Prostagladin derivatives

Details Prostagladin derivatives Prostagladin derivatives

2000-11-27

2001-12-11

Carr, Deborah D. (Department: 1621)

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

Organic compounds

Fatty compounds having an acid moiety which contains the...

C514S530000

Reexamination Certificate

active

06329539

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel prostaglandin derivatives.
BACKGROUND ART
Since prostaglandin (hereinafter referred to as “PG”) exhibits various important physiological actions in a trace amount, the syntheses of the derivatives from natural PGs and the biological activities have been investigated with the intention of a practical use as medicines and have been reported in many literatures.
Particularly, PGs have been reported on their various central nervous actions and have been clarified as to the intracerebral content, biosynthesis, metabolic pathway, their intracerebral localizations and changes with growth or aging, and there has been taken an interest in the relation of PGs with sleep and wake. Among them, PGD
2
has been known as an intracerebral humoral factor which controls the occurrence or maintenance of sleep, and it was made clear that the sleep induced by PGD
2
in monkeys is undistinguished from the spontaneous natural sleep in brain wave or behavior (Proc. Natl. Acad. Sci. USA, vol. 85, pp. 4082-4086 (1988)), therefore this compound was expected as a compound having a novel sleep-inducing action.
However, PGD
2
derivatives including PGD
2
are presently unpractical due to the problems concerning the effect and the stability as a drug.
DISCLOSURE OF THE INVENTION
As a result of the extensive studies, the present inventors have found that the prostaglandin derivatives having a triple bond between the 13- and 14-positions represented by the following Formula (I) have a characteristic sleep-inducing action, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by Formula (I):
wherein X is a halogen atom, n is an integer of 1 to 5, R
1
is a C
3-10
cycloalkyl group, a C
3-10
cycloalkyl group substituted with C
1-4
alkyl group(s), a C
4-13
cycloalkylalkyl group, a C
5-10
alkyl group, a C
5-10
alkenyl group, a C
5-10
alkynyl group or a bridged cyclic hydrocarbon group, and R
2
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group, or a pharmaceutically acceptable salt thereof.
Further, the present invention is directed to a prostaglandin derivative represented by Formula (I) wherein R
1
is a C
3-10
cycloalkyl group, a C
3-10
cycloalkyl group substituted with C
1-4
alkyl group(s) or a C
4-13
cycloalkylalkyl group, and X, n and R
2
are as defined above, or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention is directed to a pharmaceutical composition which comprises as an effective ingredient the above-mentioned prostaglandin derivative represented by Formula (I) or the pharmaceutically acceptable salt thereof.
Still furthermore, the present invention is directed to a sleep-inducing preparation which comprises as an effective ingredient the above-mentioned prostaglandin derivative represented by Formula (I) or the pharmaceutically acceptable salt thereof.
Still furthermore, the present invention is directed to a method for sleep-inducing comprising administering a pharmacologically effective amount of the above-mentioned prostaglandin derivative or the pharmaceutically acceptable salt to a human.
In the present invention, the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the C
3-10
cycloalkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
Examples of the C
3-10
cycloalkyl group substituted with C
1-4
alkyl group(s) are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
Examples of the C
4-13
cycloalkylalkyl group are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The C
5-10
alkyl group refers to a straight or branched alkyl group, and examples thereof are a pentyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group and a 2,6-dimethylheptyl group.
The C
5-10
alkenyl group refers to a straight or branched alkenyl group, and examples thereof are a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C
5-10
alkynyl group refers to a straight or branched alkynyl group, and examples thereof are a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
Examples of the bridged cyclic hydrocarbon group are a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, caryl group and a camphanyl group.
The C
1-10
alkyl group for R
2
refers to a straight or branched alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group and a decyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
The compounds of Formula (I) of the present invention can be prepared, for example, by the methods summarized by the following reaction formulae.
In the reaction formulae, R
3
is a C-
1-10
alkyl group or a C
3-10
cycloalkyl group, and X, R
1
and n are as defined above).
The above-mentioned reaction is illustrated as follows:
(1) At first, a known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of an organic aluminum compound represented by Formula (III) in an inert solvent (e.g. benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at −10 to 30° C., preferably 0 to 10° C., according to the method of Sato et al. (Journal of Organic Chemistry, vol. 53, page 5590 (1988)) to stereospecifically give a compound of Formula (IV).
(2) The compound of Formula (IV) is reacted with 0.5 to 4.0 equivalents of an organic copper compound represented by Formula (V) and 0.5 to 4.0 equivalents of trimethylchlorosilane in an inert solvent (e.g. benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane or n-pentane) at −78 to 40° C., followed by hydrolysis using an inorganic acid (e.g. hydrochloric acid, sulfuric acid or nitric acid) or organic acid (e.g. acetic acid or p-toluenesulfonic acid) or an amine salt thereof (e.g. pyridinium p-toluenesulfonate) in an organic solvent (e.g. acetone, methanol, ethanol, isopropanol, diethyl ether or a mixture thereof) at 0 to 40° C. to stereoselectively give a compound of Formula (VI).
(3) The compound of Formula (VI) is reduced with 0.5 to 5 equivalents of a reductant (e.g. potassium borohydride, sodium borohydride, sodium cyanoborohydride or lithium tri-sec-butyl borohydride) in an organic solvent (e.g. tetrahydrofuran, diethyl ether, ethyl alcohol or methyl alcohol) at −78 to 40° C. to give compounds of Formulae (VII) and (VII′). These compounds of Formulae (VII) and (VII′) can be purified by a conventional separation method such as column chromatography.
(4) The compound of Formula (VII) or (VII′) is mesylated or tosylated, for example, with 1 to 6 equivalents of methanesulfonyl chloride or p-toluenesulfonyl chloride in a proper solvent such as pyridine (if necessary, in the presence of 0.8 to 6

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