Prostaglandin derivatives

Details Prostaglandin derivatives Prostaglandin derivatives

2002-02-05

2004-11-23

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C562S473000

Reexamination Certificate

active

06822112

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
BACKGROUND ART
Since prostaglandin (hereinafter referred to as “PG”) exhibits various important physiological actions in a trace amount, the syntheses of a great number 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 Japanese Patent Kokai Sho 52-100446, Japanese Patent Kohyo Hei 2-502009, etc. Among them, Japanese Patent Kohyo Hei 2-502009 discloses a group of PG derivatives substituted with a halogen atom at the 9-position. In addition, 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).
DISCLOSURE OF THE INVENTION
As a result of the extensive studies, the present inventors have found that novel prostaglandin derivatives having a triple bond between the 13- and 14-positions represented by the following Formula (I) have an excellent PGD
2
-like agonistic activity, 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, R
1
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group, m is an integer of 0 to 5, and Y is a group represented by the formula:
wherein R
2
is a C
3-10
cycloalkyl group, a C
3-10
cycloalkyl group substituted with C
1-4
alkyl group(s), a C
1-4
alkyl group substituted with C
3-10
cycloalkyl group(s), a C
1-10
alkyl group, a C
2-10
alkenyl group, a C
2-10
alkynyl group or a bridged cyclic hydrocarbon group, or a group represented by the formula:
wherein n is an integer of 1 to 8; a pharmaceutically acceptable salt thereof or a hydrate thereof.
Furthermore, the present invention is directed to a pharmaceutical composition which comprises the compound represented by the general formula (I), the pharmaceutically acceptable salt thereof or the hydrate thereof.
MODE FOR CARRYING OUT THE INVENTION
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.
The C
1-10
alkyl group means 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, a decyl 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
2-10
alkenyl group means a straight or branched alkenyl group, and examples thereof are a vinyl group, an allyl group, a butenyl group, a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethyl-4-pentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C
2-10
alkynyl group means a straight or branched alkynyl group, and examples thereof are an ethynyl group, a 2-propynyl group, a 3-butynyl group, 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 norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, a caryl group, a bornyl group and a camphanyl 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.
The compounds of Formula (I) can be prepared, for example, by the methods summarized by the following reaction scheme.
In the reaction scheme, TBS is a tert-butyldimethylsilyl group, R
3
is a group obtained by protecting the hydroxyl group in Y with TBS or a triethylsilyl group, R
4
is a straight or branched C
1-10
alkyl group or a C
3-10
cycloalkyl group, and X, Y and m are as defined above.
The above-mentioned reaction scheme 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), an 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, lithium tri-sec-butyl borohydride or 2,6-di-tert-butyl-p-cresol/diisobutylaluminum hydride) 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 equivalents of 4-dimethylaminopyridine) at −20 to 40° C., followed by chlorination with 1 to 16 equivalents of tetra-n-butylammonium chloride to give a compound of Formula (VIII) or (VIII′) wherein X is a chlorine atom, respectively. Herein, bromination or fluorination can be also carried out in an ordinary manner. For example, bromination can be carried out by a reaction with 1 to 10 equivalents of.carbon tetrabromide in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of pyridine in acetonitrile. Fluorination can be carried out, for example, by a reaction with 5 to 20 equivalents of diethylaminosulfur trifluoride (DAST) in methylene chloride.
(5) The protective group (i.e., a tert-butyldimethylsilyl group or a triethylsilyl group) of the hydroxyl group of the compound of Formula (VIII) or (VIII′) is removed by using hydrofluoric acid, pyridinium poly(hydrogenfluoride) or hydrochloric acid under conventional conditions in a solvent (e.g., methanol, ethanol, acetonitrile, a mixture thereof or a mixture of these solvents and water) to give a PG derivative of Formula (Ia) or (Ia′) which is a compound of Formula (I) wherein R
1
is other than a hydrogen atom.
(6) The compound of Formula (Ia) or (Ia′) is hydrolyzed using 1 to 6 equivalents of a base in a conventional solvent

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