Cyclohexanediol derivatives

Details Cyclohexanediol derivatives Cyclohexanediol derivatives

1999-02-18

2001-02-06

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C556S443000, C560S231000, C568S669000, C568S670000, C568S828000

Reexamination Certificate

active

06184422

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to cyclohexanediol derivatives for treatment and prevention of hyperproliferative skin diseases and reversing conditions associated with photodamage.
SUMMARY OF THE INVENTION
The invention relates to the novel retiferol derivatives of formula I:
wherein
X is C═CH
2
or CH
2
;
Y and Z are independently of each other hydrogen, fluorine or hydroxy;
A is —C≡C—, —CH═CH— or —CH
2
—CH
2
—;
R
1
and R
2
are independently of each other alkyl or perfluoroalkyl; and
R
3
is lower alkyl.
Compounds of formula I can be utilized to treat or prevent hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis; neoplastic diseases; disorders of the sebaceous glands such as acne and seborrhoic dermatitis. The compounds of formula I can also be utilized in reversing the conditions associated with photodamage, particularly for the oral or topical treatment of the skin damaged through sun exposure, the effects of wrinkling, elastosis and premature ageing.
The present invention furthermore relates to a process for the preparation of compounds of formula I, pharmaceutical compositions containing such compounds, and the use of these compounds for the treatment and prevention of the above mentioned disorders, and for the manufacture of pharmaceutical compositions for the treatment and prevention of the above mentioned disorders.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the novel retiferol derivatives of formula I:
wherein
X is C═CH
2
or CH
2
;
Y and Z are independently of each other hydrogen, fluorine or hydroxy;
A is —C≡C—, —CH═CH— or —CH
2
—CH
2
—;
R
1
and R
2
are independently of each other alkyl or perfluoroalkyl; and
R
3
is lower alkyl.
Compounds of formula I can be utilized to treat or prevent hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis; neoplastic diseases; disorders of the sebaceous glands such as acne and seborrhoic dermatitis. The compounds of formula I can also be utilized in reversing the conditions associated with photodamage, particularly for the oral or topical treatment of the skin damaged through sun exposure, the effects of wrinkling, elastosis and premature ageing.
The present invention furthermore relates to a process for the preparation of compounds of formula I, pharmaceutical compositions containing such compounds, and the use of these compounds for the treatment and prevention of the above mentioned disorders, and for the manufacture of pharmaceutical compositions for the treatment and prevention of the above mentioned disorders.
The term “alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, amyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
The term “lower alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, amyl and 3-pentyl.
The term “perfluorinated lower alkyl” denotes alkyl groups as defined above wherein every hydrogen atom is substituted by fluorine, such as in trifluoromethyl, pentafluoroethyl, heptafluoropropyl and the like. Preferred perfluorinated lower alkyl groups are lower alkyl groups containing 1 to 3 carbon atoms, with 1 to 2 carbon atoms being especially preferred.
In the structural formulae presented herein a broken bond (
) denotes that the substituent is below the plane of the paper and a wedged bond (
) denotes that the substituent is above the plane of the paper.
Preferred compounds of formula I are compounds wherein at least one of Y and Z is hydroxy, in especially preferred compounds Y and Z are hydroxy.
Especially preferred compounds of formula I are compounds wherein A is —C═C—, for example
(1R,3R)-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene)-cyclohexane-1,3-diol;
(Z)-(1R,3S)-4-methylene-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene]-cyclohexane-1,3-diol;
(Z)-(1R,3S)-5-((2E,9E)-12,12,12-trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodec-2,9-dienylidene)-4-methylene-cyclohexane-1,3-diol;
(1R,3R)-5-[(2E,9E)-12,12,12-trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene]-cyclohexane-1,3-diol;
(1R,3R)-5-[(2E,9E)-11-hydroxy-7,7,11-trimethyl-dodeca-2,9-dien-ylidene]-cyclohexane-1,3-diol;
(Z)-(S)-3-[(2E,9E)-11-hydroxy-7,7,11-trimethyl-dodeca-2,9-dien-ylidene]-4-methylene-cyclohexane-1-ol;
(1R,3R)-5-[(2E,9E)-12,12,12-trifluoro-11-trifluoromethyl-11-hydroxy-7,7-dimethyl-dodeca-2,9-dienylidene]-cyclohexane-1,3-diol.
Especially preferred are compounds of formula I wherein A represents a cis configurated double bond —CH═CH—.
A further preferred embodiment are compounds of formula I wherein A is —CH
2
—CH
2
—, for example
(1R,3R)-5-[(2E)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-enylidene)-cyclohexane-1,3-diol;
(Z)-(1R,3S)-5-[(2E)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-enylidene]-4-methylene-cyclohexane-1,3-diol;
(Z)-(1S)-3-[(2E)-11-hydroxy-7,7,11-trimethyl-dodeca-2-en-ylidene]-4-methylene-cyclohexane-1-ol;
(Z)-(1R,3S)-5-[(E)-11-hydroxy-7,7,11-trimethyl-dodec-2-enylidene]-4-methylene-cyclohexane-1,3-diol;
(2E)-(1R,3R)-5-(11-hydroxy-7,7,11-trimethyl-dodeca-2-enylidene)-cyclohexane-1,3-diol.
Another preferred embodiment are compounds of formula I wherein A is —C≡C—, for example
(E)-(1R,3R)-5-[12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-en-9-ynylidene]-cyclohexane-1,3-diol;
(Z)-(1R,3S)-4-methylene-5-[(E)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-en-9-ynylidene]-cyclohexane-1,3-diol;
(Z)-(S)-4-methylene-3-[(E)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodec-2-en-9-ynylidene]-cyclohexane-1-ol;
(10E,12Z)-(S)-12-(5-hydroxy-2-methylene-cyclohexylidene)-6,6-dimethyl-2-methyl-dodec-10-en-3-yn-2-ol;
(10E)-(3R,5R)-12-(3,5-dihydroxy-cyclohexylidene)-6,6-dimethyl-2-methyl-dodec-10-en-3-yn-2-ol.
The compounds of formula I can be obtained by cleavage of the silyl protecting groups contained in compounds of formula II
wherein Y′ and Z′ are protected hydroxy groups and R
4
is a hydroxy protecting group. Any conventional hydroxy protecting group can be utilized to protect the free hydroxy groups in the compounds of this invention. Any cleavable or hydrolyzable ether or ester group can be utilized. Preferred hydrolyzable ester groups are alkanoic esters and preferred hydrolyzable ether groups are silyl ethers such as tert-butyldimethyl-silyl (TBDMS) for the hydroxy groups Y and Z, whereas R
4
is preferably trimethyl-silyl [Si(CH
3
)
3
].
The cleavage of the hydroxy protection groups can be effected by any standard means such as where the silyl ethers are utilized cleavage can be effected by use of tetrabutylammonium fluoride (TBAF) in an inert solvent such as tetrahydrofuran. Mild acid hydrolysis can be used to cleave the alkanoic ester groups.
The intermediates II, which are novel and as such are a further object of the present invention can be prepared by a Wittig-reaction with a compound of formula III according to the reaction scheme 1 depicted below. Compounds of formula III may be prepared according to the method described in EP-A 0 771 789.
wherein the symbols are as defined above.
Compounds of formula (1) which are oxidized to the aldehyde (2) can be prepared according to the reaction scheme 2:
wherein R
5
represents a hydroxy protecting group, preferably the tert. butyldimethylsilyl group, R
6
respresents another hydroxy protecting group, preferably the tetrahydropyranyl group whereas R
1
, R
2
and R
3
are as defined

Affiliated with

Also associated with

Rating

Cyclohexanediol derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclohexanediol derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclohexanediol derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2572713