Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-02-07
2003-09-09
Pryor, Alton N. (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S572000
Reexamination Certificate
active
06617353
ABSTRACT:
This Application is a 371 of PCT/JP00/08239 filed Nov. 22, 2000.
TECHNICAL FIELD
The present invention relates to a preparation for nasal administration comprising a prostaglandin derivative as an effective ingredient.
BACKGROUND ART
Since prostaglandin (hereinafter referred to as “PG”) exhibits various important pharmacological and physiological actions in a trace amount, the syntheses of a great number of derivatives from natural PGs and the biological activities have been investigated with the intention of a practical use as medicines. Particularly, many compounds which have a triple bond between the 13- and 14-positions were synthesized by Sato et al, and among of these compounds are PG derivatives described in Japanese Patent Kokai Hei 7-233144.
The PG derivatives in the above-mentioned gazette are described to have an excellent lowering action of ocular tension and be able to be used as eye drops or an eye ointment. However, there have not been known a preparation for nasal administration comprising said prostaglandin derivatives or its sleep-inducing effect.
DISCLOSURE OF THE INVENTION
As a result of the extensive studies to solve the above purpose, the present inventors have found that the following prostaglandin derivatives, when combined with a certain polymer, have an excellent sleep-inducing effect by nasal administration, and thereby the present invention has been accomplished.
That is, an aspect of the present invention is to provide a preparation for nasal administration (hereinafter referred to as “preparation of the present invention” or “preparation of the present applications”) which comprises as an effective ingredient a prostaglandin derivative represented by Formula (I):
wherein X is a halogen atom, 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, R
2
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group, m is an integer of 0 to 3,n is an integer of 1 to 4, and a wavy line is a bond which may be in the R or S-configuration, or a pharmaceutically acceptable salt thereof and a water-soluble polymer.
A further aspect of the present invention is to provide a preparation for nasal administration which comprises as an effective ingredient a prostaglandin derivative represented by Formula (A):
or a pharmaceutically acceptable salt thereof and a water-soluble polymer.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein the water-soluble polymer is at least one member selected from the group consisting of a bridged vinyl polymer and a water-soluble cellulose ether.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein the water-soluble polymer is at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and methyl cellulose.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein the water-soluble polymer is hydroxypropyl cellulose.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein the water-soluble polymer carries the prostaglandin derivative represented by Formula (I) or (A) or the pharmaceutically acceptable salt thereof.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein the prostaglandin derivative represented by Formula (I) or (A) or the pharmaceutically acceptable salt thereof adheres to the water-soluble polymer and/or disperses in the water-soluble polymer.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration wherein a coating layer comprising the prostaglandin derivative represented by Formula (I) or (A) or the pharmaceutically acceptable salt thereof as an effective ingredient dispersed in the water-soluble polymer adheres to the surface of the water-soluble polymer for carrying the effective ingredient.
A still further aspect of the present invention is to provide the above-mentioned preparation for nasal administration which is a sleep-inducing preparation.
A still further aspect of the present invention is to provide a kit of a preparation for nasal administration which comprises the above-mentioned sleep-inducing preparation and a device for administration thereof.
A still further aspect of the present invention is to provide a method for sleep-inducing which comprises administering nasally a pharmaceutically effective amount of the above-mentioned sleep-inducing preparation to a human.
The compounds of Formula (I) to be used in the present invention are illustrated in more detail as follows.
General preparation methods of the compound of Formula (I)
The compound of Formula (I) can be prepared according to the following reaction formulae.
In the reaction formulae, R
3
is a C
1-10
alkyl group or a C
3-10
cycloalkyl group, TBS is a tert-butyldimethylsilyl group, and X, R
1
, m and n are as defined above).
The above-mentioned reaction formulae are 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 equivalents of a compound represented by Formula (V) or (VI) and 0.05 to 2 equivalents of a radical generator (e.g. azobisisobutyronitrile, azobiscyclohexane carbonitrile, benzoyl peroxide or triethylborane) and, if desired, using 1 to 5 equivalents of a radical reductant (e.g. tributyltin hydride, triphenyltin hydride, dibutyltin hydride or diphenyltin hydride) in an inert solvent (e.g. benzene, toluene, xylene, n-hexane, n-pentane or acetone) at −78 to 100° C., thereby a compound of Formula (VII) is obtained.
Alternatively, the compound of Formula (IV) is reacted with 0.5 to 4 equivalents of a compound represented by Formula (V) or (VI) using 0.05 to 2 equivalents of a base such as organic amines (e.g. triethylamine, diisopropylamine, pyridine or dimethylaniline) or basic resins (e.g. polyvinylpolypyrrolidone, diisopropylaminomethyl-polystylene or (piperidinomethyl)polystylene) in an inert solvent (e.g. benzene, toluene, xylene, n-hexane, n-pentane or acetone) at −78 to 100° C., thereby a compound of Formula (VII) can be obtained.
(3) The compound of Formula (VII) is reduced with 0.5 to 5 equivalents of a reductant (e.g. potassium borohydride, sodium borohydride, lithium tricyanoborohydride, lithium tri-sec-butyl borohydride or aluminum diisobutyl hydride-BHT (2,6-di-tert-butyl-p-cresol) in an organic solvent (e.g. tetrahydrofuran, diethyl ether, ethyl alcohol, methyl alcohol or toluene) at −78 to 40° C. to give compounds of Formulae (VIII) and (VIII′). These compounds of Formulae (VIII) and (VIII′) can be purified by a conventional separation method such as a column chromatography.
(4) The compound of Formula (VIII) or (VIII′) is mesylated or tosylated, for example, with 1 to 6 equivalents of methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base (e.g. triethylamine, pyridine or 4-dimethylaminopyridine) in a suitable solvent (e.g. pyridine or toluene) at −20 to 40° C., followed by chlorination with 1 to 16 equivalents of tetra-n-butylammonium chloride to give a compound of Formula (IX) or (IX′) wherein X is a chlorine atom. 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
Ito Shusei
Koda Ayumi
Nakano Mari
Yamada Kenji
Pryor Alton N.
Taisho Pharmaceutical Co. Ltd.
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