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Details for Patent: 5,968,989

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Details for Patent: 5,968,989

Title: Means for the modulation of processes mediated by retinoid receptors and compounds useful therefor
Abstract:In accordance with the present invention, there are provided methods to modulate processes mediated by retinoid receptors, employing high affinity, high specificity ligands for such receptors. In one aspect of the present invention, there are provided ligands which are more selective for the retinoid X receptor than is retinoic acid (i.e., rexoids). In another aspect of the present invention, alternative ligands (other than retinoic acid) have been discovered which are capable of inducing retinoic acid receptor mediated processes. In yet another aspect, methods have been developed for the preparation of such retinoid receptor ligands from readily available compounds.
Inventor(s): Evans; Ronald M. (La Jolla, CA), Mangelsdorf; David J. (Dallas, TX), Heyman; Richard A. (Encinitas, CA), Boehm; Marcus F. (San Diego, CA), Eichele; Gregor (Houston, TX), Thaller; Christina (Houston, TX)
Assignee: The Salk Institute for Biological Studies (La Jolla, CA) Baylor College of Medicine (Houston, TX) Ligand Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:Jun 07, 1995
Application Number:08/472,817
Claims:1. A method of modulating RXR-mediated activity, said method comprising administering a pharmaceutical composition comprising:

a compound that is more potent as a modulator for retinoid X receptor (RXR) in a cotransfection assay than is all-trans-retinoic acid, and a pharmaceutically acceptable carrier therefor;

wherein said compound has the structure: ##STR16## wherein: unsaturation between carbon atoms C.sup.9 and C.sup.10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C.sup.11 through C.sup.14 optionally have a cis configuration;

"Ring" is a 5-, 6- or 7-membered carbocyclic, heterocyclic, aromatic or heteroaromatic moiety, optionally having one or more substituents thereon;

Z is selected from carboxyl (--COOH), carboxaldehyde (--CHO), hydroxyalkyl (--(CR'.sub.2).sub.n --OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n is 1 to 4), thioalkyl (--(CR'.sub.2).sub.n --SH, wherein R' and n are as defined above), hydroxyalkyl phosphate (--(CR'.sub.2).sub.n --OP(OM).sub.3, wherein R' and n are as defined above and M is hydrogen, lower alkyl, or an alkali metal cation), alkyl ether of a hydroxyalkyl group (--(CR'.sub.2).sub.n --OR', wherein R' and n are as defined above), alkyl thioether of a thioalkyl group (--(CR'.sub.2).sub.n --SR', wherein R' and n are as defined above), esters of hydroxyalkyl groups (--(CR'.sub.2).sub.n --O--CO--R', wherein R' and n are as defined above), thioesters of hydroxyalkyl group (--(CR'.sub.2).sub.n --O--CS--R', wherein R' and n are as defined above), esters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CO--R', wherein R' and n are as defined above), thioesters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CS--R', wherein R' and n are as defined above), aminoalkyl (--(CR'.sub.2).sub.n --NR'.sub.2, wherein R' and n are as defined above), N-acyl aminoalkyl (--(CR'.sub.2).sub.n --NR'--CO--R", wherein R' and n are as defined above and R" is a lower alkyl or benzyl), carbamate (--(CR'.sub.2).sub.n --NR'--CO--OR' or --(CR'.sub.2).sub.n --O--CO--NR'.sub.2, wherein R' and n are as defined above); and

each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, keto or any of the Z substituents; or

any two or more of the R groups can be linked to one another to form one or more ring structures as follows: ##STR17## wherein: X is --((CR.sub.2).sub.x --X'--(CR.sub.2).sub.y)--,

X' is selected from --O--, carbonyl (>CO), --S--, --S(O)--, --S(O).sub.2 --, thiocarbonyl (>CS), --NR"--, or --CR.sub.2 --,

R, Ring and Z are as defined above,

R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl (--CO--O-alkyl);

x is 0, 1 or 2,

y is 0, 1, or 2, and

x+y.ltoreq.2; ##STR18## wherein: X, X', R, R", Z, Ring, x and y are as defined above; ##STR19## wherein: X" is --((CR.sub.2).sub.a --X'--(CR.sub.2).sub.b)--,

X', R, R", Ring and Z are as defined above,

a is 0, 1, 2, 3 or 4,

a is 0, 1, 2, 3, or 4, and

b is 0, 1, 2, 3, or 4, and

a+b is.gtoreq.2, but.ltoreq.4; ##STR20## wherein: Y is --((CR.sub.2).sub.c --X'--(CR.sub.2).sub.d)--,

X', R, R", Ring and Z are as defined above,

c is 0, 1, 2 or 3,

d is 0, 1, 2or 3, and

c+d 1 but.ltoreq.3; ##STR21## wherein: X"' is X" or an unsaturated linking group having the structure:

wherein Q is --N.dbd. or --CR.dbd., and J is --CR.dbd.CR--, --N.dbd.CR--, --CR.dbd.N--, --O--, --S--, or --NR"--,

thereby incorporating C9 and C10 of the structure VII compound into an aromatic (or pseudo-aromatic) ring, and

X', X", R, R", Ring, Z, a and b are as defined above.

2. (New) The method according to claim 1, wherein said compound is at least about 4 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

3. The method according to claim 2, wherein said compound is at least about 10 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

4. The method according to claim 3, wherein said compound is at least about 20 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

5. The method according to claim 4, wherein said compound is at least about 30 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

6. The method according to claim 5, wherein said compound is at least about 40 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

7. A method of modulating RXR-mediated activity, said method comprising administering a pharmaceutical composition comprising:

a compound that is more potent as a modulator for retinoid X receptor (RXR) in a binding assay than is all-trans-retinoic acid, and a pharmaceutically acceptable carrier therefor,

wherein said compound has the structure: ##STR22## wherein: unsaturation between carbon atoms C.sup.9 and C.sup.10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C.sup.11 through C.sup.14 optionally have a cis configuration;

"Ring" is a 5-, 6- or 7-membered carbocyclic, heterocyclic, aromatic or heteroaromatic moiety, optionally having one or more substituents thereon;

Z is selected from carboxyl (--COOH), carboxaldehyde (--CHO), hydroxyalkyl (--(CR'.sub.2).sub.n --OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n is 1 to 4), thioalkyl (--(CR'.sub.2).sub.n --SH, wherein R' and n are as defined above), hydroxyalkyl phosphate (--(CR'.sub.2).sub.n --OP(OM).sub.3, wherein R' and n are as defined above and M is hydrogen, lower alkyl, or an alkali metal cation), alkyl ether of a hydroxyalkyl group (--(CR'.sub.2).sub.n --OR', wherein R' and n are as defined above), alkyl thioether of a thioalkyl group (--(CR'.sub.2).sub.n --SR', wherein R' and n are as defined above), esters of hydroxyalkyl groups (--(CR'.sub.2).sub.n --O--CO--R', wherein R' and n are as defined above), thioesters of hydroxyalkyl group (--(CR'.sub.2).sub.n --O--CS--R', wherein R' and n are as defined above), esters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CO--R', wherein R' and n are as defined above), thioesters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CS--R', wherein R' and n are as defined above), aminoalkyl (--(CR'.sub.2).sub.n --NR'.sub.2, wherein R' and n are as defined above), N-acyl aminoalkyl (--(CR'.sub.2).sub.n --NR'--CO--R", wherein R' and n are as defined above and R" is a lower alkyl or benzyl), carbamate (--(CR'.sub.2).sub.n --NR'--CO--OR' or --(CR'.sub.2).sub.n --O--CO--NR'.sub.2, wherein R' and n are as defined above); and

each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, keto or any of the Z substituents; or

any two or more of the R groups can be linked to one another to form one or more ring structures as follows: ##STR23## wherein: X is --((CR.sub.2).sub.x --X'--(CR.sub.2).sub.y)--,

X' is selected from --O--, carbonyl (>CO), --S--, --S(O)--, --S(O).sub.2 --, thiocarbonyl (>CS), --NR"--, or --CR.sub.2 --,

R, Ring and Z are as defined above,

R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl (--CO--O-alkyl);

x is 0, 1 or 2,

y is 0, 1, or 2, and

x+y.ltoreq.2; ##STR24## wherein: X, X', R, R", Z, Ring, x and y are as defined above; ##STR25## wherein: X" is --((CR.sub.2).sub.a --X'--(CR.sub.2).sub.b)--,

X', R, R", Ring and Z are as defined above,

a is 0, 1, 2, 3 or 4,

b is 0, 1, 2, 3, or 4, and

a+b is.gtoreq.2, but.ltoreq.4; ##STR26## wherein: Y is --((CR.sub.2).sub.c --X'--(CR.sub.2).sub.d)--,

X', R, R", Ring and Z are as defined above,

c is 0, 1, 2or 3,

d is 0, 1, 2 or 3, and

c+d 1, but.ltoreq.3; ##STR27## wherein: X"' is X" or an unsaturated linking group having the structure:

wherein Q is --N.dbd. or --CR.dbd., and J is --CR.dbd.CR--, --N.dbd.CR--, --CR.dbd.N--, --O--, --S--, or --NR"--,

thereby incorporating C.sup.9 and C.sup.10 of the structure VII compound into an aromatic (or pseudo-aromatic) ring, and

X', X", R, R", Ring, Z, a and b are as defined above, with the proviso that said compound is not 9-cis retinoic acid.

8. The method according to claim 7, wherein said compound is at least about 4 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

9. The method according to claim 8, wherein said compound is at least about 10 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

10. The method according to claim 9, wherein said compound is at least about 20 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

11. The method according to claim 10, wherein said compound is at least about 30 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

12. The method according to claim 11, wherein said compound is at least about 40 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

13. A method of modulating RXR-mediated activity, said method comprising administering a pharmaceutical composition comprising:

a compound which binds retinoid X receptor (RXR), and

a pharmaceutically acceptable carrier therefor,

wherein said compound has the structure: ##STR28## wherein: unsaturation between carbon atoms C.sup.9 and C.sup.10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C.sup.11 through C.sup.14 optionally have a cis configuration;

"Ring" is a 5-, 6- or 7-membered carbocyclic, heterocyclic, aromatic or heteroaromatic moiety, optionally having one or more substituents thereon;

Z is selected from carboxyl (--COOH), carboxaldehyde (--CHO), hydroxyalkyl (--(CR'.sub.2).sub.n --OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n is 1 to 4), thioalkyl (--(CR'.sub.2).sub.n --SH, wherein R' and n are as defined above), hydroxyalkyl phosphate (--(CR'.sub.2).sub.n --OP(OM).sub.3, wherein R' and n are as defined above and M is hydrogen, lower alkyl, or an alkali metal cation), alkyl ether of a hydroxyalkyl group (--(CR'.sub.2).sub.n --OR', wherein R' and n are as defined above), alkyl thioether of a thioalkyl group (--(CR'.sub.2).sub.n --SR', wherein R' and n are as defined above), esters of hydroxyalkyl groups (--(CR'.sub.2).sub.n --O--CO--R', wherein R' and

n are as defined above), thioesters of hydroxyalkyl group (--(CR'.sub.2).sub.n --O--CS--R', wherein R' and n are as defined above), esters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CO--R', wherein R' and n are as defined above), thioesters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CS--R', wherein R' and n are as defined above), aminoalkyl (--(CR'.sub.2).sub.n --NR'.sub.2, wherein R' and n are as defined above), N-acyl aminoalkyl (--(CR'.sub.2).sub.n --NR'--CO--R", wherein R' and n are as defined above and R" is a lower alkyl or benzyl), carbamate (--(CR'.sub.2).sub.n --NR'--CO--OR' or --(CR'.sub.2).sub.n --O--CO--NR'.sub.2, wherein R' and n are as defined above); and

each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, keto or any of the Z substituents; or

any two or more of the R groups can be linked to one another to form one or more ring structures as follows: ##STR29## wherein: X is --((CR.sub.2).sub.x --X'--(CR.sub.2).sub.y)--,

X' is selected from --O--, carbonyl (>CO), --S--, --S(O)--, --S(O).sub.2 --, thiocarbonyl (>CS), --NR"--, or --CR.sub.2 --,

R, Ring and Z are as defined above,

R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl (--CO--O-alkyl);

x is 0, 1 or 2,

y is 0, 1, or 2, and

x+y.ltoreq.2; ##STR30## wherein: X, X', R, R", Z, Ring, x and y are as defined above; ##STR31## wherein: X" is --((CR.sub.2).sub.a --X'--(CR.sub.2).sub.b)--,

X', R, R", Ring and Z are as defined above,

a is 0, 1, 2, 3 or 4,

b is 0, 1, 2, 3, or 4, and

a+b is.gtoreq.2, but.ltoreq.4; ##STR32## wherein: Y is --((CR.sub.2).sub.c --X'--(CR.sub.2).sub.d)--,

X', R, R", Ring and Z are as defined above,

c is 0, 1, 2 or 3,

d is 0, 1, 2 or 3, and

c+d 1, but.ltoreq.3; ##STR33## wherein: X"' is X" or an unsaturated linking group having the structure:

wherein Q is --N.dbd. or --CR.dbd., and J is --CR.dbd.CR--, --N.dbd.CR--, --CR.dbd.N--, --O--, --S--, or --NR"--,

thereby incorporating C.sup.9 and C.sup.10 of the structure VII compound into an aromatic (or pseudo-aromatic) ring, and

X', X", R, R", Ring, Z, a and b are as defined above, with the proviso that said compound is not 9-cis retinoic acid.

14. The method according to claim 13, wherein said compound has a higher binding affinity for retinoid X receptor than for all-trans-retinoic acid.

15. A method of modulating RXR-mediated and RAR-mediated activity, said method comprising administering a pharmaceutical composition comprising:

a compound which modulates both RXR-mediated and RXR-mediated activity, and

a pharmaceutically acceptable carrier therefor,

wherein said compound has the structure: ##STR34## wherein: unsaturation between carbon atoms C.sup.9 and C.sup.10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C.sup.11 through C.sup.14 optionally have a cis configuration;

"Ring" is a 5-, 6- or 7-membered carbocyclic, heterocyclic, aromatic or heteroaromatic moiety, optionally having one or more substituents thereon;

Z is selected from carboxyl (--COOH), carboxaldehyde (--CHO), hydroxyalkyl (--(CR'.sub.2).sub.n --OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n is 1 to 4), thioalkyl (--(CR'.sub.2).sub.n --SH, wherein R' and n are as defined above), hydroxyalkyl phosphate (--(CR'.sub.2).sub.n --OP(OM).sub.3, wherein R' and n are as defined above and M is hydrogen, lower alkyl, or an alkali metal cation), alkyl ether of a hydroxyalkyl group (--(CR'.sub.2).sub.n --OR', wherein R' and n are as defined above), alkyl thioether of a thioalkyl group (--(CR'.sub.2).sub.n --SR', wherein R' and n are as defined above), esters of hydroxyalkyl groups (--(CR'.sub.2).sub.n --O--CO--R', wherein R' and n are as defined above), thioesters of hydroxyalkyl group (--(CR'.sub.2).sub.n --O--CS--R', wherein R' and n are as defined above), esters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CO--R', wherein R' and n are as defined above), thioesters of thioalkyl groups (--(CR'.sub.2).sub.n --S--CS--R', wherein R' and n are as defined above), aminoalkyl (--(CR'.sub.2).sub.n --NR'.sub.2, wherein R' and n are as defined above), N-acyl aminoalkyl (--(CR'.sub.2).sub.n --NR'--CO--R", wherein R' and n are as defined above and R" is a lower alkyl or benzyl), carbamate (--(CR'.sub.2).sub.n --NR'--CO--OR' or --(CR'.sub.2).sub.n --O--CO--NR'.sub.2, wherein R' and n are as defined above); and

each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, keto or any of the Z substituents; or

any two or more of the R groups can be linked to one another to form one or more ring structures as follows: ##STR35## wherein: X is --((CR.sub.2).sub.x --X--(CR.sub.2).sub.y)--,

X' is selected from --O--, carbonyl (>CO), --S--, --S(O)--, --S(O).sub.2 --, thiocarbonyl (>CS), --NR"--, or --CR.sub.2 --,

R, Ring and Z are as defined above,

R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl (--CO--O-alkyl);

x is 0, 1 or 2,

y is 0, 1, or 2, and

x+y.ltoreq.2; ##STR36## wherein: X, X', R, R", Z, Ring, x and y are as defined above; ##STR37## wherein: X" is --((CR.sub.2).sub.a --X'--(CR.sub.2).sub.b)--,

X', R, R", Ring and Z are as defined above,

a is 0, 1, 2, 3 or 4,

b is 0, 1, 2, 3, or 4, and

a+b is.gtoreq.2, but.ltoreq.4; ##STR38## wherein: Y is --((CR.sub.2).sub.c --X'--(CR.sub.2).sub.d)--,

X', R, R", Ring and Z are as defined above,

c is 0, 1, 2 or 3,

d is 0, 1, 2 or 3, and

c+d 1 but.ltoreq.3; ##STR39## wherein: X"' is X" or an unsaturated linking group having the structure:

wherein Q is --N.dbd. or --CR.dbd., and J is --CR.dbd.CR--, --N.dbd.CR--, --CR.dbd.N--, --O--, --S--, or --NR"--,

thereby incorporating C.sup.9 and C.sup.10 of the structure VII compound into an aromatic (or pseudo-aromatic) ring, and

X', X", R, R", Ring, Z, a and b are as defined above, with the proviso that said compound is not 9-cis retinoic acid.

16. The method according to claim 15, wherein said compound is at least about 4 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid in a cotransfection assay.

17. The method according to claim 16, wherein said compound is at least about 40 fold more potent as a modulator for retinoid X receptor than is all-trans-retinoic acid.

18. The method according to claim 15, wherein said compound activates expression of apolipoprotein A1 to modulate lipid metabolism in a subject.

19. The method according to claim 15, wherein said compound modulates skin-related processes in a subject.

20. The method according to claim 19, further comprising administering a potentiating, effective amount of interferon-.alpha. along with said compound.

21. The method according to claim 19, wherein said skin-related process is a non-malignant skin disorder.

22. The method according to claim 21, wherein said non-malignant skin disorder is selected from the group consisting of aging, wrinkling, acne, keratinization, differentiation and proliferation disorders.

23. The method according to claim 22, further comprising administering a potentiating, effective amount of interferon-.alpha. along with said compound.

24. The method according to claim 19, wherein said skin-related process is the development of benign tumors.

25. The method according to claim 15, wherein said compound modulates malignant cell development in a subject.

26. The method according to claim 25, wherein said malignant cell development is selected from the group consisting of testicular cancer, lung cancer or acute promyelocytic leukemia.

27. The method according to claim 25, wherein said malignant cell development is skin cancer.

28. The method according to claim 25, further comprising preventing the development of malignant epithelial tumors.
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