . ' Ll 34 Reaction Scheme 8 W O 97/24116 PCT~US96/20511 o F ~M-12 ~ CC~H EDC DM~P ~H

13 1 11 ,J~ 2.6-l-n~ ~OMOM
14 ~ OMOM /\
/ ar Compound Hl Br Compou~ Ml 16 Cnmr~ln~l ~~N.OH~OH , 21 2)HC~M~H OH

22 ~
23 a, 24 rn~n~ 32 34 Reaction Scheme 9 W O 97/24116 PCT~US96/20511 ~Xf ~CO~H ~ NJ~F
6 1 l ~)Esh~1~mino-2-f~uos~ 1 d --~ ~ ~ ~.E~ /
7 / 0 - Compound C
8 1 ~~2 3 ) H2,Pd/C NH2 Compo~nt~ll 9 C~ V

N0~ ~F
14 ) N~

16 N~
17 Compo~d. 13 19 Reaction Scheme 10 Reaction Schemes g, 9 and 10 disclose esr~mrles 21 for the preparation of carbamoyl (amide) compounds 22 of the invention, first }:)y a coupling reaction of a 23 compound of ~ormula 6 with a compound of Formula 7, 24 followed by one or more reactions perfollL.ed on the carbamoyl (amide) compound that has been first 26 obtained directly in the coupling reaction. Thus, 27 as is shown in Reaction Sche~ne 8, 2a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-23 3-methoxymethoxynaphthalene-2-carboxylic acid ( Compound K) is coupled with ethyl 31 4--amino-2-fluoro~enzoate ~Compound Cl) in CH2Cl2 in 32 the presence of 1-(3-dimethylaminopropyl)-3-33 ethyicar3~odiimide hydrochloride (EDC) and 34 dime~hylaminopyridine (DMAP) to give ethyl CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20~11 2-fluoro-4-t5t,6',7',8'-tetrahydro-5',5',8',8'-tetra 2 methyl-2'-methoxymethoxy-naphthalen-~ 3 3'--yl)carbamoyl]benzoate (C; ,:-.nd Xl). The 4 methoxymethyl protecting group is removed from Compound Kl by treatment with thiophenol and 6 borontrifluoride ethereate resulting in ethyl 7 2-:Eluoro-4-t5',6',7',8'-tetrahydro-5',5',8',8'-tetra 8 methyl-2'-hydroxy-naphthalen-3'-yl)car3~amoyl]-~ benzoate (Compound 5). The hydroxy function o~
Compound 5 is converted into an n-~exyl ether by treatment with hexyl iodide in the presence of mild 2 base.
3 In accordance with Reaction Scheme 9 4 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-bromo-2-met hoxymethoxynaphthalene-3-carboxylic acid (CompouD.d 16 N) is coupled with methyl 4-amino-2,6-difluoro-17 benzoate (Compound Hl) in CH2Cl2 solvent in the 8 presence of ethylcarbodiimide hydrochloride (EDC) 1~ and DMAP to provide methyl 2,6-difluoro-4-[(5~,6~,7',8'-tetrahydro-5',5~,8~,8'-21 tetramethyl-l'-bromo-2'-methoxymethoxy-naphthalen-3' 22 -yl)carbamoyl]b.enzoate (Compound Ml), from which the 2~ esterifying methyl group and the methoxymethyl 24 protecting group are removed by treatment with base and acid, respectively to yield 26 2,6-difluoro-4-t(5',6',7',8'-tetrahydro-5',5',8',8'-27 tetramethyl-l'-bromo-2'-hydroxy-naphthalen-3~-yl)car 28 bamoyl~benzoic acid ('~rround 32).
2~ Reaction Scheme lO discloses the ex~mrle of converting 2,2,4,4-tetramethyl-8-nitrochroman-6-31 carboxylic acid (Compound V) into the corresponding 32 acid chloride by treatment with thionyl chloride, 33 followed by coupling with ethyl ~ 4-amino-2-~luorobenzoate (Compound Cl) and W O 97/24116 PCT~US96/20511 1 hydrogenation to yield ethyl 2 2-fluoro-4-~2',2',4',4'-tetramethyl-8'-amino-6'-chr 3 omanyl)carbamoyl]benzoate tCompound N1). Compound N

4 iS con~erted to the corresponding 8-azido compound, 5 ethyl 2-fluoro-4-~(2',2',4',4'-tetramethyl-8'-azido-6 6'-chromanyl)carbamoyl]benzoate (Compound 13) by 7 treatment with isoamyl nitrate and NaN3.

Y ~ ~CON, 13 ~p (W)p 4 Fon~a 6 Fonmula g ~5 16 t-~uOH
17 _ _ 18 R1 ~R, (R2)m (F~ ~NcC=O

~P
23 -- _ FoImula 10 26 ~
27 Rt ~Rl (R2)m 23 (R" ~ ~rNH2 32 Fonmula ~ 6 oL/ ~P

~ React ion Scheme 11 W O 97/24116 PCTrUS96/20511 1 Reaction Scheme 11 illustrates the synthesis of 2 the primary amine compounds of Fonmula 6a from the .~ acid chlorides (X3 = Cl) or other form of activated 4 acids of Formula 6 where the primary amine of 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 ~ sodium azide in acetone to yield the azide compound 10 of Formula 9. The azide of Formula 9 is heated in a polar high ~oiling solvent, such as t-~utanol, to provide the intermediate isocyanate of Formula 10, 13 which is hydrolyzed to yield a compound of Formula 14 6a.

17 F~ 1) E~O'3~2S04 1~ ~ ~CO2E~
18 Br~ 2) B~/CO2 HozC~

Canpound T
21 Sn~awara, S; TC?,~ N.
22 Ri7~70 ~agzL~ Z~ssh~
1~70, ~3, ~72-~79 23 F :
24 'r'~,' 1) E~O'~2S~4 ~ ~ ~CO~E~

27 E~ 2~ B~li~ HO~C'J--29 ~çh~l '~n c~ aI
J A~cd C~ C ~ V
31 1995, 38, 2S3 1-2~40 34 Reaction Scheme 12 W O 97/24116 PCTrUS96120511 ~ Reaction Scheme 12 illustrates examples for 2 preparing compounds of Formula 7a where such 3 compounds are not available commercially or by a 4 published literature procedure. Thus, by way of example 2,5-difluoro-4-bromobenzoic acid (available 6 by the literature procedure of Su~awara et al. Kogyo 7 Kaguku Zasshi 1970, 73, 972-979) is first esterified 8 by treatment with ethyl alcohol and acid to yield ~ the corresponding ester, and thereafter is reacted with butyl lithium followed by carbon dioxide to give the monoester of 2,5-difluoro terephthalic acid 12 ( Compound Tl). 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 16 al. J. Med. Chem. 1995, 38, 2531-2~40) yields the 16 monoester of 2,3,5,6-tetrafluoroterephthalic acid 17 ( Compound Vl). The just illustrated sequence of 8 reaction can be, gener2llly speaking, utilized for 1~ the synthesis of all compounds o~ Formula 7a with such modification which will become readily apparent 21 to those skilled in the art, where such compounds ~ are not available by a known literature procedure.
23 Reaction Scheme 13 provides an example for the 24 preparation of 2,6-di-tert-butylisonicotinic acid 25 ( Compound C3) which is a reagent in accordance with 26 Formula 8 for the preparation of several preferred 27 compounds of the present invention. Thus, 28 2,6-di-tert-butyl-4-methylpyridine (available 2~ commercially from Aldrich Chemical Co.) is reacted 30 with N-bromosuccinimide and benzoy~ peroxide to 31 provide 4-broInoIn~thyl-2,6-di-tert-butylpyridine 32 ( Compound A3). Compound A3 is reacted with base 33 ( sodium hydroxyde) to yield the coresponding 34 hydroxymethyl compound (Compound B3), which is CA 0224l758 l998-06-26 WO 97/24116 PCTrUS96/20 1 thereafter oxidized in a Jones oxidation reaction to 2 give 2,6-di-tert-butylisonicotinic acid (Compound 3 C~)-4 ~ Ar ~ OH

~1 NBS. ~.BzO)~ ~ NaOH
7 l CCI" l 1.1 Dio~me l 8 ~t ~ ~ N ~ ~ tBu ~t ~ ~ N ~ ~ tBu re~u~ ~ 9ut ~ ~ N ~ ~ t~u ~.~AA3 Cnmr~mA

14 JG~Ie'sJ~ eu~e ~

16 Eut ~ ~ ~ t9u r~r~mAC3 20~ Br MOAe E~'lBr ~ ~ 9r 21~ ~ ~.u~ L~l~mme t9u t9u t~u 24 C~m~-mA D ~ r~ E3 OMOM
27 9ut ~ CO2H
28 tB~-T~CO~

t~u 32 Or~-mA~

~ Reaction Scheme 13 W O 97/24116 PCTnUS96/20511 1 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 ~ (Aldrich3 is brom;n~ted in glacial acetic acid to 6 yield 2-bromo-4,6-di-tert-butylphenol (Co~pound D3) 7 which is thereafter reacted with methoxymethyl 8 chloride (MOMCl)to give ~ O-methoxymethyl-2-bromo-4,6-di-tert-butylphenol (Compound E3). Compound E3 is treated with t-butyl lithium followed by carbon dioxide to yield ~2 0-methoxymethyl-3,5-di-tert-butylsalicylic acid 3 (Compound F3). CQmround F3 is a reagent which 14 differs from the compounds generally encompassed by 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) 1~ linkage, as exemplified in Reaction Scheme 14.
Reaction of an aromatic bromo compound (such as 21 Compound D3) with t-butyl lithium followed by carbon 22 dioxide is a preferred method for preparing several 23 aromatic carboxylic acids in accordance with Formula 24 8 and Formula 7a, described in the present application.
26 The primary amine compounds of Formula 8a which 27 are not available commercially or by a published 28 literature procedure can be made from the acid 2~ chlorides ( X3 = Cl) or other form of activated acids 30 of Formula 8 substantially in accordance with the 3l steps of a Curtius rearrangement, in analogy to the 32 reaction steps described above in connection with 33 Reaction Scheme 11.

CA 0224l7~8 l998-06-26 W O 97/24116 PCT~US96/20511 4 ~ 7)Ehyl--EEE~-~=n~ ~ ~ ~
bcnzo tc (r~mr~ n~
5 BUt --N t8U Pyri&c C~ ~ a 6 t~~mr~ c3 t8U c2mpouDt!. 41 8 CO~H 8Ut ~ ~N ~:O~Et 8Ut~-- Eh~5 '0~ N~.J H
12 tBU Compoond 43 C~n"r~" C--1 3 ;7 0 ~C52E~

~ Eh ~ o~
bcDzo:~e (C'~7""r''n'i C1 ) 17 BUt ~~~U Py~dine CH-a- tBU
18 Compound 45 21 BU~ ~CO2H EDC.DI~W BU~ ~N~

23 ll Ethyl 1 ~uno-2-auoro ll H
~ ~ OCllZO;~e (rnmrl~n~ Cl ) ll ~.
24 ~ Pyridine c~.a.
tBU
26 Cnmpo~nnrl F 3 tBU CompoUnd G3 28 Uut ~1 J~ thiopbcnol ~\Jl\N/~o2F~

~J H BF3~oEt ~J

32 t8U r' ~BU
Comoound ~3 34 Reaction Scheme 14 PCT~US96/20511 S ~ z)rnm~ P ~ H ~ r~H

N 3)NaOEUE~H N

C~lmro~ ' 5n 11 Ç~ C,~3 F

14 ~ 1) SOC3~ ~HJ~ CO~H
3)NaOH~

17 r~mrrmr1 52 24 CO~H l)sr~ N~r~~H

2) C~mpound Fl~Py ~ H NO2 27 N~) 3) NaOH/E~OH N~
r~mr, Compolmd C3 ~ Reaction Scheme 14 ~continued) W O 97/24116 PCTrUS96/20511 1 Reaction Scheme 14 illustrates examples for the 2 formation of the carbamoyl (amide) compounds in ~ 3 accordance with Formula 2, b~r reaction of a reagent 4 of Formula 8 with a reagent of Formula 7. Thus, 6 2,6-di-tert-butylisonicotinic acid (Compound C3) iS
6 reacted with thionyl chloride (SOCl2) to provide the 7 intermediate acid chloride, which is then reacted 8 with ethyl 2-fluoro-4-amino-benzoate (Compound Cl) in ~ the presence of an acid acceptor (pyridine) to yield ethyl 2-fluoro-4-[(2'6'-di-tert-butylpyrid-4~-yl)carbamoyl]benzoate (Compound 41 ). As another 12 ex~mrle, 3,5-di-tert-butylbenzoic acid (available by 13 the literature procedure of Kagechika et al., J.
4 Med. Chem. 1988, 31, 2182, incorporated herein by reference) is reacted with thionyl chloride, 16 followed by ethyl 2-i~luoro-4-amino-benzoate 17 ( Compound Cl) to yield ethyl 2-fluoro-4-[(3',5'-di-18 tert-butylphenyl)carbamoyl]benzoate (Compound 45).
As still another example, O-methoxymethyl-3,5-di-tert-butylsalicylic acid (Co~pound F3)is reacted with 21 ethyl 2-fluoro-4-amino-benzoate (Compound Cl) in the 22 presence of 4-dimethylaminopyridine (DMAP) catalyst 23 and 1-~3-dimethylaminopropyl)-3-ethylcarbodiimide 24 hydrochloride (EDC) to give ethyl 2-fluoro-4-t(2~-2~ methoxymethyl-3',5'-di-tert-butylphenyl)car-26 bamoyl]benzoate (~or~round G3). The methoxymethyl 27 protecting group is removed from Compound G3 by 28 treatment with borontrifluoride ethereate and 2~ thiophenol to yield ethyl 2-fluoro-4-[~2'-hydroxy-3',5'-di-tert-butylphenyl)carbamoyl]benzoate 31 ( C~ompound 47).
32 In yet another example shown in Reaction Scheme 33 14, 2,6-di-tert-butylisonicotinic acid (Compound C3) 34 iS reacted with thionyl chloride (SOCl2), the W O 97/24116 PCT~US96/20511 1 resulting intermediate acid chloride is reacted with 2 methyl 2,6-difluoro-4-smino benzoate (Compound Hl), 3 followed by saponification of the ester group, to 4 yield 2,6-difluoro-4-[(2/,6'-di-tert-butylpyrid-~ 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 8 2,6-difluoro-4- [(3',5'-di-tert-butylphenyl~car-g bamoyl~ben20ic acid (Compound 52).
As yet another example, shown in Reaction Scheme 14, 2,6-di-tert-butylisonicotinic acid (Compound C3) 2 is reacted with thionyl chloride (SOCl2), followed by 3 methyl 2-nitro-4-aminobenzoate (Compound F1) and 4 saponification of the ester function to give 2-nitro-4-[(2',6'-di-tert-butylpyrid-4'-yl)carbamoyl 6 ] benzoic acid (Compound 54).
7 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 20 still further compounds which can be used in the 21 methods of treatment of the present invention, and 22 also for preparing the reagents of Formula 6, 23 Formula 7, Formula 8, Formula 6a, Formula 7a and 24 Formula 8a will become readily apparent to those 25 skilled in the art in light of the present 26 disclosure. In this regard the following general 27 synthetic methodology, applicable for conversion of 28 the compounds of Formula 1 and/or of Formula 2 into 29 further homologs and/or derivatives, and also for 30 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 W O 97/24116 PCTrUS96t20511 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.
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 8 Chemistry," 2nd Edition, McGraw--Hill Book Company, p 9 810). Alcohols, aldehydes and ketones all may be 0 protected by forming respectively, ethers and esters, acetals or ketals by known methods such as 12 those described in McOmie, Plenum Publishing Press, 13 1973 and Protectin~ Groups, Ed. Greene, John Wiley &
14 Sons, 1981.
The acids and salts derived ~rom compounds of 16 Formula 1 and Formula 2 are readily obtainable from 17 the corresponding esters. Basic saponification with 8 an alkali metal base will provide the acid. For 19 example, an ester may be dissolved in a polar 20 solvent such as an alkanol, preferably under an 21 inert atmosphere at room temperature, with about a 22 three molar excess of base, for example, potassium 23 or lithium hydroxide. The solution is stirred for 24 an extended period of time, between 15 and 20 hours, 25 cooled, acidified and the hydroly~ate recovered by 26 conventional means.
27 The amide (in Formula 1 or 2 B is CONRgRlo) may 28 be formed by any appropriate amidation means known 2~ in the art from the corresponding esters or 30 carboxylic acids. One way to prepare such compounds 31 iS to convert an acid to an acid chloride and then 32 treat that compound with ammonium hydroxide or an 33 appropriate amine.
34 Alcohols are made by converting the W O 97/24116 PCT~US96/20511 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 sodium borohydride (March, Ibid, pg. 1124), which 6 gives the corresponding alcohols. Alternatively, 7 esters may be reduced with lithium aluminum hydride 8 at reduced temperatures. Alkylating these alcohols g with appropriate alky halides under Williamson reaction conditions (March, Ibid, pg. 3~7) gives the corresponding ethers. These alcohols can be 12 converted to esters by reacting them with 13 appropriate acids in the presence of acid catalysts 4 or dicyclohexylcarbodiimide and dimethylaminopyridine.
6 Aldehydes can be prepared from the corresponding 7 primary alcohols using mild oxidizing agents such as 8 pyridinium dichromate in methylene chloride (Corey, 19 E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalyl chloride in methylene 1 chloride (Omura, K., Swern, D., Tetrahedron, 1978, 22 34, 1651).
23 Ketones can be prepared from an appropriate 24 aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by 26 oxidation.
27 Acetals or ketals can be prepared from the 28 corresponding aldehyde or l~etone by the method 2~ described in March, Ibid, p 810.

W O 97/24116 PCTrUS96/20511 1 Specific Examples 2 Ethyl 4-Amino-2-fluorobenzoate (Compound Cl) 3 To a mixture of 2-fluoro-4-nitrotoluene (1~0 g, 4 6.4 mmol, Aldrich) and Na2Cr2C)7 (2.74 g, 8.4 ~unol) in 13 . 7 ml of HOAc was added slowly 6.83 ml o~ H2SO4 .
6 This mixture was slowly heated to 90 ~C for 1 h to 7 give a greenish heterogeneous solution. The mixture 8 was cooled to room temperature and diluted with 9 ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq-)- The mixture was extracted 11 with more ethyl acetate. The organic layer was 12 washed with NaHCO3(sat.), then brine and dried over 13 Na2SO4. After filtration, the solution was 14 concentrated to dryness which then was dissolved in 15 6 ml of SOCl2, and heated at 80 ~C for 1 h. The 16 excess of SOCl2 was removed under reduced pressure 17 and the residue was dissolved in 5 ml of CH2Cl2, 2 ml 18 of EtOH and 2 ml of pyridine. The mixture was 1~ stirred at room temperature for 2 h and concentrated 20 to dryness. Ethyl 2-fluoro-4-nitrobenzoate was 21 obtained as a white solid after column 22 chromatography of the residue with ethyl 23 acetate/hexane (1/9). This solid was then dissolved 24 in 10 ml of ethyl acetate, and Pd/C (50 mg) was 25 added. Hydrogenation with a hydrogen balloon 26 converted ethyl 2-fluoro-4-nitrobenzoate into the 27 title compound.
28 lH NMR ~ 7.77 (t, J = 8.4 Hz, lH), 6.41 (dd, Jl =
29 8.6, J2 = 2.2 Hz, lH), 6.33 (dd, Jl = 13.0, J2 = 2.2 30 Hz, lH), 4.33 ~q, J = 7.1 Hz, 2H), 4.3 (b, 2H), 1.37 31 (t, J = 7.1 Hz, 3H).
32 Methyl 4-Amino-2,6-difluorobenzoate ~Compound Hl) 33 A solution of trifluorobenzoic acid (150 mg, 34 0.g5 mmol, Aldrich) in 0.5 ml of SOC12 was heated W O 97/24116 PCTrUS96/20511 1 under reflux for 2h. The reaction mixture was 2 cooled to room temperature, and excess of SOCl2 was 3 removed under reduced pressure. The residue was 4 dissolved in 1 ml of pyridine and 0.2 ml of methanol. After stirring at room temperature for 30 6 min, solvent was removed and the residue was 7 purified by column chromatography (ethyl 8 acetate/hexane 1/10) to give methyl trifluoro-g benzoate as a colorless oil. This oil was then dissolved in 1 ml of CH3CN, then a solution of NaN3 11 (100 mg, 1.54 mmol~ in 0.5 ml of water was added.
12 The reaction mixture was refluxed for two days.
13 Salt was filtered and the remaining solution was 14 concentrated to an oil. This oil was then dissolved 1~ in 1 ml of methanol, followed by a catalytic amount 16 of Pd/C (10%, w/w). The reaction mixture was 17 hydrogenated under a hydrogen balloon for 12 h.
18 Catalyst was removed and the solution was 19 concentrated to an oil. After column chromatography 20 (ethyl acetate/hexane 1/3), the title product was 21 obtained as colorless crystals.
H NMR ~ 6.17 (d, J = 10.44 Hz, 2H), 4.2 (b, 2H), 23 3.87 (s, 3H).
24 8-3romo-2,2,4,4-tetramethyl-6-chromanoic acid 25 ( Compound P) 26 To a solution of 2,2,4,4-tetramethyl-6-chro-27 manoic acid (200 mg, 0.85 mmol) in 0.5 ml of AcOH
28 was added Br2 (0-07 ml, 1.28 mmol). The resulting 29 dark-orange solution was stirred at room temperature 30 for overnight. The excess bromine was removed under 31 reduced pressure. Then the solution was poured into 32 5 ml of water and extracted with ethyl acetate 33 (3x3ml). The combined ethyl acetate layers were 34 further washed with NaHC03 ~sat.), brine and dried CA 0224l758 1998-06-26 W O 97/24116 PCTrUS96/20511 1 over MgSO4. After concentration, the residue was 2 purified by column chromatography (silica gel, ethyl acetate/hexane 1/3) to yield the desired product 4 (170 mg, as white solids.
lH NMR ~ 8.11 (d, J = 2.2 Hz, lH), 8.00 (d, J = 2.2 6 Hz, lH), 1.90 (s, 2H), 1.43 (s, 6H), 1.39 (s, 6H).
7 8-Iodo-2~2~4~4-tetrameth~1-6-chromanoic Aaid 8 ( Compound X) o To a solution of 2,2,4,4-tetramethyl-6-chro-o manoic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH was added ICl (O.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-chromanoic acid (compound P), the reaction gave the 16 title compound (107 mg) as white solids.
17 lH NMR ~i 8.35 (d, J = 2.2 Hz, lH), 8.03 (d, J = 2.2 18 H~, lH), 1.87 (s, 2H), 1.43 ~s, 6H), 1.38 (s, 6H).
1~ 2 r 2,4,4-Tetramethyl-8-trifluoromethylchroman-6-oic acid (Compound S) 21 A solution of 8-bromo-2,2,4,4-tetramethyl--6-~ chromanoic acid (Compound R, 150 mg, 0.48 mmol) in 1 23 ml of SOCl2 was refluxed for 2 h. After cooling to 24 room temperature, the excess of SOCl2 was removed under reduced pressure and the residue wa~ dissolved 26 in 1 ml of pyridine and 0.2 ml oi~ methanol. The 27 mixture was stirred at room temperature for 30 min.
28 Solvent was removed and the residue was passed 29 through a column (silica gel, ethyl acetate/hexane l/lO) to give the methyl 8-bromo-2,2,4,4-tetra-31 methylchromanoate (158 mg) as a colorless oil. To a 32 solution of this methyl ester in 3 ml of ?~3 N-methylpyrrolidone (NMP) was added NaCO2CF3 (502 mg, 34 3.7 mmol) and CuI (350 mg, 1.84 mmol). The W O 97/24116 PCT~US96/20511 1 resulting mixture was heated to 175 ~C (bath temp) 2 Eor 2 h. The resulting mixture was cooled to room 3 temperature and poured into ice-water. The product 4 was extracted into ethyl acetate (3x3ml). The 6 combined organic layers were dried and concentrated 6 to dryness. The crude material was purified by 7 column chromatography (ethyl acetate/chloroform 8 1/10) to give the title compound as a colorless oil 9 (120 mg). This was hydrolyzed under standard conditions to give the title compound.
H NMR ~ 8.21 (d, J = 2.1 Hz, lH), 8.17 (d, J = 2.1 12 Hz, lH)~ 1.92 (s, 2H), 1.41 (s, 12H).
13 Ethyl 8-Nitro-2,2,4,4-tetramethyl-6-chromanoate 14 ( Compound W) Ethyl 2,2,4,4-tetramethyl-6-chromanoate (150 mg, 16 0.57 mmol) was slowly added to 0.3 ml of conc. H2SO4 17 at 0 ~C. To this mixture was added very slowly 0.03 18 ml of HNO3. The reaction mixture was stirred at 0 ~C
19 for 30 min and poured into ice-water. The product 20 was extracted into 5 ml of ethyl acetate, washed 21 with NaHCO3 (sat.), brine and dried over MgSO4.
~ After concentration, the product was purified by 23 column chromatography (ethyl acetate/hexane 1/10) to 24 yield 74 mg of light-yellow oil.
25 lH NMR ~ 8.24 (d, J = 2.1 Hz, lH), 8.17 (d, J = 2.1 26 Hz, lH), 4.38 (q, J = 7.1 Hz, 2H), 1.95 (s, 2H), 27 1.43 (s, 6H), 1.42 ~s, 6H), 1.40 (t, J = 7.1 Hz, 28 3H).
29 2-Oxo-4,4,8-trimethylchroman (Compound P1) In a 500 ml of round bottom flask, NaH (1.66 g, 31 60% suspension in oil, 0.046 mol) was washed with 32 dry hexane. Then, dry THF (22 ml) was added 33 followed by o-cresol t5 g, 0.046 mol) in 10 ml of 34 dry THF. The reaction mixture was stirred at 0 ~C

CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 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 4 h, then slowly quenched with water. The mixture was then extracted with ethyl acetate. The organic 6 layer was washed with brine, water and dried over 7 MgS04. After filtration and removal of the solvent, 8 a yellow oil was obtained (10.44 g~. This oil was then dissolved in 50 ml of dry CH2Cl2, and was o canulated into a solution of AlCl3 (10.8 g, 0.069 mmol) in 10 ml of CH2Cl2. The reaction mixture was 2 stirred at room temperature for 12 h. Then 3 ice-water was carefully added and the organic layer 4 was separated, and washed with NaHC03(sat), brine, water and finally dried over MgS04. After removal of 6 the drying agent and solvent, the residue was 7 puri~ied by column chromatography (~ilica gel, ethyl 8 acetate/hexane 1/9) to yield the title compound 19 (4.408 g) as an oil.
20 lH NMR ~ 7.1 (m, 3H), 2.62 (s, 2H), 2.33 (s, 3H), 21 1.36 (s, 6H).
2~4-Dimethyl-4-(2'-hydroxy-3'-methylphenyl)pentan-2-23 ol ( Compound Rl) 24 To a solution oE 2-oxo-4,4,8-trimethylchroman 2~ ( Compound Pl, 2.20 g, 11.5 mmol) in 40 ml of dry 26 ethyl ether was added methyl magnesium bromide 27 ( 12.67 ml, 38 mmol, 3 M solution in THF). The 2R reaction mixture was stirred at room temperature for 2~ 12 h, then quenched with NH4Cl (sat.~ until all precipitate dissolved. The mixture was extracted 31 with diethyl ether and the combined organic layers 32 were separated and washed with brine, water and 33 dried over MgS04. After filtration and removal of 34 the solvent, the title compound was obtained as a W O 97/24116 PCT~US96/20511 1 tan solid (2.215 g).
2 lH NMR ~ 7.16 (d, J = 7.88 Hz, lH),7.00 (d, J = 6.72 3 Hz, lH), 6.81 (t, J = 7.6 Hz, lH),5.89 (b, lH), 4 2.21 (g, 3H), 2.17 (s, 2H), 1.48 (s, 6H), 1.10 (s, 6 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 Rl, 2.215 g, 9.98 9 mmol) in 30 ml of 1596 of H2SO4 was heated to 110 ~C.
o After cooling to room temperature, the reaction mixture was extracted with diethyl ether. The 12 organic layer was washed with NaHCO3 (sat.), brine 13 and water. After filtration and removal of solvent, 4 the residue was passed through a column (silica gel, pure hexane~ to give the title compound as a clear 6 oil (1.636 g). This oil was then dissolved in 1.5 7 ml of HOAc, then Br2 (0.4113 ml, 7.98 mmol) was 8 added. The reaction mixture was stirred at room 19 temperature for 12 h. Solvent was removed under reduced pressure and to the residue was added ethyl 21 acetate, and the resulting mixture was washed with 2~ NaHCO3 (sat.) r brine, water and dried over MgSO4.
23 After filtration and removal of solvent, the residue 24 was passed through a column (silica gel, pure hexane) to give the title compound as a white solid 26 (2.227 g).
27 lH NMR ~ 7.21 (s, lH), 7.0~ (s, lH), 2.14 (s, 3H), 28 1.79 ~s, 2H), 1.32 (s, 6H), 1.31 (s, 6H).
2~ 2,2,4,4,8-Pentamethyl-6-chromanoic Acid (Compound Al) To a solution of 2,2,4,4, 8-pentamethyl-6-bromo-31 chroman (Compound Z) (1.2 g, 4.24 mmol) in 18 ml of 32 dry THF at -78 ~C under argon gas was added slowly 33 5.48 ml of t-BuLi (1.7 M in hexane, 9.33 mmol). The ~ reaction mixture was stirred at -78 ~C for 1 h. Then W O 97/24116 PCTrUS96/20511 1 CO2 was bubbled through the solution ~or 1 h. After 2 removal of CO2 stream, the reaction mixture was 3 stirred for an additional hour at -78 ~C. Then 1096 4 of HCl 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 Na2SO4. After 8 concentration, the residue was purified by column ~ chromatography (ethyl acetate/hexane 5/95) to yield the title compound as a white solid (774 mg).
11 lH NMR ~ 7.96 (s, lH), 7.75 (s, lH), 2.23 (s, 3H), 12 1.88 (s, 2H), 1.39 (8, 6H).
13 8-Bromo-4,4-dimethyl-6-chromanoic Acid (Compound Bl) t4 Using the same procedure as for the synthesis of 15 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 18 white solid.
19 lH NMR ~ 8.10 (d, J = ~.1 Hz, lH), 7.98 (d, J = 2.1 20 Hz, lH), 4.39 (t, J = 5.44 Hz, 2H), 1.89 (t, J = 5.4 21 Hz, lH), 1.38 (s, 6H).
22 Ethyl 2-Amino-1-bromo-5,5,8,8-tetrahydro-5,5,8,8-23 tetramethylnaphthalene-3-carboxylate (Compound D) 24 To a solution of ethyl 5,6,7,8-tetrahydro-25 5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate 26 ( Compound C, 58 mg, 0.21 mmol) in 2 ml of HOAc was 2~ added Br2 ~0.02 ml, 0.42 mmol). The orange solution 28 was stirred at room temperature for 2 days. ~he 29 excess Br2 and HOAc were removed under reduced 30 pressure and the residue was passed through a column 31 (silica gel, ethyl acetate/hexane 1/10) to yield the 32 title compound as a light-orange oil (59 mg, 79.5%~.
33 lH NMR ~ 7.90 (s, lH), 6.41 (b, 2H), 4.36 (q, J = 7.2 34 Hz, 2H), 1.70 (m, 4H), 1.58 (s, 6H), 1.40 (t, J =

CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 7.2 Hz, 3H), 1.28 (s, 6H).
2 Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 3 -4-bromonaphthalene-2-carboxylate (Compound E) 4 Ethyl 2-Amino-1-bromo-5,5,8,8-tetrahydro-6 5,5,8,8-tetramethylnaphthalene-3-carboxylate 6 (Compound D, 59 mg, 0.17 mmol) was dissolved in 2 ml 7 of EtOH at 0~C. To this solution was added lml of 8 trifluoroacetic acid and 1 ml of isoamylnitrite.
~ The reaction mixture was stirred at 0~C for 30 min then H3PO2 (0.325 ml, 3.14 mmol) was added. The 11 reaction mixture was allowed to warm to room 12 temperature and stirred for 12 h. NaHCO3 (sat.) was 13 added and the reaction mixture was extracted with 14 ethyl acetate, dried over MgSO4, filtered and concentrated to give an oil. The product was 16 purified by column chromatography (silica gel, ethyl 17 acetate/hexane 1/10) to give the title compound as a 18 colorless oil.
~ lH NMR ~ 8.02 (d, J = 2.0 Hz, lH), 7.95 (d, J = 2.0 20 Hz, lH), 4.35 (q, J = 7.1 Hz, 2H), 1.71 (m, 4H), 21 1.56 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.31 (s, 22 6H).
23 Ethyl 24 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-fluoro-25 naphthalen-2-yl-carboxylate (Compound G) 26 In an ice bath, ethyl 27 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth 28 alene-2-carboxylate (Compound C, 150 mg, 0.55 mmol) 2~ was added 0.24 ml of HBF4 (48% solution in water), followed by a solution of NaNO2 (81 mg, 1.16 mmol) in 31 1 ml of water. The slurry was left in a 32 refrigerator for 3 days. The reaction mixture was 33 washed successively with ethyl acetate until ~LC
34 showed no UV visible spot at the baseline. The W O 97/24116 PCTrUS96/20511 1 ethyl acetate layer was dried with MgSO4 a~d the 2 solution was concentrated to an oil. The oil was 3 Eurther dissolved in 1 ml of toluene and the mixture 4 was heated under reflux for 2 h. After the reaction ~ cooled to room temperature, solvent was evaporated 6 and the residue was passed through a column (silica , gel, ethyl acetate/hexane 1/10) to give the title 8 compound as an oil.
~ lH NMR ~ 7.85 (d, J = 7.8 Hz, lH), 7.04 (d, J = 12.3 10 Hz, lH), 4.38 (q, J = 7.1 Hz, 2H), 1.69 (s, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 2 6H).
3 2-Bromo-3-hydroxy-5,5,8,8-tetrahydro-5,5,8,8-tetrame 4 thylnaphthalene (Compou3~d I) Using the same procedure as for the synthesis o~
6 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid 7 ( Compound P) but using 2-hydroxy-5,5,8,8-tetrahydro-8 5,5,8,8-tetramethyltetralin (700 mg, 3.43 mmol) and 19 Br2 (0.177 ml, 3.43 mmol) in 1.5 ml of HOAc, the 20 title compound was obtained as a white solid (747 21 mg)-~ lH NMR ~ 7.36 (s, lH), 6.96 (s, 2H), 5.32 (b, lH), 23 1.66 (s, 4H), 1.25 (s, 12H).
24 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-methoxymet-25 hoxy-2-bromonaphthalene (Compound J) 26 To a solution of 2-bromo-3-hydroxy-5,5,8,8-tet-27 rahydro-5,5,8,8-tetramethylnaphthalene (Compound I, 28 600 mg, 2.12 mmol) and catalytic amount of Bu4NBr in ~ 20 ml of dry CH2Cl2 at 0 ~C was added 30 diisoproylethylamine (1.138 ml, 12.75 mmol), 31 followed by methoxymethyl chloride (0.484 ml, 6.39 32 mmol). The reaction mixture was heated at 45 ~C for 33 12 h. The reaction mixture was washed with 10% of 34 citric acid, then NaHCO3 (sat.), brine and dried over CA 0224l758 l998-06-26 W O 97t24116 PCT~US96/20511 1 MgSO4. After ~iltration and removal of the solvent, 2 the residue was purified by column chromatography 3 (ethyl acetate/hexane 1/9) to yield the title 4 compound (722 mg) as a white solid.
6 1H NMR ~ 7.43 (s, lH), 7.06 (s, lH), 5.21 (s, 2H), 6 3.54 (s, 3H), 1.66 (s, 4H), 1.26 (s, 6H), 1.25 (s, 7 6H).
8 3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrah ~ ydronaphthalen-2-yl carboxylic acid (Co~pound ~) Using the same procedure as for the synthesis of 11 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound Al) 12 but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-13 3-methoxymethoxy-2-bromonaphthalene (Compound J, 722 14 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7 16 M solution in hexane~, the title compound was 16 obtained as a white solid (143 mg).
17 lH ~MR ~ 8.12 (s, lH), 7.19 (s, lH), 5.40 (s, 2~), 18 3.58 (s, 3H), 1.70 (s, 4H), 1.30 (s, 12H).
19 ~thyl 2-Fluoro-4-[(5',6',7'~8~-tetrahydro-5',5'~8',8'-tetramethylnaphthalen-2'-yl)carbamoyllbe 21 nzoate (Compound 1) 22 To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-23 2-naphthoic acid (46 mg, 0.2 mmol) was added 1 ml 24 thionyl chloride. This mixture was refluxed for 2 h. Excess thionyl chloride was removed under 26 reduced pressure and the residue was dissolved in 2 27 ml of CH2Cl2. To this solution was added ethyl 28 4-amino-2-fluorobenzoate ((Compound Cl, 37 mg, 0.2 2~ mmol) followed by 0.5 ml of pyridine. The reaction 30 mixture was stirred at room temperature for 4 h and 31 was concentrated under reduced pressure. The 32 residue was purified by column chromatography (ethyl 33 acetate/hexane 1/10) to give the title compound as 34 white solids.

W O 97/24116 PCTrUS96/20511 ~lH NMR ~ 8.06 (b, lH), 7.93 (t, J = 8.4 Hz, lH), 7.85 2(d, J = 2.0 Hz, lH), 7.78 (dd, J1 2 2.0 Hz, J2 = 12.9 3 Hz, lH), 7.55 (dd, Jl = 2.0 Hz, J2 = 8.2 Hz, lH~, 4 7.40 (d, J = 8.3 Hz, lH), 7.32 (dd,Jl = 2.02 Hz, J2 = 8.8 Hz, lH), 4.38 (q, J = 7.2 Hz,2H), 1.71 (s, 6 4H), 1.40 (t, J = 7.2 Hz), 1.32 (s,6H), 1.30 (s, 7 6H).
8 Ethyl 2-Fluoro-4- r ( 5~,6~,7',8~-tetrahydro-4~-bromo-5'~5~8'~8~-tetramethYlnaphthalen-2~-yl)carbam 0 oyl}benzoate (Compound 3) Using the same procedure as for the synthesis of 2 ethyl 2-fluoro-4-[-5',6',7',8'-tetrahydro-3 5~,5~,8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be 4 nzoate (Compound 1), but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth 16 alene-2-carboxylic acid (Compound F), the title 17 compound was obtained as a white ~olid.
18 lH NMR ~ 8.30 (b, lH), 7.92 (t, J = 8.4 Hz, lH), 7.84 19 (d, J = 2.1 Hz, lH), 7.81 (d, J = 2.1 HZ, lH), 7.74 20 (dd, Jl = 2.1 Hz, J2 = 12.8 HZ, lH), 7.35 (dd, Jl =
21 2.0 Hz, J2 = 8.4 HZ, lH), 4.36 (q, J = 7.2 HZ, 2H), 22 1.67 (m, 4H), 1.55 (s, 6H), 1.39 (t, J = 7.2 Hz, s 3~), 1.31 (s, 6H).
24 Ethyl 2-Fluoro-4- r (3'-methoxymethoxy-5',6',7',8'-tet-26 rahydro-5', 27 5',8',8~-tetramethylnaphthalen-2'-yl)car-28 bamoyllbenzoate (Compou~d K1) 29 Using the same procedure as for the synthesis o~
ethyl 2-fluoro-4-[(3~-methoxymethoxy-4~-bromo-31 S', 6~,7~,8'-tetrahydro-5',5',8',8'-tetramethylnaphth 32 alen-2'-yl)carbamoyl]benzoate (Compound Sl), but 3s using 3-methoxymethoxy-5,5,8,8-tetramethyl-34 ~, 6,7,8-tetrahydronaphthalen-2-yl carboxylic acid W O 97/24116 PCT~US96/20511 1 ( Compound K, 143 mg, 0.49 mmol) and 2 4-amino-2-f~luorobenzoate (Compound Cl, 98.5 mg, 0.54 3 mmol), the title compound was obtained as a white 4 solid.
6 lH NMR ~ 10.1 (b, lH), 8.20 (s, lH), 7.93 (t, J = 8.8 6 Hz, lH), 7.83 (d, J = 13.4 Hz, lH), 7.29 (d, J = 8.0 7 Hz, lH), 5.41 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 8 3.59 (s, 3H), 1.70 (s, 4H), 1.31 (s, 12H), 1.26 (t, ~ J - 7.1 Hz, 3H).
Ethyl 2-Fluoro-4-~(3'-hydroxy-5',6',7' 8~-tetrahydro-5',5',8', 8'-tetramethyl-2-2 naphthalenYl)carbamoyllbenzoate ( Compound 5 ) 3 A solution of ethyl 2-fluoro-4-[(3'-methoxymet-4 hoxy-5',6',7',8'-tetrahydro-5', 5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]
6 benzoate (Compound Kl, 50.7 mg, 0.11 mmol) in 2 ml of 7 CH2Cl2 was added thiophenol (0.061 ml, 0.55 mmol).
8 The reaction mixture was stirred at 0 ~C for 5 min, 1~ then BF3.Et20 (0.027 ml, 0.22 mmol) was added. The reaction mixtrue was stirred at 0 ~C for 2 h, then 1 NaHCO3 (sat.) was added. The organic layer was 2 separated, and washed with brine, water and dried 3 over MgSO4. After filtration and removal of solvent, 24 the residue was passed through a column (silica gel, ethyl acetate/hexane 1/3) to give the title compound 6 as white solid (44.2 mg).
7 lH NMR ~ 8.61 (b, lH), 7.94 (t, J = 8.42 Hz, lH), 8 7.71 (dd, J = 10.8, 2.0 Hz, lH), 7.53 (s, lH), 7.35 9 (dd, J = 6.4, 2.0 Hz, lH), 6.96 (s, lH), 4.39 (q, J
= 7.1 Hz, 2H), 1.69 (s, 4H), 1.40 (t, J = 7.1 Hz, 1 3H), 1.29 (s, 6H), 1.27 (s, 6H).
2 EthYl 2-Fluoro-4-r(4'/4'-dimethyl-8'-bromochroman-6'-yl)carbamoyl~benzoate (~r~und 7) Tn a 10 ml of round bottom flask, CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 4,4-dimethyl-8-bromo-6-chromanoic acid (Compound Bl, 2 139 mg, 0.48~ mmol) was added SOCl2 (1 ml, large 3 excess). The resulting solution was heated at 90 ~C
4 for 2 h and allowed to cool to room temperature.
The excess of SOC12 was evaporated under reduced 6 pressure. The residue was dissolved in CHzCl2 (3 7 ml). Ethyl 4-amino-2-fluorobenzoate (C~ompound Cl, 90 8 mg, 0.49 mmol) was added followed by pyridine (0.5 g ml, large excess). The reaction mixture was stirred o for overnight and then concentrated to dryness. The residue was purified by column chromatography with 2 ethyl acetate/hexane ~1/5) to yield the title 3 compound as a white solid (190 mg).
14 lH NMR ~ 7.95 (t, J = 8.31 Hz, lH), i.88 (b, lH), 7.83 ~d, J = 2.2 Hz, lH), 7.80 (d, J = 2.2 Hz, lH), 16 7.75 (dd, J = 12.89, 2.0 Hz, lH), 7.30 (dd, J =
17 8.55, 2.0 Hz, lH), 4.37 (m, 5H), 1.89 (t, J = 5.49 18 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.39 (s, 6H).
19 Ethyl 2-Fluoro-4-~(2',2',4',4'-tetramethyl-8'-bromo-chroman-6'-yl)carbamoyllbenzoate (Compound 9) 21 Using the same procedure as for ethyl 22 2-fluoro-4-~4',4'-dimethyl-8'-bromochroman-6'-yl)ca 23 rbamoyl3benzoate (r~r~und 7), but using 24 2,2,4,4-tetramethyl-8-bromo-6-chromanoic acid ( Compound P, 70 mg, 0.22 mmol) and ethyl 26 4-amino-2-fluorobenzoate (Compound Cl, 38 mg, 0.22 27 mmol), the title compound was obtained as a white 28 solid (80 mg, 76%).
2~ lH NMR ~ 8.25 (b, lH), 7.92 (t, J = 8.4 Hz, lH), 30 7.83 (s, 2H), 7.74 (dd, Jl = 2.0, J2 = 13.0 Hz, lH), 31 7.34 (dd, Jl = 2.0, J2 = 8.7 Hz, lH), 4.37 (q, J =
32 7.1 Hz, 2H), 1.88 (s, 2H), 1.41 (s, 6H), 1.39 (t, J
33 = 7.1 Hz, 3H), 1.37 (s, 6H).
34 Ethyl CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 1 2-Fluoro-4- r ( 2~,2~,4~,4~-tetramethyl-8~-trifluoromet 2 hylchroman-6r-yl)carbamoyll benzoate (Compoun~ 11) 3 Using the same procedure as for ethyl 4 2-fluoro-4-~(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 6 rbamoyl]benzoate (Compound 7), but using 6 2,2,4,4-tetramethyl-8-trifluoromethyl-6-chromanoic 7 acid (rQ~und S, 57 mg, 0.19 mmol) and ethyl 8 4-amino-2-fluorobenzoate (Compound C~, 35 mg, 0.19 9 mmol) r the title compound was obtained as white solids.
H NMR ~ 8.06 (d, J = 2.2 Hz, lH), 7.99 (b, lH), 7.95 12 (t, J -- 8.55 Hz, lH), 7.81 (d, J = 2.2 Hz, lH), 7.76 ~3 (dd, J = 12.8, 2.1 Hz, lH), 7.33 (dd, J = 8.55, 1.9 14 Hz, lH), 4.37 (q, J = 7.1 Hz, 2H), 1.93 (s, 2H), 1.41 (s, 12H), 1.40 (t, J = 7.2 Hz, 3H). Ethyl 16 2-Fluoro-4- r ( 2~,2~,4~,4~-tetramethyl-8~-amino-17 chroman-6'-yl)carbamoyllbenzoate (Compound N,) 18 Using 8-nitro-2, 2, 4, 1~ 4-tetramethylchroman-6-carboxylic acid (Compound V) and following the same procedure as for the 21 synthesis of ethyl 2-fluoro-4-[(4',4'-dimethyl-22 8'-bromochroman-6'-yl)carbamoyl]benzoate (Compound 23 7), ethyl 2-fluoro-4-~2',2',4',4'-tetramethyl-24 8'-nitrochroman-6'-yl)]carbamoylbenzoate was obtained as a white solid. This compound (50 mg, 26 0.12 mmol) was dissolved in 2 ml of methanol. A
27 catalytic amount of Pd/C was added to the solution 28 and the solution was maintained under H2 atmosphere (hydrogen balloon) for overnight. The catalyst was removed by filtration and the solvent was evaporated 31 to give the title compound as a white solid.
32 lH NMR ~ 7.93 (t, J = 8.43 Hz, lH), 7.90 (b, lH), 33 7.73 (dd, J = 12.9, 2.0 Hz, lH), 7.29 (dd, J = 8.43, 34 1.96 Hz, lH), 7.23 (d, J = 2.14 Hz, lH), 7.01 (d, J

CA 0224l758 l998-06-26 1 = 2.2 Hz, lH), 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- r ( 2~,2~,4~,4~-tetramethyl-8~-~ 5 azidochroman-6'-yl)carbamoyl~benzoate (Compound 13 6 To a solution of ethyl 7 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-aminochroman 8 -6'-yl)carbamoyl~benzoate (Compound Nl, 32 mg, 0.077 ~ mmol) in 3 ml of EtOH was added 0.5 ml of trifluoroacetic acid (TFA) and 0.~ ml of 11 isoamylnitrite at 0~C. The reaction was stirred for 12 2 h when a solution of NaN3 (5 mg, ) in 0.2 ml of 13 water was added. The reaction mixture was allowed 14 to warm to room temperature and stirred for overnight. The solvent was removed and the residue 16 was purified by column chromatography ( silica gel, 17 ethyl acetate/ hexane 1/10) to give the title 18 compound as a colorless oil.
19 lH NMR ~ 8.0 (b, lH), 7.94 (t, J = 7.8 Hz, lH3, 7.73 (d, J = 12.1 Hz, lH), 7.64 (s, lH), 7.31 (dd, J =
21 8.5, 2.0 Hz, lH), 7.21 ~d, J = 2.0 Hz, lH), 4.37 (q, 22 J = 7.1 Hz, 2H), 1.90 (s, 2H), 1.39 (t, J = 7.1 Hz, 23 3H), 1.4~ (s, 6E~), 1.40 (s, 6H).
24 Methyl 2,6-Difluoro-4-~(2'~2',4',4'-tetramethyl-8'-trifluor 26 omethylchroman-6'-yl)carbamoYl~benzoate (Compound 27 15) 28 Using the same procedure as for ethyl 29 2-fluoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca rbamoyl]benzoate (Compound 7), but using 31 2,2,4,4-tetramethyl-8-trifluoromethylchromanoic acid 32 (Compound S, 11.2 mg, 0.037 mmol) and methyl 33 4-amino-2,6-difluorobenzoate (Compound Hl, 6.6 mg, 34 0.035 mmol), the title compound was obtained as 1 white crystals.
2 lH NMR ~ 8.21 (b, lH), 8.05 (s, lH3, 7.82 (s, lH), 3 7.36 (d, J = 10.20 Hz, lH), 3.93 (s, 3H), 1.92 (s, 4 2H), 1.40 (s, 12H).
Ethyl 2--Fluoro--4--r ( 2~, 2~, 4~, 6 4~-tetramethyl-8'-iodochroman-6'-yl)carbamoyllbenzoa 7 te (Compound 17) 8 Using the same procedure as for ethyl ~ 2-fluoro-4-t(4',4'-dimethyl-8'-bromochroman-6'-yl)ca rbamoyl]benzoate (Compound 7), but using 2,2,4,4-tetramethyl-8-iodochromanoic acid (Compound 12 X, 81 mg, 0.25 mmol) and ethyl 4-amino-2-~3 fluorobenzoate ((Compound Cl, 55 mg, 0.3û mmol), the 4 title compound was obtained as a white solid.
lH N~R ~ 8.05 (b, lH), 8.01 (d, J = 2.2 Hz, lH)~ 7.94 16 (t, J = 8.4 Hz, lH), 7.86 (d, J = 2.2 Hz, lH), 7.75 7 (dd, J = 12.88, 2.1 Hz, lH), 7.33 (dd, J = 8.8, 2.1 8 Hz, lH), 4.37 (q, J = 7.1 Hz, 2H), 1.89 (s, 2H), 19 1.42 (s, 6H), 1.38 (s, 6H). Ethyl 2-Fluoro-4- r ( 2~,2~,4~,4~,8~-pentamethylchroman-21 6'-yl)carbamoyl~benzoate (Compound 19) 22 Using the same procedure as for ethyl 23 2-fluoro-4-~(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 24 rbamoyl]benzoate (Compound 9), but using 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound 26 Al, 92 mg, 0.37 mmol) and ethyl 27 4-amino-2-fluorobenzoate (Compound Cl, 75 mg, 0.41 28 mmol), the title compound was obtained as a white 29 solid (100 mg).
lH NMR ~ 8.31 (b, lH), 7.90 (t, J = 8.24 Hz, lH), 31 7.76 (dd, J = 14.29, 1.7 Hz, lH), 7.74 (s, lH), 7.43 ~ (s, lH), 7.35 (dd, J = 8.67, 1.7 Hz, lH), 4.32 (q, J
33 = 7.1 Hz, 2H), 2.18 (s, 3H), 1.84 (s, 2H), 1.38 (t, 34 J = 7.1 Hz, 3H), 1.35 (s, 6H), 1.34 (s, 6H).

W O 97t24116 PCTrUS96/20511 1 Ethyl 2 4- r ( 5'~6',7',8'-tetrahydro-5',5',8',8~-tetramethyl-2 3 -naphthalenyl)thiocarbamoyllbenzoate (Compound 21) 4 To a solution of ethyl 6 4-[(5',6',7',8'-tetrahydro-5~,5~,8~, 6 8'--tetramethylnaphthalen-2-yl)carbamoyl]benzoate 7 (CQrt~ou~d I1, 61 mg, 0.16 mmol) in 2 ml of anhydrous 8 benzene was added Lawesson's reagent (45 mg, 0.112 mmol). The resulting yellow solution was refluxed 0 under N2 for 2 h. The solvent was removed and the residue was purified by column chromatography 2 (silica gel, ethyl acetate/hexane 1/5) to give the 3 title compound as a yellow solid ~55 mg, 87%).
H NMR ~ 9.04 (b, lH), 8.11 (d, J = 8.70 Hz, 2H), 7.85 (b, 2H), 7.75 (b, lH), 7.55 (dd, J = 8.2, 1.9 6 Hz, lH), 7.36 (d, J = 8.3 Hz, lH), 4.38 (q, J = 7.1 7 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J = 7.1 Hz, 3H), 8 1.30 (s, 12H).
19 Ethyl 2-Fluoro-4- r ( 5',6',7',8'-tetrahydro-5~ 5' 8',8'-tetramethylnaphthalen-2'-yl)thiocarbamoy 21 1] benzoate (Compound 23) 22 Using the same procedure as for the synthesis of 23 ethyl 4-[(5~,6~7~,8'-tetrahydro-5~5~r8~,8~-24 tetramethyl-2-naphthalenyl)thiocarbamoyl]benzoate (Compound 21) but using ethyl 26 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetr 27 amethylnaphthalen-2'-yl)carbamoyl]benzoate (Compound 28 1, 167 mg, 0.42 mmol) in 8 ml of benzene and 29 Lawensson's reagent (220 mg, 0.544 mmol), the title compound was obtained as a bright yellow solid 31 (127.S mg).
32 lH NMR ~ 9.30 (b, lH), 8.05 (b, lH), 7.95 (t, J =
33 8.37 Hz, lH), 7.77 (d, J = 1.89 Hz, lH), 7.53 (dd, J
34 = 8.24, 2.1 Hz, lH), 7.49 (b, lH), 7.35 (d, J = 8.24 CA 0224l758 l998-06-26 wo 97/24116 PCTrUS96/205 1 Hz, lH), 4.33 (q, J = 7.1 Hz, lH), 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 4 hthalen-2-yl carboxylic acid (Compound ~) 6 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
8 at -78~C under argon was added ~lowly 2. 86 ml of 9 t-BuLi (1. 7 M in hexane, 4.8 mmol). The reaction mixture was stirred at -78~C for 1 h. Then CO2 was 11 bubbled through the solution for 1 h. After removal 12 of COz stream, the reaction mixture was stirred for 13 an additional hour at -78~C. Then 10~ of HCl was 14 added. After warming up to room temperature, the 15 reaction mixture was left overnight then extracted 16 with ethyl acetate. The organic layer was washed 17 with brine and dried over Na2SO4. After 18 concentration, the residue was purified by column 1~ chromatography (ethyl acetate/hexane 1/3) to yield 20 the title compound as a white solid.
21 lH NMR d 7.85 (s, lH), 6.93 (s, lH), 1.68 (s, 4H), 22 1.28 ~s, 12H).
23 4-Bromo-3-hydroxy-5,5 8,8-tetramethyl-5 6,7 8-tetrah 24 ydronaphthalen-2-yl carboxylic acid (Compound M) 25 3-Hydroxy-5,5,8,8-tetramethyl-5,6l7,8-tetrahydro-26 naphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) 27 was dissolved in 1 ml of HOAc. To this solution was 28 added Br2 (0.033 ml, 0.62 mmol). The reaction 2~ mixture was left at room temperature for over night.
30 A stream of air was passed through the reaction 31 mixture to remove the unreacted Br2. The remaining 32 solid was dissolved in small amount of THF and 33 purified by column chromatography (ethyl 34 acetate/hexane 1/1) to yield the desired product as W O 97/24116 PCTrUS96/20~11 1 a cream colored solid.
2 lH NMR d 7.91 (s, lH), 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 6 -tetrahydronaphthalen-2-yl carboxylic acid (~ m~ound 6 N) 7 To a solution of 4-bromo-3-hydroxy-5,5,8,8-8 tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid ~ (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (O.764 ml, 4.2 mmol) 2 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 the residue was purified by column chromatography 6 (ethyl acetate/hexane 1/9) to yield the 17 methoxymethyl ester o~ the title compound as a white 18 solid (200 mg). This white solid was further 1~ dissolved in 20 ml of EtOH. An a~ueous solution of 20 NaOH ~0.5 ml, lM) was added. The reaction mixture 21 was stirred at room temperature for over night. The 22 EtOH was removed and the residue wa~ added 2 ml of 23 ethyl acetate and 3 ml of water. This mixture was 24 very slowly acidified with 10% HCl to PH = 7. The 2~ ethyl acetate layer was separated and washed with 26 brine, dried over Na2SO4. After filtration of the 27 drying agent and removal of solvent, the reaction 28 yielded the title compound as a white solid (155 2~ mg). lH NMR d 7.99 (s, lH), 5.20 (s, 2H), 3.66 (s, 30 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 31 (S, 6H).
32 Ethyl 2-fluoro-4- r ( 3~-methoxymethoxy-4~-bromo-33 5~,6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphth 34 alen-2'-yl~carbamoyl~benzoate (Compound Sl) CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 l To a solution of 4-bromo-3-methoxymethoxy-2 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-y 3 l acid (Compound N, 80 mg, 0.22 mmol) in 4 ml of 4 CH2Cl2 was added D~AP (60 mg, 0.26 mmol), ethyl 2-fluoro-4-aminobenzoate (Compound Cl, 43 mg, 0.24 6 mmol) and EDC (50 mg, 0.26 mmol). The re~ction 7 mixture was stirred at room temperature for 8 overnight and then concentrated to dryness. The 9 residue was purified by column chromatography (ethyl acetate/hexane 1/3) to yield the title compound as a clear oil (45 mg).
2 lH NMR d 9.92 (b, lH), 8.10 (s, lH), 7.94 (t, J = 8.4 13 Hz, lH), 7.81 (dd, J = 12.9; 1.9 Hz, lH), 7.35 (dd, 4 J = 8.5; 1.8 Hz, lH), 5.20 (s, 2H), 4.39 (q, J =
7.1 Hz, 2H)~ 3.61 (s~ 3H), 1.74 (m, 2H), 1.64 (m, 16 2H), 1.60 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 17 (S, 6H).
18 Methyl 19 2,6-Difluoro-4-l(3'-methoxymethoxy-4'-bromo-5',6',7' 20 , 8'-tetrahydro-5',5',8',8'-tetramethylnaphtha-21 len-2~-yl)carbamoyllbenzoate (Compound Ml) 22 Using the same procedure as for the synthesis of 2~ compound ethyl 2-fluoro-4-l(3'-methoxymethoxy-4'-24 bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl 25 naphthalen-2'-yl)carbamoyl]benzoate (Co~round Sl) but 26 using 4-bromo-3-methoxymethoxy-5,5,8,8-tetramethyl-27 5,6,7,8- tetrahydronaphthalen-2-yl acid (Compound N, 28 80 mg, 0.22 mmol), DMAP (60 mg, 0.26 mmol~, methyl 2~ 2,6-dii~luoro-4-aminobenzoate (r~ round Hl, 52 mg, 30 0.24 mmol) and EDC (50 mg, 0.26 mmol), the title 31 compound was obtained as a clear oil.
32 lH NMR d 10.01 (b, lH~, 8.11 (s, lH), 7.42 (d, J =
33 lO.O Hz, 2H), 5.2 (s, 2H), 3.95 ~s, 3H), 3.63 (s, 34 3H), 1.75 ~m, 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.35 W O 97/24116 PCT~US96/20511 1 (s~ 6H)-2 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A3) 3 To a mixture of 2,6-di-t-butyl-4-methylpyridine 4 (Aldrichr 2.0 g, 9.73 mmol) in 25 ml of dry CCl4 was added benzoyl peroxide (24 mg, 0.097 mmol) and NBS
6 (1.9 g, 10.7 mmol~. ~he reaction mixture was 7 refluxed for 16 hours. After it cooled to room 8 temperature, the solvent was removed ln vacuo and g the residue was purified by column chromatography (silica gel, hexane) to give an oil (1.957 g) which contained 82% of the desired product and 18% of the 2 starting material. lH NMR ~ 7.09 (s, 2H), 4.39 ~s, 2H), 1.35 (s, 18H).
4 4-Hydroxymethyl-2,6-di-t-butylpyridine (Comround B3) A heterogeneous solution of 6 4-bromo~nethyl-2,6-di-t-butylpyridine (Compound A3, 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.
1~ The solution spontaneously separated into two layers 20 as it cooled to room temperature. The upper layer 21 was separated and ethyl acetate was added. This 22 organic layer was then washed with brine, water and 23 dried over MgSO4. The desired product was purified 24 by column chromatography (ethyl acetate/hexane 1/9) 25 to give a white solid. lH NMR ~i 7.09 (s, 2H), 4.67 26 (d, J = 4.4 Hz, 2H), 2.3 (b, lH), 1.36 (s, 18H).
27 2,6-Di-t-l)utylisonicotinic acid ( Compound C3) 28 Jone's reagent was added dropwise to a solution of 29 4-hydroxymethyl-2,6-di-t-butylpyridine ( Compound B3, 30 302 mg, 1.37 mmol~ in 5 ml o~ acetone until the ~1 solution changed color from light yellow to orange 32 ( 55 drops of Jone's reagent were consumed). After 5 33 minutes 2 ml of isopropanol were added to the ~ reaction mixture, and a green precipitate of Cr3+

W O 97/24116 PCT~US96/20511 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 4 over MgSO4. After filtration, the solvent was 5 removed to give the desired product as a white solid 6 (227 mg). lH NMR ~ 7.71 (s, 2H), 1.34 (s, 18H).
7 2-Bromo-4 6-di-t-butylPhenol (Compound D3) 8 To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAc was added Br2 (0-5 0 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed 2 under reduced pressure and the residue was purified 3 by column chromatography (ethyl acetate/hexane 1/20) 4 to yield the desired product (2.54 g) as a white solid. lH NMR ~ 7.33 (d, J = 2.3 Hz, lH), 7.24 (d, J
16 = 2.3 Hz, lH), 1.41 (s, 9H), 1.29 (s, 9H).
17 O-Methoxymethyl-2-bromo-4,6-di-t-butylphenol (~o~round E3) 1~ To a ~olution of 2-bromo-4,6-di-t-butylphenol 20 (Compound D3 2.54 g, 8.88 mmol) and catalytic amount 21 of Bu4NI in 20 ml of dry CH2Cl2 at 0~C was added ~ 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.
25 The reaction mixture was then washed with 10% citric 26 acid, then NaHCO3 (sat.), brine, and dried over 27 MgSO~. After filtration and removal of the solvent 28 under reduced pressure, the residue was purified by 29 column chromatography (pure hexane) to yield the 30 title compound (2.79 g) as a colorless oil. 1H NMR
31 7.40 (d, J = 2.44 Hz, lH), 7.30 (d, J = 2.4 Hz, lH), 32 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 33 9H)-34 O-Methoxymethyl-3',5'-d~-t-butylsalicylic acid W O 97/24116 PCTnUS96/20511 1 (Co~r~und F3) 2 To a solution of O-methoxymethyl-2-bromo-4,6-3 di-t-butylphenol (Compound ~3, 2.79 g, 8.5 mmol) in 4 30 ml of dry THF at -78~C under Ar was added 11 ml ~ of t-Bu~i (1.7 M in hexane, 18.7 mmol). ~hi~
6 mixture was stirred at 78~C for 1 hour. Then C02 7 (g) was bubbled into the solution at -78~C for 1 8 hour. After removal of the C02 stream, the reaction ~ mixture was stirred for an additional hour at -78~C.
Then 1096 of HC1 was added and the mixture was 11 allowed to warm to room temperature and extracted 12 with ethyl acetate. The organic layer was washed 13 with brine and dried over Na2SO". After 14 concentration, the residue was purified by column chromatography (ethyl acetate/hexane 1/1) to yield 16 the title compound as a white solid (492 mg). lH NMR
17 ~ 7.75 (d, J = 2.81 Hz, lH), 7.60 (d, J = 2.8 Hz, ~8 lH), 5.07 (s, 2H), 3.62 (s, 3H), 1.33 (s, 9H), 1.26 19 (s, 9H).
20 Ethyl 2-fluoro-4-~(2'6'-di-t-butylpyrid-4~-21 yl ) carbamoyllbenzoate (Compound 41) 22 A solution of 2,6-di-t-butylisonicotinic acid 23 (Compound C3, 47.3 mg, 0.20 mmol) in 2 ml of SOCl2 24 was heated under reflux for 2 hours. Excess SOCl2 was removed in vacuo and the residue was dissolved 26 in 2 ml of dry CH2Cl2, and ethyl 27 2-fluoro-4-aminobenzoate (romround Cl, 40.2 mg, 0.22 28 mmol) and pyridine (0.0835 ml, 0.69 mmol) were 29 added. The reaction mixture was stirred at room 30 temperature for 12 hours. Solvent was removed and 31 the residue was purified by column chromatography 32 (ethyl acetate/hexane 1/9) to yield the title 33 compound (71.2 mg) as white crystals. lH NMR ~ 8.56 34 (b, lH), 7.91 (t, J = 8.36 Hz, lH~, 7.53 (dd, J =

CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 1 12.82, 2.0 Hz, lH), 7.39 (dd, J = 8.7, 2.0 Hz, lH), 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 bamoyllbenzoate ( Compound 43 ) 6 Using the same procedure as for the synthesis of 7 ethyl 2-fluoro-4-~(2'6'-di-t-butylpyrid-4~-8 yl)carbamoyl]benzoate (Compound 41) but using 9 2,6-di-t-butylisonicotinic acid (~o~round C3~ 101 mg, o 0.43 mmol) and ethyl 4-aminobenzoate (78 mg, 0.47 11 mmol), the title compound was obtained as a white 12 solid (135 mg). lH NMR ~ 8.43 (b, lH),, 8.02 (d, J =
13 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.48 (s, 2H), 14 4.33 (q, J = 7.1 Hz, 2H~, 1.38 (t, J = 7.1 Hz, 3H), 15 1.35 (s, 18H).
16 Ethyl 17 2-Fluoro-4-~3',5'-di-t-butylphenyl)carbamoyllbenzoa 18 te (Compound 45 t9 Using the same procedure as for the synthesis o~
20 ethyl 2-fluoro-4-t(2'6'-di-t-butylpyrid-4'-21 yl)carbamoyl]benzoate (Compound 41) but using 22 3,5-di-t-butylbenzoic acid (60 mg, 0.26 mmol, 23 available by literature procedure, see Kagechika et 24 al. J. Med Chem. 1988 31, 2182 - 2192) and ethyl 25 2-fluoro-4-aminobenzoate (Compound Cl, 51.5 mg, 0.28 26 mmol), the title compound was obtained as a white 27 solid (66 mg). lH NMR ~ 8.21 (b, lH), 7.93 (t, J =
28 8.3 Hz, lH), 7.79 (dd, J = 12.8, 2.0 Hz, lH), 7.67 29 (d, J = 1.8 Hz, 2H), 7.65 (t, J = 1.7 Hz, lH), 7.35 (dd, J = 8.7, 2.1 Hz, lH), 4.36 (q, J = 7.2 Hz, 2H), 31 1.39 (t, J = 7.2 Hz, 3H), 1.36 (s, 18H).
32 Ethyl 33 2-Fluoro-4- r ( 2'-methoxymethyl-3~,5'-di-t-butylphenyl ~ )carbamoyllbenzoate (Compound G3) W O 97/24116 PCT~US96/20511 1 To a mixture of O-methoxymethyl-3r,5/-di-t-2 butylsalicylic acid ~Compound F3, 150 mg, 0.~1 mmol), 3 4-dimethylaminopyridine (142 mg, 0.61 mmol) and 4 ethyl 2-fluoro-4-aminobenzoate (Compound Cl, 102 mg, O. 56 mmol) in 5 ml of dry CH2Cl2 was added 1-(3-di-6 methylaminopropyl)-3-ethylcarbodiimide hydrochloride , (117 mg, 0.61 mmol). The reaction mixture was 8 stirred at room temperature for 12 hours. Solvent ~ was evaporated in vacuo and the residue was dissolved in ethyl acetate, then washed with brine, 11 water and dried over MgSO4. After filtration, 12 solvent was removed and the residue was purified by 3 column chromatography (ethyl acetate/hexane 1/3) to 14 give the title compound (58 mg). lH NMR ~ 8.97 (b, 16 lH), 7.94 (t, J = 8.37 Hz, lH~, 7.78 (d, J = 2.7 Hz, 16 lH), 7.61 (d, J = 13.0 Hz, lH), 7.56 (d, J = 2.~ Hz, 17 lH~, 7.35 (d, J = 8.7 Hz, lH), 5.00 (s, 2H), 3.53 8 (s, 3H), 4.38 (q, J = 7.1 Hz, 2H), 1.47 (s, 9H), 1~ 1.39 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H).
20 Ethyl 21 2-Fluoro-4- r ( 2~-hydroxy-3~,5~-di-t-butylphenyl)carba 22 moyllbenzoate (Compound 47) 23 TO a solution of ethyl 2-fluoro-4--[(2'-24 methoxymethyl-3',5'-di-t-butylphenyl)carbamoyl]benzo 25 ate (Compound G3, 34 mg, 0.07 mmol) in 1 ml of THF
26 were added 10 drops of HOAc. The reaction mixture 27 was heated to reflux for 12 hours. Solvent was 28 removed and ethyl acetate was added. The solution 23 was washed with NaCHO3 (sat.), brine, water and dried 30 over MgSO4. Solvent was rer.Lo~,ed ln vacuo to give an 31 oil. The oil was allowed to be exposed to the 32 atmosphere for 12 hours during which time crystals 33 formed. The crystals were collected and washed 34 several times with hexane to afford the title W O 97/24116 PCTrUS96/20511 1 compound as a white solid (13.5 mg). lH NMR ~ 10.73 2 (S, lH), 7~98 (d, J = 2.56 Hz, lH), 7.88 (b, lH), 3 7.75 (t, J = 8.26 Hz, lH), 7.60 (d, J = 2.44 Hz, 4 lH), 7.32 (dd, J = 12.3, 2.0 Hz, lH), 7.02 ~dd, J =
8.6, 2.0 Hz, lH), 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-~(2',6'-di-t-butylpyrid-4'yl)carbamoy 8 11 benzoic Acid (rQ~r~und 50) 9 To 2,6-di-t-butylisonicotinic acid (Compound C~3, o 20 mg, 0.085 mmol) was added 1 ml of SOCl2. The mixture was heated under reflux for 2 hours. After 2 cooling to room temperature, excess SOCl2 was removed ~3 and the residue was dissolved in 2 ml of CE~2Cl2. To 14 this solution was added methyl 2,6-difluoro-4-amino-16 benzoate (Compound ~ 16 mg, 0.085 mmol~ and 6 triethylamine (O.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 19 purified by column chromatography with ethyl ~o acetate/hexane (1/10) to yield the methyl ester of 21 the title compound. This was saponified according 22 to the general procedure (see below) to give the 23 title compound as a colorless solid. lH NMR ~ 7.44 24 (s, 2H), 7.40 (d, J = 11.8 Hz, 2H) 1.37 (s, 18H).
25 2,6-Difluoro-4- r ( 3~,5~-di-t-butylphenyl)car-bamoyl]b 26 enzoic Acid (Compound 52 ) 27 U~ing the same procedure as Eor the preparation 28 of 2,6-difluoro-4-~(2',6'-di- -butylpyrid-29 4'yl)carbamoyl]benzoic acid (Compouna 50) but using 30 3,5-di-t-butylbenzoic acid (37 mg, 0.16 mmol) and 31 methyl 2,6-difluoro-4-aminobenzoate ( Compound Hl, 29 32 mg, 0.16 mmol), the title compound was obtained as 33 colorless crystals. 1H NMR ~ 7.92 (b, lH) 7.60 (m, 34 3H), 7.42 (d, J = 10.0 Hz, 2H), 1.38 (s, 18H).

W O 97/24116 PCT~US96/Z0511 1 2-Nitro-4- r ( 2~,6~-di-t-butylpyrid-4~-yl)carbamoyl~be 2 nzoic Acid (r~mround 54) 3 Using the same procedure as for the preparation 4 o:~ 2,6-difluoro-4-[(2~,6'-di-t--butylpyrid-4'yl)carbamoyl~benzoic acid (Compound 50) but using 6 2,6-di-_-butylisonicotinic acid (40 mg, 0.17 mmol) 7 and methyl 2-nitro-4-aminobenzoate (Compound Fl, 33 8 mg, 0.17 mmol), the title compound was obtained as a 9 light yellow oil. lH N~R ~ ~acetone-d6) 10.25 (b, 10 lH), 8.32 (s, lH~, 7.97 (d, J = 8.1 Hz, lH), 7.93 11 (b, lH), 7.70 (s, 2H), 1.36 (s, 18H).
12 Methyl 2-nitro-4-[(4'-bromo-5',6',7',8~-tetrahydro-13 5 r ~ 5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl~be 14 nzoate (Compound 25) Using the same procedure as for the synthesis of 16 ~mr~und 1, but using Compound F and Compound F" the 17 desired product was obtained as a white solid.
18 lH NMR ~ 9.24 (b, lH), 9.23 (d, J = 1.8 Hz, lH), 7.92 19 (dd, J = 8.4, 2.4, Hz, lH), 7.87 (d, J = 2.1 Hz, lH), 7.84 (d, 3 = 2.1 Hz, lH), 7.80 (d, J = 8.7 Hz, 21 lH), 3.91 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.58 22 (S, 3H), 1.33 (s, 3H).
23 General procedure for the syntheses of benzoic 24 acid derivatives by hydrolyzing the corresponding methyl or ethyl esters.
26 To a solution of ester (3.0 mmol) in 20 ml of 27 EtOH was added 5 ml of 1 N NaOH in water. The 28 reaction mixture was stirred at room temperature for 2~ overnight and neutralized with 10% HCl to PH=5. The alcohol was removed by evaporation and the aqueous 31 layer was extracted with ethyl acetate (3xlOml).
32 The combined ethyl acetate layers were washed with 33 NaHCO3 (sat.), brine and dried over MgSO4. After 34 concentration, the desired acid was obtained which CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20511 ~00 1 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 6 ( Compound 2) 6 lH NMR ~ (acetone-D6) 9.86 (b, lH), 7.95 (m, 3H), 7 7.75 (dd, J = 7.9, 2.2 Hz, lH), 7.62 (dd, J = 8.5, 8 1.~ Hz, lH), 7.50 (d, J = 8.3 Hz, lH), 1.73 (s, 4H), 9 1.32 (s, 6H), 1.30 (sr 6H).
10 2-Fluoro-4- r ( 4'-bromo-5', 6~, 7',8'-tetrahydro-5',5~,8 ~,8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic Acid (Compound 4) H NMR ~ (acetone-D6) 9.97 (b, lH), 8.04 (d, J = 1.89 Hz, lH), 8.01 (d, J = 1.90 Hz, lH), 7.95 (t, J =
8.55 Hz, lH), 7.90 (dd, J = 12.28, 2.0 Hz, lH), 7.59 (dd, J = 8.67, 1.50 Hz, lH), 1.76 (m, 4H), 1.58 (s, 6H), 1.35 (s, 6H)-2-Fluoro-4- r ( 3~-hydroxy-5~,6~,7~,8~-tetrahYdro-5~, 5~
19 , 8',8'-tetramethylnaphthalen-2'-yl)carbamoyllbenzoic Acid (Compound 6) 21 lH NMR (acetone-D6) ~ 11.3 (b, lH), 10.2 (b, lH), 22 7.94 (m. 2H)I 7.85 (dd, J = 11.4, 1.95 Hz, lH), 7.53 23 (dd, J = 6.59, 2.08 Hz, lH), 6.94 (s, lH), 2.85 (b, 24 lH), 1.70 (s, 4H), 1.29 (s, 6H), 1.28 (s, 12H).
25 2-Fluoro-4- r ( 8'-bromo-4',4'-dimethylchroman-6~-yl)ca 26 rbamoyllbenzoic Acid (Compound 8) 27 lH NMR (acetone-d6) ~ 9.87 (b, lH), 8.04 (d, J = 2.1 28 Hz, lH), 8.03 (d, J = 2.1 Hz, lH), 7.94 (t, J = 8.66 29 Hz, lH), 7.91 (dd, J = 13.8, 2.0 Hz, lH), 7.57 (dd, 30 J = 8.6, 2.0 Hz, lH), 4.37 (t, J = 5.44 Hz, 2H), S1 1.92 (t, J = 5.44 Hz, 2H), 1.40 (s, 6H).
32 2-Fluoro-4-l(2',2',4',4'-tetramethyl-8'-bromochroman 33 - 6'-yl)carbamoyl~benzoic Acid (Compound lO) 34 lH NMR ~ (acetone-d6) 9.87 tb, lH), 8.06 (d, J = 2.2 CA 0224l758 l998-06-26 W O 97/24116 PCT~US96/20511 1 Hz, lH), 8.04 (d, J = 2.1 Hz, lH), 7.94 (t, J = 8.54 2 Hz, lH), 7.91 (dd, J = 14.0, 2.0 Hz, lH), 7.59 (dd, 3 J = 8.5, 2.3 Hz, lH), 1.96 (s, 2H), 1.42 (s, 6H), 4 1.41 (s, 6H).
2-Fluoro-4- r ( 2',2',4',4'-tetramethyl-8'-trifluoro-6 methylchroman-6~-Yl)carbamoyll benzoic Acid 7 (Compound 12) 8 lH NMR (acetone-d6) ~ 10.02 (b, lH), 8.31 (s, lH), 9 8.09 (s, lH), 7.92 (m, 2H), 7.56 (d, J = 7.69 Hz, 10 lH), 2.00 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).
2-Fluoro-4- r ( 2~ 2~ 4~ 4~-tetramethyl-8~-azidochroman 2 - 6'-yl ? carbamoyllbenzoic Acid (Compound 14) 13 lH NMR ~ 8.03 (t, J -- 8.4 Hz, lH), 7.87 (b, lH), 7.79 14 (dd, J = 13, 2.0 Hz, lH), 7.64 (d, J = 2.2 Hz, lH), 7.32 (dd, J ~ 8.66, 1.9 Hz, lH), 7.22 (d, J = 2.1 16 Hz, lH), 1.91 (s, 2H), 1.45 (s, 6H), 1.41 (s, 6H).
17 2, 6-Difluoro-4- r ( 2',2',4',4'-tetramethyl-8'-8 trifluoromethylchroman-6'-yl)carbamoyl~benzoic acid 1~ (Compound 16) 20 lH NMR (acetone-d6~ ~5 8.30 (d, J = 2.3 Hz, lH), 8.06 21 (d, J = 2.2 Hz, lH), 7.59 (d, J = 10.32 Hz, 2H), 22 1.954 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).
2~ 2-Fluoro-4- r ( 2~,2~,4~,4~-tetramethyl-8~-iodochroman-24 6'-yl)carbamoyllbenzoic Acid (Compound 18) 25 lH NMR ~ (acetone-d6) 10.0 (b, lH), 8.24 (s, lH), 26 8.07 (s, lH), 7.94 (m, 2H), 7.57 (d, J = 8.67 Hz, 27 lH), 1.95 (s, 2H), 1.41 (s, 12H).
28 2-Fluoro-4-[(2' 2' 4' 4' 8'-pentamethylchroman-6'-yl 2~ ) carbamoyl~benzoic Acid (Compound 20) lH NMR
30 (acetone-d6) 9.77 (b, lH), 7.90 (m, 3H), 7.65 (d, J =
31 2.0 Hz, lH), 7.56 (dd, J = 8.61, 2.0 Hz, lH), 2.19 32 (S, 3H), 1.90 (s, 2H), 1.38 (s, 6H), 1.37 (s, 6H).
33 4- r ( 5~,6',7~,8'-tetrahydro-5',5',8~,8'-tetramethylna 34 phthalen-2'-yl)thiocarbamoyllbenzoic Acid (Compound 1 22) 2 lH NMR ~ 9.08 (b, lH), 8 .17 (d, J = 8.61, 2H), 7.95 3 (b, 2H), 7.77 (b, lH), 7.57 (dd, J = 8.1, 2.1 Hz, 4 lH), 7.37 (d, J = 8.2 Hz, lH), 1.72 (s, 4H), 1.32 (s, 6H), 1.31 (s, 6H).
6 2-Fluoro-4- r ~ 5~,6~, 7~, 8~-tetrahydro-5~,5~,8~,8~-tetr 7 amethylnaphthalen-2'-yl~thiocarbamoyllbenzoic Acid 8 (Compound 24) ~ lH NMR ~ (acetone-d6) 11.1 (b, lH), 8.27 (b, J = 13.2 Hz, lH), 8.02 (t, J = 8.3 Hz, lH), 7.89 ~s, lH), 11 7.86 (d, J = 10.0 Hz, lH), 7.62 (d, J = 8.3 Hz, lH), 12 7.41 (d, J = 8.37 Hz, lH), 1.72 (s, 4H), 1.30 (s, 13 12H).
2-Fluoro-4- r ( 3'-hydroxy-4'-bromo-5',6',7' 8'-tetrahy dro-5' 5' 8' 8'-tetramethylnaphthalen-2'-16 yl) carbamoyl~benzoic Acid (Compound 30) 17 A solution of ethyl 2-fluoro-4-[(3~-18 methoxymet-hoxy-4'-bromo-5',6',7',8'-tetrahydro-5',5 19 ', 8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoa te (Compound Sl, 45 mg, 0.084 mmol) in 1 ml of EtOH
21 was added 1 ml of a~ueous solution of NaOH (lM).
22 The reaction mixture was stirred at room temperature 23 for overnight and acidified to PH = 1 with 10% HCl.
24 EtOH was removed and ethyl acetate and more water were added to the solution. The organic layer was 26 separated and washed with NaHCO3, brine and dried 27 over MgSO4. After filtration and concentration, the 28 reaction yielded 2-fluoro-4-[(3'-methoxymethoxy-29 4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramet hylnaphthalen-2'-yl)carbamoyl]benzoic acid as a 31 white solid. The methoxymethyl group was removed by 32 dissolving the white solid in ~ ml of MeOH and 3 ~3 drops of HCl (con.). After stirring for overnight, 34 the reaction mixture was concentrated to dryness.

CA 0224l758 l998-06-26 W O 97/24116 PCTrUS96/20Sll 1 The residue was partitioned between ethyl acetate 2 and water. The organic layer was separated, washed 3 with NaHCO3, brine and dried over MgSO4. After 4 filtration and concentration, the residual solid was purified in a mini (pipette) column with ethyl 6 aaetate /hexane (1/1) to give the title compound as 7 a white solid (5.0 mg).
8 lH NMR d (acetone-d6) 10.19 (b, lH), 8.01 (s, 1~), 9 7.96 (t, J = 8.6 Hz, lH), 7.76 (dd, J = 11.2; 2.0 10 Hz, lH), 7-54 (dd, J = 8.8; 2.0 Hz, lH), 1.75 (m, 1l 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.32 (s, 6H).
12 2,6-Difluoro-4- r ( 3'-hydroxy-4'-bromo-5~,6~,7~,8~-tet 13 rahydro-5', 5',8',8'-tetramethylnaphthalen-2'-14 yl) carbamoyllbenzoic Acid (Compound 32) Using the same procedure as for the synthesis of 16 2-f luoro-4-l(3'-hydroxy 4'-bromo-5',6',7',8'-tetrahy t7 -dro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamo 18 yl] benzoic acid (C!ompound 30) the title compound was 19 obtained as a white solid.
20 l~I NMR d(acetone-d6) 10.23 (b, lH), 8.01 (s, lH), 21 7.52 (d, J = 10.2 Hz, 2H), 4.8 (b, lH), 1.75 (m, 22 2H), 1.65 (m, 2H), 1.60 ~s, 6H), 1.31 (s, 6H).
23 2,6-Difluoro-4- r ( 5',6',7',8'-tetrahydro-5~,5~,8~,8~-24 tetramethylnaphthalen-2'-yl)carbamoyl]benzoic Acid 25 ( Compound 34) 26 To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-27 2-naphthoic acid (43 mg r 0-l9 mmol) was added 1 ml 28 of thionyl chloride. This mixture was refluxed for 2~ 2 h. Excess thionyl chloride was removed under 30 reduced pressure and the residue was dissolved in 2 31 ml of CH2Cl2. To this solution was added methyl ~ 4-amino-2,6-difluorobenzoate (Compound ~1~ 7 mg, 0.2 33 mmol) followed by 0.5 ml of pyridine. The reaction ~ mixture was stirred at room temperature for 4 h and W O 97/24116 PCTrU~6/20511 tO4 1 was concentrated under reduced pressure. The 2 residue was purified by column chromatography (ethyl 3 acetate/hexane l/S) to give the methyl ester of the 4 desired product as a colorless oil.
5 lH NMR d 8.11 (d, J = 1.9 Hz, lH), 8.05 (b, lH), 7.86 6 (dd, J = 6.2, 2.2 Hz, lH), 7.41 (m, 3H), 3.93 (s, 7 3H), 1.69 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H). This 8 colorless oil was hydrolyzed to the desired product o with NaOH/H2O/EtOH according to the general o procedure.
H NMR d (acetone-d6) 9.74 (b, lH), 7.95 (s, lH), ~2 7.70 (d, J = 6.8 Hz, lH), 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 5 , 8',-tetramethylnaphthalen-2'-yl)carbamoyllbenzoic 6 acid ( rO ~l-O~a 26 ) 7 lH NMR ~ (acetone-d6): 10.16 (b, lH), 8.42 (d, J =
8 2.0 Hz, lH), 8.09 (dd, J = 8.6; 2.1 Hz, lH), 8.06 1~ (d, J = 2.2 Hz, lH), 8.04 (d, J = 2.2 Hz, lH), 7.93 (d, J = 8.6 Hz, lH), 1.75 (m, 2H), 1.65 (m, 2H), 21 1.57 (s, 3H), 1.34 (s, 3H).
22 2-Fluoro-4- r ( 2~,6~-di-t-butylpyrid-4~-yl)carbamoyl~b 23 enzoic Acid (Compound 42) 24 lH NMR ~ (CD30D) 7.92 (t, J = 8.36 Hz, lH), 7.82 (dd, J = 12.82, 2.0 Hz, lH), 7.63 (s, 2H), 7.55 (dd, 26 J = 8.7, 2.1 Hz, lH), 1.39 (s, 18H).
27 4- r ~ 2',6'-Di-t-butylpyrid-4'-yl)carbamoyllbenzoic 28 acid (Compound 44) 2~ lH NMR ~ (CD30D) 8.02 (d, J = 8.85 Hz, 2H), 7.85 (d, J = 8.85 Hz, 2H), 7.63 (~, 2H), 1.40 (s, 18H).
31 2 -F luoro-4- r ( 3~,5~-di-t-butyl)phenylcarbamoyllbenzoi 32 C acid (Compound 46) 33 lH NMR ~ (CD30D) 7.92 (t, J = 8.3 Hz, lH), 7.80 34 (dd, J = 12.8, 2.0 Hz, lH), 7.79 (d, J = 1.8 Hz, W O 97/24116 PCTAUS96/20Sll 1 2H), 7.69 (t, J = 1.7 Hz, lH), 7.57 (dd, J = 8.7, 2 2.1 Hz, lH), 1.37 (s, 18H).
3 2-Fluoro-4- r ( 2~-hydroxy 3~,5~-di-t-butyl)phenylcarba 4 moyllbenzoic acid (Compound 48) H NMR ~ (acetone-d6) 12.3 (b, lH), 10.07 (b, 6 lH), 7.98 (t, J = 8.48 Hz, lH), 7.80 (m, 2H), 7.58 7 (d, J = 2.3 Hz, lH), 7.56 (dd, J 5 8.8, 2.0 Hz, lH), 8 1.44 (s, 9H), 1.31 (s, 9H).

Claims (27)

WHAT IS CLAIMED IS:
1. A process of administering to a mammal a retinoid campound which binds specifically or selectively to a RAR.alpha. retinoid receptors in preference over RAR.beta. and RAR.GAMMA. retinoid receptors, for the purpose of treating or preventing a disease or condition which is responsive to treatment by RAR.alpha.
specific or selective retinoid agonists.
2. A process in accordance with Claim 1 where the RAR.alpha. specific or selective retinoid compound binds approximately 500 times stronger to RAR.alpha.
retinoid receptors than to RAR.beta. and RAR.GAMMA. retinoid receptors.
3. A process in accordance with Claim 1 where the RAR.alpha. specific or selective retinoid compound is administered to a mammal for the treatment or prevention of 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).
4. A process in accordance with Claim 3 where the RAR.alpha. specific or selective retinoid compound is administered in a dose of approximately 0.5 to 5 mg per kg body weight per day.
5. A process in accordance with Claim 1 where the RAR.alpha. specific or selective retinoid compound is administered to a mammal for the treatment or prevention of the disease or condition selected from actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, topical microbial 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.alpha. specific or selective retnoid compound has the formula (i) or the formula (ii) where X1 is O or X1 is [C(R1)2]n where n is an integer between 0 and 2;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
R3 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;
X2 i s 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 R2 groups;
W1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH, with the provisos that:
(i) when the compound is in accordance with formula (i) and Z is O then the sum of p and r is at least 1 and W1 is not a fluoro group in the 3 position of a tetrahydronaphthalene ring;
(ii) when the compound is in accordance with formula (i) and r is zero and p is 1 and W1 is OH
then the OH group is positioned a to the L group;
W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
W3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-6 alkyl, NO2, and OH with the proviso that when the compound is in accordance with Formula 2 and X2 is CH and r is 0 then p is not 0 and at least one W3 group is not alkyl;

L is -(C=Z)-NH- or -NH-(C=Z)- Z is O or S, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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 R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
7. A process in accordance with Claim 6 where the RAR.alpha. 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.alpha. specific or selective retinoid compound X1 is [C(R1)2]n and n is 1.
9. A process in accordance with Claim 8 where in the formula of the RAR.alpha. specific or selective retinoid compound Y is phenyl.
10. A process in accordance with Claim 6 where the RAR.alpha. 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.alpha. 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.alpha. retinoid receptors in preference over RAR.beta. and RAR.GAMMA. retinoid receptors, for the purpose of treating or preventing a disease or condition which is responsive to treatment by RAR.alpha.
specific or selective retinoid agonists, the retinoid compound being specific or selective for RAR.alpha. retinoid receptors in preference over RAR.beta. and RAR.GAMMA. retinoid receptors when in a binding assay the Kd value of binding to RAR.alpha. receptors is approximately 500 times smaller than the Kd value for binding to RAR.beta. and RAR.GAMMA. retinoid receptors.
13. A process in accordance with Claim 12 where the RAR.alpha. specific or selective retinoid compound is administered to a mammal for the treatment or prevention of the disease or condition selected from actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, topical microbial 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 ammune system, and wound healing.
14. A process in accordance with Claim 13 where the RAR.alpha. specific or selective retinoid compound is administered to a mammal for the treatment or prevention of 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).
15. A process in accordance with Claim 13 where the RAR.alpha. specific or selective retinoid compound has the formula (i) or the formula (ii) where X1 is O or X1 is [C(R1)2]n where n is an integer between 0 and 2;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
R3 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;
X2 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 R2 groups;
W1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH, with the provisos that:
(i) when the compound is in accordance with formula (i) and Z is O then the sum of p and r is at least 1 and W1 is not a fluoro group in the 3 position of a tetrahydronaphthalene ring;
(ii) when the compound is in accordance with formula (i) and r is zero and p is 1 and W1 is OH
then the OH group is positioned .alpha. to the L group;
W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
W3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-6 alkyl, NO2, and OH with the proviso that when the compound is in accordance with Formula 2 and X2 is CH and r is 0 then p is not 0 and at least one W3 group is not alkyl;
L is -(C=Z)-NH- or -NH-(C=Z)-Z is O or S, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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 R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
16. A process in accordance with Claim 15 where the RAR.alpha. specific or selective retinoid compound is in accordance with formula (i).
17. A process in accordance with Claim 15 where the formula the RAR.alpha. 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.alpha. retinoid receptors in preference over RAR.beta. and RAR.GAMMA. 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.alpha. retinoid receptors in preference over RAR.beta. and RAR.GAMMA. retinoid receptors when in a binding assay the Kd value of binding to RAR.alpha.
receptors is approximately 500 times smaller than the Kd value for binding to RAR.beta. and RAR.GAMMA. retinoid receptors, the retinoid compound having the formula (i) or the formula (ii) where X1 is O or X1 is [C(R1)2]n where n is an integer between 0 and 2;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
R3 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;
X2 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 R2 groups;
W1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH, with the provisos that:
(i) when the compound is in accordance with formula (i) and Z is O then the sum of p and r is at least 1 and W1 is not a fluoro group in the 3 position of a tetrahydronaphthalene ring;
(ii) when the compound is in accordance with formula (ii) and r is zero and p is 1 and W1 is OH
then the OH group is positioned .alpha. to the L group;
W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
W3 is a substituent selected independently from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-6 alkyl, NO2, and OH with the proviso that when the compound is in accordance with Formula 2 and X2 is CH and r is 0 then p is not 0 and at least one W3 group is not alkyl;
L is -(C=Z)-NH- or -NH-(C=Z)-Z is O or S, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR(OR12)2, CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 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 R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
19. A process in accordance with Claim 18 where the RAR.alpha. specific or selective retinoid compound is in accordance with formula (i), and Y is phenyl.
20. A process in accordance with Claim 19 where the RAR.alpha. specific or selective retinoid compound is selected from the group consisting of:
ethyl 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be nzoate;
2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be nzoic acid;
ethyl 2-fluoro-4-[(5',6',7',8'-tetrahydro-4'-bromo-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbam oyl]benzoate;
2-fluoro-4-[(4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be nzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromochroman -6'-yl)carbamoyl]benzoate;

2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromochroman - 6'-yl)carbamoyl]benzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'-yl)carbamoyl] benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoro-methylchroman-6'-yl)carbamoyl] benzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azidochroman-6'-yl)carbamoyl]benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azidochroman- 6'-yl)carbamoyl]benzoic acid;
ethyl 2-fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-iodochroman-6'-yl)carbamoyl]benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochroman-6'-yl)carbamoyl]benzoic acid;

ethyl 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-naphthalenyl)thiocarbamoyl]benzoate, and 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)thiocarbamoyl]benzoic acid.
21. A process in accordance with Claim 18 where the RAR.alpha. specific or selective retinoid compound is in accordance with formula (ii), and Y is phenyl.
22. A process in accordance with Claim 19 where the RAR.alpha. specific or selective retinoid compound is:
ethyl 2-fluoro-4-[(2'6'-di-tert-butylpyrid-4'-yl)carbamoyl]benzoate, or 2-fluoro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic acid.
23. (ADDED) A process of administering to a mammal an effective amount of a retinoid compound which binds specifically or selectively to RAR.alpha., retinoid receptors in preference over RAR.beta. and RAR.gamma. retinoid receptors, for the purpose of treating or preventing a malignant tumor or leukemic disease or condition which is responsive to treatment by RAR.alpha. specific or selective retinoid agonists, where the RAR.alpha. specific or selective retinoid compound has the formula where R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
R3 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;
Y is phenyl or naphthyl 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 R2 groups;
W1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, N3 and OH, with the provisos that:
when Z is O then the sum of p and r is at least 1, and when Z is O and the sum of p, r is 1 and Y is phenyl then W1 is not a Cl group in the 8 position of the chroman ring;
W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
L is -(C=Z)-NH- or -NH-(C=Z)-;
Z is O or S, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, where R8 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 R8 is phenyl or lower alkylphenyl.
24. (ADDED) A process of Claim 23 where Y is phenyl or naphthyl.
25. (ADDED). A process in accordance with Claim 24 where the RAR.alpha., specific or selective retinoid compound is selected from the group consisting of:
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromochroman-6'-yl)-carbamoyl]benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromochroman-6'-yl)carbamoyl]benzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'- yl)carbamoyl]- benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'-yl)carbamoyl] benzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azidochroman-6'-yl)carbamoyl]benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azidochroman-6'-yl)carbamoyl]benzoic acid;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochroman-6'-yl)carbamoyl]benzoate;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochroman-6'-yl)carbamoyl]benzoic acid.
26. (ADDED) A process of administering to a mammal an effective amount of a retinoid compound which binds specifically or selectively to a RAR.alpha. retinoid receptors in preference over RAR.beta. and RAR.gamma. retinoid receptors, for the purpose of treating or preventing a malignant tumor or leukemic disease or condition, the retinoid compound being specific or selective for RAR.alpha. retinoid receptors in preference over RAR.alpha. and RAR.gamma. retinoid receptors when in a binding assay the Kd value of binding to RAR.alpha. receptors is approximately 500 times smaller than the Kd value for binding to RAR.beta. and RAR.gamma. retinoidreceptors, the retinoid compound having the formula where R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently hydrogen, or lower alkyl of 1 to 6 carbons;
R3 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;
Y is phenyl or naphthyl 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 R2 groups;
W1 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2 N3 and OH, with the provisos that:
when Z is O then the sum of p and r is at least 1, and when Z is O and the sum of p, r is 1 and Y is phenyl then W1 is not a Cl group in the 8 position of a chroman ring;
W2 is a substituent selected independently from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, and OH;
L is -(C=Z)-NH- or -NH-(C=Z)-;
Z is O or S, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, where R8 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 R8 is phenyl or lower alkylphenyl.
27. (ADDED) A process of Claim 26 where Y is phenyl or naphthyl.
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