Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
• • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/58—[b]- or [c]-condensed
  • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/74—Naphthothiophenes

Definitions

• Bridges, et al. (EP 568289 A2) disclosed the thienothiopheneamidine B as a urokinase inhibitor.
• R is hydrogen, alkyl of 1-6 carbon atoms, -COR 1 , -(CH ⁇ CO ⁇ 1 , -CH(R l a )CO 2 R 1 ,
• the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
• the compounds of this invention may be atropisomers by virtue of possible restricted or slow rotation about the aryl-tricyclic or aryl-bicyle single bond. This restricted rotation creates additional chirality and leads to enantiomeric forms. If there is an additional chiral center in the molecule, diasteriomers exist and can be seen in the NMR and via other analytical techniques. While shown without respect to atropisomer stereochemistry in Formula I, the present invention includes such atoropisomers (enantiomers and diastereomers; as well as the racemic, resolved, pure diastereomers and mixutures of diasteomers) and pharmaceutically acceptable salts thereof.
• Preferred compounds of this invention include compounds of formula (I), having the structure
• B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR;
• R is hydrogen or alkyl of 1-6 carbon atoms;
• E is S, or O;
• X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR 2 R 2a ,
• NR 2 COR 2a cycloalkylamino, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
• R 1 , R la , R 2 , R a , R 3 , and R 3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
• Y is hydrogen, halogen, OR 3 , SR 3 , NR 3 R 3a or morpholine;
• R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, -CH 2 ( lH-imidazol-4-yl), -CH 2 (3- 1 H-indolyl), -CH 2 CH 2 ( 1 ,3-dioxo- 1 ,3- dihydro-isoindol-2-yl), -CH 2 CH 2 ( 1 -oxo- 1 ,3-dihydro-isoindol-2-yl), or -CH 2 (3-pyridyl);
• R 6 , R 6a , R 6b ,R 7 , R 7a , and R 7b are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;
• R 9 and R 10 are independently, hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptable salt thereof.
• More preferred compounds of this invention include compounds of formula (I), having the structure
• E is S or O
• X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, arylsulfanyl;
• R 4 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R 5 )W, or 5-thiazolidine-2,4-dione;
• the compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. These schemes show the preparation of representative compounds of this invention.
• 3-dimethylthiophene (II: E is S) is prepared from commercially available 3-methyl-thiophene-carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOH/ethylene glycol reflux).
• Compound (II: E is S or O) is treated with one to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from -78°C to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative.
• an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from -78°C to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative.
• the compounds of formula (la: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OH; E is S or O) can be prepared starting from the compound of formula (III: Q is H; E is S or O) and the appropriate benzoic acid chloride (TV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe).
• the benzoic acid chloride (IN: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe).
• the starting benzoic acid of the benzoic acid chloride (TV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe) is commercially available or can be easily prepared by known procedures.
• the acid starting material for benzoic acid chloride (IV: A is H; B, D is isopropyl; C is OMe) can be prepared using a modification of the method of Schuster, et al., J. Org. Chem. 1988, 53, 5819.
• the monoiodo methylether derivative of formula (lb: B is I; X, D is H; C is OMe; E is S or O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S or O) can be reacted with one or more molar equivalents of copper (I) cyanide for the monoiodo analog or two or more molar equivalents of copper (I) cyanide for the diiodo derivative to produce the monocyanomethyl ether of formula (lb: B is CN; X, D is H; C is OMe; E is S or O) or the dicyanomethyl ether of formula (lb: B, D is CN; X is H; C is OMe; E is S or O).
• the monoiodo methylether derivative of formula (lb: B is I; X, D is H; C is OMe; E is S or O) or the diiodo methylether of formula (lb: B, D is I; X is H; C is OMe; E is S or O) (Scheme 2) can be reacted with one or more molar equivalents of copper (I) bromide for the monoiodo analog or two or more molar equivalents of copper (I) bromide for the diiodo derivative to produce the monobromo methyl ether of formula (lb: B is Br; X, D is H; C is OMe; E is S or O) or the dibromo-methyl ether of formula (lb: B, D is Br; X is H; C is OMe; E is S or O).
• the bromine/idodine exchange reaction is generally performed at temperatures ranging from 100°C to 250°C employing polar aprotic solvents such as DMF, l-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used.
• the mono or dibromo methoxy analogs of formula (lb: B is Br; D is H or Br X is H; C is OMe; E is S or O) can be converted to the corresponding mono or dibromo phenol analogs of formula (Ic: B is Br; D is H or Br; X is H; E is S or O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; excess neat pyridinium hydrochloride at 190 to 280°C; hydrobromic acid in acetic acid at 0°C to 50°C; excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; lithium iodide in pyridine or quinoline at temperatures from 100° to 250°
• This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from - 78 °C to room temperature.
• This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from -78 °C to room temperature.
• These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a 1-6 carbon alcohol such as methanol or mixtures of THF and a 1-6 carbon atom alcohol at temperatures ranging from 0°C to 40°C.
• Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
• the nitro compounds of formula (Ie: B, C, D is H or OCOR; C, D cannot both be H; R is alkyl fo 1-6 carbon atoms, aryl; X is NO 2 ; E is S or O) can be further reduced to the primary amine of formula (le: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl fo 1-6 carbon atoms, aryl; X is NH 2 ; E is S or O) using a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, tin dichloride in aqueous HC1 or in ethyl acetate.
• a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, tin dichloride in aqueous HC1 or in ethyl acetate.
• the acylated bromophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3) can be converted to the acylated cyanophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) by reaction with one or more molar equivalents of copper (I) cyanide.
• the acyl group can also be removed from the isolated acylated cyanophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) to provide the cyanophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) using standard conditions.
• These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
• Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
• the compounds of formula (Id: B, C, D is H or OH; with the B, C, D combination having at least one OH group; E is S or O) (Scheme 3) can be sulfonylated on the phenolic oxygen using one or more molar equivalents of suitable sulfonylating agent to provide the sulfonic acid esters of formula (Id: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O).
• the sulfonylating agent is generally a alkyl of 1-6 carbon atoms or aryl sulfonic acid anhydride or a alkyl of 1-6 carbon atoms or aryl sulfonic acid chloride.
• the reaction is run under standard conditions such as using pyridine as solvent with or without a co-solvent such as dichloromethane at 0°C to room temperature.
• the sulfonic acid esters of formula (Id: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be treated with iodinating reagents to effect iodination at the 9-position of the naphtho[2,3-d]thiophene or the naphtho[2,3-d]furan ring to afford the iodo sulfonic acid esters of formula (Ie: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S or O).
• a suitable iodinating reagent includes a mixture of 0.7 or more molar equivalents of molecular iodine and 0.25 or more molar equivalents of iodic acid in a mixture of THF and 80% aqueous acetic acid with a small amount of concentrated sulfuric acid at temperatures ranging from room temperature to 80 °C.
• the sulfonic ester group can then be removed from the iodo-sulfonic acid esters of formula (Ie: B, C, D is H or OSO 2 R; with the B, C, D combination having at least one OSO 2 R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S or O) to provide the iodophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is I; E is S or O) (Scheme 3) using standard conditions.
• the reagent and conditions to effect this exchange include reacting (If) under anhydrous conditions with one to ten molar equivalents of a sodium perfluorocarboxylate (RCO 2 Na: R is perfluoroalkyl) and one to five molar equivalents of copper (I) iodide in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
• a sodium perfluorocarboxylate RCO 2 Na: R is perfluoroalkyl
• copper (I) iodide in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
• the compound of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is lower perfluoroalkyl; E is S or O) can be prepared from the compound of formula (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) by reacting the former with one to ten molar molar equivalents of a perfluoroalkyl iodide and one to five molar molar equivalents of activated Cu° in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
• a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
• the compound of formula (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be reacted with 0.5 to two molar equivalents of bis(trifluoromethyl)mercury and two to four molar equivalents of activated Cu° in a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C to produce the compound of (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is CF 3 ; E is S or O).
• a high boiling inert solvent such as DMF, DMA or l-methyl-2-pyrrolidinone
• 9-alkyl derivatives of the compound of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms; E is S or O) (Scheme 4) can be prepared by reaction of (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with three or more molar equivalents of lower tetra-alkyltin in the presence of a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium II chloride in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 140°C to 200°C.
• a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)pal
• the sulfonic ester group can then be removed from the sulfonic acid esters of formula (Ig: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms or lower perfluoroalkyl; E is S or O) to provide the phenols of formula (Ig: C, D is H or OH; C, D cannot both be H; X is alkyl of 1-6 carbon atoms or lower perfluoroalkyl; E is S or O) using standard conditions.
• 9-Alkoxy derivatives of the compound of formula (Ig: C, D is H, OH; C, D cannot both be H; X is alkoxy of 1-6 carbon atoms; E is S or O) can be prepared by reaction of (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with three or more molar equivalents of lower alkali metal alkoxide such as sodium methoxide in the presence of a copper (I) or copper (II) catalyst such as 1 to 10 mole % copper (II) chloride in a suitable solvent such as DMF, DMA or l-methyl-2-pyrrolidinone at temperatures ranging from 80°C to 180°C. Under the reaction conditions, the sulfonic acid group of formula (If: C, D is H or OSO 2 R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
• E is S or O
• R la is alkyl of 1-6 carbon atoms aralkyl and aryl).
• acylations can be performed in the presence of one or more equivlents of a suitable base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine and with or without a suitable solvent such a chloroform, dichloromethane, THF, dioxane and water or mixtures of these solvents and with or without the presence of a catalyst such as 4-N, N-dimethylpyridine .
• a suitable base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine
• a suitable solvent such as chloroform, dichloromethane, THF, dioxane and water or mixtures of these solvents and with or without the presence of a catalyst such as 4-N, N-dimethylpyridine .
• the bisphenols of formula (Ij: C, D is OH;
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
• E is S or O
• A is H;
• B is Br;
• C, D is OH;
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridyls
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
• R 6 , R 6a is alkyl of 1 - 6 carbon atoms, aralkyl, aryl;
• E is S or O) as well as the diesters of formula (Im:
• A, B is H or Br;
• C is OCH 2 CO 2 R 6 ,
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,
• the conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
• a co-solvent such as THF, dioxane or a lower alcohol
• methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
• acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl; Y is H; E is S or O) can be reacted with a halogenating agent, specifically one that causes benzylic type bromination or chlorination such as one or more molar equivalents of N-bromosuccinimide, N-chlorosuccinimide or sulfuryl chloride to provide the halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluor
• halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) can be reacted with one or more equivalents of nucleophiles such as alkoxides (MOR 1 ), sulfides (MSR 1 ) or amines (NHR'R 2 ) (wherein M is a alkali metal such as Na, Li or K; R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl) in a suitable solvent such as THF, DMF or dichloromethane to
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) with nucleophiles there can be concomitent loss of the acetyl group to afford the compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl;
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
• Y is OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be deacylated to produce the compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon
• the deacylation conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0°C to 40°C.
• Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HC1 or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80°C.
• the compounds of formula (Io: B, D is H;
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
• Y is Cl, Br, OR 1 , SR 1 , NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be brominated in two positions to afford the dibromphenols of formula (Io: B, D is Br;
• X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms
• the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy carboxylic acid ester of formula CH(OH)(R 5 )CO 2 R
• the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C.
• the 2-hydroxy carboxylic acid ester of formula CH(OH)(R 5 )CO 2 R 6 (R 5 is H , alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-1 H-indolyl), CH 2 CH 2 ( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl), CH 2 CH 2 ( 1 -oxo- 1 ,3-dihydro-isoindol- 2-yl), CH 2 (3-pyridyl), CH 2 CO 2 R 6 , R 6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.
• (S)-(+)-2-Hydroxy-l-oxo-3-dihydro-2- isoindolinebutyric acid, methyl ester can be prepared from (S)-(+)-2-hydroxy-l,3- dioxo-2-isoindolinebutyric acid, methyl ester via sequential treatment with 1) sodium borohydride in THF-water; 2) trifluoroacetic acid / chloroform; 3) triethylsilane / trifluoroacetic acid and 4) aqueous sodium bicarbonate.
• 3-(Pyridin-3-yl)-phenyllactic acid, ethyl ester can be prepared according to the two step procedure of B.A. Lefker, W.A. Hada, P.J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208, from commericially available 3-pyridinecarboxaldehyde and ethyl chloroacetate.
• esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 R 6 ;
• R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2
• halogen alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 H;
• R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-imidazol-4-yl), CH 2 (3-lH-indolyl), CH 2 CH 2 (l,3-dioxo- 1 ,3-dihydro-isoindo
• ester to acid transformation leading to (Iq) include reacting the carboxylic acid ester of formula (Iq) with one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; one or more molar equivalents hydrobromic acid in acetic acid at 0°C to 50°C; one or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; one or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 100° to 250°C.
• the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR', NR'R 2 , where R ⁇ R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of diethyl trifluoromethylsulfonyloxymethylpho
• D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl
• Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R 1 , R 2 is
• the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R', R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy phosphonic acid diester of formula CH(OH)(R 5 )PO 3 (R
• the 2-hydroxy phosphonic acid diester of formula CH(OH)(R 5 )PO 3 R 6 (R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R 6 is alkyl of 1-6 carbon atoms) can be prepared by reacting a dialklylphosphonate of formula HP(O)(OR 6 ) 2 (R 6 is alkyl of 1-6 carbon atoms) with an aldehyde of formula R 5 CHO (R 5 is alkyl of 1-6 carbon atoms, aryl, aralkyl) under standard conditions.
• the phosphonic acid diesters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO 3 (R 6 ) 2 ;
• R 5 is H, alkyl of 1-6 carbon atoms, aralky
• esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 R 6 ;
• R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (1H
• the carboxylic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR', NR'R 2 , where R", R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO 2 H;
• R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH 2 (lH-
• This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide.
• Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0°C to 60°C.
• the phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Br, OR', SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of a haloacetonitrile of formula (X 2 CH 2
• the carboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR !
• One set of conditions to effect this transformation include reacting the said primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent such as dioxane at temperatures ranging from 60°C to 120°C.
• nitriles analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R' , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CN;
• R 5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH
• R 4 is (R, S)-5-thiazolidine-2,4-dione
• B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylamino-ethylsulfanyl
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H
• the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with one or more molar equivalents of tetrazole and di-tert-butyl
• the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR', SR 1 , NR'R 2 , where R 1 , R 2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the carboxylic acids of formula (Is: R 4 is C(CH 3 ) 2 CO 2 H; B,
• the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;
• Y is H, Cl, Br, OR 1 , SR 1 , NR !
• the other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from -20°C to 120°C at temperatures ranging from -20°C to 120°C.
• the 3-hydroxy carboxylic acid ester of formula CH(OH)(R 7 )CH 2 CO 2 R 6 (R 7 is H or alkyl of 1-6 carbon atoms; R 6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.
• esters of formula (Is) include reacting the esters of formula (Is) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at -78°C to room temperature; two or more molar equivalents hydrobromic acid in acetic acid at 0°C to 50°C; two or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at -78°C to 50°C; two or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 60° to 250°C.
• X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N- dimethylaminoethylsulfanyl;
• Y is H, OR 1 , SR', NR'R 2 , where R 1 , R 2 is H, alkyl of 1- 6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl or aralkyl halide of formula (XR 4 where X is Cl, Br or I and R 4 is alkyl of 1-6 carbon atoms,
• Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
• Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
• Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
• Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
• Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
• the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
• Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a 10 minute period to a stirred, -78°C solution of 2-benzyl-4, 5 -dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6 mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere. After 5 hours at -78°C, the reaction mixture was slowly warmed to room temperature over a 2 h period. The reaction mixture was added to water and extracted with ether. The ether extract was washed with sat. aq. sodium bicarbonate and brine.
• Neat boron tribromide (20 mL, 212 mmol) was added dropwise to a stirrred solution of (2-benzyl-4, 5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone (9.40 g, 27.9 mmol) in dichloromethane (95 mL) at -78°C under a dry nitrogen atomosphere.
• the solution was allowed to warm to ambient temperature and was stirred for 4 h.
• the reaction mixture was cooled to 0°C and carefully quenched with water and the solvent was removed. More water was added and the resultant solid was filtered and washed with water and triturated with pet.
• Acetic anhydride (0.68 mL, 7.20 mmol) was added to a 0°C, stirred solution of 4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 6.57mmol) in pyridine (8.6 mL). After 17 h the reaction mixture was added to 5% aqueous HCl and the resulting solid was filtered and washed with 5% aqueous HCl, water and triturated with pet. ether.
• Acetic Acid 4-(9-bromo-2. 3-dimethyl-naphthor2.3-blthiophen-4-ylVphenyl ester A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (9 mL) was added dropwise over a 15 minute period to a solution that was stirred in the absence of light of acetic acid 4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.87 g, 5.41 mmol) and iron (IU) chloride (50 mg, 0.31 mmol) in dichloromethane (47 mL) at -78°C under a dry nitrogen atmosphere.
• the vial was sealed and heated at 102°C.
• the reaction was done (as indicated by thin layer chromatography) the mixture was cooled to room temperature, diluted with water, and acidified with hydrochloric acid. The organics were extracted with ether, combined with silica gel and the solvents were removed.
• the ether was removed and the solid (0.162 g, 0.265 mmol) was dissolved in tetrahydrofuran (100 mL) and a 1 N aqueous solution of sodium hydroxide (0.265 mL, 0.265 mmol) was added dropwise. After sti ⁇ ing 20 minutes the solvent was removed and the residue was stirred in water (100 mL). The water was removed by decantation and the residue was stirred in petroleum ether overnight. The solvent was removed. The residue was dissolved in tetrahydrofuran ether and silica gel was added.
• Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirred suspension of potassium carbonate (0.223 g, 1.61 mmol), 2-bromo-4-(9-bromo-2, 3-dimethyl- naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixture was added to water and extracted with ethyl acetate. Silica gel was added to the ethyl acetate and the solvent was removed.
• the adsorbate was flashed (9:1 petroleum ether: ethyl actetate) to provide the title compound as a yellow solid (0.305 g, 67%).
• This solid (0.050g, 0.086 mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min the reaction mixture was diluted with water, acidified with 10% aqeous HCl and extracted with ether.
• Step 1 ( ' 2R -2-f4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-isopropyl- phenoxyl-3-phenyl-propionic acid methyl ester
• 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-isopropyl-phenol (0.26 g, 0.67 mmol)
• (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.32 g, 1.8 mmol
• triphenylphosphine (0.46 g, 1.8 mmol
• diethylazodicarboxylate (0.28 mL, 1.8 mmol
• anhydrous benzene (7.0 mL) in an oil bath (90°C) for 4.5 h the tide compound as a white
• Step 2 (RV2-r4-(2.3-Dimethyl-naphthor2.3-b1thiophen-4-vn-2.6-dimethyl-phenoxyl- 3-phenyl-propionic acid
• (R)-2-[4-(2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxy]-3- phenyl-propionic acid methyl ester (0.23 g, 0.46 mmol)
• aqueous potassium hydroxide (0.91 mL of a 1 N solution, 0.91 mmol), tetrahydrofuran (12 mL), and methanol (4 mL) the title compound as a white solid (0.19 g, 86%):
• Opt. Rot. [a]25/D +33.04° (10.170 mg/mL, MeOH); (DMSO-d6): ⁇ 12.9 (broad s,
• reaction mixmre was then poured onto ice water (IL) containing some sodium bisulfite, and the resulting mixmre was extracted once with diethyl ether (1 L), and a second time with diethyl ether (300 mL).
• the combined diethyl ether extracts were washed twice with water (1 L), brine (IL), and then dried (Na2SO4).
• Step 7 ('2RV2-r4-(9-bromo-2.3-dimethyl-naphthol2.3-b1thiophen-4-ylV2.6-dimethyl- phenoxyl-3-phenyl-propionic acid
• aqueous potassium hydroxide (19.5 mL of a IN solution, 19.5 mmol) was added, and the reaction mixmre was allowed to stir at room temperature for 9.5 h. Concentration under reduced pressure gave a residue which was diluted with water (1 L). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1, and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL), and then dried (Na2SO4).
• Step 1 (2-Benzyl-4.5-dimethyl-thiophen-3-yl -(3.5-diisopropyl-4-methoxy-phenylV methanone
• Step 1 there was obtained from 3,5-diisopropyl-p-anisic acid (5.0 g, 21.2 mmol, RN- 117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol), N,N-dimethylformamide (2 drops), 2,3-dimethyl-5- benzyltiiiophene (4.3 g, 21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrous methylene chloride (82 mL) the title compound as a yellow oil (4.1 g, 45%):
• Step 4 (2R -2-r4-f2.3-Dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diisopropyl- phenoxyl-3-phenyl-propionic acid
• Step 3 there was obtained from 2-fluoro-4-(2,3-dimethyl-naphtho[2.3-b]thiophen-4-yl)-phenol (1.0 g, 3.1 mmol), acetic anhydride (0.36 mL, 3.8 mmol), and pyridine (7.5 mL) a yellow solid (1.1 g), which was used without further purification.
• Step 4 there was obtained from acetic acid 2-fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester
• Step 3 (RV2-r4-( ' 9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-fluoro- phenoxyl-3-phenyl-propionic acid methyl ester
• Step 4 (RV2-r4-f9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2-fluoro- phenoxy]-3-phenyl-propionic acid
• Step 1 Acetic acid 4-(2.3-dimethyI-naphthor2.3-blthiophen-4-ylV2.6-diisopropyl- phenyl ester
• Step 3 4-(9-Bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-yl ' )-2.6-diisopropyl-phenol
• Step 1 C2RV2-r4-( " 9-bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diiso- propyl-phenoxyl-3-phenyl-propionic acid methyl ester
• 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.46 g, 0.98 mmol)
• (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.70 g, 3.9 mmol
• triphenylphosphine (1.02 g, 3.9 mmol
• diethylazodicarboxylate 0.62 mL, 3.9 mmol
• anhydrous benzene 1.0 mL in an oil bath (90°C) for 24 h the tide compound as
• Step 2 C2RV2-r4-( ' 9-Bromo-2.3-dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diiso- propy 1-phenoxy 1 -3-phenyl-propionic acid
• Step 7 ( ' 2R -2-r4-(9-Bromo-2.3-dimethyl-naphthor2.3-blthio ⁇ hen-4-ylV2.6-diethyl- phenoxyl-3-phenyl-propionic acid
• (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl- phenoxy]-3-phenyl-propionic acid methyl ester (0.70 g, 1.16 mmol)
• aqueous potassium hydroxide (2.3 mL of a 1 N solution, 2.3 mmol)
• tetrahydrofuran (11.6 mL)
• methanol methanol
• reaction mixture was adsorbed onto silica gel and chromatographed with hexane:ethyl acetate (90:10) to give a solid (0.17 g), which was treated with potassium hydroxide (1.32 mL of a IN solution, 1.32 mmol), tetrahydrofuran (10 mL), and enough methanol to create a homogeneous solution.
• the reaction mixture was diluted with diethyl ether, washed once with IN aqueous hydrochloric acid, once with water, once with brine, and then dried (Na2SO4).
• the solution was concentrated under reduced pressure, dissolved in methylene chloride, and dried (Na2SO4). Concentration under reduced pressure gave a white solid (0.14 g, 26%): NMR (DMSO-d6): ⁇ 12.51
• Step 7 there was obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3- phenyl-propionic acid methyl ester (0.6 g, 1.10 mmol), aqueous potassium hydroxide (1.3 mL of a 1 N solution, 1.3 mmol), tetrahydrofuran (15.7 mL), and enough methanol to create a homogeneous solution the title compound as a solid (0.58 g, 99%):
• Step 2 (2R -2-r4-( , 2.3-Dimethyl-naphthor2.3-blthiophen-4-ylV2.6-diethyl-phenoxyl- 3 -phenyl-propionic acid
• Step 1 (2-Benzyl-4.5-dimethyl-furan-3-yl -(4-methoxy-3.5-diethyl-phenyl)-methanone
• 3,5-diethyl-p-anisic acid (10.66 g, 51.2 mmol; prepared in three steps from 4- bromo-2,6-diethyl aniline by the methods of J. Lipowitz and T. Cohen, J. Org. Chem. 1965, 30, 3891-3894; C.K. Bradsher. et al; J. Am. Chem. Soc. 1954, 76, 2357- 2362; J. Alexander, Org. Prep. Proced.
• Step 3 there was obtained from 4-(2,3-dimethyl-naphtho[2.3-b]furan-4-yl)-2,6-diethyl-phenol (1.75 g, 5.1 mmol), acetic anhydride (0.62 mL, 6.6 mmol), and pyridine (10.2 mL) a solid (2.23 g), which was used without further purification.
• Step 6 there was obtained from 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol (0.26 g, 0.64 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.38 g, 7.66 mmol), triphenylphosphine (1.98 g, 7.55 mmol), diethylazodicarboxylate (1.2 mL, 7.62 mmol), and anhydrous benzene (0.85 mL) at 100° for 36 h a solid (0.15 g, 39%), which was used without further purification.
• Step 7 there was obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phen- oxy]-3-phenyl-propionic acid methyl ester (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.98 mL of a 1 N solution, 0.98 mmol), tetrahydrofuran (2.5 mL), and enough methanol to create a homogeneous solution the tide compound as a white solid
• Step 2 2RV2-r2-Cvclopentyl-4-( ' 2-.3-dimethyl-naphthor2.3-b1thiophen-4-ylV phenoxy] -propionic acid
• Step 2 4-(9-Bromo-2-.3-dimethyl-naphthor2.3-b1thiophen-4-ylV2-cvclopentyl- phenoxyl-butyric acid
• Step 7 there was obtained from 4-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl- phenoxy]-butyric acid methyl ester (0.23 g, 0.42 mmol), aqueous potassium hydroxide
• Example 75 Acetic acid 2-cvclopentyl-4-(2-.3-dimethyl-naphthor2.3-b]furan-4-y -phenyl ester
• 2- cyclopentyl-4-(2,3-dimethyl-naphtho[2.3-b]furan-4-yl)-phenol (4.81 g, 13.5 mmol)
• acetic anhydride (1.60 mL, 17.0 mmol
• pyridine 27 mL
• methylene chloride 27 mL
• Step 2 Acetic acid 4-(9-bromo-2.3-dimethyl-naphthor2.3-b1thiophen-4-yl -2-ethyl- phenyl ester
• Step 1 there was obtained from 3-bromo-5-ethyl-p-anisic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 mL,
• Step 6 there was obtained from 2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.30 g, 0.76 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.54 g, 3.0 mmol), triphenylphosphine (0.80 g, 3.1 mmol), diethylazodicarboxylate (0.48 mL, 3.0 mmol), and anhydrous benzene (1.0 mL) at 100° for 12 h the title compound as a solid (0.37 g,
• Step 7 there was obtained from (2R)-2-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3- phenyl-propionic acid methyl ester (0.34 g, 0.61 mmol), aqueous potassium hydroxide (1.2 mL of a 1 N solution, 1.2 mmol), tetrahydrofuran (6.0 mL), and enough methanol to create a homogeneous solution the tide compound as a white foam (0.31 g, 94%):
• Step 1 4-r2-Bromo-4-(2.3-dimethyl-naphthol2.3-b1furan-4-yl)-6-ethyl-phenoxy]- butyric acid methyl ester
• Step 2 4-[2-Bromo-4-f2.3-dimethyl-naphthor2.3-blfuran-4-ylV6-ethyl-phenoxyl- butyric acid
• Step 7 there was obtained from 4-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyric acid methyl ester (0.31 g, 0.63 mmol), aqueous potassium hydroxide (1.25 mL of a 1 N solution, 1.25 mmol), tetrahydrofuran (6.3 mL), and enough methanol to create a homogeneous solution the tide compound as a white foam (0.26 g, 87%): NMR
• Step 2 4-( , 2.3-Dimethyl-naphthor2.3-blfuran-4-ylV2-ethyl-phenol
• Step 2 there was obtained from (2-benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3-ethyl-phenyl)-methanone (7.0 g, 20.1 mmol), boron tribromide (14.4 mL, 152.3 mmol), and methylene chloride (69 mL) the title compound as an off-white solid (0.61 g, 9.6%): (DMSO-d6): ⁇ 9.45 (s,
• Step 6 there was obtained from 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol (0.77 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.12 g, 6.2 mmol), triphenylphosphine (1.60 g, 6.1 mmol), diethylazodicarboxylate (0.96 mL, 6.1 mmol), and anhydrous benzene (2.5 mL) at 85° for 3 days a solid, (2R)-2-[4-(9-bromo-2,3- dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionic acid methyl ester (0.23 g), which was used without further purification.
• Step 2 4-(9-Bromo-2-.3-dimethyl-naphtho[2.3-b1thien-4-ylV2-methyl-phenyl acetate
• Step4 there was obtained from acetic acid 4-(2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenyl ester (10.0 g, 26.7 mmol), ferric chloride (0.23 g, 1.42 mmol), bromine (1.51 mL in methylene chloride (38 mL), 29.4 mmol), and methylene chloride (231 mL) acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenyl ester (6.68 g, 55%) and the title compound as a yellow solid (1.60 g):
• Step 1 4-( ' 9-Bromo-2-diethylaminomethyl-3-methyl-naphthor2.3-blthiophen-4-yl ' )-2.6- dimethyl-phenol
• Step 6 there was obtained from 4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6- dimethyl-phenol (0.90 g, 1.87mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.67g, 3.73 mmol), triphenylphosphine (0.98 g, 3.73 mmol), diethylazodicarboxylate (0.59 mL, 3.73 mmol), and anhydrous benzene (10 mL) at
• Step 7 there was obtained from (2R)-2-[4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4- yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid methyl ester (0.35 g, 0.98 mmol), aqueous potassium hydroxide (1.95 mL of a 1 N solution, 1.95 mmol), tetrahydrofuran (9 mL), and methanol (3 mL) the tide compound as a solid (0.35 g, >100%): NMR (DMSO-d6): ⁇ 12.90 (br s, IH), 8.19 (d, IH), 7.66-7.61 (m. IH), 7.50-7.43 (m,

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