Claims
- 1. A compound of Formula I: ##STR56## wherein: A, B and C are CH, CH.sub.2, O, or S wherein no more than one heteroatom is present;
- D is (CH).sub.m, and m is an integer 0 to 1; or D is (CH.sub.2).sub.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: ##STR57## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are hydrogen, (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy or trifluoromethyl;
- a moiety of the formula: ##STR58## wherein R.sub.5 is hydrogen, (C.sub.1 -C.sub.3)alkyl, methoxy or trifluoromethyl;
- R.sub.6 is hydrogen, methyl or ethyl;
- or a moiety of the formula: ##STR59## wherein R.sub.6 is hydrogen, methyl or ethyl; R.sub.7 is hydrogen, methyl or ethyl; Y is hydrogen, and X is CH.sub.2 OH, CHO, CO.sub.2 H, CN, CH.sub.2 CONH.sub.2, or a moiety of the formula: ##STR60## and R.sub.8 is straight or branched (C.sub.1 -C.sub.8)alkyl, or ##STR61## wherein R.sub.9 is hydrogen, straight or branched (C.sub.1 -C.sub.10)alkyl, glycosyl, 2-methoxyethyl, 2-dimethylaminoethyl, (1,2 or 3)-pyridyl, or (1,2 or 3)-pyridylmethyl; or X and Y taken together form the thiazolidinedione ring of the formula: ##STR62## and the pharmaceutically acceptable salts and esters.
- 2. A compound of Formula I: ##STR63## wherein: A, B and C are CH, CH.sub.2, O, or S wherein no more than one heteroatom is present;
- D is (CH).sub.m, and m is an integer 0 to 1; or D is (CH.sub.2).sub.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: ##STR64## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are hydrogen, (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy or trifluoromethyl; and
- X is CH.sub.2 OH, CHO, CO.sub.2 H, CN, CH.sub.2 CONH.sub.2, or a moiety of the formula: ##STR65## and R.sub.8 is straight or branched (C.sub.1 -C.sub.8)alkyl, or ##STR66## wherein R.sub.9 is hydrogen, straight or branched (C.sub.1 -C.sub.10)alkyl, glycosyl, 2-methoxyethyl, 2-dimethylaminoethyl, (1,2 or 3)-pyridyl, or (1,2 or 3)-pyridylmethyl; Y is hydrogen,
- and the pharmaceutically acceptable salts and esters.
- 3. A compound of Formula I: ##STR67## wherein: A is CH or CH.sub.2 ;
- B and C are CH, CH.sub.2, O, or S wherein no more than one heteroatom is present;
- D is (CH).sub.m, and m is an integer 0 to 1; or D is (CH.sub.2).sub.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: ##STR68## wherein R.sub.5 is hydrogen, (C.sub.1 -C.sub.3)alkyl, methoxy or trifluoromethyl;
- R.sub.6 is hydrogen, methyl or ethyl, and
- X is CH.sub.2 OH, CHO, CO.sub.2 H, CN, CH.sub.2 CONH.sub.2, or a moiety of the formula: ##STR69## and R.sub.8 is straight or branched (C.sub.1 -C.sub.8)alkyl, or ##STR70## wherein R.sub.9 is hydrogen, straight or branched (C.sub.1 -C.sub.10)alkyl, glycosyl, 2-methoxyethyl, 2-dimethylaminoethyl, (1,2 or 3)-pyridyl, or (1,2 or 3)-pyridylmethyl; Y is hydrogen,
- and the pharmaceutically acceptable salts and esters.
- 4. A compound of Formula I: ##STR71## wherein: A is CH or CH.sub.2 ;
- B and C are CH, CH.sub.2, O, or S wherein no more than one heteroatom is present;
- D is (CH).sub.m, and m is an integer 0 to 1; or D is (CH.sub.2).sub.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: ##STR72## wherein R.sub.6 is hydrogen, methyl or ethyl; R.sub.7 is hydrogen, methyl or ethyl; and
- X is CH.sub.2 OH, CHO, CO.sub.2 H, CN, CH.sub.2 CONH.sub.2, or a moiety of the formula: ##STR73## and R.sub.8 is straight or branched (C.sub.1 -C.sub.8)alkyl, or ##STR74## wherein R.sub.9 is hydrogen, straight or branched (C.sub.1 -C.sub.10)alkyl, glycosyl, 2-methoxyethyl, 2-dimethylaminoethyl, (1,2 or 3)-pyridyl, or (1,2 or 3)-pyridylmethyl; Y is hydrogen,
- and the pharmaceutically acceptable salts and esters.
- 5. A compound according to claim 3, 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.
- 6. A compound according to claim 3, 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.
- 7. A compound according to claim 3, 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.
- 8. A compound according to claim 3, 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.
- 9. A compound according to claim 3, Z,E,- and E,E-3-Methy-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.
- 10. A compound according to claim 3, 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.
- 11. A compound according to claim 3, 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.
- 12. A compound according to claim 3, 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.
- 13. A compound according to claim 3, 3-Methyl-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)phenyl]-2,4-pentadienoic Acid.
- 14. A compound according to claim 3, (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.
- 15. A compound according to claim 3, 3-Methyl-5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)phenyl]-2,4-pentadienoic Acid.
- 16. A compound according to claim 4, E,E-3-Methyl-5-[2-(1,1,3,3-tetramethyl-1,3-dihydro-5-isobenzofuranyl)-1-cyclopent-1-yl]-2,4-pentadienoic Acid.
- 17. A method for the treatment of coronary artery disease in a mammal which comprises administering a therapeutically effective amount of a compound of claim 1.
- 18. 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.
- 19. A method for the treatment of atherosclerosis in a mammal which comprises administering a therapeutically effective amount of a compound of claim 1.
- 20. A method according to claim 17 wherein said compound is E,E-3-Methyl-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1yl-2,4-pentadienoic Acid.
- 21. A method according to claim 17 wherein said compound is 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.
- 22. A method according to claim 18 wherein said compound is E,E-3-Methyl-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopenten-1yl-2,4-pentadienoic Acid.
- 23. A method according to claim 18 wherein said compound is 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.
- 24. A method according to claim 19 wherein said compound is 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.
- 25. A method according to claim 19 wherein said compound is 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.
- 26. 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 of claim 1.
- 27. A compound according to claim 26, 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.
- 28. A compound according to claim 26, 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.
- 29. A process for preparing a compound according to claim 1, ##STR75## wherein Ar, A, B, C, D, a, b, R and the dotted line (----) are as defined in claim 1;
- which comprises reacting a compound of the formula ArBr or ArI with an alkyllithium, in an inert solvent, at -78.degree. C. to +30.degree. C., followed by adding ZnCl.sub.2 ; to give a compound of formula:
- ArZnCL
- reacting the ArZnCl with a compound of Formula II: ##STR76## in the presence of a palladium(0) catalyst, in an inert solvent, at 10.degree. C. to 60.degree. C.; to obtain a compound of Formula III: ##STR77## reducing the compound of Formula III with a hydride reducing agent in an inert solvent at 0.degree. C. to 60.degree. C.; to give a compound of Formula IV: ##STR78## reacting the compound of Formula IV with a trisubstituted phosphine hydrobromide to give a compound of Formula V: ##STR79## reacting the compound of Formula V with a base, in an inert solvent, at 0.degree. C.; followed by addition of an aldehyde of the formula: ##STR80## wherein R is as defined in claim 1; and X is CO.sub.2 R.sub.8 and R.sub.8 is as defined in claim 1; to obtain a compound of Formula I.
- 30. A process for preparing a compound according to claim 1, ##STR81## wherein Ar, A, B, C, D, a, b, R and the dotted line (---) are as defined in claim 1; and
- X is --CHO;
- which comprises reacting a compound of Formula I: ##STR82## wherein Ar, A, B, C, D, a, b, R and the dotted line (---) are as defined in claim 1; and
- X is --CO.sub.2 H or --CO.sub.2 R.sub.8 and R.sub.8 is as defined in claim 1;
- with a hydride reducing agent, in an inert solvent, at 0.degree. C. to 60.degree. C.; to obtain a compound of Formula I wherein X is --CH.sub.2 OH; treating the compound of Formula I wherein X is CH.sub.2 OH with an oxidizing agent to give a compound of Formula I wherein X is --CHO.
- 31. A process for preparing a compound according to claim 1, ##STR83## wherein Ar, A, B, C, D, a, b and R are as defined in claim 1; and X is --C(O)--NHR.sub.9 wherein R.sub.9 is as defined in claim 1;
- which comprises reacting a compound of Formula I: ##STR84## wherein Ar, A, B, C, D, a, b and R are as defined in claim 1; and X is --CO.sub.2 R.sub.8 and R.sub.8 is as defined in claim 1:
- with a base under hydrolysis conditions at 30.degree. C. to 100.degree. C., followed by acidification with a mineral acid; to obtain a compound of Formula I wherein X is --CO.sub.2 H; reacting the compound of Formula I wherein X is --CO.sub.2 H with an activating reagent in an inert solvent, at 0.degree. C. to 25.degree. C.; to give an intermediate; adding an amine of the formula R.sub.9 NH.sub.2 to the intermediate, wherein R.sub.9 is as defined in claim 1; to obtain a compound of Formula I.
- 32. The process for preparing a compound according to claim 1: ##STR85## wherein Ar, A, B, C, D, a, b and R are as defined in claim 1; and X is --CO.sub.2 R.sub.8 and R.sub.8 is as defined in claim 1;
- which comprises reacting a compound of Formula IV: ##STR86## wherein Ar and Y are as defined hereinabove; with an oxidizing agent, in an inert solvent, at 0.degree. C. to 40.degree. C.; to give a compound of Formula VIII: ##STR87## reacting the compound of Formula VIII with an ylide of the formula: ##STR88## in the presence of a base in an inert solvent; to give a compound of Formula I.
- 33. A pharmaceutical composition which comprises a compound of claim 1 and a suitable carrier.
Parent Case Info
This is a continuation-in-part of U.S. Ser. No. 08/359,141, filed Dec. 19, 1994.
Foreign Referenced Citations (3)
Number |
Date |
Country |
94112461 |
Aug 1994 |
EPX |
95110460 |
Jul 1995 |
EPX |
WO 9605165 |
Feb 1996 |
WOX |
Continuation in Parts (1)
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Number |
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Parent |
359141 |
Dec 1994 |
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