Lipase inhibiting polymers

Details Lipase inhibiting polymers Lipase inhibiting polymers

2000-11-16

2003-05-06

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

C514S909000, C424S009100, C424S078170

Reexamination Certificate

active

06558657

ABSTRACT:

BACKGROUND OF THE INVENTION
Human obesity is a recognized health problem with approximately ninety-seven million people considered clinically overweight in the United States. The accumulation or maintenance of body fat bears a direct relationship to caloric intake. Therefore, one of the most common methods for weight control to combat obesity is the use of relatively low-fat diets, that is, diets containing less fat than a “normal diet” or that amount usually consumed by the patient.
The presence of fats in a great many food sources greatly limits the food sources which can be used in a low fat diet. Additionally, fats contribute to the flavor, appearance and physical characteristics of many foodstuffs. As such, the acceptability of low-fat diets and the maintenance of such diets are difficult.
Various chemical approaches have been proposed for controlling obesity. Anorectic agents such as dextroamphetamine, the combination of the non-amphetamine drugs phentermine and fenfluramine (Phen-Fen), and dexfenfluramine (Redux) alone, are associated with serious side effects. Indigestible materials such as olestra (OLEAN®), mineral oil or neopentyl esters (see U.S. Pat. No. 2,962,419) have been proposed as substitutes for dietary fat. Garcinia acid and derivatives thereof have been described as treating obesity by interfering with fatty acid synthesis. Swellable crosslinked vinyl pyridine resins have been described as appetite suppressants via the mechanism of providing non-nutritive bulk, as in U.S. Pat. No. 2,923,662. Surgical techniques such as temporary ileal bypass surgery, are employed in extreme cases.
However, methods for treating obesity, such as those described above have serious shortcomings with controlled diet remaining the most prevalent technique for controlling obesity. As such, new methods for treating obesity are needed.
SUMMARY OF THE INVENTION
The invention features a method for treating obesity in a patient by administering to the patient a polymer that has been substituted with or comprises one or more groups which can inhibit a lipase. Lipases are key enzymes in the digestive system which break down tri- and diglycerides, which are too large to be absorbed by the small intestine into fatty acids which can be absorbed. Therefore, inhibition of lipases results in a reduction in the absorption of fat. In one embodiment, the lipase inhibiting group can be a “suicide substrate” which inhibits the activity of the lipase by forming a covalent bond with the enzyme either at the active site or elsewhere. In another embodiment, the lipase inhibiting group is an isosteric inhibitor of the enzyme. The invention further relates to the polymers employed in the methods described herein as well as novel intermediates and methods for preparing the polymers.
DETAILED DESCRIPTION OF THE INVENTION
The invention features a method for treating obesity in a patient by administering to the patient a polymer comprising one or more groups which can inhibit a lipase. Since lipases are responsible for the hydrolysis of fat, a consequence of their inhibition is a reduction in fat hydrolysis and absorption. The invention further relates to the polymers employed in the methods described herein as well as novel intermediates and methods for preparing the polymers.
In one aspect of the invention, the lipase inhibiting group inactivates a lipase such as gastric, pancreatic and lingual lipases. Inactivation can result by forming a covalent bond such that the enzyme is inactive. The covalent bond can be formed with an amino acid residue at or near the active site of the enzyme, or at a residue which is distant from the active site provided that the formation of the covalent bond results in inhibition of the enzyme activity. Lipases contain a catalytic triad which is responsible for the hydrolysis of lipids into fatty acids. The catalytic triad consists of a serine, aspartate and histidine amino acid residues. This triad is also responsible for the hydrolysis of amide bonds in serine proteases, and it is expected that compounds that are serine protease inhibitors will also inhibit lipases. Therefore, serine protease inhibitors that can be covalently linked to a polymer are preferred lipase inhibiting groups. For example, a covalent bond can be formed between the lipase inhibiting group and a hydroxyl at or the catalytic site of the enzyme. For instance, a covalent bond can be formed with serine. Inactivation can also result from a lipase inhibiting group forming a covalent bond with an amino acid, for example cysteine, which is at some distance from the active site. In addition, non-covalent interaction between the lipase inhibiting group and the enzyme can also result in inactivation of the enzyme. For example, the lipase inhibiting group can be an isostere of a fatty acid, which can interact non-covalently with the catalytic site of the lipase. In addition, the lipase inhibiting group can compete for lipase hydrolysis with natural triglycerides.
In one aspect of the invention, a lipase inhibiting group can be represented by formula I:
wherein,
R is a hydrogen, hydrophobic moiety, —NR
2
R
3
, —CO
2
H, —OCOR
2
, —NHCOR
2
, a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aromatic group;
R
1
is an activating group;
Y is oxygen, sulfur, —NR
2
— or is absent;
Z and Z
1
are, independently, an oxygen, alkylene, sulfur, —SO
3
—, —CO
2
—, —NR
2
—, —CONR
2
—, —PO
4
H— or a spacer group;
R
2
and R
3
are, independently, a hydrogen, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aromatic group;
m is 0 or 1; and
n is 0 or 1.
In one embodiment, the lipase inhibiting group of formula I can be represented by the following structures:
wherein R, R
1
and Y are defined as above.
In another embodiment, the lipase inhibiting group of structural formula I can be represented by the following structures:
wherein R, R
1
, R
2
, R
3
and Y are defined as above, and p is an integer (e.g. an integer between zero and about 30, preferably between about 2 and about 10).
In another embodiment, the lipase inhibitor of formula I is a mixed anhydride. Mixed anhydrides include, but are not limited to, phosphoric-carboxylic, phosphoric-sulfonic and pyrophosphate mixed anhydride lipase inhibiting groups which can be represented by the following structures, respectively:
wherein R, R
1
, Y and Z
1
are defined as above.
In another aspect, a lipase inhibiting group of the invention can be an anhydride. In one embodiment, the anhydride is a cyclic anhydride represented by formula II:
wherein R, Z and p are defined as above, X is —PO
2
—, —SO
2
— or —CO—, and k is an integer from 1 to about 10, preferably from 1-4.
In another embodiment, the anhydride lipase inhibiting groups can be a cyclic anhydride which is part of a fused ring system. Anhydrides of this type can be represented by formula III:
wherein X and Z are defined as above, and ring A is an optionally substituted cyclic aliphatic group or aromatic group, or combinations thereof, which can include one or more heteroatoms in the ring. In a particular embodiment, the cyclic anhydride is a benzenesulfonic anhydride represented by the following structure:
wherein Z is defined as above and the benzene ring can be further substituted.
In another aspect, the lipase inhibiting group is an &agr;-halogenated carbonyl which can be represented by formula IV:
wherein R and Y are defined as above, and W
1
and W
2
are each independently hydrogen or halogen, for example, —F, —Cl, —Br, and —I, wherein at least one of W
1
and W
2
is a halogen.
In yet another aspect, a cyclic compound having an endocyclic group that is susceptible to nucleophilic attack can be a lipase inhibiting group. Lactones and epoxides are examples of this type of lipase inhibiting group and can be represented by formulas V and VI, respectively:
wherein R, Z, m and p are defined as above.
In a further aspect, the lipase inhibiting group can be a sulfonate or disulfide group represented by formulas VII and VIII, respectively:
wherein R, Z an

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