Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-12-01
2001-08-07
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S078010, C424S078080, C424S078360, C424S078370, C424S078380, C514S183000, C514S210160, C514S212020, C514S214010, C514S222800, C514S230500, C514S249000, C514S278000, C514S279000, C514S409000, C514S410000, C514S411000, C514S412000, C514S413000, C514S434000, C514S456000, C514S459000, C514S646000, C514S660000, C514S661000, C514S662000, C514S727000, C514S729000, C514S740000, C514S741000
Reexamination Certificate
active
06271264
ABSTRACT:
BACKGROUND OF THE INVENTION
Biologically, cholesterol is eliminated from the body by conversion into bile acids and excretion as neutral steroids. Bile acids are synthesized from cholesterol in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in the digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed by active transport in the ileum, complexed with proteins, and returned to the liver through hepatic portal veins. The small amount of bile acid salts not reabsorbed in the ileum is excreted via the distal ileum and large intestine, as a portion of the fecal material.
Therefore, reabsorption of bile acids, which can be present as the corresponding salts or conjugates, from the intestine conserves lipoprotein cholesterol in the bloodstream. As such, reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acids circulating in the enterohepatic system thereby promoting replacement of bile acids through de novo synthesis from cholesterol, in the liver. The result is a lowering of circulating blood cholesterol levels.
One method of reducing the quantity of bile acids that are reabsorbed is the oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
A need exists for sequestrants that bind bile acid salts and conjugates.
SUMMARY OF THE INVENTION
The invention relates to polymers comprising a spirobicyclic ammonium moiety-containing repeat unit, and to a method of using the polymers for sequestering bile acids in a patient.
In one aspect, the polymer comprises spirobicyclic ammonium-moiety containing repeat units represented by Structural Formulas (I) and (II), copolymers and salts thereof.
In one embodiment, the spirobicyclic ammonium moiety-containing polymers further comprise one or more additional monomers wherein the additional monomer is non-spirobicyclic. In another embodiment, the additional monomer is a multifunctional crosslinking co-monomer. In another embodiment the additional monomer is a nitrogen-containing monomer. In specific embodiments, the nitrogen-containing monomer comprises an amine, wherein one or more substituents are bonded to available amino nitrogen atoms of the polymer. Amino nitrogen atoms which are available for substitution include the nitrogen atoms of primary, secondary, and tertiary amines. Suitable substituents can include hydrophobic and/or quaternary ammonium-containing groups.
In a preferred aspect, the copolymers of the invention are crosslinked. In one embodiment, crosslinking is achieved through a multifunctional crosslinking co-monomer which is incorporated into two or more polymer chains. In another embodiment, crosslinking is achieved by means of a multifunctional crosslinking agent.
The method of the invention comprises orally administering to a mammal a therapeutically effective amount of a polymer comprising a spirobicyclic ammonium moiety-containing repeat unit, whereby, bile acids are sequestered and consequently excreted. The method of the invention is useful to reduce the levels of circulating cholesterol, to treat atherosclerosis and/or to treat hypercholesterolemia.
The spirobicyclic ammonium moiety-containing polymers provide many advantages over certain known bile acid sequestrants having a non-spirobicyclic quaternary ammonium group. Quaternary ammonium compounds can undergo degradation by, for example, Hofmann elimination. This type of degradation involves the cleavage of at least one of the four bonds involving the ammonium nitrogen atom thereby producing a double bond and a tertiary amine. As such, Hofmann elimination can result in the elimination of, for example, the trialkylamine from an alkyl trialkylammonium moiety, possibly diminishing the effectiveness of a bile acid sequestrant that comprises alkyl trialkylammonium moieties. In addition, the elimination products can, in some instances, cause undesirable side effects.
However, the spirobicyclic ammonium moieties of the invention have a structure which overcomes the disadvantages associated with Hofmann elimination. Namely, even though the spirobicyclic ammonium groups of the invention can still undergo cleavage of a bond between a carbon atom and the ammonium nitrogen atom, all of the carbon atoms which are bonded to the quaternary nitrogen atom are part of the spirobicyclic junction. Thus, tertiary amines and undesirable elimination products are not released from the polymers of the invention as a result of Hofmann elimination.
Additionally, the spirobicyclic ring structure of the polymers of the invention can provide improved structural matching with the steroidal skeleton of bile acids.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to polymers and to methods of using the polymers for removing bile acids from a patient. The polymers of the invention comprise a spirobicyclic ammonium moiety-containing repeat unit and physiologically acceptable salts thereof.
The term “spirobicyclic” refers to a ring system comprising two rings which share a common atom. The shared atom can be referred to as the spiro atom or the spiro center. In the case of the spirobicyclic ammonium moiety-containing polymers of the invention the spiro atom is a nitrogen atom.
In one aspect the spirobicylic ammonium moiety-containing polymers can comprise, for example, a diallylamine repeat unit wherein the amino nitrogen atom is quaternized to form the spiro center of the spirobicylic ammonium moiety-containing polymer of the invention.
In this aspect, the polymer can comprise a repeat unit represented by Structural Formula (I) and/or (II).
The rings labeled “A” and “B” are referred to herein as Ring A and Ring B. Ring A can be a five or six membered ring, and can be formed by the polymerization of diallylamine or certain diallylamine derivatives.
m can be an integer, such as an integer from zero to about seven.
Y is a negatively charged counterion.
Ring A and Ring B can each, independently, be unsubstituted or can have one or more substituents as described herein.
In particular embodiments, Ring B can contain one or more units of unsaturatiori and/or one or more additional heteroatoms such as oxygen, nitrogen and sulfur. For example, Ring B can be selected from Structural Formulas (III-XI).
The symbol “∫” is used to indicate the bond between the spiro nitrogen atom and a carbon atom of Ring A. Thus, the nitrogen atom of Ring B that is bonded to two “∫”, is the spiro atom that is shared by Ring A and Ring B.
Polymers comprising a repeat unit represented by Structural Formula (I) and/or (II), can be prepared by polymerization of suitable quaternary ammonium-containing diallylamine derivatives, which are also referred to herein as spirobicyclic ammonium-moiety containing monomers. For example, N,N-diallylpyrrolidinium bromide, N,N-diallylpiperidinium bromide, N,N-diallylhomopiperidinium bromide, N,N-diallyl(4-hydroxy)piperidinium bromide, N,N-diallyl 1,2,3,4-tetrahydroisoquinolinium bromide, N,N-diallyldecahydroquinolinium bromide and the like, which can be prepared by reacting a nitrogen-containing heterocycle with allyl bromide as described herein. Other pharmaceutically acceptable salts of diallylamine derivatives (e.g., N,N-diallylpyrrolidinium chloride, N,N-diallylpyrrolidinium acetate, N,N-diallylpyrrolidinium bicarbonate and the like) can also be used to prepare polymers comprising a repeat unit represented by Structural Formula (I) and/or (II).
Polymerization can be accomplished using techniques known in the art of polymer synthesis. (See, for example, Shalaby et al., ed.,
Water
-
Soluble Polymers
, American Chemical Society, Washington, D.C. [1991]). The appropriate monomers can be polymerized by methods known in the art, for example, via a free radical addition process. In this case, the polymerization mixture includes a free-radical initia
Dhal Pradeep K.
Polomoscanik Steven C.
Choi Frank
Dees Jose′ G.
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
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