Prostaglandin derivatives

Details Prostaglandin derivatives Prostaglandin derivatives

2002-03-11

2004-05-25

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C562S503000, C514S530000

Reexamination Certificate

active

06740772

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
BACKGROUND ART
Since prostaglandin (PG) exhibits various important physiological actions in a trace amount, the biological activities of a great number of natural PGs and synthesized PG derivatives have been investigated with the intention of a practical use as medicines and have been reported in many literatures and patents. Among them, Japanese Patent Kohyo Hei 2-502009 discloses a group of PG derivatives substituted with a halogen atom at the 9-position. Furthermore, PG derivatives having a PGD
2
-like agonistic activity are reported by K-H Thierauch et al., in Drug of the Future, vol. 17, page 809 (1992).
In addition, PGs have been not only reported on their various central nervous actions and but also clarified as to the intracerebral content, biosynthesis, metabolic pathway, their intracerebral localization and changes with growth or aging, and there has been taken an interest in the relation between sleep and wake by PGs. 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 their 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 new compound having a sleep-inducing action.
However, PGD
2
derivatives including PGD
2
are presently unpractical due to the problems concerning their intracerebral transition and stability. Furthermore, there has not been specifically reported about sleep-inducing action of PG derivatives other than PGD
2
derivatives.
An object of the present invention is to provide novel PG derivatives having a PGD
2
-like agonistic activity and a sleep-inducing action.
DISCLOSURE OF THE INVENTION
As a result of the continued extensive studies, the present inventors have found that novel prostaglandin derivatives represented by the following Formula (I) achieve the above-objects, 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 in the &agr;- or &bgr;-position, Y is an ethylene group, a vinylene group or an ethynylene group, A is a group represented by the formula: O(CH
2
)
n
,
S(O)
p
(CH
2
)
n
,
O(CH
2
)
q
O(CH
2
)
r
,
O(CH
2
)
q
S(O)
p
(CH
2
)
r
,
S(O)
p
(CH
2
)
q
S(O)
p
(CH
2
)
r
or
S(O)
p
(CH
2
)
q
O(CH
2
)
r
(wherein n is an integer of 1 to 5, p is 0, 1 or 2, q is an integer of 1 to 3, and r is 0 or 1),
R
1
is a C
3-10
cycloalkyl group, a C
1-4
alkyl-C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-4
alkyl 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,
R
2
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group, and
m is 0, 1 or 2], a pharmaceutically acceptable salt thereof or a hydrate thereof.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective Ingredient the compound represented by formula (I), the pharmaceutically acceptable salt thereof or the hydrate thereof.
In the present invention, the vinylene group refers to a cis- or a trans-vinylene group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C
3-10
cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C
1-4
alkyl-C
3-10
cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted with a straight or branched alkyl group having 1 to 4 carbon atoms, examples of which are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C
3-10
cycloalkyl-C
1-4
alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, examples of which 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 means a straight or branched alkyl group having 5 to 10 carbon atoms, and examples of which 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 means a straight or branched alkenyl group having 5 to 10 carbon atoms, examples of which 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 means a straight or branched alkynyl group having 5 to 10 carbon atoms, examples of which 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, a caryl group and a camphanyl group.
The C
1-10
alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, examples of which 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, an nonyl group and a decyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metals (e.g., sodium or potassium), alkali earth metals (e.g., calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
Preferable compounds of the present invention are those of Formula (I) wherein R
1
is a C
3-10
cycloalkyl group, a C
1-4
alkyl-C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-4
alkyl group, a branched C
5-10
alkyl group, a branched C
5-10
alkenyl group, a branched C
5-10
alkynyl group or a bridged cyclic hydrocarbon group. Further preferable compounds of the present invention are those of Formula (I) wherein X is a chlorine or bromine atom in the &agr;- or &bgr;-position, R
1
is a C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-4
alkyl group or a branched C
5-10
alkenyl group, and R
2
is a hydrogen atom or a C
1-10
alkyl group.
Furthermore, Y is preferably a vinylene group or an ethynylene group, and more preferably an ethynylene group. A is preferably a group represented by the formula: S(O)
p
(CH
2
)
n
, S(O)
p
(CH
2
)
q
S(O)
p
(CH
2
)
r
or S(O)
p
(CH
2
)
q
O(CH
2
)
r
, and more preferably a group represented by the formula: S(CH
2
)
n
, S(CH
2
)
q
S(CH
2
)
r
or S(CH
2
)
q
O(CH
2
)
r
.
The compounds of Formula (I) can be prepared, for example, by the methods summarized by the following reaction scheme.
In the reaction scheme, A
1
is a group represented by the formula: O(CH
2
)
n
, S(CH
2
)
n
, O(CH
2
)
q
O(CH
2
)
r
, O(CH
2
)
q
S(CH
2
)
r
, S(CH
2
)
q
S(CH
2
)
r
or S(CH
2
)
q
O(CH
2
)
r
(wherein n, q and r are as defined above), A
2
is a group as defined for A except for p=O. Y′ is an ethylene group or a vinylene group, R
3
is a C
1-10
alkyl group or a C
3-10
cycloalkyl group, TBS is a tert-butyldimethylsilyl group, and X, Y, R
1
and m are as defined above.
The above-mentioned reaction scheme is illus

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