Vitamin D3 analogs

Details Vitamin D3 analogs Vitamin D3 analogs

2000-08-25

2002-09-17

Qazi, Sabiha (Department: 1616)

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

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C514S167000

Reexamination Certificate

active

06452028

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to Vitamin D
3
analogs, particularly 20epi-16-ene analogs of Vitamin D
3
.
SUMMARY OF THE INVENTION
The invention relates to compounds of the formula
wherein R is hydrogen, fluorine, or hydroxyl, R
2
is lower alkyl or C(R
3
)
3
and R
3
is halogen, X is ═CH
2
or when R is hydroxy, X is hydrogen or ═CH
2
,
and A is —C≡C—,
or
—CH
2
—CH
2
—, provided that when A is —CH
2
—CH
2
—, R
2
is lower alkyl.
Compounds of formula I induce differentiation and inhibition of proliferation in various skin and cancer cell lines. Accordingly, the compounds of formula I are useful as agents for the treatment of hyperproliferative skin diseases, such as, psoriasis. Compounds of formula I are also useful in the treatment of neoplastic diseases, such as, leukemia or breast cancer and sebaceous gland diseases, such as, acne or seborrheic dermatitis.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “lower alkyl” denotes a straight or branched chain alkyl group containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Preferably lower alkyl is methyl or ethyl. Halogen means fluorine, iodine, bromine or chlorine, preferably, fluorine.
In the formulas presented herein, the various substituents are illustrated as joined to the nucleus by one of the following notations: a wedged solid line (
) indicating a substituent which is above the plane of the molecule, (&bgr;-orientation) and a wedged dotted line (
) indicating a substituent which is below the plane of the molecule (&agr;-orientation).
As used herein, the term “E” denotes
that is, a stereochemical configuration about a carbon-carbon double bond, such that the two hydrogens are attached to different carbon atoms, and are on opposite sides of the carbon-carbon double bond.
The term “Z” denotes
that is a stereochemical configuration about a carbon-carbon double bond, such that the two hydrogens are attached to different carbon atoms and are on the same side of the carbon-carbon double bond.
The invention relates to compounds of the formula
wherein R is hydrogen, fluorine, or hydroxyl, R
2
is lower alkyl or C(R
3
)
3
and R
3
is halogen, X is ═CH
2
, or when R is hydroxy X is hydrogen or ═CH
2
, and A is —c≡c—,
or
—CH
2
—CH
2
—, provided that when A is —CH
2
—CH
2
—, R
2
is lower alkyl.
Compounds of formula I induce differentiation and inhibition of proliferation in various skin and cancer cell lines. Accordingly, the compounds of formula I are useful as agents for the treatment of hyperproliferative skin diseases, such as, psoriasis. Compounds of formula I are also useful in the treatment of neoplastic diseases, such as, leukemia or breast cancer and sebaceous gland diseases, such as, acne or seborrheic dermatitis. Compounds of formula I, particularly 1&agr;-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-chole-calciferol, are useful in the treatment of osteoporosis, see U.S. copending patent application Ser. No. 08/857,569, filed May 16, 1997, which is incorporated by reference herein.
The invention also relates to a pharmaceutical composition comprising a compound of formula I and a method of treating neoplastic diseases, sebaceous gland diseases and hyperproliferative skin diseases by administration of a compound of formula I.
The invention also relates to a process for preparing compounds of formula I and intermediates of formula XII.
In a preferred embodiment, R is hydroxyl. In a compound of formula I, R
2
is preferably hydrogen or fluorine. In a preferred compound of formula I, A is double bond or triple bond or single bond. Preferred compounds of formula I are:
1,25-dihydroxy-16-ene-23-yne-20-epi-cholecalciferol;
1,25-dihydroxy-16-ene-20-epi-cholecalciferol;
1,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-20-epi-cholecalciferol;
1&agr;-fluoro-25-hydroxy-16,23Z-diene-26,27-hexafluoro20-epi-cholecalciferol;
1&agr;-fluoro-25-hydroxy-16-ene-23-yne-26,27-hexafluoro20-epi-cholecalciferol;
1,25-dihydroxy-16,23E-diene-26,27-hexafluoro-20-epi-cholecalciferol;
1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-20-epi-cholecalciferol;
1,25-dihydroxy-16,23Z-diene-19-nor-26,27-hexafluoro-20epi-cholecalciferol.
The compounds of formula I are prepared as hereafter described in Schemes I-V and the Examples.
wherein R
2
is as described above.
In above Scheme I, the compound of formula II, a known compound (B. M. Trost, P. R. Bernstein, P. C. Funfschilling, J. American Chemical Society 101, 4378 (1979)), is converted to the compound of formula III by reaction with acetic anhydride, pyridine and dimethylaminopyridine in a chlorinated hydrocarbon solvent, such as dichloromethane. The reaction is carried out at 0° C. to 50° C., preferably room temperature, preferably under an argon atmosphere.
The compound of formula III is converted to the compound of formula IV by reaction with a base, such as, sodium carbonate in an alcohol solvent, such as methanol, under, preferably, an argon atmosphere.
The compound of formula IV is converted to the compound of formula V by reaction with oxalyl chloride and dimethylsulfoxide in a chlorinated hydrocarbon solvent, such as, dichloromethane, under an argon atmosphere.
The compound of formula V is converted to the compound of formula VI by reaction with benzalacetone in the presence of palladium on charcoal catalyst.
The compound of formula VI is converted to the compound of formula VII by reaction with a 3-trimethylsilylpropynal and a Lewis acid such as dimethylaluminum chloride in a chlorinated hydrocarbon solvent, such as dichloromethane.
The compound of formula VII is converted to the compound of formula VIII by reaction of the corresponding phenylthiono-carbonate with tri-n-butylhydride and triethylborane in toluene.
The compound of formula VIII is converted to the compound of formula IX by reaction with a base, such as, sodium hydroxide in an alcohol solvent, such as ethanol. The reaction is carried out at a temperature in the range of 50° C. to 100° C., preferably 80° C.
The compound of formula IX is converted to the compound of formula X by reaction with 1-(trimethylsilyl)imidazole in a chlorinated hydrocarbon solvent, such as anhydrous methylene chloride.
The compound of formula X is converted to a compound of formula XI by reaction with the corresponding compound
of formula
wherein R
2
′ is hydrogen, or lower alkyl in the presence of a base such as n-butyllithium.
The reaction is preferably carried out at −78° C.
When the compounds of formula I wherein R
2
is halogen are prepared, the compound of formula X is reacted with a halogenated acetone, such as hexafluoroacetone in the presence of a base such as n-butyllithium.
The compound of formula XI is converted to the corresponding compound of formula XII by reaction with tetrabutylammonium fluoride in an ether solvent such as, tetrahydrofuran.
wherein R, X and R
2
are as described above.
As set forth in Scheme II, a compound of formula XII is converted to a corresponding compound of formula XIII by reaction with an oxidizing agent such as, pyridinium dichromate in a chlorinated hydrocarbon solvent such as, anhydrous methylene chloride.
A compound of formula XIII is converted to a corresponding compound of formula XIV by reaction with 1-(trimethylsilyl)imidazole in a chlorinated hydrocarbon solvent, such as, anhydrous methylene chloride.
A compound of formula XIV is converted to a corresponding compound of formula Ia wherein R is hydroxy and X is ═CH
2
, by reaction with [3S-(1Z,3&agr;,5&bgr;)]-[2-[3,5-bis[[1,1-dimethylethyl)-dimethylsilyl]oxy]-2-methylene-cyclohexylidene]ethyl]diphenyl-phosphine oxide in an ether like solvent such as tetrahydrofuran in the presence of n-butyllithium as a base.
Alternatively, a compound of formula XIV is converted to the corresponding compound of formula Ia wherein R is hydrogen by reaction with [5S,Z]-2-[2-[2-methylene-5-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]

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