Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/14—All rings being cycloaliphatic
  • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
  • C07C2602/28—Hydrogenated naphthalenes

Definitions

• the present invention relates to compounds that have the property of reducing serum glucose and serum triglyceride levels in diabetic mammals without the undesirable properties of reducing serum thyroxine levels and transiently raising triglyceride levels. More particularly, the present invention relations to 7-[(7- alkoxy)-chrom-3-en-6-yl]-heptatrienoic acid and 7-[(3-alkoxy)-5,6-
• RAR ⁇ 25 in the RAR family the subtypes are designated RAR ⁇ , RAR ⁇ and RAR ⁇
• the subtypes are: RXR ⁇ , RXRp and RXR ⁇ . It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes.
• a disadvantage of the prior art retinoid compounds that reduce serum glucose levels is that their administration usually also results in the pharmacologically undesirable reduction of serum thyroxine levels and a transient increase in serum triglyceride levels.
• the present invention is directed to novel compounds that do not have one or both of these undesirable side effects.
• SUMMARY OF THE INVENTION The present invention generally relates to compounds of Formula 1
• A is independently an alkyl group of 1 to 6 carbons, halogen, or alkoxy of 1 to 6 carbons;
• m is an integer having the values of 0 to 3;
• W is H, alkyl of 1 to 8 carbons or phenyl;
• E is independently an alkyl group of 1 to 6 carbons, halogen, or alkoxy of 1 to 6 carbons;
• n is an integer having the values of 0 to 2;
• Z is an alkyl group of 1 to 8 carbons;
• G is H or an alkyl group of 1 to 8 carbons;
• J is independently H, halogen, or alkyl of 1 to 6 carbons;
• Y is O, or [C(R 3 ) 2 ] 0 where R 3 independently is H or alkyl of 1 to 6 carbons and o is an integer having the value of zero (0) or one (1), and R4 is H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5
• the present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of diabetic mammals with pharmaceutical compositions containing one or more compounds of Formula 1 to reduce serum glucose levels in said mammals.
• the present invention also relates to the methods of using the compounds of the invention to treat diseases and conditions which are responsive to treatment by retinoids.
• alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl.
• a pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality.
• a pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
• Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium.
• Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
• the compounds of the present invention include olephinic double bonds about which trans and cis (E and Z) stereoisomerism can exist. All orientations with regard to the olephinic bonds are within the scope of the invention, as is indicated by wavy lines in Formula 1. Nevertheless specific examples of the compounds of the present invention have the specific orientations of substituents relative to the double bonds as is indicated in the name of the respective compound, and/or by specific showing in the structural formula of the orientation of the substituents relative to the respective double bonds.
• the compounds of the present invention may also contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
• the scope of the invention is intended to cover all possible orientations of the substituents relative to the chiral center or centers, thus including pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers.
• the compound of the invention can be obtained as shown in Reaction Schemes 1 and
• Reaction Scheme 1 (continued) In accordance with Reaction Scheme 1 a chroman, tetrahydrohydronaphthalene or indane derivative of Formula 2 is reacted with a Grignard reagent of the formula WMgBr, preferably in the presence of cerium (III) chloride (CeCls), and thereafter with acid to form a chromene, dihydronaphthalene or indene derivative of Formula 3.
• the variables A, Y, E, m, n and W are defined as in Formula 1 with the exception that in this scheme W is not H.
• the starting compounds of Formula 2 are either available in accordance with the chemical scientific or patent literature, or by such modifications of these literature procedures which are well within the skill of the practicing organic chemist.
• the bromo substituted chromene or dihydronaphthalene derivative of Formula 3 is then reacted with tributyl(l-ethoxyvinyl)tin in the presence of dichlorobis(triphenylphosphine)palladium(II) and thereafter with acid to introduce an acetyl group in place of the bromo group and obtain a chromene or dihydronaphthalene derivative of Formula 4.
• Treatment of the compound of Formula 4 with boron tribromide removes the methyl group from the 7- ⁇ osition of the chromene, or from the 3 position of the dihydronaphthalene compound, as applicable, and provides a free hydroxyl function in its place.
• Treatment of this hydroxyl compound with an alkyl iodide (or other halide) of the formula Zl introduces the alkyl group Z (defined as in connection with Formula 1) into the molecule and provides the 7-alkoxy-chromene or 3-alkoxy-dihydronaphthalene derivative, as applicable, of Formula 5.
• alkyl halide Zl other types of alkylating agents can also be used to introduce the alkyl group Z.
• the compound of Formula 5 is then subjected to a.
• the Homer - Emmons reaction is conducted in the presence of strong base, such as lithium di-t ' r ⁇ -propylamide (LDA) as is indicated in the scheme, or n-butyllithium, in the presence of an inert solvent, such as tetrahydrofuran (THF) as indicated in the scheme, or in hexane.
• strong base such as lithium di-t ' r ⁇ -propylamide (LDA) as is indicated in the scheme, or n-butyllithium
• an inert solvent such as tetrahydrofuran (THF) as indicated in the scheme, or in hexane.
• THF tetrahydrofuran
• the product of the Homer - Emmons reaction is a carboxylic acid ester compound of Formula 6 which is thereafter reduced to the primary alcohol level with a suitable reducing agent such as diisobutylaluminum hydride (DIBAL-H) to give a compound in accordance with
• the primary alcohol of Formula 7 is then oxidized to the aldehyde level by treatment with 4-methylmorpholine N-oxide ( ⁇ MO) and tetrapropylammonium perruthenate (TPAP) to give a compound in accordance with Formula 8.
• ⁇ MO 4-methylmorpholine N-oxide
• TPAP tetrapropylammonium perruthenate
• the aldehyde compound of Formula 8 is then subjected to still another Homer - Emmons reaction conducted in the presence of strong base (n-butyllithium) and l,3-dimethyl-3,4,5,6-tehahydro-2(iH)-pyrimidinone (DMPU) with the reagent ethyl 4-(diethoxyphosphoryl)-3-methylbut-2- enoate in T ⁇ F or in other suitable inert solvent, to provide a 7-[(7-alkoxy)- chrom-3-en-6-yl]-heptatrienoic acid ethyl ester or 7-[(3-alkoxy)-5,6- dihydronaphthalen-2-yl]-heptatrienoic acid ethyl ester, as applicable, in accordance with Formula 9.
• strong base n-butyllithium
• DMPU l,3-dimethyl-3,4,5,6-tehahydro-2(iH)-pyrimidin
• Ethyl 4-(diethoxyphosphoryl)-3-methylbut- 2E-enoate can be obtained in accordance with the literature reference: JOC, 1974, 39, 821, incorporated herein. Sometimes this reagent is also referred to as triethylphosphono-3-methyl-2£'-butenoate.
• the compounds of Formula 9 are within the scope of the invention. They are saponified by treatment of sodium hydroxide (or other suitable base) to give free acid compounds, or their pharmaceutically acceptable salts in accordance with Formula 10.
• the free acids of Formula 10 can also be esterifiedby procedures well known in the art to obtain ester compounds, within the full scope of the variable j in Formula 1.
• Reaction Scheme 1 and all other reactions schemes of this specification indicate the presently preferred specific orientation (cis) or (trans) of the applicable groups relative to each olephinic bond in the intermediate and final compounds.
• a person having ordinary skill in the art can obtain the compounds with different orientations based on the present description coupled with state-of-the-art knowledge regarding analogous reagents, reaction and separation techniques.
• the variable G in the 7 position of the heptatrienoic acid moiety of the compounds of Formula 1 is shown as methyl in Reaction Scheme 1.
• variable J in the 3 position of the heptatrienoic acid moiety of the compounds of Formula 1 is also shown as methyl in Reaction Scheme 1 and in all other reactions schemes of this specification.
• Some of the specific reactions schemes below provide examples for the preparation of compounds of the invention where the variable G in the 7 position of the heptatrienoic acid moiety of the compounds of the invention is an alkyl group other than methyl.
• Reaction Scheme 2 discloses an alternative general method for obtaining compounds of the invention. In accordance with this scheme an iodo-substituted allyl alcohol of Formula 11 serves as a starting material.
• the variables G and J are defined as in connection with Formula 1.
• the allyl alcohol of Formula 11 is oxidized to the aldehyde level by treatment with 4-methylmorpholine N-oxide ( ⁇ MO) and tetrapropylammonium perruthenate (TPAP) and the resulting aldehyde is subjected to a Homer - Emmons reaction with the reagent ethyl 4- (diethoxyphosphoryl)-3-methylbut-2E-enoate in THF, hexane or in other suitable inert solvent, to provide a 7-iodo-substituted heptatrienoic acid ester of Formula 12.
• ⁇ MO 4-methylmorpholine N-oxide
• TPAP tetrapropylammonium perruthenate
• Another starting material in this reaction scheme is a 6-bromo- substituted-chroman-4-one derivative, or a 2-bromo-substitituted tetrahydronaphthalen-8-one derivative, as applicable, of Formula 2, which can be obtained as described in connection with Reaction Scheme 1.
• the bromo compound of Formula 2 is reacted with boron tribromide to remove the methyl group from the 7-position of the chroman-4-one or from the 3 position of the tetrahydronaphthalen-8-one derivative, as applicable, and the resulting free hydroxyl group is reacted with an alkyl iodide (or other halide) of the formula Zl to introduce the alkyl group Z (defined as in connection with Formula 1) into the molecule and to provide a 7-alkoxy-chroman-4-one or 3-alkoxy-tetrahydronaphthalen-8-one derivative, as applicable, in accordance with Formula 13.
• alkyl halide Zl instead of the alkyl halide Zl other types of alkylating agents can also be used to introduce the alkyl group Z.
• the compound of Formula 13 is reacted with a Grignard reagent of the formula WMgBr, and thereafter with acid, such as jMr ⁇ -toluenesulfonic acid (PTSA) to form a 6-bromo-chromene, or 2-bromodihydronaphthalene derivative, as applicable, in accordance with Formula 14.
• a Grignard reagent of the formula WMgBr and thereafter with acid, such as jMr ⁇ -toluenesulfonic acid (PTSA) to form a 6-bromo-chromene, or 2-bromodihydronaphthalene derivative, as applicable, in accordance with Formula 14.
• PTSA jMr ⁇ -toluenesulfonic acid
• the bromo compound of Formula 14 is reacted with bis(pinacolato)diboron in the presence of potassium acetate and [l,l'-bis(disphenyl ⁇ hosphino)- ferrocene]dichloropalladium(II) complex in dichloromethane and dimethylformamide under an inert gas (argon) atmosphere.
• This reaction yields a mixture of the boronic ester compound of Formula 15 and the boronic acid analogue that is not shown in the reaction scheme.
• the mixture of the boronic ester compound of Formula 15 and of thethe boronic acid analogue is reacted with the reagent of Formula 12 in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in toluene and ethanol to provide a 7-[(7-alkoxy)-chrom-3-en ⁇ 6-yl]- heptatrienoic acid ethyl ester or 7-[(3-alkoxy)-5,6-dihydronaphthalen-2-y ⁇ ]- heptatrienoic acid ethyl ester, as applicable, in accordance with Formula 16.
• the compounds of Formula 16 are within the scope of the invention.
• the compounds of the invention are partial agonists of the RXR receptors.
• one such assay is a chimeric receptor transactivation assay which tests for agonist-like activity in the AR ⁇ , RAR ⁇ and R R ⁇ receptor subtypes, and which is based on work published by Feigner, P. L. and Holm, M. (1989) Focus, 112 is described in detail in United States Patent No. 5,455,265. The specification of United States Patent No. 5,455,265 is hereby expressly incorporated by reference.
• a holoreceptor transactivation assay and a ligand binding assay which measure the antagonist/agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application No. WO W093/11755 (particularly on pages 30-33 and 37-41) published on June 24, 1993, the specification of which is also incorporated herein by reference.
• a detailed experimental procedure for holoreceptor transactivations has been described by Heyman et al. Cell 68, 397-406, (1992); Allegretto et al J. Biol. Chem.268, 26625-26633, and Mangelsdoif et al.
• Efficacy in a transactivation assay is expressed as a percentage of the maximum potency attained by the compound compared to a standard which, in this case, is the compound named (2E, 4E, 1 'S, 2 'S) ⁇ 3-methyl-5-[2'- methyl-2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)- cyclopropyl]-penta-2,4-dienoic acid.
• This standard compound is described in United States Patent No. 6,114,533.
• mice Female diabetic db/db (9-10 weeks old) mice were maintained on standard laboratory food and treated by oral gavage with vehicle (corn oil), standard compound (2E, 4E, 1 'S, 2'S)- 3-methyl-5-[2'-methyl-2'-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclo ⁇ ropyl]-penta-2,4- dienoic acid (5 mg/kg) or the test compound (5-100 mg/kg, as described in Table 2) daily for seven days at 8:00 AM. Blood samples (70 ⁇ l) were taken by orbital bleeding at 11:00 AM on day 0 (pre-treatment), day 3, and day 6.
• Tables that disclose the activity of certain exemplary compounds of the invention in the above- described assay testing the effect of compounds of the invention on serum glucose, triglyceride and thyroxine levels are found in the corresponding sections. Any modification of the assay procedure, if applicable, is also indicated in the corresponding section.
• a pharmaceutical composition containing one or more compound of the invention is administered to the mammal in daily doses in the range of 1 to 100 mg per kg body weight of the mammal.
• the daily dose is between 10 to 50 mg per kg body weight of the mammal.
• the compounds of the invention are also useful for preventing or treating diseases and conditions that are responsive to compounds that promote the expression of or bind to receptors belonging to the steroid or thyroid receptor superfamily.
• the compounds of the invention can be used for preventing or treating skin-related diseases, including, without limitation, actimc keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
• skin-related diseases including, without limitation, actimc keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease,
• the compounds are also useful for the prevention and treatment of metabolic diseases and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma.
• the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal .
• PVR proliferative vitreoretinopathy
• Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
• HPV Human papilloma virus
• various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease
• the compounds of this invention are preferably administered, orally.
• the compounds of the invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
• the drug in the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used.
• Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used.
• topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.
• these compounds could also be administered as a powder or spray, particularly in aerosol form.
• the drug may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration.
• the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection.
• these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
• Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
• Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention.
• a therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion.
• the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
• a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 1 and 50 mg per kg of body weight per day would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
• variable Y represents O (chromene derivatives) or Y is [C(R 3 ) 2 ] 0 where o represents the integer one (1) (dihydronaphthalene derivatives). Even more preferably when the compounds are dihydronaphthalene derivatives, ' then Y represents C(CH 3 ) 2 .
• variable group (A) m in the presently preferred compounds of the invention (A),, represents a ge inal dimethyl group when Y is O (chromene derivatives). When the compounds are dihydronaphthalene derivatives then in the preferred compounds m is zero
• the group (E) either represents a single halogen or alkyl substituent in the 8-position of chromenes, or in the 4-position of dihydronaphthalenes, as applicable, or the variable n is zero (0), that is, there is no E substituent.
• W it is preferred as an alkyl group of 1 to 6 carbons, or phenyl. Alkyl groups of 1 to 4 carbons are even more preferred, and in several preferred compounds of the invention W represents a branch-chained alkyl group of 3 or 4 carbons.
• the variable Z preferably represents an alkyl group of 1 to 4 carbons.
• the variable G in the preferred compounds of the .
• invention G represents an alkyl group of 1 to 4 carbons, even more preferably an alkyl group of 1 to 3 carbons.
• the variable J in the 7-position of the heptatrienoic acid moiety is preferably fluoro (F) or hydrogen (H).
• the variable J In the 3 position of the heptatrienoic acid moiety the variable J preferably represents an alkyl group, even more preferably methyl.
• the presently preferred configurations E or Z (cis or trans) relative to the olephinic bonds are shown in the structures of the exemplary compounds.
• the presently most preferred compounds of the invention are shown below in Sections A through F by general Formulas A through F, and the syntheses of these preferred compounds is also described below in detail.
• Formula A discloses a specific class of preferred and exemplary compounds of the invention.
• Formula A discloses a specific class of preferred and exemplary compounds of the invention.
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 2 carbons;
• R 1 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 3 carbons;
• R 2 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 2 carbons;
• R 4 represents H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, and
• X represents H or halogen, more preferably H or CI, or a pharmaceutically acceptable salt of said compound.
• 6-Bromo-7-methoxy-2.2-dimethyl-chroman-4-one (Compound 4).
• General Procedure A To a solution of 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one (Compound 3, 2.00 g, 7.4 mmol) in acetone (100 mL) were added potassium carbonate (500 mg) and iodomethane (5.22 g, 36.8 mmol). The mixture was then heated to reflux for 2 h.
• 6-Bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5) As described in General Procedure A, 6-bromo-7-hydroxy-2,2- dimethyl-chroman-4-one (Compound 3, 2.0 g, 7.35 mmol) was treated with potassium carbonate (500 mg) and iodoethane (1.5 mL, 18.75 mmol) to give rise to the title compound as a white solid after purification by flash chromatography (silica gel, 5 % ethyl acetate in hexanes).
• 6-Bromo-7-isopropoxy-2,2-dimethyl-chroman-4-one (Compound 6) As described in General Procedure A, 6-bromo-7-hydroxy-2,2-dimethyl- chroman-4-one, (Compound 3, 1.0 g, 3.8 mmol) in acetone (50 mL) was treated with anhydrous potassium carbonate (2.1 g, 14.9 mmol) and 2- iodopropane (0.7 mL, 7.5 mmol) to give the title compound as a white solid after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
• Trifluoro-methanesulfonic acid 6-bromo-7-methoxy-2,2-dimethyl- H- chromen-4-yl ester (Compound 7)
• 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one Compound 2, 1.00 g, 3.52 mmol
• frifluoromethanesulfonic anhydride 2.38 g, 8.45 mmol
• 2,6-di-tert-butyl-4-methyl-pyridine (1.08 g, 5.28 mmol).
• the mixture was heated to 45 °C for 2 h.
• 6-Bromo-8-chloro-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 9)
• General Procedure B To a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 2.80 g, 9.8 mmol) in methylene chloride (50 mL) at 0 °C were added sulfuryl chloride (1.59 g, 11.7 mmol) followed by treatment with pyridine (0.87 g, 11.7 mmol). After stirring at 0 °C and slow warming room temperature over 3 h, the reaction was quenched with ice water.
• 6-Bromo-8-chloro-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 10) Following General Procedure B, 6-bromo-7-ethoxy-2,2-dimethyl- chroman-4-one (Compound 5, 2.8 g, 9.33 mmol) and sulfuryl chloride (1.51 g, 11.2 mmol) in dichloromethane were reacted to yield the title compound as a colorless oil.
• 6-Bromo-7-methoxy-2,2,4-trimethyl-2H-chromene (Compound 12)
• General Procedure C A solution of methylmagnesium bromide (3.0 M in THF, 1.67 mL, 5.0 mmol) was added slowly into a solution of 6-bromo-7-methoxy-2,2- dimethyl-chroman-4-one (Compound 4, 710 mg, 2.5 mmol) in 10 mL of THF at -30 °C. The mixture was stirred and warmed to 10 °C for 2h. The reaction mixture was quenched with 10% HC1 and extracted with ethyl acetate.
• 6-Bromo-4-ethyl-7-methoxy-2.2-dimethyl-2H-chromene (Compound 13) Following General Procedure C, ethylmagnesium bromide (2.0 M in T ⁇ F, 4.7 mL, 14.08 mmol) was added to a solution of 6-bromo-7-methoxy- 2,2-dimethyl-chroman-4-one (Compound 4, 800 mg, 2.81 mmol) in T ⁇ F. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-4-isopropyl-7"methoxy-2,2-dimethyl-2H-chromene (Compound 14) Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 6.1 mL, 21.3 mmol) was added to a solution of 6-bromo-7- methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 700 mg, 2.46 mmol) in THF. The crude alcohol was treated with ?-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromene (Compound 15) Following General Procedure C, tert-butylmagnesium chloride (1.0 M in THF, 45.5 mL, 45.5 mmol) was added to a solution of 6-bromo-7- methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 2.6 g, 9.1 mmol) in THF. The crude alcohol was treated with y?-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-4-ethyl-7-ethoxy-2,2-dimethyl-2H-chromene (Compound 16) Following General Procedure C, ethylmagnesium bromide (3.0 M in THF, 7.04 mL, 21.1 mmol) was added to a solution of 6-bromo-7-ethoxy- 2,2-dimethyl-chroman-4-one (Compound 5, 1.2 g, 4.2 mmol) in THF. The crude alcohol was treated with/?-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-4-methyl-7-ethoxy-2.2-dimethyl-2H-chromene (Compound 17) Following General Procedure C, methylmagnesium chloride (3 M in THF, 1.38 mL, 4.14 mmol) was added to a solution of 6-bromo-7-ethoxy- 2,2-dimethyl-chroman-4-one (Compound 5, 588 mg, 2.07 mmol) in THF. The crude alcohol was treated with y?-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-7-ethoxy-4-isopropyl-2.2-dimethyl-2H-chromene (Compound 18) Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.3 mL, 6.6 mmol) was added to a solution of 6-bromo-7- ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 1.0 g, 3.3 mmol) in THF. The crude alcohol was treated with ?-toluenesulfonic acid to afford the title compound as a colorless oil.
• 6-Bromo-8-chloro-4-isopropyl-7-methoxy-2.2-dimethyl-2H-chromene (Compound 19) Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.15 mL, 6.29 mmol), 6-bromo-8-chloro-7-methoxy-2,2- dimethyl-chroman-4-one (Compound 9, 400 mg, 1.26 mmol) and 1,3- dimethyl-3,4,5,6-tetrahydro-2(iH)-pyrimidinone (DMPU, 2 mL) in T ⁇ F was reacted then quenched with 10 % ⁇ C1, andstored at room temperature for 12 h.
• DMPU 1,3- dimethyl-3,4,5,6-tetrahydro-2(iH)-pyrimidinone
• 6-Bromo-8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromene (Compound 20) Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 11 mL, 22 mmol), 6-bromo-8-chloro-7-ethoxy-2,2-dimethyl- chroman-4-one (Compound 10, 1.5 g, 4.5 mmol), and l,3-dimethyl-3,4,5,6- tetrahydro-2(iH)-pyrimidinone (DMPU, 2.6 mL) in THF was reacted then quenched with 10 % HC1, and stored at room temperature for 12 h. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) gained the title compound as a yellow oil.
• reaction mixture was then treated with [l,l'-bis(disphenylphosphino)- ferrocene]dichloropalladium(II) (1:1 complex with dichloromethane, 50 mg) and purged with argon for another 5 min.
• the reaction was continuously stirred at 80 °C for 4 days under argon.
• the boronic ester mixture was treated with 3-iodo-but- 2E-en-l-ol (U.S. Patent No.
• the reaction mixture was slowly warmed to room temperature and stirred for 2 h.
• the reaction mixture was quenched with a saturated solution of NH C1 and extracted with diethyl ether.
• the combined organic layers were washed with water and brine, dried (MgS0 4 ), filtered and concentrated under reduced pressure.
• the crude boronic acid was treated with 3-iodo-but-2E-en-l-ol (334 mg, 1.93 mmol), 2 M sodium carbonate (2 mL), and tetrakis(triphenylphosphine)palladium (0) (30 mg) in toluene (10 mL) and methanol (1 mL).
• the reaction mixture was degassed via bubbling argon for 5 min.
• Ethyl 7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl- octa-2E,4E,6Z-trienoate (Compound 33) As described in General Procedure F, 3-(4-isopropyl-7-methoxy-2,2- dimethyl-2H-chrornen-6-yl)-but-2-en-l-ol (Compound 23, 66 mg, 0.22 mmol), tetrapropylammonium perruthenate (50 mg) and 4- methylmorpholine N-oxide (52 mg, 0.44 mmol) were reacted to produce the corresponding aldehyde.
• Ethyl 7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl- nona-2E,4E,6Z-trienoate (Compound 34) As described in General Procedure F, 3-(4-isopropyl-7-methoxy-2,2- dimethyl-2H-chromen-6-yl)-pent-2-en-l-ol (Compound 24, 62 mg, 0.20 mmol), tefrapropylammonium perruthenate (5 mg) and 4-methylmorpholine N-oxide (46 mg, 0.39 mmol) were reacted to produce the corresponding aldehyde.
• Ethyl 7-(7-ethoxy-4-ethyl-2.2-dimethyl-2H-chromen-6-yl)-3-methyl-octa- 2E.4E,6Z-trienoate (Compound 35) As described in General Procedure F, 3-(7-ethoxy-4-ethyl-2,2- dimethyl-2H-chromen-6-yl)-but-2-en-l-ol (Compound 25, 55 mg, 0.18 mmol), tefrapropylammonium perruthenate (5 mg) and 4-methylmorpholine N-oxide (50 mg, 0.36 mmol) were reacted to produce the corresponding aldehyde.
• Ethyl 7-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl -3-methyl-nona- 2E.4E,6Z-trienoate (Compound 36) As described in General Procedure F, 3-(7-ethoxy-2,2,4-trimethyl- 2H-chromen-6-yl)-pent-2-en- 1 -ol (Compound 26, 37 mg, 0.16 mmol), tefrapropylarnmonium perruthenate (3 mg) and 4-methylmorpholine N- oxide (21 mg, 0.20 mmol) were reacted to produce the corresponding aldehyde.
• Ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2.2-dimethyl-2H-chromen-6-yl)- 3-methyl-octa-2E.4E,6Z-trienoate (Compound 39) As described in General Procedure F, 3-(8-chloro-4-isopropyl-7- methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-en-l-ol (Compound 29, 73 mg, 0.21 mmol), tefrapropylammonium perruthenate (10 mg) and 4- methylmorpholine N-oxide (57 mg, 0.43 mmol) were reacted in acetonitrile and dichloromethane to produce the corresponding aldehyde.
• Ethyl 7-(8-chloro-4-isopro ⁇ yl-7-ethoxy-2.2-dimethyl-2H-chromen-6-yl)-3- methyl-octa-2E,4E,6Z-trienoate (Compound 40) As described in General Procedure F, 3-(8-chloro-4-isopropyl-7- ethoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-en-l-ol (Compound 30, 51 mg, 0.15 mmol), tefrapropylammonium perruthenate (10 mg) and 4- methylmorpholine N-oxide (34 mg, 0.29 mmol) were reacted in acetonitrile and dichloromethane to produce the corresponding aldehyde.
• Ethyl 7-(8-chloro-4-isopropyl-7-emoxy-2,2-dimethyl-2H-chromen-6-yl)-3- methyl-nona-2E,4E.6Z-trienoate (Compound 41) As described in General Procedure F, 3-(8-chloro-4-isopropyl-7- ethoxy-2,2-dimethyl-2H-chromen-6-yl)-pent-2-en-l-ol (Compound 31, 699 mg, 1.88 mmol), tefrapropylammonium perruthenate (20 mg) and 4- methylmorpholine N-oxide (440 mg, 3.76 mmol) were reacted in acetonitrile and dichloromethane to produce the corresponding aldehyde.
• Ethyl 7-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-3- methyl-nona-2E,4E,6Z-trienoate (Compound 51) Following General Procedure G, ethyl 7-(8-chloro-4-isopropyl-7- ethoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-nona-2E,4E,6Z-trienoate (Compound 41, 296 mg, 0.63-mrno ⁇ ) was hydrolyzed with IM NaOH. Purification by column chromatography (silica gel, 10% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.
• Formula B discloses a specific class of preferred and exemplary compounds of the invention.
• Formula B :
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• R 1 represents phenyl, alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• R 2 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 2 carbons, and
• R represents H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
• 6-Bromo-2,2-dimethyl-4-phenyl-2H-chromen-7-ol (Compound 61) General Procedure J To a solution of 6-bromo-7-methoxy-2,2-dimethyl-4-phenyl-2H- chromene (Compound 52, 992 mg, 3.22 mmol) in dichloromethane (20 mL) under argon at 0 °C was added boron tribromide (IM in dichloromethane, 3.8 mL, 3.8 mmol). The mixture was stirred at 0°C for 1 h, then quenched with ice. The product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na S0 4 .
• Ethyl (-2EV2-fluoro-3-f4-z:grt-butyl-7-methoxy-2.2-dimethyl-2H " -chromen-6- yl)-but-2-enoate (Compound 70) Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.47 mL, 2.3 mmol) and l-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H- chromen-6-yl)-ethanone (Compound 55, 133 mg, 0.46 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
• Ethyl r2EV3-r7-ethoxy-2.2-dimethyl-4- ⁇ henyl-2H-chromen-6-yl -2-fluoro- but-2-enoate (Compound 75) Following General Procedure K, triethyl-2-fluoro-2-phos ⁇ honoacetate (0.42 mL, 1.70 mmol) and l-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen- 6-yl)-ethanone (Compound 66, 183 mg, 0.57 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
• Ethyl 6-fluoro-7-(7-methoxy-2-2,4-trimethyl-2H-chromen-6-yl)-3-methyl- nona-2E,4E,6E-trienoate (Compound 116) Following General Procedure N, a solution of 2-fluoro-3-(7-methoxy- 2,2,4-trimethyl-2H-chromen-6-yl)-pent-2-en-l-ol (Compound 90, 171 mg, 0.56 mmol) in THF, 4-methylmorpholine N-oxide (132 mg, 1.12 mmol) and tefrapropylammonium perruthenate (5 mg) were reacted to give the corresponding aldehyde, Compound 103.
• 6-Fluoro-7-(4-isopropyl-7-methoxy-2.2-dimethyl-2H-chromen-6-v ⁇ -3- methyl-nona-2E,4E,6E-trienoic acid (Compound 130) Following General Procedure G, a solution of ethyl 6-fluoro-7-(4- isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-nona- 2E,4E,6E-trienoate (Compound 117, 86 mg, 0.20 mmol) in ethanol and THF was hydrolyzed with IM NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a light yellow solid.
• Formula C discloses a specific class of preferred and exemplary compounds of the invention.
• Formula C discloses a specific class of preferred and exemplary compounds of the invention.
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 3 carbons;
• R 1 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 2 carbons, and
• R 4 represents H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
• Ethyl (2E)-3-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen- 6-yl -2-fluoro-pent-2-enoate (Compound 147) Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.4 mL, 2.14 mmol) and l-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl- 2H-chromen-6-yl)-propan-l-one (Compound 140, 229 mg, 0.71 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
• Ethyl f2E)-3-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl- H-chromen-6- yl)-2-fluoro-pent-2-enoate (Compound 149) Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.14 mL, 0.67 mmol) and l-(8- chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-l-one (Compound 141, 75 mg, 0.23 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
• Formula D discloses a specific class of preferred and exemplary compounds of the invention.
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and most preferably alkyl of 1 to 2 carbons
• R 1 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and
• R 4 represents H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
• reaction was allowed to warm to room temperature over 5h The reaction was quenched with ice water and extracted with ether. The organic layer was washed successively with water, brine, dried over Na 2 S0 4 , and concentrated in vacuo. The crude material was then dissolved in methanol (20 mL). After catalytic amount of p-toluenesulfonic acid was added, the reaction was stirred at 50 °C for 2 h. The solvent was removed in vacuo.
• Ethyl 7-(8-tgrt-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl -3- methyl-nona-2E,4E,6Ztrienoate (Compound A-15) Following General Procedure B-l, 6-bromo-4-tert-butyl-7-ethoxy- 1, 1-dimethyl- 1,2-dihydronaphthalene (Compound A-6, 350 mg, 1.04 mmol) and bis(pinacolato)diboron (370 mg, 1.46 mmol) afforded the corresponding boronic ester. Further treatment with ethyl 7-iodo-3-methyl- nona- -2E,4E,6Z-trienoate (Compound A-12,119 mg, 0.36 mmol) yielded the title compound as a pale yellow oil.
• Formula E discloses a specific class of preferred and exemplary compounds of the invention.
• Formula E discloses a specific class of preferred and exemplary compounds of the invention.
• R represents H, alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• R 1 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• R 2 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, and still more preferably alkyl of 1 to 2 carbons, and
• R 4 represents H, alkyl of 1 to 6 carbons, CH2OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
• the crude product was purified by flash column chromatography (silica gel, 100% hexanes to 10% ethyl acetate in hexane) to give a mixture of alcohols Compounds A-21 and A-22 as a yellow oil.
• a solution of this mixture in acetone (4 mL) was titrated with Jones' reagent at room temperature until a pale orange color persisted.
• the reaction mixture was diluted with ethyl acetate, washed with brine, dried over Na 2 S0 4 , and concentrated in vacuo.
• the residue was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to give the title compound as nearly colorless oil and a single isomer.
• Cerium (III) chloride heptahydrate (18.0 g, 73.0 mmol) was dried at 150 °C under high vacuum for 16 h without stirring and then 3 h with stirring. The white solid in the flask was cooled to room temperature and switched to argon atmosphere. The flask was placed in an ice-water bath and THF (100 mL) was added. The suspension of cerium (III) chloride in THF was stirred for 15 h at room temperature before placing it back into an ice water bath.
• Ethyl (2E)-3-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro- pent-2-enoate (Compound A-41) Following General Procedure F-l, triethyl-2-fluoro-2- phosphonoacetate (0.52 g, 2.15 mmol) and l-(3-ethoxy-5,5-dimethyl-5,6- dihydro-naphthalen-2-yl)-ethanone (Compound A-26, 112 mg, 0.43 mmol) were reacted to give the title compound as a clear oil after purification by flash chromatography (silica gel, 2% ethyl acetate in hexanes).
• Ethyl (2E -3-(3-ethoxy-8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl - 2-fluoro-pent-2-enoate (Compound A-42) Following General Procedure F-l, triethyl-2-fluoro-2- phosphonoacetate (0.12 mL, 0.58 mmol) and of l-(3-ethoxy-8-ethyl-5,5- dimethyl-5,6-dihydro-naphthalen-2-yl)-propan-l-one (Compound A-23, 55 mg, 0.19 mmol) were reacted to give the title compound as a clear oil after purification by preparative TLC (5% ethyl acetate in hexane).
• Ethyl (2E -2-Fluoro-3 -(4,4-dimethyl-6-ethoxy- 1 -isopropyl-3 ,4- dihydronaphthalen-7-ylV2-butenoate (Compound A-43) As described in General Procedure F-l, l-(4,4-dimethyl-6-ethoxy-l- isopropyl-3,4-dihydronaphthalen-7-yl)ethanone (Compound A-24, 240 mg, 0.840 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.51 mL, 2.52 mmol) were reacted with lithium diisopropylamide (2.60 mmol) in THF (2 mL) to produce the title compound after purification by flash column chromatography (silica gel, 97:3 hexane/ethyl acetate).
• Ethyl (2E -2-Fluoro-3-(4,4-dimethyl-6-t ⁇ -propoxy-l-isopropyl-3,4- dihydronaphthalen-7-yl)-2-butenoate (Compound A-44) As described in General Procedure F-l, l-(7-bromo-4,4-dimethyl-6- ⁇ -propoxy-l-isopropyl-3,4-dihydronaphthalen-yl)ethanone (Compound A- 36, 0.034 g, 0.113 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.17 mL, 0.86 mmol) were reacted with lithium diisopropylamide (0.86 mmol) in THF (2 mL) to produce the title compound as a yellow oil after purification by flash column chromatography (silica gel, 97:3 hexane/ethyl acetate).
• EthvU2E -2-Fluoro-3-(4,4-dimethyl-6-ethoxy-l-tert-butyl-3,4- dihydronaphthalen-7-yl)-2-butenoate (Compound A-46) As described in General Procedure F, l-(7-bromo-4,4-dimethyl-6- ethoxy- l-tert-butyl-3,4-dihydronaphthalen-yl)ethanone (Compound A-38, 43 mg, 0.14 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.17 mL, 0.86 mmol) were reacted with lithium diisopropylamide (0.86 mmol) in THF (2 mL) to produce the title compound as a yellow oil after purification by flash column chromatography (silica gel, 97:3 hexane/ethyl acetate).
• (2E)-2-Fluoro-3-(4,4-dimethyl-6-ethoxy- 1 -isopropyl-3 ,4- dihydronaphthalen-7-yl)-2-butenal (Compound A-61) As described in General Procedure H-l, (2E)-2-fluoro-3-(4,4- dirnethyl-6-ethoxy- 1 -isopropyl-3 ,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-52, 0.180 g, 0.54 mmol), tetrapropylammonium perruthenate (0.027 g, 0.081 mmol) and 4-methylmorpholine N-oxide (0.158 g, 1.35 mmol) were reacted in acetonitrile (1.5 mL) and dichloromethane (7.5 mL) to give the title compound.
• (2E)-2-Fluoro-3 -(4,4-dimethyl-6-t?-propoxy- 1 -isopropyl-3 ,4- dihydronaphthalen-7-yl)-2-butenal (Compound A-62) As described in General Procedure H-l, (2E)-2-fluoro-3-(4,4- dimethyl-6- «-propoxy- 1 -isopropyl-3 ,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-53, 0.024 g, 0.069 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
• (2E)-2-Fluoro-3-f4,4-dimethyl-6-(cyclopropyl methoxy-l-isopropyl-3.4- dihydronaphthalen-7-yl)-2-butenal (Compound A-63) As described in General Procedure H-l, (2E)-2-fluoro-3-(4,4- dimethyl-6-(cyclopropyl)methoxy- 1 -isopropyl-3 ,4-dihydronaphthalen-7-yl)- 2-butenol (Compound A-54, 0.025 g, 0.070 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
• (2E)-2-Fluoro-3-(4,4-dimethyl-6-ethoxy- 1 -tgrt-buyl-3 ,4-dihydronaphthalen- 7-yl)-2-butenal (Compound A-64) As described in General Procedure H-l, (2E)-2-fluoro-3-(4,4- dimethyl-6-ethoxy- 1 -tert-butyl-3 ,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-55, 0.023 g, 0.066 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
• (2E)-2-Fluoro-3-(4,4-dimethyl-6-n-propoxy- 1 -tert-buyl-3 ,4- dihydronaphthalen-7-yl)-2-butenal (Compound A-66) As described in General Procedure H-l, (2E)-2-fluoro-3-(4,4- dimethyl-6- «-propoxy- 1 -tert-butyl-3 ,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-57, 0.027 g, 0.075 mmol), tetrapropylammonium perruthenate (12 mg, 0.038 mmol) and 4-methylmorpholine N-oxide (22 mg, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
• Ethyl (2E.4E,6E)-6-Fluoro-3-(4,4-dimethyl-6- ⁇ -propoxy- 1 -isopropyl-3 ,4- dihydronaphthalen-7-yl)-3-methyl-2,4,6-octatrienoate (Compound A-71) As described in General Procedure 1-1, (E)-2-fluoro-3-(4,4-dimethyl- 6-n-propoxy- 1 -isopropyl-3 ,4-dihydronaphthalen-7-yl)-2-butenal (Compound A-62, 0.018 g, 0.052 mmol) reacted with the ylide of ethyl 4- (diethylphos ⁇ horyl)-3-methylbut-2Z-enoate (0.053 g, 0.202 mmol) in THF (1 mL) and DMPU (0.01 mL) to produce the title compound after purification by flash column chromatography silica gel, 97:
• EthvK2E,4E,6E)-6-Fluoro-3-f4,4-dimethyl-6-ethoxy-l-tert-butyl-3,4- dihydronaphthalen-7-yl -3-methyl-2,4,6-octatrienoate (Compound A-73) As described in General Procedure 1-1, (E)-2-fluoro-3-(4,4-dimethyl- 6-ethoxy- 1 -tert-butyl-3 ,4-dihydronaphthalen-7-yl)-2-butenal (Compound A-64, 0.011 g, 0.032 mmol) reacted with the ylide of ethyl 4- (diethyl ⁇ hos ⁇ horyl)-3 -methylbut-2Z-enoate (0.053 g, 0.202 mmol) in THF /
• Ethyl (2E,4E,6E)-6-Fluoro-3-(4,4-dimethyl-6-w- ⁇ ropoxy-l-tert-butyl-3,4- dihvdronaphthalen-7-yl)-3-methyl-2,4,6-octatrienoate (Compound A-75) As described in General Procedure 1-1, (E)-2-fluoro-3-(4,4-dimethyl- 6-n-propoxy- 1 -tgr?-butyl-3 ,4-dihydronaphthalen-7-yl)-2-butenal (Compound A-66, 0.024 g, 0.067 mmol) reacted with the ylide of ethyl 4- (diethyl ⁇ hosphoryl)-3-methylbut-2Z-enoate (0.053 g, 0.202 mmol) in THF (1 mL) and DMPU (0.01 mL) to produce the title compound after purification by flash column chromatography (silica gel,
• Formula F discloses a specific class of preferred and exemplary compounds of the invention.
• Formula F discloses a specific class of preferred and exemplary compounds of the invention.
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons, still more preferably z-jo-propyl or tgrt-butyl;
• R 1 represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• R represents alkyl of 1 to 8 carbons, more preferably alkyl of 1 to 4 carbons;
• X represents halogen, more preferably Br or CI
• R 4 represents H, alkyl of 1 to 6 carbons, CH 2 OR 5 or CH 2 OCOR 5 where R 5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
• reaction mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na 2 S0 ), filtered and concentrated in vacuo to give the title compound as a yellow oil. The material was used in the next step without further purification.
• 6-Bromo-8-chloro-7-ethoxy-4-isopropyl-l , 1 -dimethyl- 1 -2- dihvdronaphthalene (Compound A-120)
• a solution of 7-bromo-5-chloro-6-ethoxy-4,4-dirnethyl-3,4- dihydro-2H-naphthalen-l-one (Compound A-119, 0.78 g, 2.35 mmol) in THF (10 mL) and DMPU (3 mL) at -30°C was added a solution of isopropylmagnesium bromide (2M in THF, 5.8 mL, 11.79 mmol). The reaction was allowed to warm to 10 °C during 3 h.
• N,N-dimethylformamide (1 mL) was added and the reaction mixture was allowed to warm up-40 °C during 5 min.
• the reaction mixture was quenched with water and extracted with ether.
• the combined organic layers were washed with water and brine, dried over MgS0 4 and concentrated under reduced pressure.
• the crude material was then dissolved in THF (4 mL) at 0 °C.
• a solution of ethylmagnesium bromide (2.0 M in THF, 1.26 mL, 2.52 mmol) was added.
• the reaction was stirred at 0 °C for 30min and at room temperature for 1 h.
• the reaction mixture was quenched with water and extracted with ether.
• Ethyl (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5.5-dimethyl-5,6-dihydro- naphthalen-2-yl -2-fluoro-but-2-enoate (Compound A-1 4) As described in General Procedure F-l, l-(4-bromo-8-iso ⁇ ropyl-3- methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-103, 358 mg, 1.02 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.83 mL, 4.08 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 2.55 mL, 4.08 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
• EthyK2EV3-(4-bromo-3-ethoxy-8-isopropyl-5.5-dimethyl-5.6-dihydro- naphthalen-2-yl)-2-fluoro-pent-2-enoate (Compound A-126) As described in General Procedure F- 1 , 1 -(4-bromo-3 -ethoxy-8- isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-propan-l-one (Compound A-110, 970 mg, 2.56 mmol) and triethyl 2-fluoro-2- phosphonoacetate (2.48 g, 10.24 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 6.4 mL, 10.24 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
• Ethyl (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro- naphthalen-2-yl -2-fluoro-but-2-enoate (Compound A-128) As described in General Procedure F-l, l-(4-bromo-3-isopropoxy-8- isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-112, 262 mg, 0.69 mmol) and triethyl 2-fluoro-2-phosphonoacetate (669 mg, 2.76 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.73 mL, 2.76 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
• Ethyl (E -3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5.6- dihydronaphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-133)
• l-(4-chloro-3-ethoxy-8- isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-ethanone Compound A-121, 0.23 g, 0.72 mmol
• triethyl 2-fluoro-2-phosphonoacetate 566 mg, 2.3 mmol
• n-butyllithium 1.6 M in hexanes, 1.46 mL, 2.3 mmol
• (2E)-3-r4-Bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5.6-dihydro- naphthalen-2-yl -2-fluoro-but-2-enal (Compound A-146) As described in General Procedure H-l, (2E)-3-(4-bromo-8- isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro- but-2-en-l-ol (Compound A-135, 130 mg, 0.33 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4- methylmorpholine N-oxide (77 mg, 0.66 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
• (2E)-3-(4-Bromo-3-propoxy-8-isopropyl-5.5-dimethyl-5.6-dihydro- naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-151) As described in General Procedure H-l, (2E)-3-(4-bromo-8- isopropyl-5,5-dimethyl-3-propoxy-5,6-dihydro-naphthalen-2-yl)-2-fluoro- but-2-en-l-ol (Compound A-140, 158 mg, 0.37 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4- methylmorpholine N-oxide (109 mg, 0.93 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
• (2E)-3 -(4-Chloro-3-ethoxy-8-isopropyl- 5 , 5-dimethyl-5 , 6- dihydronaphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-155)
• (2E)-3-(4-chloro-3-ethoxy-8- isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-but-2-en-l-ol Compound A-144, 0.18 g, 0.49 mmol
• tetrapropylammonium perruthenate 25 mg, 0.071 mmol
• 4-methylmorpholine N-oxide (115 mg, 0.98 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 10%) ethyl acetate in hexanes).

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