Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Reexamination Certificate
2000-02-28
2002-07-02
Gerstl, Robert (Department: 1628)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
C556S418000
Reexamination Certificate
active
06413945
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to silyl ether prodrugs containing at least one hydrophilic group on the silicon atom. The prodrugs hydrolyze at low pH, enabling release of the active drug in the gastric pH range. The invention further relates to a method of preparation of the silyl ether prodrugs, and to a method of treatment or prevention of gastric ulcers with a prodrug of misoprostol.
2. Related Background Art
It is known in the art that trialkylsilyl ether groups can be employed in pH-selective delivery systems for drug molecules. J. Chem. Soc. Perkin Trans., Vol. 10, p. 3043 (1992); J. Pharm. Sci., Vol. 77, p. 116 (1988); Int. J. Pharm., Vol. 28, p. 1 (1986); J. Pharm. Sci., Vol. 71, p. 1 (1982); Scientia Pharmaceutica, Vol. 43, p. 217 (1975); and JP 8,165,301. In these references, prodrugs containing trialkylsilyl ethers were formed from hydroxyl-containing drugs and found to undergo hydrolysis to release the drug only at low pH values. Such systems are of particular interest for selective delivery of drugs to the stomach, where pH values are typically in the range from 1 to 4. When any remaining prodrug passes into the intestine, where pH values are typically about 7, release of the drug ceases, thus avoiding the side effects usually associated with intestinal absorption.
Trialkylsilyl ethers formed at one or more of the hydroxyl groups of drugs in the prostaglandin series are also well known. In U.S. Pat. No. 3,965,143, a triethylsilyl ether is formed at position 16 of misoprostol, a prostaglandin drug. In U.S. Pat. Nos. 5,055,604 and 5,075,478, and in ES 545634, the 11-triethylsilyl ether of misoprostol is formed. U.S. Pat. No. 5,252,763 discloses a process for making a trialkylsilyl ether, in which the alkyl groups contain from 1 to 6 carbon atoms, at the 11 position of misoprostol. Finally, PCT Application No. WO 96/28419 discloses a trialkylsilyl ether at the 11 position, in which the alkyl groups contain from 1 to 8 carbon atoms. In all of the aforementioned references, the trialkylsilyl ethers are disclosed only as intermediates in the synthesis of prostaglandins. No suggestion is made that these compounds would be useful as delivery systems for prostaglandins, or that hydrophilic groups be substituted for the alkyl groups in the trialkylsilyl ether.
A polymeric delivery system in which a drug, such as a prostaglandin, is covalently bonded through a hydroxyl substituent, and is selectively released at a predetermined pH is described in PCT Application No. WO 92/01477; U.S. Pat. No. 5,474,767; and Journal of Medicinal Chemistry, Vol. 36, p. 3087 (1993). The pH-selective drug delivery systems described in these references comprise a drug covalently bonded to a linker by reaction with a silyl chloride functional group on the linker, thus forming an acid-sensitive silyl ether bond, and a polymer which is covalently bonded to the linker-drug combination. The polymer is crosslinked following bonding of the linker, or in some cases, prior to bonding of the linker. In an acidic environment, the silyl ether bonds hydrolyze, allowing the drug molecules to diffuse from the polymer matrix. However, unlike many prodrugs, the polymer-bound drug has no significant hydrophilic nature. No suggestion is made in these references to attach a hydrophilic group to the drug.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula
AW—SiR
1
R
2
R
3
wherein R
1
and R
2
are independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, or a hydrophilic group; R
3
is a hydrophilic group; and AW is the covalently bonded form of a drug AWH, wherein W is O, CO
2
, NH, S, or an enolate group. Of course, each of R
1
, R
2
or R
3
or all may independently contain hydrophilic groups. The hydrophilic group may be non-neutral, or may be a polyol. In a most preferred embodiment the hydrophilic group is a tertiary amine or polyethylene glycol. This compound serves as a prodrug for the drug AWH.
This invention also provides a method for preparing these compounds by first reacting the drug AWH with a compound of formula
YSiR
1
R
2
R
7
wherein Y is halo, or an alkyl-, haloalkyl-, aryl-, alkaryl-, aralkyl-, or haloaryl- sulfonate ester; R
1
and R
2
are as previously described; R
7
is a group substituted by a halo group. The product of this first step is reacted with either (1) a compound containing at least one amino group or (2) a polyol. In a preferred embodiment, the product of the first step is reacted with a compound containing at least one tertiary amine. In another preferred embodiment, the product of the first step is reacted with an amine-substituted polyol, or an alkylamine of twenty carbons or less which can then be further reacted with a transformed polyol to provide an amine-substituted polyol. In another preferred embodiment, the product of the first step can be reacted with an unmodified polyol which may optionally be transformed and then reacted with a tertiary amine. In a preferred embodiment, the polyols of this invention are polyethylene glycol (PEG).
This invention also provides a method of treatment or prevention of gastric ulcers by administering the prodrug compounds of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The following terms used herein are defined. The term “THF” indicates the solvent tetrahydrofuran. The term “DMF” indicates the solvent N,N-dimethylformamide. The term “mercapto” refers to the substituent moiety SH, bonded through its sulfur atom to a carbon atom on a substrate. The term “alkyl” refers to a straight or branched alkyl group containing from 1 to 20 carbon atoms. The term “alkenyl” refers to a straight or branched hydrocarbon group containing from 1 to 20 carbon atoms and at least one carbon-carbon double bond. The term “alkynyl” refers to a straight or branched hydrocarbon group containing from 1 to 20 carbon atoms and at least one carbon-carbon triple bond. The term “cycloalkyl” refers to a cyclic alkyl group containing up to 20 carbon atoms. The term “aryl” refers to a substituent derived from a cyclic aromatic compound having up to 20 carbon atoms. The term “aralkyl” refers to an alkyl group substituted by an aryl group. The term “alkaryl” refers to an aryl group substituted by an alkyl group. The term “halo” means a fluoro, chloro, bromo, or iodo group. The term “Ph” refers to a difunctional phenylene moiety substituted at the 1 and 4 positions. The term “polyol” refers to polyhydroxyl-containing compounds, containing 2 or more hydroxyl moieties, preferably on a carbon backbone which may be substituted by oxygen. Exemplary polyol compounds include, but are not limited to, glycols, e.g., ethylene glycol, propylene glycol; polyglycols, e.g.,PEG, polypropylene glycol; and polyhydric alcohols.
The term “transform” refers to the reaction by which a hydroxyl group on a polyol has been substituted with a leaving group, and the term “transformed polyol” refers to a polyol which has been thus reacted. Polyols may be transformed by reaction with tosylate, mesylate, triflate or other methods well-known in the art. The term “unmodified polyol” refers to a polyol which has not been transformed.
The prodrug compounds of this invention have the general formula
AW—SiR
1
R
2
R
3
wherein R
1
and R
2
are independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, or a hydrophilic group; R
3
is a hydrophilic group; and AW is the covalently bonded form of a drug AWH, wherein W is O, CO
2
, NH, S or an enolate group. Each of R
1
, R
2
or R
3
or all may independently contain hydrophilic groups. The hydrophilic group may be non-neutral, or may be a polyol. The AW-Si bond in these molecules is susceptible to hydrolysis at low pH values. Hydrolysis of the AW-Si bond releases the drug AWH from the prodrug when the prodrug reaches the low-pH environment of the stomach. Conversely, any remaining prodrug which passes into the higher-pH environment of the intestines will no longer release the drug, thereby avoiding the side effects usually associated with intestinal releas
Collins Paul W.
Fenton Ricky L.
Tremont Samuel J.
Gerstl Robert
Pharmacia Corporation
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