Restricted 9-cis-retinoids

Claim 2

A compound of Formula I: wherein: A, B and C are CH, CH₂, O, or S wherein no more than one heteroatom is present; D is (CH) m , and m is an integer 0 to 1; or D is (CH₂) n , and n is an integer 0 to 2; the dotted line, -----, represents the presence or absence of a double bond whereby if only one double bond is present, it is disposed to the a-b position; or if multiple double bonds are present they are in a conjugated position to produce an aromatic ring; R is hydrogen, methyl, ethyl, t-butyl, or trifluoromethyl; Ar is: a moiety of the formula: wherein R₁, R₂, R₃, and R₄ are hydrogen, (C₁-C₃)alkyl, (C₁-C₃)alkoxy or trifluoromethyl; and X is CH₂OH, CHO, CO₂H, CN, CH₂CONH₂, or a moiety of the formula: and R₈ is straight or branched (C₁-C₈)alkyl, or wherein R₉ is hydrogen, straight or branched (C₁-C₁₀)alkyl, glycosyl, 2-methoxyethyl, 2-dimethyl-aminoethyl, (2,3 or 4)-pyridyl, or (2,3 or 4)-pyridyl-methyl; Y is hydrogen, and the pharmaceutically acceptable salts and esters.

Claim 3

A compound of Formula I: wherein: A is CH or CH₂; B and C are CH, CH₂, O, or S wherein no more than one heteroatom is present; D is (CH) m , and m is an integer 0 to 1; or D is (CH₂) n , and n is an integer 0 to 2; the dotted line, -----, represents the presence or absence of a double bond whereby if only one double bond is present, it is disposed to the a-b position; or if multiple double bonds are present they are in a conjugated position to produce an aromatic ring; R is hydrogen, methyl, ethyl, t-butyl, or trifluoro-methyl; Ar is: a moiety of the formula: wherein R₅ is hydrogen, (C₁-C₃)alkyl, methoxy or trifluoromethyl; R₆ is hydrogen, methyl or ethyl, and X is CH₂OH, CHO, CO₂H, CN, CH₂CONH₂, or a moiety of the formula: and R₈ is straight or branched (C₁-C₈)alkyl, or wherein R₉ is hydrogen, straight or branched (C₁-C₁₀)alkyl, glycosyl, 2-methoxyethyl, 2-dimethyl-aminoethyl, (2,3 or 4)-pyridyl, or (2,3 or 4)-pyridyl-methyl; Y is hydrogen, and the pharmaceutically acceptable salts and esters.

Claim 4

A compound of Formula I: wherein: A is CH or CH₂; B and C are CH, CH₂, O, or S wherein no more than one heteroatom is present; D is (CH) m , and m is an integer 0 to 1; or D is (CH₂) n , and n is an integer 0 to 2; the dotted line, -----, represents the presence or absence of a double bond whereby if only one double bond is present, it is disposed to the a-b position; or if multiple double bonds are present they are in a conjugated position to produce an aromatic ring. R is hydrogen, methyl, ethyl, t-butyl, or trifluoro-methyl; Ar is: a moiety of the formula: wherein R₆ is hydrogen, methyl or ethyl; R₇ is hydrogen, methyl or ethyl; and X is CH₂OH, CHO, CO₂H, CN, CH₂CONH₂, or a moiety of the formula: and R₈ is straight or branched (C₁-C₈)alkyl, or wherein R₉ is hydrogen, straight or branched (C₁-C₁₀)alkyl, glycosyl, 2-methoxyethyl, 2-dimethyl-aminoethyl, (2,3 or 4)-pyridyl, or (2,3 or 4)-pyridyl-methyl; Y is hydrogen, and the pharmaceutically acceptable salts and esters.

Claim 5

A compound according to Claim 1 which is one of the following Z,E and E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid Ethyl Ester. E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid. Z,E and E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl)-1-cyclopenten-1-yl]-2,4-pentadienoid Acid Ethyl Ester. E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclopenten-1-yl]-2,4-pentadienoic Acid. Z,E,- and E,E-3-Methyl-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8,-tetrahydro-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid Ethyl Ester. E,E-3-Methyl-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid. Z,E- and E,E-3-Methyl-5-[2-(2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1-yl]-2,4-pentadienoic Acid Ethyl Ester. E,E-3-Methyl-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1-yl-2,4-pentadienoic Acid. 3-Methyl-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)phenyl]-2,4-pentadienoic Acid. ( Z , E )-5-[3-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-cyclohexen-1-yl]-2-propenylidene]-2,4-thiazolidinedione. 3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]-2,4-pentadienoic Acid. E,E-3-Methyl-5-[2-(1,1,3,3-tetramethyl-1,3-dihydro-5-isobenzofuranyl)-1-cyclopent-1-yl]-2,4-pentadienoic Acid.

Claim 6

A method for the treatment and prevention of coronary artery disease in a mammal which comprises administering a therapeutically effective amount of a compound of Claim 1.

Claim 7

A method of increasing plasma HDL levels in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Claim 1.

Claim 8

A method for the treatment of prevention of atherosclerosis in a mammal which comprises administering a therapeutically effective amount of a compound of Claim 1.

Claim 9

A method according to Claim 6 wherein said compound is E,E-3-Methyl-5-[2-(3,5,5,8,8-penta-methyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1yl-2,4-pentadienoic Acid. or E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid.

Claim 10

A method according to Claim 7 wherein said compound is E,E-3-Methyl-5-[2-(3,5,5,8,8-penta-methyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1yl-2,4-pentadienoic Acid. or E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexen-1-yl-2,4-pentadienoic Acid.

Claim 11

A method according to Claim 8 wherein said compound is E,E-3-Methyl-5-[2-(3,5,5,8,8-penta-methyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1-yl-2,4-pentadienoic Acid or E,E-3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexen-1-yl]-2,4-pentadienoic Acid.

Claim 12

A method of treating cancers by induction of tumor cell differentiation in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound as claimed in Claim 1.

Claim 14

A process for preparing a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt or ester thereof which comprises one of the following: a) reacting a compound of formula with an aldehyde of formula in which formulae Ar, A, B, C, D, R, and the dotted line are as defined in claim 1, X is CO₂R₈ and Y is hydrogen to give a corresponding compound of formula I; or b) hydrolysing a compound of formula I where X is COR₈ to give a carboxylic acid wherein X is CO₂H; or c) reducing a compound of formula I where X is CO₂R₈ or CO₂H to give a compound of formula I wherein X is CH₂OH; or d) reacting a compound of formula I wherein X is CO₂H with an activating reagent and followed by an amine of formula R₉NH₂ to give an amide of formula I wherein X is CONHR₉; or e) reacting a compound of formula VIII with a ylide of formula to give a corresponding compound of formula I wherein Ar, A, B, C, D, R, Y and R₈ are as defined above; or f) oxidising a compound of formula I wherein X is CH₂OH to give a compound of formula I wherein X is CHO; or g) dehydrating a compound of formula I wherein X is CONH₂ to give a compound of formula I wherein X is CN, eg using P₂O₅; or h) reacting a a compound of formula I wherein X is CN with sodium azide to give a compound of formula I wherein X is or i) reacting an aldehyde of formula wherein Ar, A, B, C, D and the dotted line are as defined above with 2,4-thiazolidinedione to give a compound of formula I wherein X and Y taken together represent

Claim 15

A process for preparing a compound of formula I according to Claim 1, which comprises reacting a compound of the formula ArBr or ArI with an alkyllithium, in an inert solvent, at -78°C to +30°C, followed by adding ZnCl₂; to give a compound of formula: ArZnCl reacting the ArZnCl with a compound of Formula II: in the presence of a palladium(0) catalyst, in an inert solvent, at 10°C to 60°C; to obtain a compound of Formula III: reducing the compound of Formula III with a hydride reducing agent in an inert solvent at 0°C to 60°C; to give a compound of Formula IV: reacting the compound of Formula IV with a trisub-stituted phosphine hydrobromide to give a compound of Formula V: reacting the compound of Formula V with a base, in an inert solvent,at 0°C; followed by addition of an aldehyde of the formula: wherein R is as defined in Claim 1; and X is CO₂R₈ and R₈ is as defined in Claim 1; to obtain a compound of Formula I.

Claim 16

A process for preparing a compound of formula I defined in Claim 1 wherein X is -CHO; which comprises reacting a compound of Formula I wherein X is -CO₂H or -CO₂R₈ and R₈ is as defined in Claim 1; with a hydride reducing agent, in an inert solvent, at 0°C to 60°C; to obtain a compound of Formula I wherein X is -CH₂OH; treating the compound of Formula I wherein X is CH₂OH with an oxidizing agent to give a compound of Formula I wherein X is -CHO.

Claim 17

A process for preparing a compound according to Claim 1 wherein X is -C(O)-NHR₉ wherein R₉ is as defined in Claim 1; which comprises reacting a compound of Formula I wherein X is -CO₂R₈ and R₈ is as defined in Claim 1: with a base under hydrolysis conditions at 30°C to 100°C, followed by acidification with a mineral acid; to obtain a compound of Formula I wherein X is -CO₂H; reacting the compound of Formula I wherein X is -CO₂H with an activating reagent in an inert solvent, at 0°C to 25°C; to give an intermediate; adding an amine of the formula R₉NH₂ to the intermediate, wherein R₉ is as defined in Claim 1; to obtain a compound of Formula I.

Claim 18

The process for preparing a compound according to Claim 1 wherein X is -CO₂R₈ and R₈ is as defined in Claim 1; which comprises reacting a compound of Formula IV: wherein Ar and Y are as defined hereinabove; with an oxidizing agent, in an inert solvent, at 0°C to 40°C; to give a compound of Formula VIII: reacting the compound of Formula VIII with an ylide of the formula: in the presence of a base in an inert solvent; to give a compound of Formula I.

Claim 19

A pharmaceutical composition which comprises a compound as claimed in any one of Claims 1 to 5 and a pharmaceutically acceptable carrier.