Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-21
2002-01-29
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S328000, C424S001730, C424S439000
Reexamination Certificate
active
06342519
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel oxetanone derivative compounds and processes for producing such derivatives which are useful as lipase inhibitors. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases. In one aspect the invention relates to lipase inhibitors which include on the same molecule an oxetanone derivative portion capable of inhibiting a lipase and a non-absorbable moiety such a polysaccharide, which are covalently linked or are in the form of a salt. In a preferred aspect of the invention the non-absorbable moiety is lipophilic and will associate with oils or fats. An absorbable oxetanone lipase inhibitor may be rendered non-absorbable by covalent linking it directly or indirectly to a non-absorbable moiety and thereby producing a novel non-absorbable lipase inhibitor.
BACKGROUND OF THE INVENTION
Some lipase-inhibiting oxetanones and intermediates for making them are well known. See for example, U.S. Pat. Nos. 5,931,463, 4,189,438 and 4,202,824. However, there is a need for improved oxetanones that are have low toxicity and are essentially not absorbable by the digestive system of mammals such as dogs, cats, non-human primates and human primates.
Lipase inhibitors such as esterastin (see U.S. Pat. No. 4,189,438), tetrahydroesterastin (3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, are well-known as lipase inhibitors and as pancreatic cholesterol esterase inhibitors. However, such lipase inhibitors are, inter alia, also substantially orally active as immunosuppressants (see U.S. Pat. No. 4,189,438 and U.S. Pat. No. 4,202,824), which can be a highly undesired side activity in a normal or immunosuppressed person. Such lipase inhibitor compounds are 3,5 dihydroxy 1,3 lactone derivative compounds, wherein the 5-hydroxyl group may be esterified at the 5 position or is hydrolyzed to the free hydroxyl group.
A popular lipase inhibiting compound which is substantially non-absorbable is known as Orlistat ((2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, see U.S. Pat. No. 5,643,874). This compound is a steric isomer derivative of tetrahydroesteratin and its 5-hydroxyl group is esterified with a [S-2-formamido-4-methyl-valeryloxy] group. Orlistat has been used to inhibit lipases in the body and thereby prevent the absorption of dietary fat. At a 120 mg dose of Orlistat, taken before consuming a fat-containing meal (or up to one hour after eating such a meal), up to one-third of the fat eaten at a given meal will not be absorbed by the average person and utilized as dietary fat calories. The undigested fat passes directly through the digestive system as an oil and is eliminated from the bowel in its oily undigested form.
Certain polysaccharides are non-absorbable and some polysaccharides have the side benefit of reducing lipid absorption by the body. Defatted rice germ polysaccharides and sulfated polysaccharides are also lipase inhibitors, which are high molecular weight compounds that do not appear to have any lactone moieties and seem to work by a different mechanism, binding the lipase and removing it from the digestive system when they are discharged from the digestive system. The super fiber Chitosan, which is a deacylated polysaccharide derived from shellfish chitan, has an ability to absorb fat and cholesterol, particularly in combination with vitamin C. Chitosan compositions may actually absorb up to 6 to 8 times their weight in fat and oils. While the polysaccharide from shellfish is similar to crude cellulose plant fiber, it has the ability to significantly bind fat in the digestive system as compared to plant fiber. Further, since polysaccharides, including those which do not preferentially bind oils over water, are not absorbed by the digestive systems of animals such as humans, non-human primates, dogs and cats, there is no caloric value to such polysaccharides and they pass through the such digestive systems unabsorbed and substantially intact. Examples of non-absorbable polysaccharides are polysaccharides having a molecular weight of greater than 8 kDa such as dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the like.
There is a need in the art for non-absorbable lipase inhibitors, as well as for improved antiadiposity compositions and methods which do not require an absolute low-fat diet in order to lower the absorption of dietary fat as calories.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to novel derivatives of lipase inhibitors which are non-absorbable compounds comprising at least one lipase inhibitor moiety and at least one non-absorbable polymeric moiety in the same molecule or salt. The lipase inhibitor moiety is preferably present in the non-absorbable compound in a weight ratio of from about 1:10 to about 1:60 with respect to the weight of the polymeric moiety, preferably from about 1:20 to about 1:40, and more preferably from about 1:25 to 1:35. In one aspect, such lipase inhibitors comprise at least one lipase inhibitor moiety (or moieties) linked directly or indirectly to such a polymeric moiety. The invention also includes pharmaceutical compositions comprising an effective amount of such lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent, which compositions may further comprise an effective amount of a lipophilic, non-absorbable biocompatible, pharmaceutically acceptable oil absorbing polymer.
In another aspect the present invention relates to novel salts of non-absorbable lipase inhibitors and a non-absorbable biocompatible, pharmaceutically acceptable oil absorbing polymer. The invention also includes pharmaceutical compositions comprising an effective amount of such lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent, which compositions may further comprise an effective amount of a lipophilic, non-absorbable biocompatible, pharmaceutically acceptable oil absorbing polymer.
In a preferred aspect the present invention relates to novel non-absorbable derivatives of a 1,3 oxetanone lipase inhibitor, which include at least one 1,3 oxetanone lipase inhibiting moiety that is covalently or non-covalently linked to a non-absorbable biocompatible, pharmaceutically acceptable polymer moiety to provide a novel lipase inhibitor compound. Preferred compounds have the dual function of inhibiting lipases and absorbing fat, in that the non-absorbable biocompatible, pharmaceutically acceptable polymer moiety of the novel lipase inhibitor will bind to fat, carry the bound fat with it through portions of the digestive system and cause the non-absorbed fat to be eliminated removed from the digestive system as undigested fat. The 1,3 oxetanone moiety that is derivatized directly or indirectly with the polymer moiety according to the invention may be initially an absorbable or non-absorbable moiety and is derivatized by directly or indirectly linking it to the polymer moiety to form a novel non-absorbable lipase inhibitor, preferably at the 5 hydroxyl position of a 1,3 oxetanone moiety.
In a preferred aspect the invention provides compounds having either non-covalent linkages of such two moieties or covalent linkages that are hydrolyzed or digested in the digestive system, providing that the lipase inhibiting 1,3 oxetanone derivative moiety that is released in the digestive system is substantially non-absorbable.
In another preferred aspect the invention provides compounds having either a non-covalent linkage of such two moieties or a covalent linkage that is not hydrolyzed or digested in the digestive system, whereby the lipase inhibiting
2 Pro Chemical
Lev Robert G.
Solola T. A.
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