MXPA01006755A

MXPA01006755A - Oxetanone derivatives.

Info

Publication number: MXPA01006755A
Application number: MXPA01006755A
Authority: MX
Inventors: Jason Gentry Mullins John
Original assignee: Jason Gentry Mullins John
Priority date: 1999-10-29
Filing date: 2000-10-27
Publication date: 2003-05-15
Also published as: JP2003524685A; CN1342169A; WO2001032616A2; AU1238101A; EP1144377A1; AU1347701A; CA2358921A1; WO2001032670A1; WO2001032616A3; EP1144377A4; IL144045A0

Abstract

This invention relates to novel oxetanone derivative compounds and processes for producing such derivatives that 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.

Description

DERIVATIVES OF OXETANONE FIELD OF THE INVENTION This invention relates to novel compounds derived from oxetanone and processes for producing said derivatives which are used as lipase inhibitors. Furthermore, the invention relates to processes for producing salts and for producing compounds of pharmaceutical compositions comprising at least one derivative of the oxetanone or salt, as well as methods for using said compounds and compositions for inhibiting lipases. In one aspect the invention relates to lipase inhibitors which include in the same molecule a portion derived from oxetanone capable of inhibiting a lipase and a non-absorbable portion of said polysaccharide, which are covalently linked or in the form of a salt. In a preferred aspect of the invention the non-absorbable portion is lipophilic and will be associated with oils or fats. An absorbable oxetane lipase inhibitor can be rendered non-absorbable by covalently binding directly or indirectly to a nonabsorbable portion and thus producing a novel non-absorbable lipase inhibitor.

BACKGROUND OF THE INVENTION Some oxetanones that inhibit lipases and intermediates to make them are well known. See, for example, US Patents 5,931, 463, 4,189,438 and 4,202,824. However, there is a need for improved oxetanones which have low toxicity and which are essentially non-absorbable by the digestion system of mammals such as dogs, cats, non-human primates and human primates.

The lipase inhibitors such as esterastine (see the American Patent 4,189,438), tetrahydroesterastine (3,5-hydroxy-2-hexadeca-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 esterase inhibitors of the pancreatic cholesterol. However, said lipase inhibitors are, inter alia, also substantially orally active as immunosuppressants (see US Patent 4,189,438 and 4,202,824) which may be in highly undesirable side activity in an immunosuppressed or normal person. Said lipase inhibitor compounds are 3,5-dihydroxy-1,3-lactone derivative compounds, wherein the 5-hydroxyl group may be stearified at the 5-position or hydrolyzed to the free hydroxyl group.

A popular compound that inhibits lipase that is substantially non-absorbable is known as Orlistat ((2S, 3S, 5S) -5 - [(s)] -2-formamido-4-methyl-valeryloxy] -2-hexyl-3 acid Orlistat. -hydroxy-hexadecanoic 1,3 lactone, see U.S. Patent 5,643,874). This compound is a steric isomer derivative of tetrahydrosteratin and its 5-hydroxyl group is esterified with a [S-2-formamido-4-methyl-valeryloxy] group. Orlistat has been used to inhibit lipase in the body and therefore prevent the absorption of dietary fat. In a dose of 120 mg of Orlistat, taken before the consumption of a food containing fat (or more than one hour after ingesting that food), more than a third of the fat ingested in a given food will not be absorbed by the person average and is used as calories from dietary fats. Undigested fats pass directly through the digestive system as an oil and are removed from the intestine in their undigested oily form.

Certain polysaccharides are not absorbable and some polysaccharides have side benefits of reducing lipid absorption by the body. Dehydrated rice germ polysaccharides and sulfated polysaccharides are also inhibitors lipase, which are high molecular weight compounds that appear to have no lactone portion and appear to work by a different mechanism, binding the lipase and removing it from the digestive system when discharged from the digestive system. The super fiber Chitosan, which is a deacylated polysaccharide derived from seafood, has an ability to absorb fat and cholesterol particularly in combination with vitamin O Chitosan compositions can actually absorb more than 6 to 8 times their weight in fat and oils. While the seafood polysaccharide is similar to the raw cellulose fiber of plants, it has the ability to significantly bind fat in the digestive system as compared to plant fiber. Furthermore, since polysaccharides, including those that do not preferentially bind to oils in water, are not absorbed by the digestive systems of animals such as humans, non-human primates, dogs and cats, there is no caloric value for said polysaccharides and they pass through said digestive systems not absorbed and substantially intact. Examples of non-absorbable polysaccharides are polysaccharides having a molecular weight greater than 8 kDa such as dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, cellulose raw, argar, chitosan and the like.

There is a need in the art for non-absorbable lipase inhibitors, as well as for improved anti-tumor compositions and methods, which do not require an absolute low fat diet to decrease the absorption of dietary fats such as calories.

SUMMARY OF THE INVENTION In one aspect the present invention relates to novel derivatives of lipase inhibitors which are nonabsorbable compounds comprising at least one lipase inhibitory moiety and in at least one non-absorbable polymer moiety in the same molecule or salt. The lipase inhibitory portion is preferably present in the nonabsorbable compound in a weight ratio of from about 1: 10 to about 1: 60 with respect to the weight of the polymer portion, preferably from about 1: 20 to about 1: 40 and more preferably from about 1: 25 to 1: 35. In one aspect, said lipase inhibitors comprise at least one lipase inhibitory portion (or portions) linked directly or indirectly to said polymer portion. The invention also includes pharmaceutical compositions comprising an effective amount of said lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent, which compositions may further comprise an effective amount of a pharmaceutically acceptable, biocompatible nonabsorbable, lipophilic oil absorption polymer.

In another aspect the present invention relates to novel salts of nonabsorbable lipase inhibitors and a non-absorbable, biocompatible, pharmaceutically acceptable oil absorption polymer. The invention also includes pharmaceutical compositions comprising an effective amount of said lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent, which compositions may further comprise an effective amount of a pharmaceutically acceptable, biocompatible non-absorbable, lipophilic oil absorption polymer.

In a preferred aspect the present invention relates to novel nonabsorbable derivatives of an inhibitor lipase 1,3-oxetanone, which includes at least a portion that inhibits lipase 1,3-oxetanone which binds covalently or non-covalently to a non-absorbable biocompatible pharmaceutically acceptable polymer portion to provide a novel lipase inhibitor compound. Preferred compounds have a dual function of inhibiting lipase and absorbing fats, whereby the pharmaceutically acceptable, biocompatible nonabsorbable polymer portion of the novel lipase inhibitor will bind the fat, carrying fat with it through the portions of the digestive system and causing the non-absorbed fat to be removed by removing it from the digestive system as undigested fat. The 1, 3 oxetanone portion which is derived directly or indirectly with the polymer portion according to the invention may initially be a nonabsorbable portion and is derived by directly or indirectly linking to the polymer portion to form a novel nonabsorbable lipase inhibitor, preferably in the 5-hisroxyl position of a 1,3-oxetanone portion.

In a preferred aspect the invention provides compounds having non-covalent bonds of said two covalent bonds or portions that are hydrolyzed or digested in the digestive system, providing that the portion of the 1,3-oxetanone derivative which inhibits the lipase that is released in The digestive system is substantially non-absorbable.

In another preferred aspect the invention provides compounds having a non-covalent bond of said portions or a covalent bond that is not hydrolyzed or digested in the digestive system, whereby the portion derived from 1,3-oxetanone which inhibits the lipase remains bound. to the polymer portion via said covalent or non-covalent bond and is not released in the digestive system.

In one aspect of the invention, the absorbable lipases such as the portion sterastin, tetrahydrostrastine or a similar portion are rendered non-absorbable by direct or indirect coupling to a non-absorbable, biocompatible, pharmaceutically-acceptable polymer portion, such as a polysaccharide to present the lipase essentially non-absorbable through the digestive system of an animal, such as an animal. dog, a cat, non-human primates or humans. The absorbable lipase inhibitory portions that become non-absorbable by such coupling include at least one lipase inhibitor which is a member selected from the group consisting of esterastine, tetrahydro-esterastine (3,5-hydroxy-2-hexadeca-7,10-dienoic). 1,3-lactone), 3,5-dihydro-2-hexylhexadeca-7,10-dienoic 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone and the like. Preferably, said lipase inhibitor is coupled to a non-absorbable, biocompatible, pharmaceutically acceptable polymer portion, such as a polysaccharide to produce the lipase non-absorbable by the digestive system of an animal such as a dog, a cat, a non-human primate or humans. Particularly the preferred polysaccharides have at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan, a chitosan derivative of the ester ether of methylbenzoic acid and the like. Particularly preferred lipase-linked inhibitors are lipase inhibitors linked via a derivative group in the lipase such as a nitrogen derived, acid or alcohol group for a group in the polymeric portion such as an alcohol derivative, acid or amino group. Preferably, a diether bridge is formed between the lipase inhibitor and the portion, wherein the bridge is derived from an alcohol group in the lipase and an alcohol group in the portion, each reacting with the bridging etherification group.

Compounds wherein the oxetanone moiety is derived are also preferred. to provide an amino group which is further derivatized to form a carboxamide group, followed by the linking of the carboxamide group to provide an alcohol or acid group in the polymeric portion via a bridging group, which polymer portion may have been derivatized to provide said acid or group alcohol for aggregates. Examples of said aggregates are illustrated below by a preferred embodiment of the invention.

In another aspect the present invention relates to pharmaceutical compositions comprising an amount effective to inhibit the lipase of at least one lipase inhibitor which is coupled to a digestibly nonabsorbable portion. Preferred are pharmaceutical compositions comprising an effective amount of lipases coupled to a pharmaceutically acceptable, non-absorbable biocompatible polymer portion, such as a polysaccharide, wherein the lipase is essentially absorbed by the digestive system of an animal such as a dog, a cat , a non-human primate or humans.

In still another aspect, the present invention relates to a method for treating adiposity or obesity by administering to a patient before a food containing fat or more than one hour after the food was consumed, an amount of at least a lipase inhibitor that binds to a non-absorbable polymer portion in an amount effective to inhibit the absorption of more than one-third of the dietary fat in said food. In particular, a preferred method comprises administration in a lipase inhibitor which is a member selected from the group consisting of esterastine, tetahydro-esterastine (3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone), , 5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1. 3 lactone, 3,5-di-hydroxy-2-hexylhexadecanoi 1,3-lkactone and the like, wherein said lipase inhibitor is coupled to a polymeric portion pharmaceutically acceptable, non-absorbable biocompatible, such as a polysaccharide to produce the non-absorbable lipase by the digestive system of an animal such as a dog, a cat, a non-human primate or humans. Particularly preferred polysaccharides are at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the similar ones. Particularly preferred lipase-linked inhibitors are lipase inhibitors linked via a nitrogen derivative, acid or alcohol group to an alcohol derivative, acid or amino group in the polymeric moiety.

} A finished diether bridge or a terminal ester / terminal ether bridge, between the lipase inhibitory portion and the polymeric portion that is derived from an alcohol group in the lipase inhibitory portion and an alcohol group in the polymeric portion, respectively reacting with a bridging group is a preferred coupling of the lipase inhibitor to the portion.

Another preferred bridge between the lipase inhibitor portion and the polymer portion includes at least one ether bridge formed from an alcohol group in the polymer portion and in at least one carboxamide bond. Further preferred compounds are those in which at least one amino acid derivative is located in the bridge and is linked directly or indirectly to the 5-hydroxyl position in the 1,3-oxetanone moiety via an ester linkage.

Preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrugs.

DETAILED DESCRIPTION OF THE INVENTION Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings unless explicitly stated otherwise.

The term "alkenyl" refers to a trivalent long chain or branched unsaturated aliphatic radical. The term "alkynyl" refers to a long or branched chain aliphatic radical that includes at least two carbons attached by a triple bond. If the carbon, alkenyl and alkynyl number is not specified, each refers to radicals having 2-12 carbon atoms.

The term "alkyl" refers to saturated aliphatic groups that include cyclic and long chain and branched chain groups having the specified number of carbon atoms or if the number is not specified, they have more than 12 carbon atoms. The term "cycloalkyl" as used herein refers to a mono-, bi- or tricyclic aliphatic ring having from 3 to 14 carbon atoms and preferably from 3 to 7 carbon atoms.

The term "bridging group" refers to a bifunctional chain or a spacer group capable of reacting with one or more of the functional groups on a lipase inhibitor compound and subsequently reacting with a second thereof or a different functional group on a polymeric compound to form a linked or conjugated structure between the two compounds. The bond formed between the bridge group and each of the two portions preferably is of a type that is resistant to penetrate through the digestive environment when the bound lipase portion would be absorbable at the penetration of the bond. In one aspect, the bridging group is of the formula XRX, wherein R is a selected member of a branched or long-chain alkyl group, a branched or long-chain alkenyl group, a branched or long-chain alkynyl group, a group mono acyl, a diacyl group and the like, whose R portion of the chain may include an aryl or cycloalkyl group and X is a functionally reactive group such as a halogen or an acid group, under special reaction conditions as described later in this document. Particularly preferred bridging groups form a diether, diacyl or acyl / ether bridge which is resistant to penetration through the digestive environment. In one aspect, bridging groups that are penetrated by the digestive group to release a nonabsorbable lipase inhibitor are preferred. Examples of the alkylene dichloride bridge group forming the compounds are dichloromethane, 1,2-dichloroethane, 1,2 and 1,3-dichloropentane, 1,2-, 1,3 and 1,4-diclurobutane and the like. Examples of the acyl dichloride bridge group forming the compounds are oxalic acid dichloride, malonic acid dichloride, succinic acid dichloride, glutaric acid dichloride, adipic acid dichloride, pimelic acid dichloride, suberic acid dichloride, fumaric acid dichloride, malic acid dichloride, glutamic acid dichloride, terephthalic acid dichloride, isophthalic acid dichloride, haloalkylbenzoic acid and the like. Other reagents of such bridging groups are compounds such as epichlorohydrin, phosphorus oxychloride and diphosphoryl tetrachloride and the like.

As used herein, the terms "carbocyclic ring structure" and "mono, bicyclic or tricyclic ring structure C3-? 6" or the like, each meaning stable ring structures having only carbon atoms as ring atoms wherein the structure of the ring is a substituted or unsubstituted member selected from the group group consisting of: a stable monocyclic ring which is an aromatic ring ("aryl" having six carbon atoms, a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms, a stable ring structure having a total of 7 to 12 atoms in two rings wherein the structure of the bicyclic ring is selected from the group consisting of ring structures in which both rings are aromatic, the ring structures in which one of the rings is aromatic and the structures of rings in which both of the rings are non-aromatic and a stable tricyclic ring structure having a total of 10 to 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of: ring structures in which the three rings are aromatic, the ring structures in which the two rings are aromatic and the ring structures in which the three rings are not In each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure can be independently saturated, partially saturated or fully saturated. Examples of such carbocyclic ring structures include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamathyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] biciclononane, [4.4.0] bicyclodecane (decalin) , [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin). On the other hand, the ring structures described herein may be added to one or more indicated pendant groups via any carbon atom resulting in a stable structure. The term "substituted" as used in conjunction with the carbocyclic ring structures means that the hydrogen atoms added to the ring carbon atoms of the ring structures described herein may be substituted by one or more substituents indicated for that structure if said substitution (s) result in a stable compound.

The term "aryl" that is included with the term "carbocyclic ring structure" refers to a substituted or unsubstituted aromatic ring, substituted with one, two or three substituents selected from lower alkoxy, lower alkyl, lower alkylamino, hydroxy, halogen , cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl and biaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, lower alkyl phenyl, naphthyl, biphenyl, phenanthrenyl and naphthacenyl.

The term "arylalkyl" which is included in the term "carbocyclic aryl" refers to one, two or three aryl groups having the designated carbon atom number, attached to an alkyl group having the designated carbon atom number. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzylhydryl, trityl and the like, all of which may be optionally substituted.

As used herein, the term "heterocyclic ring" or "heterocyclic ring system" means a substituted or unsubstituted member selected from the group consisting of a stable monocyclic ring having 5-7 members in the same ring and has from 1 to 4 heteroatoms in the ring selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 heteroatoms selected from N, O and S, including the bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings are fused to a benzene or hexane ring and a stable tricyclic heterocyclic ring structure having a total of 10 to 16 atoms in all three rings where at least one of the three rings has from 1 to 4 heteroatoms selected from the group consisting of N, O and S. Any sulfur and nitrogen atom present in a heterocyclic ring of said heterocyclic ring structure can be oxidized. Unless otherwise indicated, the terms "heterocyclic ring" or "heterocyclic ring system" include aromatic rings, as well as non-aromatic rings which may be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless otherwise indicated, the term "heterocyclic ring system" includes ring structures wherein all rings contain at least one heteroatom as well as structures that have less than all rings in the ring structure which contains at least one heteroatom, for example, the bicyclic ring structures wherein one ring is a benzene ring and one ring has one or more heteroatoms are included in the term "heterocyclic ring system" as well as ring structures bicyclic in which each of the two rings has at least one heteroatom. On the other hand, the ring structures described herein may be added to one or more indicated pendant groups via any carbon atom or hetero atom which results in a stable structure. In addition, the term "substituted" means that one or more hydrogen atoms on the nitrogen atoms or on the ring carbon atoms of each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if said displacement could result in a stable compound. The nitrogen atoms in a ring structure may be quaternary, but such compounds are specifically indicated or included in the term "pharmaceutically acceptable salt" for a particular compound. When the total number of S and O atoms in a heterocyclic ring is greater than 1, it is preferred that said atoms are not adjacent to each other. Preferably, there is no more than 1 atom in the O and S ring in the same ring of a given heterocyclic ring structure.

Examples of bicyclic and monocyclic heterocyclic ring systems are, in alphabetical order, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H.6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolinyl, indolizinyl, indolyl , 3H-indolyl, isobenzofuranyl, isochromanil, isoindazolyl, isoindolinyl, idoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,3-oxadiazolyl, 1,4-oxadiazolyl, 1,2, 5-Oxadiazolyl, 1,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenatrolinyl, phenazinyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperadin il, pteridinyl, purinyl, pyranyl, pyrazinyl, piroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2,5-thiazinyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,4-triazolyl, 1, 2,5-triazolyl, 1,4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include but are not limited to pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1 H-indazolyl, oxazolinyl, isatinoyl. Also included are spiro compounds and fused rings containing, for example, the above heterocyclic ring structures.

As used herein, the term "aromatic heterocyclic ring system" has essentially the same definition as for bicyclic and monocyclic ring systems except that at least one ring of the ring system is a ring The aromatic heterocyclic or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms "halo" or "halogen" as used herein refers to substituents Cl, Br, F or I. The term "heteroalkyl" and the like, refers to an aliphatic carbon radical having at least one hydrogen atom replaced by an atom of Cl, Br, F or I, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like, for example, as preferred radicals.

The term "methylene" refers to -CH2-.

The term "pharmaceutically acceptable salts" includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful both in their free base and in their salt form. In practice, the use of the amounts of the salt form to use the base form, both the acid addition and basic salts are within the scope of the present invention.

"Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid and the like and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

"Pharmaceutically acceptable basic addition salts" include those derived from organic bases such as sodium, potassium, lithium, ammonia, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonia, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include the primary, secondary and tertiary amine salts, substituted amines including the naturally occurring substituted amines, the cyclic amines and the basic ion exchange resins, such as isopropylamine, trimethylamine , diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine , polyamine resins and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.

"Biological property" for the purposes of this document means an in vivo effector or an antigenic function or activity that is performed directly or indirectly by a compound of this invention that is commonly shown by in vitro testing. The functions of the effector include binding of the ligand or receptor, any enzymatic activity or the modulating activity of the enzyme, any binding activity of the carrier, any hormonal activity, any activity in promoting or inhibiting the adhesion of the cells to a matrix. extracellular or cell surface molecules or any structural role. Antigenic functions include the possession of an antigenic or epitope site that is capable of reacting with the antibodies that arise against it.

In the compounds of this invention, the carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds can exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereoisomers as starting materials or intermediates. The diastereomeric products resulting from said syntheses can be separated by crystallization or chromatographic methods or by other methods known in the art. In addition, mixtures of enantiomeric products can be separated using the same technique or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, can be in one of two configurations (R or S) and both are within the scope of the present invention.

Preferred Modes In one aspect, the present invention relates to novel derivatives of lipase inhibitors that are non-absorbable and that have a lipase inhibitory moiety and a polymer moiety in the same molecule. The invention also includes pharmaceutical compositions comprising an effective amount of said lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent and further comprising an effective amount of a pharmaceutically acceptable, biocompatible non-absorbable, lipophilic oil absorption polymer. The lipase inhibitory moiety is present in a weight ratio of from about 1: 10 to about 1: 60 with respect to the weight of the polymer portion, preferably from about 1: 20 to about 1: 40 and more preferably from about 1: 25 to 1: 35 In one aspect, said lipase inhibitors comprise at least one lipase inhibitory portion (or portions) linked directly or indirectly to said polymer portion.

In another aspect, the present invention relates to novel salts of nonabsorbable lipase inhibitors and a non-absorbable, biocompatible pharmaceutically acceptable oil absorbency polymer. The invention also includes pharmaceutical compositions comprising an effective amount of said lipase inhibitors in combination with a pharmaceutically acceptable carrier or diluent, which compositions may further comprise an effective amount of a pharmaceutically acceptable, biocompatible, non-absorbable, lipophilic oil absorbency polymer.

In a preferred aspect, the present invention relates to novel nonabsorbable derivatives of a lipase-1, 3-oxetanone inhibitor, which includes at least a portion of inhibition of lipase 1,3-oxetanone that is covalently or non-covalently linked to a polymeric moiety pharmaceutically acceptable biocompatible nonabsorbable to provide a novel lipase inhibitor compound. Preferred compounds have a dual function of lipase inhibition and fat absorption, as the non-absorbable biocompatible pharmaceutically acceptable polymer portion of the novel lipase inhibitor that will bind to fat, bringing the fat linked thereto through portions of the fat. digestive system and causing the non-absorbed fat to be removed removed from the digestive system as undigested fat. Portion 1, 3 oxetanone is derived directly or indirectly with the polymer portion, according to the invention can initially be an absorbable or non-absorbable portion and is derived by directly or indirectly linking to the polymer portion to form a novel nonabsorbable lipase inhibitor , preferably in the 5-hydroxyl position of a 1,3-oxetanone portion.

In a preferred aspect, the invention provides compounds having non-covalent linkages of such two covalent portions or linkages that are hydrolyzed or digested in the digestive system by providing the 1,3-oxetanone derivative portion of lipase inhibition that is released into the digestive system it is substantially non-absorbable.

In another preferred aspect, the invention provides compounds having a non-covalent bond of said two portions or a covalent bond that are not hydrolyzed or digested in the digestive system, wherein the portion of lipase-inhibiting 1, 3-oxetanone derivative remains bound to the polymer portion via said covalent or non-covalent bond and is not released in the digestive system.

In one aspect of the invention, an absorbable lipase such as a sterastine, tetrahydrostrastine, or a similar portion, is rendered non-absorbable by direct or indirect coupling to a pharmaceutically acceptable non-absorbable biocompatible polymer portion, such as a polysaccharide to produce the lipase essentially non-absorbable by the digestive system of an animal such as a dog, a cat, a non-human primate or humans. The preferred absorbable lipase inhibitory portions that are rendered non-absorbable by such coupling include at least one lipase inhibitor which is a member selected from the group consisting of esterastine, tetrahydro-esterastine (3,5-hydroxy-2-hexadeca-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. Preferably, said lipase inhibitor is coupled to a non-absorbable biocompatible pharmaceutically acceptable polymer portion to produce the nonabsorbable lipase by the digestive system of an animal such as a dog, a cat, a non-human primate or humans. Particularly preferred polysaccharides have at least one member selected from the group consists of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, agar, chitosan, an ester derivative of chitosan methylbenzoic acid ester and the like . Particularly preferred lipase-linked inhibitors are lipase inhibitors linked via a derivative group in the lipase such as a nitrogen derivative, an acid or alcohol group for a group in the polymeric portion such as an alcohol derivative, acid or amino group. Preferably, the diether bridge is formed between the lipase inhibitor and the portion, wherein the bridge is derived from an alcohol group in the lipase and an alcohol group in the portion, each reacting with an ether bridging group. Also preferred are compounds wherein the oxetanone moiety is derived to provide an amino group that is further derivatized to form a carboxamide group, followed by the linking of the carboxamide group to an acid or alcohol group in the polymer portion that can be derived to provide said acid or alcohol group for its adhesion. Examples of such accessions are illustrated below by the preferred embodiments of the invention.

A finished diether bridge or an ester / ether bridge ends, between the lipase inhibitory portion and the polymeric portion that is derived from an alcohol group in the lipase inhibitory portion and an alcohol group in the polymeric portion, respectively reacting with a bridging group , is a lipase inhibitor coupling for the portion.

Another preferred bridge between the lipase inhibitor portion and the polymer portion includes at least one bridge formed from an alcohol group in the polymer portion in at least one carboxamide bond. The compounds are further preferred where minus one amino acid derivative is located in the bridge and is linked directly or indirectly to the 5-hydroxyl position in the 1,3-oxetanone moiety via an ester linkage.

Preferred compounds also include pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.

A preferred aspect of the present invention relates to novel oxetanone derivatives of the formula I, as follows: wherein: t is an integer from 0 to 1 XOQ is an ether bond where: X of the ether bond is a bridging group and Q of the ether bond is a polysaccharide of sufficient molecular weight or property so that said polysaccharide is not absorbed by the digestive system of a mammal such as a dog, a cat, a non-human primate or a human primate, whose polysaccharide is further defined; R is a member selected from the group consisting of: a long chain or branched C? -? 7 alkyl group which is saturated or optionally interrupted by more than eight double or triple bonds; a long chain or branched C alquilo alkyl group which is saturated or optionally interrupted by one or more members selected from the group it consists of an oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group; a long chain or branched CW7 alkyl group which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for an unsaturated carbon atom by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, an atom of the sulfonyl group or of the sulfinyl group; phenyl substituted by 0-4 members selected from the group consisting of -alkyl Ci-β-C-alkyloxy, -alkyl C? 6-alkylthio C? -6, -alkyl C? .6-OH and C-alkyl. 6- SH; benzyl substituted by 0-4 members selected from the group consisting of -I rent -alkyl C6- OH and alkyl C6.6 SH; biphenylene substituted by 0-6 members selected from the group consisting of -alkyl Ci-β-alkyloxy-d-β, -alkyl C? 6-alkylthio -6, -alkyl C? 6-OH and alkyl C1.6-SH; phenoxyphenylene substituted by 0-6 members selected from the group consisting of-Ci-β-alkyloxy-Ci-β alkyl. -alkyl Cv-alkylthio C? -6, -alkyl Ci-6-OH and alkyl C? 6-SH; phenylthiophenylene substituted by 0-6 members selected from the group consisting of-C6-6alkyloxy-C6-6alkyloxy, -C6alkyl -6-alkylthio C6.6 > -Ci-β-OH alkyl and Cvß-SH alkyl and phenyl-C ?6-phenyl alkyl wherein 0-6 carbon atoms in one or more of the phenyl ring and the-Cal -6 alkyl group is / are replace independently by a member selected from the group consisting of-Ci-β-alkyloxy-d-β alkyl. - alkyl d-6-alkylthio d-6, -alkyl C 1-6 -OH and alkyl d-6-SH; R1 is a member selected from the group consisting of: Hydrogen, Ar, Ar-alkyl d-5 and C1.10 alkyl interrupted by 0-3 members independently selected from the group consisting of an oxygen atom, a sulfur atom, a Sulfinyl group, a sulfonyl group, a group -N (-R4) -, a group -C (= O) -N (-R4) -, a group -N (-R4) -C (= O) -, in where 0-3 carbon atoms of the CMO alkyl group can be independently substituted by a member selected from the group consisting of a hydroxy group, thiol group, C alco.10 alkoxy group. an alkylthio group d-10, a group -N (-R5, -R6), a group -C (= O) -N (-R7, -R8) and a group -N (-R9) -C (= O ) -R10; R2 is a member selected from the group consisting of: hydrogen and C1.6alkyl or R2 taken together with R1 forms a 4-6 membered saturated ring containing from 0-4 nitrogen atoms wherein the ring can be replaced by groups of 0-4 R11; R3 is a member selected from the group consisting of: a long or branched chain d.17 alkyl group, which is saturated or optionally interrupted by more than eight double or triple bonds; a long chain or branched C? -17 alkyl group, which is saturated or optionally interrupted by one or more members selected from the group it consists of an oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group; a long chain or branched chain alkyl group, which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for a carbon atom Unsaturated by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, a sulfonyl group or an atom of the sulfinyl group; phenyl substituted by 0-4 members of -alkyl d-β-alkyloxy-d-β, -alkyl d-6-alkylthio C? -6, -alkyl C1.6-OH and C 1-6 alkyl-SH; benzyl substituted by 0-4 members selected from the group consisting of -C6 alkyl -6-C6-alkyloxy -6, -C6 alkyl -6-C1-6 alkylthio, -C1-6alkyl-OH and C6-C6-SH alkyl; biphenylene substituted by 0-6 members selected from the group consisting of -C6-alkyl-C6-alkyloxy -6, -alkyl d-6-alkylthio d-6, -C1.6 -OH alkyl and alkyl phenoxy-phenylene substituted by 0-6 members selected from the group consisting of -Calkyl-6-alkyloxy-C? -6 >; -alkyl d-6-alkylthio C, .6, -alkyl C? 6-OH and alkyl d-6-SH; phenylthiophenylene substituted by 0-6 members selected from the group consisting of-C6_6alkyl-C6_alkyloxy, -alkyl d-6-alkylthio d-6, -alkyl d-β-OH and C_alkyl. 6-SH and phenyl-C? -6-phenyl alkyl wherein 0-6 carbon atoms in one or more of the phenyl ring and the C1.6 alkyl group is / are independently replaced by a member selected from the group consisting of of -alkyl d-β-alkyloxy-d-β, -alkyl C? 6-alkylthio C? .6) -alkyl C 1-6 -OH and alkyl C? .6-SH; R4-R10 are each independently a member selected from the group consisting of: hydrogen and alkyl d-6; n is an integer of 0-3; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of the mimes.

A preferred compound according to formula 1 is a compound wherein X is a member selected from the group consisting of: - (C (= O)) o-rXa-, wherein Xa is a member selected from the group consisting of: a long chain or branched divalent CM7 alkylene group which is saturated or optionally interrupted by more than eight double or triple bonds; a long chain or branched divalent C 1 7 alkylene group which is saturated or optionally interrupted by one or more members selected from the group consisting of: an oxygen atom, a sulfur atom, a sulfonyl group, a sulfinyl group, a monocyclic bicyclic aryl of 6-10 members substituted or unsubstituted or a heteroaryl group having from 1-4 heteroatoms selected from group consisting of O, N, S, an NH group, wherein the hydrogen atom can be replaced with a CMO alkyl group. a group -C (= O) -, a group -NH-C (= O), wherein the hydrogen atom can be replaced with an alkyl group d.10 and a group -C (= O) -NH-, where the hydrogen atom can be replaced with a CMO alkyl group, a divalent long or branched chain alkylene d.sub.17 group which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for an atom of unsaturated carbon by one or more members selected from the group consisting optionally of one or more interrupted members selected from the group consisting of: an oxygen atom, a sulfur atom, a sulfonyl group, a sulfinyl group, a monocyclic bicyclic aryl 6-10 substituted or unsubstituted members or a heteroaryl group having from 1-4 heteroatoms selected from the group consisting of O, N, S, an NH group, wherein the hydrogen atom may be replaced with a C1-10 alkyl group , a group -C (= O) -, a group -NH-C (= O), wherein the hydrogen atom can be replaced with an alkyl group C? .10y a group -C (= O) -NH-, wherein the hydrogen atom can be replaced with a divalent phenylene alkyl group or divalent naphthylene substituted in the ring structure by 0-4 members selected from the group consisting of C1-6alkyl 6- C 1-6 alkyloxy, -alkyl d-6-alkylthio C? 6l -alkyl d-6-OH and alkyl d-6-SH; divalent biphenylene substituted by 0-6 members selected from the group consisting of C6-6alkyloxy-d.6alkyl-6-alkyl-C6-6alkyl) -alkyl d-6-OH and alkyl d-6-SH; phenoxyphenylene substituted by 0-6 members selected from the group consisting of d6-alkyloxy-C? -6 alkyl, -alkyl d-6-alkylthio C? 6, -alkyl C1-6-OH and alkyl d.6- SH; divalent phenylthiophenylene substituted by 0-6 members selected from the group consisting of d-6-alkyloxy-C6-6 alkyl, d6-alkyl-C1-6alkyl, -6-6alkyl-OH and C? -6-SH alkyl and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

Preferred sub-groups of said compounds are the compounds wherein R is - (CH 2) 3.6-CH 3 and R 3 is a member selected from the group consisting of - (CH 2) 8. -CH3 and -CH2-CH = CH-CH2-CH = CH- (CH2) 2.8 -CH3. Even the most preferred compounds are those wherein R is - (CH 2) 5 -CH 3 and R 3 is a member of the group consisting of - (CH 2) 10 -CH 3 and -CH 2 -CH = CH-CH 2 -CH = CH- ( CH2) 4-CH3.

In a preferred embodiment, the present invention relates to novel oxetanone derivatives wherein n of the preceding formula is zero to provide compounds of the formula: wherein: X, t, Q, R, R1, R2 and R3 are defined as above and isomers, salts, hydrates, solvates and prodrug derivatives thereof. Preferred sub-groups of such compounds are the compounds wherein R is - (CH2) 3.6-CH3 and R3 is a member selected from the group consisting of - (CH2) 8-14 -CH3 and -CH2-CH = CH- CH2-CH = CH- (CH2) 2.8 -CH3. The most preferred compounds are those wherein R is - (CH 2) 5 -CH 3 and R 3 is a member selected from the group consisting of - (CH 2) 10 -CH 3 and -CH 2 -CH = CH-CH 2 -CH = CH- ( CH2) -CH3. Further preferred compounds are those wherein t is 0 and X is -C (= O) -Xa - as set forth above.

Even the additional preferred compounds are those wherein t is 1 and X is a member selected from the group consisting of: wherein R1a is independently defined in the same manner as defined R1, R2a is independently defined in the same manner as R2 was defined, m is an integer from 0 to 10, preferably 0-5 and more preferably 0-2 and wherein z is an integer from 1 to 20, preferably from 2 to 10 and more preferably from 2-4 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

In another preferred embodiment, the present invention relates to said novel oxetanone derivatives of the formula 1 having the following formula: wherein: X, Q, R and R3 are defined as above and isomers, salts, hydrates, solvates and prodrug derivatives thereof. Preferred sub-groups of such compounds are the compounds wherein R is - (CH2) 3.6-CH3 and R3 is a member selected from the group consisting of - (CH2) 8.14 -CH3 and -CH2-CH = CH-CH2- CH = CH- (CH2) 2.8 -CH3. The most preferred compounds are those wherein R is - (CH2) 5 -CH3 and R3 is a member selected from the group consisting of - (CH2)? 0-CH3 and -CH2-CH = CH-CH2-CH = CH- (CH2) -CH3.

Even the preferred compounds are additionally those wherein X is a member selected from the group consisting of: - and "-C? '- N? C - f- CH - - and" - V C-N? C- wherein z is an integer from 0 to 10, preferably from 0-5 and more preferably from 0-2.

And all pharmaceutically acceptable isomers, salts, hydrates, solvates and derivatives of the prodrugs thereof.

Other preferred compounds are the compounds, wherein t is 0 or 1 and X is a member selected from the group consisting of: wherein R1a is independently defined in the same manner as defined R1, R2a is independently defined in the same manner as R2 was defined, m is an integer from 0 to 10, preferably 0-5 and more preferably 0-2 and wherein z is an integer from 1 to 20, preferably from 2 to 10 and more preferably from 2-4 and all the pharmaceutically acceptable isomers, salts, hydrates, solvates and derivatives of the prodrugs thereof.

Further preferred compounds are said compounds wherein X is a member selected from the group consisting of: and where z is an integer of 6-12, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

The most preferred compounds are those wherein X is a member selected from the group consisting of: - I- C- - c- -c- - and - c-t-c- - and where z is an integer of 6-12, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

Particularly preferred groups Q for the above compounds are non-absorbable biocomparable pharmaceutically acceptable polymers, such as a polysaccharide, which are preferably lipophilic and bind to fat and are non-absorbable through the digestive system of an animal, such as a dog, a cat, a non-human or human primate. Particularly preferred polysaccharides have at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the similar ones. Particularly preferred Q groups have an alcohol, acyl group or amino group or can be derived herein such as an alcohol, amino or acyl group, which can be linked to the R portion or the X-R-X group. Preferably, in at least one or two of the ether bridges that can be formed between a portion of the lipase inhibitor and the polymer portion via an XRX bridge, wherein the bridge is derived from an alcohol group or an amine group in the lipase and a alcohol group, acyl group or amino group in the Q group. Even the most preferred compounds are those of the Q groups that are chitosan derivatives that have been modified by an ether group which is terminated by an organic acid group. Further preferred are those modified chitosan Q groups wherein the organic acyl groups are independently a long or branched chain alkanoyl group. Most preferred are those modified chitosan Q groups wherein the polarity resulting from the modification of chitosan with the organic acyl groups allows the modified chitosan to absorb the lipids and water to form a substantially homogeneous gel with oil and water.

The most preferred compounds are the compounds set forth above, wherein the Q group is a modified chitosan compound with a sufficient number of organic acyl groups to cause the modified chitosan to absorb both the lipids as water to form a substantially homogeneous gel with oil and water. The number of the organic acyl groups present in the modified chitosan chains are present in a molar ratio of 1 to 8 times the number of the molar ratio of the groups of esterified lipase inhibiting alcohol and more preferably a ratio of 2 to 5 times and more preferably a ratio of 3 to 4 times the number of esterified lipase inhibitor alcohol groups.

Preparation of the Compounds The lipase inhibitor compounds, the polymeric portions and the bridging groups of the present invention can be synthesized or rapidly obtained from commercially available sources. Polymer bridge groups, bridge coupling processes and compound purification methods are described and referenced in standard textbooks, particularly the coupling of alcohol groups via diether bridge, ether / ester bridges, ether / ketone bridges and the similar ones. Standard polymer textbooks refer to typical bridge groups and coupling procedures.

The starting materials used in any of these methods are commercially available with sellers of chemicals such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences and the like or can be rapidly synthesized by known methods.

The reactions can be carried out in reaction vessels and standard laboratory glassware under standard temperature and pressure reaction conditions except where otherwise indicated.

During the synthesis of these compounds, the functional groups can be protected by blocking groups to prevent cross reaction during the coupling procedure. Examples of appropriate blocking groups and their use are described in "The Peptides: Analysis, Synthesis, Biology," Academic Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), descriptions of which are incorporated in this document as a reference.

The lipase inhibitor portions having a hydroxy group such as tetrahydro-esterastine (3,5-hydroxy-2-hexadeca-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 easily coupled to a polymeric moiety having free hydroxy groups such as cellulose, chitosan and other polysaccharides having groups free hydroxyl. One or both of the lipase inhibitor portion and the polymer portion may be derivatized to form part of the binding bridge before reacting with another portion. For example, the inhibitor molecule lipase can be condensed with a terminal dihalide or acyl halide group (the acyl group can be protected with an acid group) to form an ether or ester linkage and subsequently condensed with a polymeric portion having a free hydroxyl group as It is shown in the polysaccharide chemistry. In a process a polymeric portion such as chitosan can be reacted with a compound such as a halomethylbenzoic acid ester or the like and de-esterified to present a free acid group that can react to form a ketone, carboxamide or the like with the inhibitory moiety derived lipase. In a preferred aspect of the invention, one of the two portions is reacted with an asymmetric dihalide linking group, such as an alkylene dihalide (i.e., 1,2-bromochloroethyl, 1,3-bromochloropropyl and the like) in a proportion molar of 1: 1 to etherify the free hydroxyl groups, replace a hydrogen atom in an amino group or a ketone with an acidic group and the resulting intermediate can be reacted with the polymeric portion to form an ether group with a free alcohol group, replace a nitrogen atom in an amino group or form a ketone with an acid group. Particularly preferred polymeric moieties are polysaccharides having multiple free hydroxyl groups which after coupling can optionally be sulfonated to produce the lipase portion itself of a lipase inhibitor compound. Esterification, amination and ketone forming processes are well known in the art and by an expert therein. In addition, other linking groups and techniques for linking a compound having a functional group reactive to a polymeric moiety are well known in the art. Preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives. The bridging group refers to a bifunctional chain or a spacer group capable of reacting with one or more functional groups on a lipase inhibitor compound and subsequently reacting with a same or a different functional group on a polymeric compound to form a linked or conjugated structure between two compounds. The bond formed between the bridge group and each of the two compounds preferably is of a type that is resistant to penetrate through the digestive environment. In one aspect, the bridging group is of the formula XRX, wherein R is a selected member of a branched or long-chain alkyl group, a branched or long-chain alkenyl group, a branched or long-chain alkynyl group, a group mono acyl, a diacyl group and the like and X is a functionally reactive group such as a halogen, under special reaction conditions as will be described later. Particularly preferred bridging groups form a diacyl or diether bridge that is resistant to penetration through the digestive environment.

Examples of the dichloride-alkylene bridge group forming compounds are dichloromethane, 1,2-dichloroethane, 1-2 and 1-3, dichloropropane, 1,2-, 1,3- and 1,4-dichlorobutane, 1,2-bromochloroethane, 1,2- and 1,3-bromochloropropane and the like.

Examples of the acyl dichloride bridge group forming compounds are oxalic acid dichloride, malonic acid dichloride, succinic acid dichloride, glutaric acid dichloride, adipic acid dichloride, pimelic acid dichloride, suberic acid dichloride, fumaric acid dichloride, malic acid dichloride, glutamic acid dichloride, terephthalic acid dichloride, isophthalic acid dichloride and the like.

Examples of haloacyl bridging groups include chloromethylbenzoic acid or an ester thereof, 3-bromopropanoic acid, 2-chloroacetic acid, 6-bromohexanoic acid and an ester thereof, 12-bromododecanoic acid or an ester thereof, other haloalkanoic acids or esters of them and the like.

Other reagents of said bridging group are compounds such as epichlorohydrin, phosphorus oxychloride and diphosphoryl tetrachloride and the like.

Preferred bridging groups are the dihalide groups terminated with a chloro and bromo group or the groups terminated with an acyl group and a halogen group. Even the most preferred bridging groups are the n-halo acids (preferably n-bromo) -C4-C? 8 (preferably C? -C? 4) alkanoics or esters thereof. The reaction is carried out by the slow addition of a bifunctional reagent such as a diacyl dichloride, an alkylene dichloride or a substituted bromo acyl ester compound, dissolved in an organic solvent substantially immiscible with water for an aqueous alkaline solution of the lipase inhibitor in a substantially proportion molecular 1: 1 The reaction proceeds in the interface between the two immiscible solutions to provide an interfacial condensation and produce the sucrose derivative or analogue. It has been found that this reaction at the interface of the organic solution and in the aqueous solution imparts a specificity for the reaction for the primary alcohol groups of the polysaccharide. It should be understood that equivalent reagents such as diepoxides and halohydrocarbyloxyranos such as epichlorohydrin also react in the process to provide new and useful ether bridges.

By appropriate selection of the bridge group reagent type, different structural groups with various chemical properties can be incorporated into the resulting bridge and various types of lipase inhibitors can be connected to a nonabsorbable polymer portion, such as a polysaccharide and preferably chitosan. The reaction temperatures and other reaction conditions, as well as the proportions of the reactants are known to those skilled in polymer chemistry. Other groups and modifications will be apparent to one skilled in the art.

The functionality of the lipase inhibitor of coupled lipase inhibitors can be determined by well-known lipase inhibitor tests. A therapeutically effective amount of the linked lipase inhibitor can be administered to a patient. The fat binding polymers optionally can be added to the composition.

The following non-limiting Reaction Schemes I, II, III and IV illustrate the preferred embodiments of the invention with respect to the preparation of the compounds according to the invention.

Scheme I (absorbable lipase inhibitor) Scheme II (methyl chloromethylbenzoate) (chitosan derivative) (lipase inhibitor non-absorbable) Scheme lll (tetrahydroesterastine derivative) (tetrahydroesterastine) (absorbable lipase inhibitor) H-0 (chitosan) (lipase inhibitor non-absorbable) Scheme IV (Chloride ether (hexanoic acid chloride, activated chitosan derivative) 6-bromohexanoic, Aldrich 235555 (tetrahydroesterastine) (absorbable lipase inhibitor) (lipase inhibitor non-absorbable) Therefore, in a preferred aspect, the invention provides a method for producing a compound, which comprises reacting a compound of the formula: with a compound of the formula wherein t is 0 or 1 and Y is a removal group for an etherification reaction or esterification with the hydroxyl group to produce a compound of the formula: or a salt of it.

Pharmaceutical Compositions and Edible Compositions In one aspect, the present invention provides a beverage for athletes, snacks, nutritional supplements, food or energy that can be formulated to contain a therapeutically effective inhibitory amount of the lipase of the lipase inhibitor composition according to the invention.

In another aspect, the present invention relates to pharmaceutical compositions comprising an effective amount of the lipase inhibitor of at least one lipase inhibitor that couples to a digestibly nonabsorbable portion. The preferred compositions are those that comprise an effective amount of a lipase coupled to a non-absorbable biocompatible pharmaceutically acceptable polymer portion, such as a polysaccharide wherein the lipase is essentially non-absorbable by the digestive system of an animal such as a dog, a cat, a primate not human or human. The pharmaceutical composition can be administered to a patient before or within one hour of having consumed a food containing fat to prevent the absorption of more than a third of the dietary fat consumed in the food.

In another aspect, the present invention relates to a method for treating adiposity or obesity by administering to a patient before a food containing fat or after more than one hour of consuming said food, an amount of at least one lipase inhibitor which binds to a non-absorbable polymer portion in an amount effective to inhibit the absorption of more than one third of the dietary fat in said food. In particular, a preferred method comprises administering a lipase inhibitor which is a member selected from the group consisting of esterastine, tetrahydro-esterastine (3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone), 3,5-dihydroxy- 2-hexylhexadeca-7,10-dienoic acid 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone and the like, wherein said lipase inhibitor is coupled to a pharmaceutically acceptable biocompatible polymer portion not absorbable, such as a polysaccharide, to produce the non-absorbable lipase by the digestive system of an animal such as a dog, a cat, a non-human primate or humans. Particularly preferred polysaccharides are at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the similar ones. Particularly preferred lipase-linked inhibitors are lipase inhibitors linked via a nitrogen derivative, acid or group of alcohol for a derivative alcohol, acid or amino group in the polymer portion. A diether bridge between the lipase inhibitor and the portion that is derived from an alcohol group in the lipase and a group of alcohol in the portion, respectively reacting with a bridging group is the preferred coupling of the lipase inhibitor for the portion.

The compounds of this invention can be isolated as the free or basic acid or converted to the salts of various organic and inorganic acids and bases. Said salts are within the scope of this invention. Physiologically compatible and non-toxic salts are particularly useful although other less desirable salts can be used in the isolation and purification process.

Numerous methods are useful for the preparation of the salts described above and are well known in the art. For example, the free base or free acid forms of a compound of one of the above compounds can be reacted with one or more molar equivalents of the desired acid or base in the solvent or mixture of solvents in which the salt is insoluble or in a solvent such as water after which the solvent is removed by evaporation, distillation or freeze drying.

Alternatively, the base form or free acid of the product can be passed over an ion exchange resin to form the desired salt or a salt form of the product can be converted to another using the same general process.

Derivatives Prodrugs of the Compounds This invention also encompasses prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a derivative pharmacologically inactive of a drug origin molecule that requires biotransformation, the spontaneous or enzymatic base / acid reaction in the body to release the active drug. The prodrugs are variations or derivatives of the compounds of this invention that have penetration groups under conditions of the digestive system. The prodrugs become the compounds of the invention that are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or suffer from enzymatic degradation. The prodrug compounds of this invention can be called simple, double, triple, etc. , depending on the number of biotransformation steps required to release the active drug in the organism and indicating the number of functionalities present in a precursor type form. Prodrug forms sometimes offer advantages of solubility, digestion compatibility or delayed release in mammalian organisms (see, Bundgard, Design of-Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the source acids with an appropriate alcohol or amides prepared by reaction of the acidic starting compound with an amine or basic groups reacted to form an acylated base derivative. Accordingly, the prodrug derivatives of this invention can be combined with other characteristics that can improve bioavailability.

The formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers, etc., and can be provided in sustained release or formulations of timed release. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro, 1985). Said materials are non-toxic to the receptors in the doses and concentrations employed and include stabilizers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight peptides (less than about ten residues) such as polyarginine, proteins, such as albumin serum, gelatin or immunoglobulins, hydrophilic polymers such as polyvinyl pyrrolidione, amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins , chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counters such as nonionic and / or sodium surfactants such as Tween, Pluronics or polyethylene glycol.

Formulations of the doses of the compounds of this invention to be used for therapeutic administration may be sterile. Sterility is rapidly achieved by filtration through sterile membranes such as 0.2 micron membranes or by other conventional methods. The formulations will typically be stored in lyophilized forms or as an aqueous solution. The pH of the preparations of the invention will typically be 3-11, more preferably 5-9 and more preferably 7-8. It will be understood that the use of certain of the preceding excipients, carriers or stabilizers will result in the formation of salts of cyclic polypeptides.

Therapeutically effective doses can be determined by in vitro or in vivo methods. For each particular compound of the present invention, they can be made individual determinations to determine the optimal dose required. The range of therapeutically effective doses will influence the route of administration, the objectives and the therapeutic conditions of the patient. Therefore, it may be necessary for the therapist to indicate the dose and modify the means of administration as required to obtain the optimal therapeutic effect. The determination of the effective dose levels, which are the dose levels necessary to achieve the desired result, will be quickly determined by a person skilled in the art. Typically, applications of the compound are initiated at low dose levels, with dose levels being increased until the desired effect is achieved.

The compounds of the invention can be administered orally in an effective amount in a dose range of about 10 to 400 mg / kg, preferably about 50 to 300 mg / kg and more preferably about 100 to 200 mg / kg per food containing fat in a regimen in one or in 2 to 4 doses divided daily. A preferred dose is an amount (ie, approximately 100 to 200 mg / kg) that has a similar lipase inhibitory effect for the inhibition of lipase of 120 mg (approximately a dose of 1-2 mg / kg) of Orlistat taken orally. The determination of said equivalent of the lipase inhibitor can be determined via well-known lipase inhibition tests and can be in vitro tests or in vivo tests or both. The fat absorption properties of the lipophilic lipase inhibitor of the invention can be observed by comparing the amount of anal oil discharged in a patient taking a lipase inhibitor equivalent to the amount of lipase inhibitor according to the invention as compared to a patient that only Orlistat takes. The preparation of mice with anal oil is a comparison as compared Orlistat or the actual comparison of anal discharge in animals or patients which will also show a reduction in the amount of oily anal discharge when a lipophilic lipase inhibitor according to the invention is administered.

Typically, about 500 mg to 2 g of a compound or mixture of compounds of this invention, such as the free acid or base form or as a pharmaceutically acceptable salt is composed of a physiologically acceptable carrier, carrier, excipient, binder, preservative, stabilizer. , drying, flavoring, etc., so called by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that an appropriate dose is obtained in the indicated range.

Typical adjuvants that can be incorporated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin and excipients such as microcrystalline cellulose, disintegrating agents such as corn starch or alginic acid, lubricants such as magnesium stearate, agents sweeteners such as sucrose or lactose or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline or a fatty oil. Other materials of various types can be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated in accordance with conventional pharmaceutical practice. For example, the dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle such as ethyl oleate or in a liposome may be desired. The stabilizers, preservatives, antioxidants and the like can be incorporated in accordance with accepted pharmaceutical practice.

In certain aspects of this invention, the compounds are provided in such a way that they are useful as diagnostic agents for determining lipase activity. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In another aspect, the present invention includes methods comprising the use of the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesirable lipids or fat absorption such as obesity, hyperlipidemia, arteriosclerosis and diseases related to atherosclerosis of the blood coagulation process in mammals or to stabilize fat by preventing lipase function in stored samples and fat products. Optionally, the methods of this invention comprise the administration of the pharmaceutical composition in combination with an additional therapeutic agent such as an anti-cholesterol agent, appetite suppressant, metabolic stimulant and the like.

Preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.

In one embodiment the present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier excipient and an amount of at least one of the compounds described above according to the invention in a therapeutically effective amount with respect to limiting or preventing the absorption of some dietary fat. In a preferred embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the slow release lipoprotein lipase, preferably from a source of plants or microbes, which selectively hydrolyse the terminal triglyceride groups in combination with an effective amount of oil absorption of a polysaccharide such as chitosan, wherein the lipoprotein lipase is present in a proportion of less than 25% with respect to the oil absorption polysaccharide.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier excipient, an amount of at least one of the compounds described above for the invention in a therapeutically effective amount with respect to limiting or preventing the absorption of some fat. dietary and an effective amount of the oil absorption of the polysaccharide such as chitosan, wherein said lipase inhibitor is effectively selected to inhibit the different lipases to the lipases involved in the hydrolysis of the terminal triglyceride groups and said lipase inhibitor does not substantially inhibit absorption of vitamins A, D and E.

In another embodiment the present invention provides a method for using said compounds and pharmaceutical compositions as therapeutic agents for disease states in mammals having at least one disease which is due to unwanted absorption of dietary fat or for the reduction of intake effective calorie in a mammal that consumes dietary fat, which method can be useful in the treatment of unwanted weight gain or obesity.

The compounds of this invention also find utility as intermediates for producing the therapeutic agents or as therapeutic agents for disease states in mammals, which have diseases due to the unsuitable absorption of dietary fat. Methods for producing the starting materials can be found in U.S. Patent 4,931, 463, which is incorporated completely in this document. Preferred oxetanones of the invention are compounds wherein R is methyl, ethyl, propyl, hexyl, decyl, hexadecyl, allyl and benzyl and more preferably hexyl; R1 is hydrogen, methyl, ethyl, propyl, 2-butyl, isobutyl, benzyl and methylthio-ethyl, more preferably hydrogen or isobutyl; R2 is hydrogen, methyl or ethyl; more preferably hydrogen; N is 0 or 1 and when t is 1, then X is preferably added to N via an amino acid, such as valine, alanine and the like, preferably alanine and R 3 is preferably a long or branched chain C 1-17 alkyl group which is saturated or optionally interrupted with more than eight double or triple bonds or R3 is a long chain or branched C? .17 alkyl group which is saturated or optionally interrupted by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group or R3 is a C1.17 long or branched chain alkyl group which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for an unsaturated carbon atom by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, a sulfonyl group or atoms of a sulfinyl group.

The compounds produced according to the present invention can also be used as intermediates in the formation of compounds that can be administered in combination or in contact with other diagnostic or therapeutic agents. In certain preferred embodiments, the compounds produced by the intermediates according to the present invention can be co-administered together with other compounds typically prescribed for these conditions in accordance with generally accepted medical practice such as other dietary maintenance drugs and for related diseases. or impacted by the absorption of dietary fat. The compounds produced from the intermediaries in accordance with the present invention they can act as a synergistic design with other medicaments. Said compounds can also make it possible to reduce the doses of other metabolic stimulants and appetite suppressant drugs and cholesterol inhibitors and the like. Such compounds can be used in vivo, ordinarily in mammals such as primates (non-human and human), sheep, horses, cattle, pigs, dogs, cats and mice or in vitro.

The initial materials used in the above processes are commercially available with sellers of chemicals such as Aldrich, Sigam, Lancaster, TCl and the like or can be rapidly synthesized by known methods, for example, by using methods such as those indicated above.

The reactions can be carried out in reaction vessels and standard laboratory glassware under standard temperature and pressure reaction conditions, except as otherwise indicated or well known in the literature available in the art. In addition, the above processes of the processes of the invention can be carried out on a commercial scale by using reactors and standard increase equipment available in the art to produce large quantities of compounds in the commercial environment. Such equipment and methods of increase are well known to one skilled in the art in the field of commercial chemical production.

During the synthesis of these compounds, the acid or amino functional groups can be protected by blocking the groups to prevent undesired reactions with the amino group or the acid group during certain procedures. The procedures for such protection and removal of protection groups are routine in this technique and well known to the expert in this area.

Three exemplary non-limiting synthesis schemes are shown above, each of which is a preferred embodiment of the invention, comprising the steps of the process outlined above which may also include the initial steps such as those set forth in J. Med. Chem. Vol. 15, No. 8 (1972) or additional steps of the process that modify the amino group comprising a desired functional group such as the groups described in the field of lipase inhibition. Amino coupling reactions are well known in the art. On the other hand, the specific steps are established in the reaction scheme of the preferred embodiment described above. The reaction products are isolated and purified by conventional methods, typically by solvent extraction in a compatible solvent. Preferred solvents are lower alkane ethers and alcohols, ethyl ether and isopropyl alcohol are preferred for solvent extraction or recrystallization processes. The esters of the carboxylic acid side groups can be formed to allow selective separation of the R and S enantiomers by solvent extraction or recrystallization. D-alaninol is the preferred enantiomeric resolving agent, but other resolving agents or analogous procedures can be used, ie, tartaric acid derivatives and the like. The products can also be purified by column chromatography or other appropriate methods.

Enantiomeric Resolution and Acid Salt Formation As is clear from the above formula and the above description, by using the above racemic reactions, chroman acetic acid is obtained which can optionally be resolved to produce the racemic mixture enriched in the R or S enantiomers or results completely in a substantially pure composition of one of the enantiomers. The literature in this field describes examples of conventional processes in which the enantiomers can be resolved.

Coupling Reaction of Intermediate Hydrochlorohydric Compounds The above compounds produced according to the invention can be isolated and further reacted to replace a desired group with one or more of the hydrogen atoms or an amino group, on a free hydroxyl group or a free acyl group by a coupling reaction with the desired group.

Compositions and Formulations The compounds of this invention can be isolated as the free or base acid or converted to salts of various acids and organic and inorganic bases. Said salts are within the scope of this invention. The physiologically non-toxic and compatible salts are particularly useful although less desirable salts can be used in the isolation or purification processes.

A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, the reaction of the free acid or the free basic form of a compound of the structures indicated above with one or more molar equivalents of the desired acid or base in a solvent or mixture of solvents in which the salts are insoluble or in a solvent like water after the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or the basic form of the product can be passed over an ion exchange resin to form the salt desired or a salt form of the product can be converted into another using the same general process.

Diagnostic applications of the compounds of this invention will typically use formulations such as solution or suspension. In the management of unwanted fat absorption, the compounds of this invention can be used in compositions such as tablets, capsules or elixirs for oral administration, sterile solutions or suspensions and the like or incorporated into shaped articles. Subjects in need of treatment (typically mammals) using the compounds of this invention can be administered doses that will provide optimal efficacy. The dosage and method of administration will vary in each subject and will be dependent on such factors as the type of mammal being treated, its sex, weight, diet, current medication, total clinical condition, the particular compounds used, the specific use for the which compounds are used and other factors that will be recognized by those skilled in the medical art.

The formulations of the compounds of this invention are prepared for storage and administration by mixing the compound having a desired degree of purity with pharmaceutically acceptable carriers, excipients, stabilizers, etc., and can be provided in sustained release or time-release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described for example in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edt, 1985). Said materials are non-toxic to the receptors in the doses and concentrations employed and include stabilizers such as phosphate, citrate, acetate and organic acid salts, antioxidants such as ascorbic acid, low molecular weight peptides (less than about ten resins) such as polyarginine, proteins, such as serum albumin, gelatin or hydrophilic polymers immunoglobulins such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides and other carbohydrates including cellulose and its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counters such as nonionic and / or sodium surfactants such as Tween, Pluronics or polyethylene glycol.

Formulations of the doses of the compounds of this invention to be used for therapeutic administration may be sterile. Sterility is rapidly achieved by filtration through sterile membranes such as 0.2 micron membranes or by other conventional methods. The formulations will typically be stored in lyophilized forms or as an aqueous solution. The pH of the preparations of this invention will typically be 3-11, more preferably 5-9 and more preferably 7-8. It will be understood that the use of certain of the preceding excipients, carriers or stabilizers will result in the formation of salts of cyclic polypeptides. While the preferred route of administration is by oral tablets, capsules or other unit dose mechanisms, such as liquids, other methods of administration are also anticipated such as in food fillings, employing a variety of dosage forms. The compounds of this invention are desirably incorporated into food items which may include fat to prevent their absorption.

The compounds of this invention can also be coupled with appropriate polymers to improve their therapeutic effects. Such polymers may include lipophilic polymers, such as polysaccharides and the like.

Therapeutically effective doses can be determined by in vitro or in vivo methods. For each particular compound of the present invention, individual determinations can be made to determine the optimum dose required. The range of therapeutically effective doses will be naturally influenced by the route of administration, the therapeutic objectives and the condition of the patient. For the routes of administration, the activity of the lipase inhibitor, in view of the amount of fat consumed, should be determined individually for each inhibitor by methods well known in pharmacology. Therefore, it may be necessary for the therapist to indicate the dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of the effective dose levels, which are the dose levels necessary to achieve the desired result, will be determined by a person skilled in the art. Typically, applications of the compound are initiated at low dose levels, with dose levels being increased until the desired effect is achieved.

Typically, about 500 mg to 3 g of a compound or mixture of lipase inhibitor compounds of this invention, such as the free acid or the basic form or as a pharmaceutically acceptable salt is composed of a physiologically acceptable carrier, carrier, excipient, binder, / ador, stabilizer, drying, flavoring, etc., so called by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that an appropriate dose is obtained in the indicated range. The addition of one or more therapeutic ingredients such as a fat or fiber absorption polysaccharide, a specific fat lipase inhibitor or lipase, as well as other dietary agents can be used in therapeutically effective amounts.

Typical adjuvants that can be incorporated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin and excipients such as microcrystalline cellulose, disintegrating agents such as corn starch or alginic acid, lubricants such as magnesium stearate, agents sweeteners such as sucrose or lactose or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline or a fatty oil. Other materials of various types can be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated in accordance with conventional pharmaceutical practice. The stabilizers, preservatives, antioxidants and the like can be incorporated in accordance with accepted pharmaceutical practice.

In practice the methods of this invention, the compounds of this invention can be used alone or in combination with other diagnostic or therapeutic agents. In certain preferred embodiments, the compounds of this invention may be coadministered together with other compounds typically prescribed for these conditions in accordance with generally accepted medical practice.

The compounds of this invention can be used in vivo, ordinarily in mammals such as non-human primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice or in vitro.

The following non-limiting examples are provided to better illustrate the present invention.

EXAMPLE 1 10 grams of low viscosity chitosan are dissolved in a 500 milliliter flask equipped with a stirring thermometer and an electric heater, in a mixture of 190 g of dimethyl sulfoxide and 10 g of paraformaldehyde at 50 ° C. At this temperature, after the addition of 0.1 g of very fine powdered sodium hydroxide, a solution of 400 mg of methyl ester of p-chloromethyl benzoic acid in 10 g of dimethylsulfoxide is added over a period of about 30 minutes. The mixture was stirred for four hours at 50 ° C. The reaction mixture was cooled to room temperature, then poured into ethanol while the latter was stirred vigorously. The solid was filtered by suction, repeatedly resuspended in ethanol until all the soluble substances were removed to produce a crude product. The crude product was stirred in an aqueous basic solution of 1N sodium hydroxide ethanol, which was subsequently acidified with HCl until the pH was neutral for chitosan. The solid was washed twice with cold ethanol and cold water and the solid was subsequently dried to yield about 10 grams of the chitosan functionalized with ether. The analysis indicates that from 1% to 3% of the free hydroxyl groups in the chitosan polymeric main element are etherified by the entry of the p-methylbenzoic acid group.

Example 2 A colorless powder of 3,5-dihydroxy-2-hexyl-hexadecanoic 1,3-lactone (6 g, produced as described on pages 11 and 12 of US Pat. No. 4,202,824) was dissolved in 500 ml of THF on which was added to the Boc- (L) -2-amino-4-methylpentanoic acid chloride (3g, Boc- (L) -Leucine). The reaction mixture was stirred and refluxed until HPLC indicated that the esterification is essentially complete. The organic phase was evaporated and the residue was purified by chromatography in silica gel with toluene-ethyl acetate to produce 5- [Boc- (L) -2-amino-4-methylvaleroxy] -2-hexyl-hexadecanoic 1,3-lactone (6 g).

Example 3 The BOC group of the product (6 mg) of Example 2 was removed by hydrogenation at room temperature in 120 ml of THF in the presence of 10% Pd / C. After the hydrogenation was completed, the catalyst was filtered and the filtrate was evaporated to yield a crude product of the free amino group, which is taken in more than 100 ml of THF. The functionalized chitosan product produced in Example 1 is taken in more than 200 ml of THF and stirred while the crude free amino product was added dropwise at room temperature. The mixture was gradually heated to 40 ° C with stirring while HPLC indicated the formation of the bonded carboxamide product. It occurred 5- [2-. { (4-chitosan methyl ether) benzoylamido} -4-methylvaleroxy] -2-hexyl-hexadecanoic 1,3-lactone (approximately 15 grams).

Example 4 To a one liter flask was added 20 g of chitosan that had been dissolved in 350 ml of DMF (NN-dimethylformamide), with stirring and the temperature was raised to 50 ° C. A mixture of 0.2 g of NaOH and 1 g of 6-bromohexanoic acid in 20 ml of DMF was slowly added during 30 minutes with stirring. The reaction mixture was stirred at 50 ° C for 4 hours. The reaction mixture was cooled to room temperature and poured into 500 ml of ethanol. The solid was filtered by suction and washed three times with cold ethanol. The precipitate was treated in a NaOH solution of 1 N ethanol for 3 hours, then the pH was reduced to neutral by the addition of 1 N HCl. The solid was washed with cold ethanol and H2O (4: 1 ratio) 3 times. and dried to provide 19.7 g of functionalized chitosan.

Example 5 To 200 ml of THF (tetrahydrofuran) 9.3 g of the functionalized chitosan of Example 4 was added with stirring. To this mixture was added 10 mmol of HBTU (1 H-benzotriazolium-1- [bis, (dimethylamino) methylene] -hexafluorophosphate (1 -) - 3-oxide) dissolved in 10 ml of DMF with stirring over a period of 10 minutes . The tetrah id rostatin ester L-leucine (approximately 525 mg) dissolved in 100 ml of THF was added dropwise with stirring. The pH was subsequently adjusted to about 8.5 by the addition of DIEA (disopropylethylamine) and the mixture was stirred at room temperature overnight. The reaction mixture was reduced in volume by evaporation in vacuo to approximately 50% of the volume and 500 ml of hexane was added. The mixture was filtered and the solid paste was washed with cold hexane three times and then with ethanol / cold water solution (3: 1). The filtered pulp was dried under a lyophilizer to produce 9.3 grams of the final product 2S, 3S, 4S [2-. { (chitosan modified hexanoic acid 6-hexanoylamido.) -4-methylvaleryloxy] -2-hexyl-hexadecanoic 1,3-lactone (Compound A).

Example 6 To 200 ml of THF was dissolved with stirring 9.65 g of chitosan functionalized from Example 5, above, followed by 2 mmoles of HBTU. The mixture was stirred together for 15 minutes and subsequently 3.50 mg of 2S, 3S, 4S 2-hexyl-4-hydroxy-hexadecanoic 1,3-lactone which was dissolved in 30 ml of THF (tetrahydrofuran) was added. The pH was adjusted to approximately 8.5 by the addition of DIEA and the mixture was stirred overnight. The reaction mixture was filtered and the solid was washed with cold hexane 3 times and subsequently washed 3 times with a cold water / ethanol mixture (3: 1). The filtered paste was dried under a freeze dryer to produce 11.1 g of the final product 4- [. { modified chitosan hexanoic acid 6-hexanoyloxy} -2-hexyl-hexadecanoic 1,3-lactone (Compound B).

Examples of the Biological Properties Test and Other Properties Example 7 The lipase inhibition tests were performed essentially as follows using each of Compounds A and B. A 1 L stock solution of 1 N NaOH was made and a stock solution of 500 ml of 0.025 N NaOH was manufactured by diluting a portion of the 1 N stock solution. Also a stock solution of 0.2 N HCl was manufactured. A 100 ml TRIZMA solution (from the Aldrich Lipase Test Catalog No. 800B) was diluted with 100 ml of denatured EtOH and 300 ml of water to form a 500 ml TEW solution. Compound A of Example 6 (100 mg) was added to a portion of the stock solution of 0.2 N HCl and diluted to a final volume of 300 ml with the same stock HCl to form a stock solution of compound A. The compound B from Example 6 was added to a portion of the 0.2N HCl stock solution and diluted to a final volume of 80 ml with the same stock solution HCl to produce a stock solution of compound B. Lipase Standard PS Aldrich (human lipase 3 ml x 3) Product Aldrich No. 8054 was diluted with isotonic saline to a volume of 25 ml (Lipase solution # 1). Likewise, Aldrich Pig Pancreas Lipase [EC 3.1.1.3] Product No. 32313 was diluted to a final volume of 25 ml with isotonic saline solution (Lipase solution # 2). Sigma Aldrich Lipase Substrate Standard Catalog. Product No. 62314 (3 x 100, 300 ml) was obtained to be used as a source of lipids.

Into a precipitation tank equipped with a heat source and a magnetic stirrer was added to 100 ml of distilled water, 10 ml of TEW solution, 10 ml of Sigma Lipase substrate and a 20 ml sample (the control sample was 20 ml of the 0.2 N HCl stock solution, Sample A was 20 ml of the stock solution of the compound A and sample B was 20 ml of the stock solution of compound B). The pH was adjusted to approximately 8 with 1 N NaOH using a pH meter, whose readings were recorded and recorded as a base reading after pH adjustment. The temperature was set at 37.5 ° C and 1 ml of Lipase # 1 or Lipase # 2 was added and a stopwatch was started for 30 minutes. The mixture was stirred and the temperature was maintained between 35 ° C and 37 ° C. At the end of the period of time, the mixture was stirred and triturated with 0.025 N NaOH. The volume of the NaOh solution to be returned to the base pH reading was recorded and recorded. The percent inhibition for Sample A or Sample B was calculated by subtracting the volume of NaOH used to return it to the base pH for Sample A or Sample B from an average volume of NaOH used to return it from the base pH for the control sample (three runs), the difference was divided by the average volume of NaOH used to return it to the base pH for the control sample and the result was multiplied by 100% to obtain the percent inhibition of Sample A or Sample B (two runs each). Each of Sample A and Sample B showed an inhibition percentage of approximately 50% with respect to the control for each Lipase # 1 and Lipase # 2.

Example 8 The oil binding test was performed using each of Compounds A and B using the procedures essentially as follows.

Six controls were obtained by adding Dark Star Olive Oil (light extra virgin colored olive oil) to 4 or 7 ml sample bottles, which were photographed at a distance of 25.4 cm by using an IZONE POLAROID camera as follows . Control 1 was obtained by adding 3 ml of olive oil to a 7 ml bottle, which showed the light and light reflector oil. Control 2 was obtained by adding 3 ml of olive oil to a 7 ml bottle and 10 drops were added of Red Food Coloring Schilling McCormick (RFC), which showed the color of the food insoluble in oil at the bottom of the bottle and the floating on top of the red food coloring are the 3 ml of light olive oil reflector. Control 3 was obtained by adding 3 ml of olive oil to a 7 ml bottle and adding 3 ml of water after 5 drops of RFC, which showed the clear separation of the red aqueous layer on the bottom of the bottle and the Floating on the top was the light reflector olive oil. Control 4 was obtained by adding 1.5 g of olive oil to 1 g of chitosan (Natural Max Bran, greater than 90% of deacylated chitin) and the two were mixed with a stirrer, after the addition of 4 ml of water and 5 drops of RFC, which showed the oil tightly bound to chitosan at the bottom of the bottle, which was the red layer of watery floating food (a clean red meniscus with substantially non-floating oil was observed). The control 5 was obtained by adding 1.5 g of olive oil to 1 g of cellulose (Avicel) and the two were mixed with a stirrer, after the addition of 4 ml of water and 5 drops of RFC, which showed some oil bound at the bottom to the cellulose, which was the red layer of the watery floating food, in addition to that it was a clear layer of floating oil, approximately% ml (a clear light oily coat of meniscus was observed to show that the cellulose did not Closely linked an excess of its weight in oil Control 6 was obtained by the addition of 8 g of olive oil to 1 g of chitosan and the two were mixed together with an agitator, followed by the addition of 1 ml of water and 5 drops of RFC, which shows a glass shape of 1 hour of oil bound by the chitosan around the middle of the bottle at the near point with the red solution of the aqueous food (the chitosan binds the oil and substantially excludes the water of the linked mixture).

In comparison with Control 4 (ace ite / ch ratio 1.5 / 1 ratio) each of Compounds A and B were mixed with oil in the same proportion (oil / compound 1.5 / 1 ratio, green food dye was added to the aqueous portion of the sample bottle of compound A and blue food dye was added to the aqueous portion of the sample bottle of compound B). The same results occurred with each of Compounds A and B as for Control 4 chitosan, in which the oil is tightly bonded to the bottom of the bottle and there is substantially no floating oil, ie the meniscus for each is a Meniscus blue and green clean. However, Compound B appears to bind the oil more closely than chitosan or compound A.

By comparison with Control 6 (oil / chitosan ratio 8: 1 and 1 ml of aqueous solution with food coloring), compound B was added to 8 times its weight of the oil and stirred for a uniform consistency. 1 ml of water was added and 5 drops of red food coloring were added. After mixing, the oil and compound B were increased to form a granulated gel consistency and uniformly absorb 1 ml of the aqueous food dye solution to form a homogeneous gel composition, which appeared substantially homogeneously even after 24 hours . This shows that compound B has the ability to bind the oil and subsequently absorb at least its weight in water to form a homogeneous mixture like granulated gel and continue to bind the oil while hydrating with water.

In view of the above description it is believed that one skilled in the art can practice the invention. The examples given above are not limiting and one skilled in the art will be able to make changes or permutations to the invention without departing from the main concepts. Said variations and permutations are within the scope of the invention.

Claims

CLAIMS 1. A novel oxetanone derivative of the formula: wherein: t is an integer from 0 to 1 XOQ is an ether bond where: X of the ether bond is a bridging group and Q of the ether bond is a polysaccharide of sufficient molecular weight or property so that said polysaccharide is not absorbed by the digestive system of a mammal such as a dog, a cat, a non-human primate or a human primate, whose polysaccharide is further defined; R is a member selected from the group consisting of: a long chain or branched CM7 alkyl group which is saturated or optionally interrupted by more than eight double or triple bonds; a long or branched chain d-17 alkyl group which is saturated or optionally interrupted by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group; a long chain or branched C?.? 7 alkyl group which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for a carbon atom unsaturated by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, an atom of the sulfonyl group or of the sulfinyl group; phenyl substituted by 0-4 members selected from the group consisting of - alkyl d-β-alkyloxy-d-β, -alkyl d-6-alkylthio d-6, -alkyl d-6-OH and C alquilo-alkyl 6- SH; benzyl substituted by 0-4 members selected from the group consisting of -alkyl d-e-alkyloxy-d-e, -alkyl d.6-alkyl C 1-6, -alkyl C? 6-OH and alkyl d-6-SH; biphenylene substituted by 0-6 members selected from the group consisting of -alkyl d-β-alkyloxy-d-e, -alkyl d.6-alkylt d.6, -alkyl d-6-OH and alkyl C1-6-SH; phenoxyphenylene substituted by 0-6 members selected from the group consisting of -alkyl-alkyloxy-d-β, -alkyl d.6-alkyllium C? -6, -alkyl C? .6-OH and alkyl of-SH; phenylthiophenylene substituted by 0-6 members selected from the group consisting of -alkyl d-6-alkyloxy-C? -6, -alkyl d.6-alkylthio d-6, -alkyl d-6-OH and alkyl d -6-SH and phenyl-C? .6-phenyl alkyl wherein 0-6 carbon atoms in one or more of the phenyl ring and the -6-alkyl group is / are independently replaced by a member selected from the group consists of -alkyl d-β-alkyloxy-Cvβ, -alkyl-6-alkylthio d-6, -alkyl C? 6-OH and C 1-6 -alkyl-SH; R1 is a member selected from the group consisting of: Hydrogen, Ar, Ar-C C-alkyl and CMO alkyl interrupted by 0-3 members independently selected from the group consisting of an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a -N (-R4) - group, a group -C (= O) -N (-R4) -, a group -N (-R4) -C (= O) -, wherein 0-3 carbon atoms of the CMO alkyl group can be independently replaced by a member selected from the group consisting of a hydroxy group, thiol group, CMO alkoxy group, an alkylthio group CMO, a group -N (-R5, -R6), a group -C (= O) -N (-R7, -R8 ) and a group -N (-R9) -C (= O) -R10; R is a member selected from the group consisting of: hydrogen and C? -6 alkyl or R2 taken together with R1 forms a saturated 4-6 membered ring containing from 0-4 nitrogen atoms wherein the ring can be substituted by groups of 0-4 R11; R3 is a member selected from the group consisting of: a long or branched chain CM7 alkyl group, which is saturated or optionally interrupted by more than eight double or triple bonds; a long chain or branched C?-alquilo alkyl group, which is saturated or optionally interrupted by one or more members selected from the group consisting of an oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group; a long or branched chain CM7 alkyl group, which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted at a position other than alpha for an unsaturated carbon atom by one or more members selected from the group consists of an oxygen atom, a sulfur atom, an atom of the sulfonyl group or an atom of the sulfinyl group; phenyl substituted by 0-4 members of -alkyl d-e-alkyloxy-d-β, -alkyl d -6-alkylthio d.6, -C1-6alkyl-OH and C1.6-SH alkyl; benzyl substituted by 0-4 members selected from the group consisting of -alkyl d-6-alkyloxy-C? -6, -alkyl C? -6-alkylthio d-6, -alkyl C1-6-OH and alkyl C? .6-SH; biphenylene substituted by 0-6 members selected from the group consisting of -alkyl d-e-alkyloxy-d-e, -alkyl d-6-alkylthio C1.6, -alkyl C1-6-OH and alkyl d-6-SH; phenoxy-phenylene substituted by 0-6 members selected from the group consisting of-C6-alkyl-6-alkyloxy-C6-, -6-C6-alkyl-6-alkylthio, -6-alkyl and -alkyl C1.6-SH; phenylthiophenylene substituted by 0-6 members selected from the group consisting of -alkyl d-β-alkyloxy-d-β, -alkyl C1.6-alkylthio C? -6, -alkyl C? .6-OH and C1.6alkyl -SH and phenyl-alkyl d-6-phenyl wherein 0-6 carbon atoms in one or more of the phenyl ring and the group-C 1-6 alkyl is / are independently replaced by a member selected from the group consisting of - C alquilo-6-alkyloxy-d-6 alkyl, C C-6-alkylthio d-6 alkyl, -alkyl d-6-OH and alkyl d 6 -SH; R4-R10 are each independently a member selected from the group consisting of: hydrogen and C1-6alkyl; n is an integer of 0-3; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of the mimes. 2. A compound according to claim 1, wherein X is the group- (C (= O)) or -? - Xa-, wherein Xa is a member selected from the group consisting of: a chain-branching alkylene group CM7 long or branched that is saturated or optionally interrupted by more than eight double or triple links; a long chain or branched divalent C C. al alkylene group which is saturated or optionally interrupted by one or more members selected from the group consisting of: an oxygen atom, a sulfur atom, a sulfonyl group, a sulfinyl group, a 6-10 membered substituted or unsubstituted monocyclic bicyclic aryl or a heteroaryl group having 1-4 heteroatoms selected from the group consisting of O, N, S, an NH group, wherein the hydrogen atom can be replaced with a group C1-10 alkyl, a group -C (= O) -, a group -NH-C (= O), wherein the hydrogen atom can be replaced with a C? -? 0 alkyl group and a -C (= O) group ) -NH-, wherein the hydrogen atom can be replaced with a CMO alkyl group, a long chain or branched divalent C? -? 7 alkylene group which is saturated or optionally interrupted by more than eight double or triple bonds and is interrupted in a position other than alpha for an unsaturated carbon atom by one or more members selected from the group consisting optionally of one or more interrupted members selected from the group consisting of: an oxygen atom, a sulfur atom, a group sulfonyl, a sulfinyl group, a substituted or unsubstituted 6-10 membered bicyclic or monocyclic aryl or a heteroaryl group having 1-4 heteroatoms selected from the group consisting of O, N, S, an NH group, wherein the Hydrogen atom can be replaced with an alkyl group d.10, a group -C (= O) -, a group -NH-C (= O), wherein the hydrogen atom can be replaced with a C? -? alkyl group? 0 and a group -C (= O) -NH-, wherein the hydrogen atom can be replaced with a divalent d-10 phenylene alkyl or divalent naphthylene group substituted on the ring structure by 0-4 members selected from the group consisting of C1.6-alkyloxy-C? .6 alkyl, -a alkyl d-6-alkylthio C? -6, -alkyl d.6-OH and C? -6-SH alkyl; divalent biphenylene substituted by 0-6 members selected from the group consisting of C1.6alkyl-C1.6alkyloxy, -C6alkyl -6-alkylthio C6-6, -alkyl C6-6-OH and alkylC? -6-SH; phenoxyphenylene substituted by 0-6 members selected from the group consisting of alkyl d-e-alkyloxy-d-β, -alkyl d-6-alkylthio C? 6, -C 1-6 alkyl-OH and C 1-6 alkyl-SH; divalent phenylthiophenylene substituted by 0-6 members selected from the group consisting of d-6-alkyloxy-C? -6 alkyl, -alkyl C? -6-alkylthio d-6, -alkyl C1-6-OH and alkyl d.6-SH and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 3. The compound according to claim 2, wherein R is - (CH2) 3-6-CH3 and R3 is a member selected from the group consisting of - (CH2) 8.14-CH3 and -CH2-CH = CH-CH2- CH = CH- (CH2) 2.8-CH3 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 4. The compound according to claim 2, wherein R is - (CH2) 5- CH3 and R3 is a member selected from the group consisting of - (CH2)? 0-CH3 and -CH2-CH = CH-CH2-CH = CH- (CH2) -CH3 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 5. The compound according to claim 2, wherein z is zero to provide compounds of the formula: wherein: X, t, Q, R, R1, R2 and R3 are as defined in accordance with claim 2, and isomers, salts, hydrates, solvates and prodrug derivatives thereof. 6. The compound according to claim 5, wherein R is - (CH 2) 3-6-CH 3 and R 3 is a member selected from the group consisting of - (CH 2) 8. -CH3 and -CH2-CH = CH-CH2-CH = CH- (CH2) 2.8 -CH3. and isomers, salts, hydrates, solvates and prodrug derivatives thereof. 7. The compound according to claim 5, wherein R is - (CH2) 5- CH3 and R3 is a member selected from the group consisting of - (CH2) 10-CH3 and -CH2-CH = CH-CH2-CH = CH- (CH2) 4-CH3. and isomers, salts, hydrates, solvates and prodrug derivatives thereof. 8. The compounds according to claim 5, wherein t is 0 and isomers, salts, hydrates, solvates and prodrug derivatives thereof. 9. The compounds according to claim 2, wherein t is 0 or 1 and X is a member selected from the group consisting of: wherein R1a is independently defined in the same manner as defined R \ R2a is independently defined in the same manner as R2 was defined, m is an integer from 0 to 10, preferably 0-5 and more preferably 0-2 and wherein z is an integer from 1 to 20, preferably from 2 to 10 and more preferably from 2-4 and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 10. The compound according to claim 9, wherein X is a member selected from the group consisting of: wherein z is an integer from 0 to 10, preferably from 0-5 and more preferably from 0-2. and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 11. The compound according to claim 9, wherein X is a member selected from the group consisting of: and wherein z is an integer from 0 to 18, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 12. The compound according to claim 9, wherein X is a member selected from the group consisting of: and wherein z is an integer of 6-12, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 13. The compound according to claim 9, wherein X is a member selected from the group consisting of: -crt? r and where z is an integer of 6-12, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 14. The compound according to claim 13, wherein the Q group is a modified chitosan compound with a sufficient number of organic acyl groups to cause the modified chitosan to absorb or associate with both the lipids and the water to form a gel substantially homogeneous with oil and water. 15. A method for producing a compound according to claim 1, which comprises reacting a compound of the formula: with a compound of the formula wherein t is 0 or 1 and Y is a removal group for an etherification or esterification reaction with the hydroxy group to produce a compound of the formula: or a salt of it. 16. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier excipiand an amount of at least one compound according to claim 1 in a therapeutically effective amount with respect to limiting or prevng the absorption of some dietary fat. 17. A pharmaceutical composition according to claim 16, further comprising a therapeutically effective amount of an effective amount of oil absorption of a polysaccharide such as chitosan. 18. A method for using a compound according to claim 1, as a therapeutic agfor disease states in a mammal having at least one disease that is due to unwanted absorption of dietary fat or to reduce the effective caloric intake of a mammal that consumes dietary fat. 19. A composition comprising at least one lipase inhibitory moiety that is linked to a biocompatible or absorbable pharmaceutically acceptable polymer supported by at least one chemical bond that is substantially not penetrated by the digestive system of a dog, cat, nonhuman primate or human , wherein the lipase is essally non-absorbable. tw. A composition according to claim 19, wherein the nonabsorbable polysaccharide is a member selected from the group consisting of: a dextran, microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin , chitin, crude cellulose, argar and chitosan. tw-one. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 19 and a pharmaceutically acceptable carrier or dilu 22. A food product composition comprising an effective amount of a lipase inhibitor of at least one compound according to claim 19. 23. A method for treating adiposity comprising treating a dog, cat, non-human primate or human with an effective amount of the lipase inhibitor of at least one composition according to claim 19.