Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F8/00—Chemical modification by after-treatment
  • C08F8/42—Introducing metal atoms or metal-containing groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/785—Polymers containing nitrogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F8/00—Chemical modification by after-treatment
  • C08F8/44—Preparation of metal salts or ammonium salts
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
  • C08G73/02—Polyamines
  • C08G73/0206—Polyalkylene(poly)amines
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
  • C08G79/08—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing boron

Definitions

• Lipases are key enzymes in the digestive system which break down diglycerides and triglycerides into monoglycerides and fatty acids. Diglycerides and triglycerides have a high caloric content but are not absorbed by the small intestine until broken down by the lipases. Therefore, inhibition of lipases within the digestive system results in a reduction in the absorption of fat and consequently a decrease in caloric uptake.
• XE ⁇ ICAL is an example of a commercially available lipase inhibitor that is used for treating obesity.
• Administration of lipase inhibitors results in stools with a high fat or oil content from the undigested diglycerides and triglycerides.
• Leakage of oil from the stool is an unpleasant side effect that often occurs when stools have a high fat or oil content. This condition is referred to as "oily stool” or "leaky stool”.
• novel polymers including fat-binding polymers, with cleavable aryl boronate ester, boronamide and/or boronate thioester groups and the use of such polymers for treating obesity are disclosed herein.
• One embodiment of the present invention is a polymer comprising one or more aryl boronate ester, boronamide and/or boronate thioester groups represented by Ar-B-(Z-) 2 or Ar-B-(ZH)(Z-), wherein each Z is -O-, -NH- or -S- and is independently selected.
• each Z is -O-.
• the aryl boronate ester, boronamide or boronate thioester can be cleaved or hydrolyzed to release the corresponding aryl boronic acid.
• the aryl group represented by Ar is substituted or unsubstituted.
• the aryl boronic ester groups are phenyl boronic esters represented Structural Formulas (I) or (IT):
• Phenyl Ring A in Structural Formulas (I) and (H) is substituted or unsubstituted.
• compositions comprises the polymer described above and a pharmaceutically acceptable carrier or diluent.
• Another embodiment of the present invention is a method for removing fat from the gastrointestinal tract (or inhibiting uptake of fat in the gastrointestinal tract) of a subject in need of such treatment (e.g., treating a subject for obesity).
• the method comprises the step of administering an effective amount of the polymer described above to the subject.
• the polymers disclosed herein are believed to release aryl boronic acids in the gastrointestinal tract.
• Aryl boronic acids are potent inhibitors of lipase enzymes.
• the polymers of the present invention are therefore effective in removing fat from the gastrointestinal tract of subjects for whom reduced fat absorbtion can be clinically beneificial. Thus, these polymers are useful in the treatment of obesity. Because many of the disclosed polymers bind the lipids, the unpleasant leakage of oil from the stools that often accompames the administration of lipase inhibitors is reduced or eliminated compared with other lipase inhibiting drugs.
• the disclosed polymer drugs and many of the liberated boronic acid groups are largely unabsorbed by the intestines and therefore also have the advantage of causing minimal systemic side effects.
• Figure 1 is a schematic showing the synthesis of 4-(14'-trimethylammonium- 3'-thia-r-ketotetradecyl)-3-fluorophenylboronic acid chloride (6).
• Figure 2 is a schematic showing the synthesis of 4-(14'-hydroxy-3'-thia- - ketotetradecyl)-2,5-difluorophenylboronic acid (11).
• Figure 3 is a schematic showing the synthesis of (neopentyl glycolato) 4-
• Figure 4 is a schematic showing the synthesis of poly-N-(3- diethanolaminopropyl)acrylamide (17).
• Figures 5A-5F are a compilation of the structures of boronic acids which can be incorporated into the boronate functionalized polymers of the present invention.
• R in Figure 5D is a C12 straight chained alkyl group.
• the polymers of the present invention comprise one or more cleavable aryl boronate ester, boronamide or boronate thioester groups.
• the invention is described below with respect to aryl boronate esters, i.e., wherein each Z is -O-. It is to be understood that these descriptions apply to the corresponding boronamides and boronate thioesters, i.e., wherein one or both Zs are -NH- or -S-.
• polymers of the present invention are limited to polymers in which the boronate ester group is "between" Ar (or Phenyl Ring A) and the polymer backbone and that the only covalent linkage between the Ar (or Phenyl Ring A) and the remainder of the polymer is through the boronate ester bond(s).
• Applicants do not wish to be bound by any particular mechanism, it is believed that the boronate ester functional group is hydrolyzed in vivo, thereby liberating an aryl boronic acid, which then acts to inhibit the lipase.
• Ar and Phenyl Ring A in Structural Formulas (I) or (H) are substituted or unsubstituted.
• Ar and Phenyl Ring A are "substituted" when Ar comprises at least one substituent and Phenyl Ring A comprises at least one substituent other than the boronate ester group. Suitable substituents are as described below for aryl groups.
• Ar and Phenyl Ring A are substituted with at least one electron with drawing group.
• An electron withdrawing group is a substituent which results in a phenyl ring that has less electron density when the group is present than when it is absent. Electron withdrawing groups have a Harnmet sigma value greater than one (see, for example, C. Hansch, A.
• Examples of electron withdrawing groups include halogens, -NO 2 , -CN and -X-R.
• X is -CHD-, -CD 2 -, -COO-, -CONH-, -CO- or -SO 2 -;
• D is a halogen; and
• R is a substituted or unsubstituted straight chained hydrocarbyl group with an ether, thioether, phenylene, amine or ammonium linkage. Additional values for X include -S(O)- and -S(O) 2 O-.
• the hydrocarbyl group represented by "R” is a straight chained hydrocarbyl group with an ether or thioether linkage and optionally substituted at the terminal position with an amine, halogen, -CF 3 , thiol, ammonium, alcohol, -COOH, -SO 3 H, -OSO 3 H or phosphonium group.
• the hydrocarbyl group represented by R is a straight chained hydrocarbyl group with an ammonium linkage and optionally substituted at the terminal position with an amine, halogen, -CF 3 , thiol, ammonium group, alcohol, -COOH, -SO 3 H, -OSO 3 H or phosphonium group
• the hydrocarbyl group represented by R is a straight chained hydrocarbyl group substituted at the terminal position with an amine, halogen, -CF 3 , thiol, ammonium group, alcohol, -COOH, -SO 3 H, -OSO 3 H or phosphonium group.
• R is -CH 2 -O[-(CH 2 ) p O] m -(CH 2 ) p -Y or -C(O)CH 2 - S[-(CH 2 ) p O] m -(CH 2 ) p -Y, p is 2 or 3, m is an integer from 1-5 and Y is an ammonium group.
• a “straight chained hydrocarbyl group” is a polyalkylene group, i.e., -(CH 2 ) X - where x is a positive integer (e.g., between 1 and about 30), preferably between about 6 and about 30, more preferably between about 6 and about 15.
• a “linkage group” refers to a functional group which replaces a methylene in a straight chained hydrocarbyl. Examples of suitable linkage groups include an alkene, alkyne, phenylene, ether (-O-), thioether (-S-), amine [-N ⁇ R 3 )]- or ammonium [-N + (R a R b )-].
• R a and R b are independently -H, alkyl, substituted alkyl, phenyl, substituted phenyl, or, taken together with the nitrogen atom to which they are bonded, a non-aromatic, nitrogen-containing heterocyclic group.
• R a and R b are not -H. More preferably, R a and R b are both alkyl groups and even more preferably, both methyl. R a and R b can be the same or different, but are preferably the same.
• terminal position refers to the methylene carbon of the straight chained hydrocarbyl group most distant from Ar, Phenyl Ring A or Phenyl Ring B, as described below.
• Substituents at the terminal position of a straight chained hydrocarbyl group are referred to herein as "terminal substituents".
• suitable terminal substituents include amine (-NR c R d ), halogen, -CF 3 , thiol, ammonium (-N + R ⁇ R 6 ), alcohol (-OH), -COOH, -SO 3 H, -OSO 3 H or phosphonium group.
• R c , R d and R e in an ammonium group are independently -H, alkyl, substituted alkyl, phenyl, substituted phenyl, or, taken together with the nitrogen atom to which they are bonded, a nitrogen-containing, non-aromatic heterocyclic group.
• R c , R and R e are not -H. More preferably, R c , R d and R e are all alkyl groups (i.e., a trialkylammonium group) and even more preferably, all methyl (i.e., a trimethylammonium group).
• R c , R d and R e can be the same or different, but are preferably all the same.
• the hydrocarbyl group represented by R is substituted at the terminal position with a group -Y, wherein -Y is selected such that YH is a small molecule polyamine.
• -Y can be represented by -[NH-(CH 2 ) q ] r -NH 2 ).
• q is an integer from 2 to about 10 and r is an integer from 1 to about 5.
• small molecule polyamines include spermine, spermidine, 1,2-diaminoethane, 1,3-diaminopropane or 1,4-diaminobutane.
• one or more of the secondary amine can optionally be N-alkylated or NN-dialkylated; the primary amine is optionally N-alkylated, NN-dialkylated or NNN-trialkylated.
• a "substituted hydrocarbyl group” has one or more substituents bonded at one or more positions other than at the terminus. Suitable substituents are those which do not significantly lower the lipase inhibiting ability or fat binding ability of the polymer, for example, do not lower either activity by more than a factor of about two. Examples of suitable substituents include C1-C3 straight chained or branched alkyl, C1-C3 straight chained or branched haloalkyl, -OH, halogen (-Br, -Cl, -I and - F), -O(Cl-C3 straight chain or branched alkyl) or -O(Cl-C3 straight chain or branched haloalkyl).
• the polymer of the present invention comprises one more phenyl boronate ester group represented by Structural Formula (1TI):
• Phenyl Ring B is substituted with one or more electron withdrawing groups.
• Fluorine is a preferred electron withdrawing group for Phenyl Ring B.
• suitable substitution patterns for Phenyl Ring B include 3-fluoro and 2,5-difluoro, wherein position 1 is the carbon bonded to boron.
• phenyl boronate ester groups in the polymers of the present invention are represented by Structural Formula (IV):
• Y is an ammonium group (preferably trialkylammonium) and more preferably trimethylammonium) and n is an integer from 1 to about 30, preferably from about 3 to about 30 and more preferably from about 6 to about 15.
• An arylboronate ester group (or phenyl boronate ester group) comprises an aryl boronate portion (or a phenyl boronate portion) and an "ester portion".
• the aryl boronate portion (or phenyl boronate portion) can be connected directly or "linked" directly to the polymer by one or two boronate ester bonds, in which case the "ester portion" is the polymer backbone.
• polymers of this type include polyvinyl alcohol or a polysaccharide with an aryl boronate group(s) (or phenyl boronate group(s)) bonded directly to the polymer backbone through one or two boronate ester bonds formed between the boronate group and alcohol groups from the polymer backbone.
• the "ester portion” is a side chain which is pendent from the polymer backbone and serves to link or connect the aryl boronate group (or phenyl boronate group) to the polymer backbone, hi this case, the "ester portion” typically comprises at least one and preferably at least two alcohol functionalities which are suitably positioned to form boronate ester bonds with an aryl boronic acid (or a phenyl boronic acid), e.g., an alkyldiol.
• Structural Formulas (V), (VI) and (VH) each show an example of a phenyl boronate ester formed from an alkyl- 1,2-diol, an alkyl- 1,3-diol or an alkyl-l,5-diol, respectively, and a phenyl boronic acid:
• the monomers can be polymerized and the alkyl- 1,2-diol groups of the resulting polymer esterified with an aryl boronic acid to form a boron-functionalized polymer of the present invention.
• the alkyl- 1,2-diol groups of the monomers can be esterified with an aryl boronic acid and the resulting boron-functionalized monomer polymerized to form a boron-functionalized polymer of the present invention.
• Each of the alkyl- 1,2-diol functionalized monomers depicted above can be esterified, for example, with any one of the boronic acids shown in Figure 5.
• the above monomers can be polymerized and the alkyl- 1,3-diol groups of the resulting polymer esterified with an aryl boronic acid to form a boron-functionalized polymer of the present invention.
• the alkyl-l,3-diol groups of the monomers can be esterified with an aryl boronic acid and the resulting boron- functionalized monomer polymerized to form a boron-functionalized polymer of the present invention.
• Each of the alkyl- 1,3-diol containing monomers depicted above can be esterified, for example, with any one of the boronic acids shown in Figure 5.
• polymers comprising phenyl boronamide and/or boronate esters groups corresponding to the structures represented by Structural Formulas (i ⁇ )-(VI ⁇ ), i.e., wherein one or both boronate oxygen atoms is replaced with -S- and or -NH-.
• the polymer side chains comprises a group which increases the ability of the polymer to bind fat, e.g., an amine group or a cationic group such as an ammonium group.
• the side chain typically comprises an aminoalkyldiol, i.e., a moiety with one amine and two alcohol groups or the corresponding ammonium group; or a dialkanolamine such as diethanolamine or the corresponding ammonium group.
• the "corresponding ammonium group” refers to the alkylated or benzylated form of, for example, an aminoalkyldiol or dialkanolamine.
• Examples include a phenyl boronate esters shown below in Structural Formulas (VHI)-(X ⁇ ), which are formed from an aminoalkyl- 1,2-diol, ammomumalkyl-1 ,2-diol, a diethanolamine and diethanolammonium group and a phenyl boronic acid:
• R 10 is -H, a substituted or unsubstituted alkyl group or a substituted or unsubstituted benzyl group, preferably -H.
• R e and R f are independently -H, a substituted or unsubstituted alkyl group or a substituted or unsubstituted benzyl group, preferably - H.
• Specific examples of monomers and polymers with side chains comprising diethanol amine groups are shown below:
• the monomers shown above can be polymerized and the diethanolamine groups of the resulting polymer esterified with an aryl boronic acid to form a boron- functionalized polymer of the present invention.
• the diethanolamine groups of the monomers can be esterified with an aryl boronic acid and the resulting boron-functionalized monomer polymerized to form a boron-functionalized polymer of the present invention.
• Each of the diethanolamine-containing monomers depicted above can be esterified, for example, with any one of the boronic acids shown in Figure 5.
• side chains of the polymer are polyols with four or more alcohol groups which can form boronate esters.
• a boronate ester is formed from two diols in the side chain and the boronic acid.
• the side chain can comprise more than one aryl boronate ester. Examples of suitable monomers with polyol side chains are shown below:
• the monomers shown above can be polymerized and the polyols of the resulting polymer esterified with an aryl boronic acid to form a boron-functionalized polymer of the present invention.
• the polyols of the monomers can be esterified with an aryl boronic acid and the resulting boron-functionalized monomer polymerized to form a boron-functionalized polymer of the present invention.
• Each of the polyol-containing monomers shown above can be esterified, for example, with any one of the boronic acids shown in Figure 5.
• R and Phenyl Ring B in Structural Formulas (V)-(XI) are as described above.
• R' in the structures shown above is -H or an alkyl group.
• Structural Formula (XII) shows a preferred example of a phenyl boronate ester formed from a phenyl boronic acid and an alkyldiol moiety
• Structural Formula (XIH) shows a preferred example of a phenyl boronate ester formed from a phenyl boronic acid and diethanol amine moiety
• Structural Formula (XIN) shows a preferred example of a phenyl boronate ester formed from a phenyl boronic acid and a diethanolammonium moiety:
• R 3 -R 6 are independently -H or -F; R and R e are as described above.
• R is -CH 2 S-(CH 2 ) n Y, wherein Y and n are as described above.
• R 3 and R 5 are -F and R 4 and R 6 are -H; and R 3 , R 5 and R 6 are -H and R 4 is -F.
• the present invention also includes polymers comprising one or more phenyl boronate ester group(s) formed from a phenyl boronic acid and an alkyldiol, a diethanolamine, or an aminoalkydiol group, e.g., a polymer comprising one or more groups represented by Structural Formula (V)-(XIV).
• the term "monomer” refers to both (a) a single molecule comprising one or more polymerizable functional groups prior to polymerization, or (b) a repeat unit of a polymer.
• An unpolymerized monomer capable of addition polymerization can, for example, comprise an olefinic bond which is lost upon polymerization.
• a "boronate functionalized monomer” is a monomer with a boronate ester group in the side chain that release the corresponding boronic acid when the ester is hydrolyzed.
• a “boronate functionalized polymer” is a polymer with or formed from boronate functionalized monomers that releases the corresponding boronic acid when the ester is hydrolyzed.
• the present invention is a polymer comprising boronate functionalized monomers represented by Structural Formula (XV):
• M is a covalent bond, -CH 2 -, 1,3-phenylene, 1,4-phenylene, -C(O)O-, -C(O)NR l5 -C(O)-, -O-, -NR r , -CH 2 NR r or -CH 2 O-.
• M is-C(O)NH.
• Other possible values of M include -N ⁇ R J R J )- and -CH 2 N + (R 1 R 1 )-.
• Q is a covalent bond or an inert spacer group.
• a spacer group serves to separate the phenyl boronate ester from the polymer.
• a spacer group is "inert" when it contains no functionality that substantially interferes with the fat binding ability of the polymer.
• Inert spacer groups are preferably hydrocarbyl groups optionally containing one or more linkage groups and is preferably an alkylene group, preferably C1-C30, more preferably Cl to C15 and even more preferably C1-C8. Typically, inert spacer groups are hydrophobic.
• ! is -H, an aliphatic group or a substituted aliphatic group.
• R 2 is -H or a C1-C6 alkyl group.
• W is a group comprising a phenyl boronate ester formed from a phenyl boronic acid and an diethanolamine, an alkyldiol or an aminoalkyldiol group, e.g., a group represented by a Structural Formula selected from (V)-(XIV).
• -MQW comprises a boronate ester formed from -C(O)NH-(CH 2 ) 2 -N-(CH 2 CH 2 OH) 2 , -C(O)NH-(CH 2 ) 3 -N-(CH 2 CH 2 OH) 2 , -C(O)NH-(CH 2 ) 4 -N-(CH 2 CH 2 OH) 2 , -C(O)O-(CH 2 ) 2 -N-(CH 2 CH 2 OH) 2 , -C(O)O-(CH 2 ) 3 -N-(CH 2 CH 2 OH) 2 , -C(O)O-(CH 2 ) 4 -N-(CH 2 CH 2 OH) 2 , -NH-(CH 2 ) 2 -N-(CH 2 CH 2 OH) 2 , -NH-(CH 2 ) 3 -N-(CH 2 CH 2 OH) 2 , -NH-(CH 2 ) 3 -N-
• boronic acids are those prepared in Examples 1-10 and variants thereof in which the alkylene group has from 5 to 15 carbon atoms.
• -MQW comprises a boronate ester formed from -C(O)NH-(CH 2 ) 1 CHOHCH 2 OH, -C(O)NH-(CH 2 ) 2 CHOHCH 2 OH, -C(O)NH-(CH 2 ) 3 CHOHCH 2 OH, -C(O)O-(CH 2 ) 1 CHOHCH 2 OH, -C(O)O-(CH 2 ) 2 CHOHCH 2 OH, -C(O)O-(CH 2 ) 3 CHOHCH 2 OH, -NH-(CH 2 ) 1 CHOHCH 2 OH, -NH-(CH 2 ) 2 CHOHCH 2 OH, -NH-(CH 2 ) 3 CHOHCH 2 OH, -O(CH 2 ) !
• boronic acids are those prepared in Examples 1-10 and variants thereof in which the alkylene group has from 5 to 15 carbon atoms.
• the polymers of the present invention can be homopolymers, which have a uniform backbone composed of a boronate functionalized monomers derived from a common polymerizable unit, such as boronate functionalized acrylamide. Also included are copolymers and terpolymers, i.e., polymers comprising a mixed backbone of two or three different monomer units, respectively, one or more of which is boronate functionalized.
• Polymer backbone or “backbone” refers to that portion of the polymer which is a continuous chain, comprising the bonds which are formed between monomers upon polymerization.
• the composition of the polymer backbone can be described in terms of the identity of the monomers from which it is formed, without regard to the composition of branches, or side chains, off of the polymer backbone.
• a poly(acrylamide) polymer is said to have a poly(acrylamide) backbone, without regard to the substituents on the acrylarnide nitrogen atom, which are components of the polymer side chains.
• a poly(acrylamide-co-styrene) copolymer for example, is said to have a mixed acrylamide/styrene backbone.
• a “side-chain” refers to a branch off of the polymer backbone.
• Preferred polymers are "fat binding” polymers.
• “Fat-binding polymers” are polymers which absorb, bind or otherwise associate with fat thereby inhibiting (partially or completely) fat digestion, hydrolysis, or absorption in the gastrointestinal tract and/or facilitate the removal of fat from the body prior to digestion.
• the fat-binding polymers comprise one or more fat-binding regions.
• “Fat-binding regions” include a positively charged region, and, optionally, a hydrophobic region, or a region which is both positively charged and hydrophobic.
• the fat-binding region has a positive charge when the region comprises an ionic group such as a quarternary amine or an atom, for example, the nitrogen of an amine, that possesses a positive charge under conditions present in the gastrointestinal tract.
• the polymers of the present invention include addition polymers such as a boronate functionalized polyacrylate, alkylpolyacrylate, polyacrylamide, alkylpolyacrylamide, poly(allylalcohol), poly(vinylalcohol), poly(vinylamine), poly(allylamine), poly(diallylamine) backbone or a substituted polystyrene backbone.
• these addition polymers have side chains comprising aryl boronate groups formed from an alkyldiol, a diethanolamine, or aminoalkyldiol and an aryl boronic acid.
• the side chains are attached, for example, by ester linkages to carboxylate groups of a polyacrylate, by a covalent bond to the amide nitrogens of a polyacrylamide, by ether linkages to alcohols of a poly(vinylalcohol) or poly(allylalcohol), by a covalent bond to the amines of a poly(vinylamine,) a poly(allylamine) or a poly(diallylamine) or by a covalent bond to a substituent on the phenyl ring of a polystyrene.
• Polyacrylamide is a preferred polymer. Suitable addition polymers are described below.
• the polymer comprises monomers having both cationic and hydrophobic groups.
• fat-binding polymers ofthis type can be a homopolymer, copolymer or terpolymer comprising a boronate functionalized monomer with an diethanolamine or aminoalkyldiol in the polymer side chains, as in Structural Formulas (VET), (X) and (XU) (or the corresponding ammonium groups in Structural Formulas (LX), (XI) and (XIV)), provided that the side chain comprises a hydrophobic group (e.g., wherein M in Structural Formula (XV) is a hydrophobic group).
• hydrophobic group is defined below.
• the diethanolamine or aminoalkyldiol comprises an amine which can be protonated in vivo to form a cationic group.
• a fat-binding polymer ofthis type is a copolymer or terpolymer comprising a boronate functionalized monomer and a monomer having both cationic and hydrophobic groups.
• the fat-binding polymer comprises boronate functionalized monomers together with a combination of separate monomers each having either a cationic or a hydrophobic functional groups. Examples of monomers having a cationic group and monomers having hydrophobic groups are provided below.
• the fat-binding polymer comprises monomers having both cationic and neutral functional groups (e.g., a hydroxy group or a carboxamide group).
• Fat-binding polymer ofthis type include homopolymers, copolymers or terpolymers comprising a boronate functionalized monomer with a diethanolamine or an aminoalkyldiol in the polymer side chains, as in Structural Formulas (VIH), (XI) and (XHI) (or the corresponding ammonium groups in Structural Formulas (IX), (XI) or (XrV).
• the aminoalkyldiol comprises an amine which can be protonated in vivo and diols which are released when the boronate ester is hydrolyzed.
• the fat-binding polymer ofthis type is a co-polymer or terpolymer comprising a boronate functionalized monomer and a monomer have both a neutral and a cationic functional group.
• monomers ofthis type include aliphatic amine monomers wherein the amine group is derivatized with a hydroxy alkyl group (e.g., N-( ⁇ -hydroxyalkyl)allylamine and N-( ⁇ - hydroxyalkyl)vinylamine).
• the fat-binding polymer comprises a combination of separate monomers each having either a cationic or a neutral functional group.
• hydrolysis in the gastrointestinal tract of the phenyl boronate ester of a boronate functionalized monomer "releases" a diol functionality.
• fat-binding polymers ofthis type include copolymers comprising a boronate functionalized monomer and a cationic monomer such an aliphatic amine monomer.
• the fat-binding polymer is a terpolymer comprising a boronate functionalized monomer, a cationic monomer (e.g., an aliphatic amine monomer) and a neutral co-monomer(e.g., vinyl alcohol, allyl alcohol and acrylamide).
• a boronate functionalized monomer e.g., an aliphatic amine monomer
• a neutral co-monomer e.g., vinyl alcohol, allyl alcohol and acrylamide
• Cationic monomers include monomers which contain amine groups, i.e., "amine monomers".
• amine monomers include allylamine, diallylamine, diallylmethylamine and vinylamine.
• Other amine monomers include aminostyrene, vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene and diallylmethylammonium chloride.
• Yet other examples of amine monomers include amine or quaternary amine- containing moieties used in conjunction with acrylate or acrylamide polymers.
• Examples include aminoalkyl esters or ammoniumalkyl (e.g., trialkylammomum alkyl) esters of an acrylate monomer (e.g., trimethylammonium ethyl methacrylate and trimethylammonium ethyl acrylate) or N-aminoalkyl amide or N- ammoniumalkyl amides (e.g., N-trialkylammonium alkyl) of acrylamides (e.g., N- trimethylammonium ethyl methacryamide and N-trimethylammonium ethyl acrylamide).
• an acrylate monomer e.g., trimethylammonium ethyl methacrylate and trimethylammonium ethyl acrylate
• N-aminoalkyl amide or N- ammoniumalkyl amides e.g., N-trialkylammonium alkyl
• acrylamides
• an amine monomer can comprise one or more hydrophobic regions which are bound to the amine nitrogen of the amine monomer to form a monomer with both a cationic and hydrophobic group.
• examples include N-(C4- C30)alkylvinylamine, N-(C4-C30)alkylallylamine, N-(C4-C30)alkyldiallylamine, N- (C4-C30)alkylaminostyrene and N,N-(C1-C30)dialkylaminostyrene.
• Hydrophobic monomers are monomers which lack a cationic group and comprise a hydrophobic group. Examples include styrene, (C6-C30) olefmic monomers (e.g., hexene, heptene, octene), (C4-C30)alkylacrylates, (C4- C30)alkylmethacrylates, N-(C4-C30)alkylacrylamides, N-(C4- C30)alkylmethacrylamides, styrene (e.g., fluorstyrene and pentaflourostyrene), vinylnaphthalene, ethylvinylbenzene, vinylbiphenyl, vinylanisole.
• fat-binding polymers can comprise hydrophilic monomers.
• Examples include acrylic acid, methacrylic acid, acrylamide and methacrylamide.
• the present invention also includes condensation polymers, which are formed from reactions in which a small molecule such as water is released.
• condensation polymers include a polyamide, polyalkyleneimine or a polyester.
• the cationic groups in a polyalkyleneimine can be the amine or ammonium nitrogens in the backbone or, alternatively ammoniumalkyl (e.g., a trialkylammonium alkyl group) or hydroxylated alkyl (e.g., hydroxyethyl) bonded to nitrogen in the polymer backbone or an amine group in the side chain connecting the boronate ester to a nitrogen in the backbone.
• the hydrophobic group can be a C4-C30 alkylene group in the polymer backbone, a hydrophobic alkyl group bonded to a backbone nitrogen atom or a hydrophobic spacer group Q, between nitrogen in the backbone and W, wherein Q and W are as defined above.
• a group -Q-W can be bonded to amide nitrogens in the polymer backbone, wherein Q and W are as defined above and are selected such that Q is hydrophobic and W comprises a diethanolamine or an aminoalkyldiol or the corresponding ammonium compounds, as shown in Structural Formulas (V)-(XIV).
• a group -Q-W can be bonded to a carbon atom in the backbone wherein Q and W are as defined above and are selected such that Q is hydrophobic and W comprises a diethanolamine or an aminoalkyldiol or the corresponding ammonium compounds, as shown in Structural Formulas (N)-(XIN).
• the polymer can be linear or crosslinked.
• Crosslinking can be performed by reacting the copolymer with one or more crosslinking agents having two or more functional groups, such as electrophihc groups, which react with, for example, amine groups to form a covalent bond.
• Crosslinking in this case can occur, for example, via nucleophilic attack of the polymer amino groups on the electrophilic groups. This results in the formation of a bridging unit which links two or more amino nitrogen atoms from different polymer strands.
• Suitable crosslinking agents ofthis type include compounds having two or more groups selected from among acyl chloride, epoxide, and alkyl-X, wherein X is a suitable leaving group, such as a halo, tosyl or mesyl group.
• X is a suitable leaving group, such as a halo, tosyl or mesyl group.
• Examples of such compounds include, but are not limited to, epichlorohydrin, succinyl dichloride, acryloyl chloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, and dihaloalkanes.
• These crosslinking agents are refened to herein as multifunctional crosslinking agents.
• the polymer composition can also be crosslinked by including a multifunctional co-monomer as the crosslinking agent in the polymerization reaction mixture.
• a multifunctional co-monomer can be incorporated into two or more growing polymer chains, thereby crosslinking the chains.
• Suitable multifunctional co-monomers include, but are not limited to, diacrylates, triacrylates, and tetraacrylates, dimethacrylates, diacrylamides, and dimethacrylamides.
• ethylene glycol diacrylate propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate.
• suitable multifunctional monomers include polyvinylarenes, such as divinylbenzene.
• the amount of cross-linking agent is typically between about 0.01 and about 10 weight % based on the combined weight of crosslinking agent and monomers, with 0.1-3% being preferred.
• the amount of cross-linking agent that is reacted with the polymer, when the crosslinking agent is a multifunctional agent, is sufficient to cause between about 0.1 and 6 percent of the nucleophiles present on the monomer, for example, an amine to react with the crosslinking agent.
• the polymers can be further characterized by one or more substituents such as substituted and unsubstituted, saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups.
• Suitable groups to employ include cationic or neutral groups, such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, ammonium groups, substituted or unsubstituted oxypolyethylene oxide, and mono, di or higher hydroxyalkyl groups.
• hydrophobic moiety is a moiety which, as a separate entity, is more soluble in octanol than water.
• the octyl group C 8 H 17
• the hydrophobic moieties can be a saturated or unsaturated, substituted or unsubstituted hydrocarbon group.
• Such groups include substituted and unsubstituted, normal, branched or cyclic alkyl groups having at least four carbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkyl groups and substituted or unsubstituted aryl or heteroaryl groups.
• the hydrophobic moiety includes an alkyl group of between about four and thirty carbons.
• hydrophobic moieties include the following alkyl groups n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tetradecyl, n-octadecyl, 2-ethylhexyl, 3-propyl-6-methyl decyl, phenyl and combinations thereof.
• hydrophobic moieties include haloalkyl groups of at least six carbons (e.g., 10-halodecyl), hydroxyalkyl groups of at least six carbons (e.g., 11-hydroxyundecyl), and aralkyl groups (e.g., benzyl).
• a "hydrophobic alkyl group”, as that term is employed herein, includes a substituted or unsubstituted alkyl group having from four to about thirty carbons and which is hydrophobic, as earlier defined.
• the hydrophobic alkyl group can be, for example, normal or branched.
• aliphatic groups include straight chained, branched or cyclic C1-C30 (preferably C5-C22) hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
• Preferred aliphatic groups are completely saturated and acyclic, i.e., straight chained or branched alkyl groups.
• Suitable substituents for an aliphatic group are those which do not significantly lower the lipase inhibiting ability or fat binding ability of the polymer, for example, do not lower either activity by more than a factor of about two.
• Each R' is independently an alkyl group or an aryl group.
• a substituted aliphatic group can have more than one substituent.
• Aryl groups include carbocyclic aromatic groups such as phenyl and naphthyl, heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrazinyl, thiazole, oxazolyl and fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings (e.g., benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole, benzooxazole, benzimidazole and quinolinyl).
• heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrazinyl, thiazole, oxazolyl and fused polycycl
• Suitable substituents for an aryl group are those which do not significantly lower the lipase inhibiting ability or fat binding ability of the polymer, for example, do not lower either activity by more than a factor of about two.
• Examples include alkyl, halogenated alkyl, -OH, halogen (-Br, -Cl, -I and -F), -O(R'), -O-CO-(R'), -CN, -NO 2 , -COOH,-NH 2 , -NH(R'), -N(R') 2 , -COO(R'), -CONH 2 , -CONH(R'), -CON(R') 2 , -SH and -S(R').
• Each R' is independently an alkyl group or an aryl group.
• a substituted aryl group can have more than one substituent.
• Non-aromatic nitrogen-containing, heterocyclic rings are non-aromatic carbocyclic rings which include at least one nitrogen atom and, optionally, one or more other heteroatoms such as oxygen or sulfur in the ring.
• the ring can be five, six, seven or eight-membered. Examples include morpholino, thiomorpholino, pyrrolidinyl, piperazinyl and piperidinyl.
• the corresponding symbol in Structural Formulas (I) and (H) boronate ester bond by which the phenylboronate group is connected to the polymer.
• pharmaceutically acceptable salts of the disclosed polymers can also be present in the anionic, or conjugate base, form, in combination with a cation. Suitable cations include alkaline earth metal ions, such as sodium and potassium ions, alkaline earth ions, such as calcium and magnesium ions, and unsubstituted and substituted (primary, secondary, tertiary and quaternary) ammonium ions.
• Polymers which have basic groups such as amines can also be protonated with a pharmaceutically acceptable counter anion, such as chloride, bromide, acetate, formate, citrate, ascorbate, sulfate or phosphate.
• a pharmaceutically acceptable counter anion such as chloride, bromide, acetate, formate, citrate, ascorbate, sulfate or phosphate.
• ammonium groups similarly comprise a pharmaceutically acceptable counteranion.
• Boronic acid groups can react with anions such as sodium or potassium hydroxide, alkoxide or carboxylate to form a salt such as -B " (OH) 3 Na + , -B " (OH) 3 K + , -B-(OH) 2 (OCH 3 )Na + , -B " (OH) 2 (OCH 3 )K + , -B (OH) 2 (OCOCH 3 )Na + , -B (OH) 2 (OCOCH 3 )K + , and the like
• the positive charge of ammonium groups in the disclosed polymers are counterbalanced with a suitable counteranion such as Cl “ , Br “ , I “ , NO 3 “ , HSO 4 " , CO 3 “2 ' HCO 3 “ or SO 4 "2 .
• the counteranions on a polymer can be the same or different. An anion with a charge greater than one will counterbalance the positive charge of more than one ammonium group.
• a "subject” is preferably a mammal, such as a human, but can also be a companion animal (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) or laboratory animals (e.g., rats, mice, guinea pigs, and the like) in need of treatment for obesity.
• a companion animal e.g., dogs, cats, and the like
• farm animals e.g., cows, sheep, pigs, horses, and the like
• laboratory animals e.g., rats, mice, guinea pigs, and the like
• the polymers of the present invention are suitable as a medicament for promoting weight reduction in mammals because they inhibit lipases and bind fat molecules such as diglycerides and triglycerides, in the gastrointestinal tract. As such, they are administered in a manner suitable for reaching the gastrointestinal tract during digestion. They are therefore preferably administered orally as soon as up to about one hour prior to a meal and as late as to up to about one hour subsequent to a meal.
• the polymer of sufficiently high molecular weight to resist abso ⁇ tion, partially or completely, from the gastrointestinal tract into other parts of the body.
• the polymers can have molecular weights ranging from about 500 Daltons to about 500,000 Daltons, preferably from about 2,000 Daltons to about 150,000 Daltons.
• "n" represents an integer chosen such that the polymer has the desired molecular weight.
• the polymers of the present invention are administered to inhibit of uptake of fat in the gastrointestinal tract (or to promote removal of fat from the gastrointestinal tract).
• they can be also be advantageously used to in the treatment or one or more of the following conditions: obesity, Type II (non-insulin- dependent) diabetes mellitus, impaired glucose tolerance, hypertension, coronary thrombosis, stroke, lipid syndromes, hyperglycemia, hypertriglyceridemia, hyperlipidemia, sleep apnea, hiatal hernia, reflux esophagisitis, osteoarthritis, gout, cancers associated with weight gain, gallstones, kidney stones, pulmonary hypertension, infertility, cardiovascular disease, above normal weight, and above normal lipid levels; or where the subject would benefit from reduced platelet adhesiveness, weight loss after pregnancy, lowered lipid levels, lowered uric acid levels, or lowered oxalate levels.
• a subject with one or more of these conditions is said to be "in need of treatment" with an
• an “effective amount” is the quantity of polymer which results in a greater amount of excretion of fat from the gastrointestinal tract over a period of time during which a subject is being treated with the polymer drug compared with the corresponding time period in absence of such treatment.
• an “effective amount” is the quantity of polymer which results in a greater amount of weight reduction over a period of time during which a subject is being treated with the polymer drug compared with the corresponding time period in absence of such treatment.
• Typical dosages range from about 5 milligrams/day to about 10 grams/day, preferably from about 50 milligrams/day to about 5 grams/day.
• the polymer can be administered alone or in a pharmaceutical composition comprising the polymer, an acceptable carrier or diluent and, optionally, one or more additional drugs, typically one or more additional drugs used for weight reduction (e.g., XENICAL or MEP DIA).
• the pharmaceutical composition comprises an effective concentration of the polymer, which is a concentration which can administer an effective amount of the polymer.
• the precise amount of polymer being administered to a subject will be determined on an individual basis and will depend on, at least in part, the subject's individual characteristics, such as general health, age, sex, body weight and tolerance to drugs, and the degree to which the subject is overweight and the amount of weight reduction sought.
• the disclosed polymers can be administered to the subjects in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition for treatment of obesity.
• Formulations vary according to the route of administration selected, but for oral administration are typically capsule. Solutions and emulsions are also possible. Suitable pharmaceutical carriers may contain inert ingredients which do not interact with the compound. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. s for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al, "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).
• the polymer of the present invention can be prepared by synthesizing monomer comprising side chains with diethanol amine alkyldiol or aminoalkyldiol groups, as is described, for example, in Example 11 and shown schematically in Figure 4, and then polymerizing.
• a suitable aryl boronic acid is prepared and then coupled to the diol groups in the polymer product.
• boron functionalized monomers are prepared and then polymerized according to standard means.
• the polymerization includes direct polymerization of a diethanol amine alkyldiol or aminoalkyldiol functionalized monomer (or boron functionalized) or with a set of monomers, one of which is diethanolamine, alkyldiol or aminoalkyldiol functionalized (or boron functionalized). This can be accomplished via standard s of free radical, cationic or anionic polymerization which are well known in the art. Due to reactivity differences between two monomers, the composition of a copolymer produced in this way can differ from the composition of the starting mixture. This reactivity difference can also result in a non-random distribution of monomers along the polymer chain.
• phenyl boronic acid compounds The preparation of representative phenyl boronic acid compounds is described in Examples 1-10 and shown schematically in Figures 1-3.
• the person of ordinary skill in the art will be able to select suitable starting materials to obtain the desired aryl boronic acid and, when carrying out these reactions with different starting materials to modify reaction conditions, if necessary, using no more than routine experimentation.
• the 4-bromoacetophenone in Figure 2 (Compound 7) can be replaced with any suitable aryl compound substituted with bromine or iodine and acetyl.
• 2-Acetyl-5-bromothiophene is commercially available from the Aldrich Chemical Co., Milwaukee, WI.
• the length of the hydrocarbyl group in the aryl boronic acids can be varied according to the length of the l, ⁇ -alkanethioalcohol.
• esterification of diol groups with aryl boronic acids can be carried out be s known in the art, for example, by reacting in suitable solvent, e.g., alcohol, toluene, methylene chloride, tetrahydrofuran or dimethylsulfoxide. Specific conditions are provided in Example 12. Analogous conditions can be used to esterify diol groups in monomers comprising diethanolamine, alkyldiol or aminoalkyldiol side chains.
• a transesterification reaction can be used to prepare a boronate ester from a boronic acid and polymer comprising a diethanolamine, alkyldiol or aminoalkyldiol side chains, for example, as is disclosed in D. H. Kinder and M. M. Ames, Journal of Organic Chemistry 52:2452 (1987) and D. S. Matteson and R. Ray, Journal of American Chemical Society 102:7590 (1980). The entire teachings of these references are incorporated herein by reference.
• Step 1 Synthesis of 4-acetyl-3-fluorophenylboronic acid (1).
• An oven-dried, 3 -liter, 3 -necked, round-bottomed flask (fitted with a nitrogen inlet, addition funnel, and overhead stirrer) was charged with 50 grams (0.25 mole) of 4-cyano-3 -fluorophenyl bromide.
• Anhydrous tetrahydrofuran (200 milliliters) was added to the flask resulting in a clear solution. The solution was cooled to 0° C using an ice bath.
• reaction mixture was stirred at -78° C for 3 hours.
• 170 milliliters of trimethylborate (6.0 equivalents, 1.5 mole) slowly using an addition funnel and the temperature was maintained at -78° C. While stirring, the reaction mixture was allowed to warm up to room temperature overnight. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C (using an ice bath) the contents were transferred into a 5 liter beaker. The flask was rinsed with 100 milliliters of methanol and the washing was combined with the reaction mixture. To the reaction mixture, 500 milliliters of 1 N HCI was slowly added. Subsequently, the pH of the mixture was brought to 4 by the addition of concentrated HCI.
• Step 2 Synthesis of 4-(2'-bromoacetyl)-3-fluorophenylboronic acid (2).
• An oven-dried, 500-milliliter, 3 -necked, round-bottomed flask was charged with 5 grams (27.4 millimole) of 4-acetyl-3 -fluorophenyl boronic acid and 25 milliliters of methanol under a nitrogen atmosphere.
• the solution was cooled to 0° C using an ice bath. To this solution was added 0.2 milliliters (0.55 equivalents) of glacial acetic acid.
• Step 4 Synthesis of neopentyl glycol protected 4-(14'-hydroxy-3'-thia-r- ketotetradecyl)-3-fluorophenylboronic acid (4).
• reaction was carried out under N 2 atmosphere.
• An oven-dried, 500-milliliter, 3 -necked, round-bottomed flask was charged with 5.13 grams (11.33 millimole) of the neopentyl glycol protected boronic acid (4) and 50 milliliters of anhydrous dichloromethane under a nitrogen atmosphere.
• To this solution was added 7.52 grams (22.67 millimole, 2 equivalents) of carbon tetrabromide.
• the resulting solution was allowed to stir at 0° C using an ice bath.
• Step 6 Synthesis of 4-(14'-trimethylammonium-3'-thia-r-ketotetradecyl)-3- fluorophenylboronic acid chloride (6).
• Example 2 Synthesis of 2,5-difluoro-4-(14'-hydroxy-3'-thia-r- ketotetradecyl)phenylboronic acid (11).
• the synthesis of Compound (11) is shown out schematically in Figure 2. A detailed description of the procedure is provided below.
• Anhydrous aluminum chloride was mixed (5 grams, 37.5 millimoles, 2.4 equivalents) with l-bromo-2,5 difluorobenzene in a dry, round-bottom flask blanketed with nitrogen and fitted with a condenser. The mixture was heated to 60° C and acetyl chloride (1.7 milliliters, 23.3 millimole, 1.5 equivalents) was added by syringe. The wet yellow solid changed then into a scarlet solution and was heated at 90° C for 1 hour. The reaction mixture was poured onto 38 grams of ice, HCI was added (3 milliliters, 37% concentration) and the mixture was extracted with ether. The crude material was dried over magnesium sulfate and evaporated down. The crude material was purified by column chromatography or distilled. The product (1.2 grams, 31 %) was obtained as a yellow oil.
• Step 2 Synthesis of neopentyl glycol protected 4-acetyl-2,5- difluorofluorophenylboronic acid (8).
• the boronic ester (8) (4.1 grams, 14.93 millimole, 1 equivalent) was dissolved in methylene chloride (50 milliliters) and cooled down to -10° C. Acetic acid (0.82 milliliters, 14.32 millimole, 1 equivalent) was added, followed by bromine (0.7 milliliters, 13.4 millimole, 0.9 equivalents) and the reaction was warmed up to room temperature. After stirring for two hours the reaction mixture was diluted with more methylene chloride and washed once with water and once with brine. The crude was dried over magnesium sulfate, evaporated down and used in the next step without further purification.
• Step 5 Synthesis of 2,5-difluoro-4-(14'-hydroxy-3 , -thia-r- ketotetradecyl)phenylboronic acid (11).
• Example 3 Synthesis of 2,5-difluoro-4-(13'-trimethylamonium-3'-thia-r- ketotridecyl)phenyl (neopentyl glycolato) boron chloride (14).
• the synthesis of Compound (14) is shown schematically in Figure 3. A detailed description of the procedure is provided below.
• Step 1 Synthesis of 10-bromodecyltrimethylammonium bromide 1,10-Dibromodecane (20 grams, 66.7 mmoles) and THF (100 milliliters) were placed in a 500-mL, three-necked flask. The solution was cooled to 0 °C with an ice-water bath. Anhydrous trimethylamine (3 grams, 50.8 mmoles) was added to the mixture by slowly bubbling trimethylamine gas for about 15 minutes. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The solid material was filtered and washed with THF (5 x 30 milliliters).
• Step 2 Synthesis of 10-mercaptodecyltrimethylammonium bromide 10-Bromodecyltrimethylammonium bromide (10 grams, 27.9 mmoles) in 50 mL of methanol was placed in a 250-milliliter, three-necked flask. The mixture was degassed vigorously by bubbling nitrogen for 30 minutes. Potassium thioacetate (3.8 grams, 33.5 mmoles, 1.2 equivalents) was added to the reaction mixture. The mixture was heated at 50° C for 12 hours under nitrogen.
• the reaction mixture was cooled to 0° C with an ice-water bath, degassed sodium hydroxide (50%, 2.7 grams, 33.5 mmoles, 1.2 equivalents) was added, and the mixture was stined for lh at room temperature.
• the mixture was cooled to 0° C, and degassed concentrated hydrochloride acid was added dropwise to achieve pH 2.
• Degassed methanol 100 milliliters was added to the reaction mixture, followed by the addition of 40 grams of magnesium sulfate. Magnesium sulfate was filtered off and washed with methanol. The methanol solution was concentrated to about 20 milliliters, and ether (300 milliliters) was added to the mixture.
• Step 3 Synthesis of 2,5-difluoro-4-(13'-trimethylammonium-3'-thia-l'- ketotridecyl)fluorophenylboronic acid bromide 4-(2'-Bromoacetyl)-2,5-difluorophenyl (neopentyl glycolato) boron
• Step 2 4-( 14'-hydroxy-3'-thia- -ketotetradecyl)phenylboronic acid.
• the organic phase was washed with deionized water (2 X 200 ml), IN HCI (3 X 200 ml), deionized water (200 ml), and brine (200 ml).
• the washed organic layer was then dried over anhydrous sodium sulfate for 15 minutes.
• the solution was filtered and concentrated to one fourth of its volume. While stirring, hexane was added slowly to this solution until permanent cloudiness appeared.
• the solution was kept in the freezer to crystallize the product. After filtration, the residue was dried under vacuum at room temperature yielding 17 grams of the product as an off-white solid.
• Step 3 Synthesis of (neopentyl glycolato) 4-(14'-hydroxy-3'-thia- - ketotetradecyl)phenylboronate ester.
• Step 4 Synthesis of (neopentyl glycolato) 4-(14'-bromo-3'-thia-r- ketotetradecyl)phenylboronate ester.
• Step 5 4-( 14'-trimethylammonium-3 '-thia- 1 '-keto-tetradecyl)phenylboronic acid chloride.
• a mixture of 4-carboxyphenylboronic acid (1.0 grams), potassium hydrogen carbonate (2.01 g), 11-bromo-l-undecanol, and NN-dimethylformamide (60 mL) was heated at 60 °C under a nitrogen atmosphere for 18 hours. After the heating period, the mixture was allowed to cool to room temperature. The mixture was then filtered and the filtrate was concentrated on a rotary evaporator. The concentrated filtrate was diluted with ethyl acetate (500 mL) and the ethyl acetate was washed successively with saturated aqueous sodium bicarbonate (3 X 300 mL), followed by saturated aqueous sodium chloride (300 mL).
• the ethyl acetate extract was concentrated on a rotary evaporator and dried under reduced pressure to afford 2.2 grams of the desired product as a light yellow viscous oil that solidified upon standing to a white powder.
• Step 1 Synthesis of 2-(4-carboxyphenyl)-l,3-dioxa-2-borinane.
• a mixture of 4-carboxyphenylboronic acid (5.0 grams) and 1,3-propanediol (2.5 grams) in toluene (300 mL) was refluxed with a Dean-Stark apparatus for 6 hours. After the heating period the reaction solution was concentrated on a rotary evaporator and dried under reduced pressure to afford 6.39 grams of the desired product as a white solid.
• Example 11 Synthesis of Poly(N-diethanolaminopropyl)acrylamide (17)
• the synthesis of Polymer (17) is shown out schematically in Figure 4. A detailed description of the procedure is provided below.
• Step 1 Synthesis of (N-diethanolaminopropyl)acrylamide (16) A 2-liter, 3-necked, round-bottomed flask with overhead stirring was charged with 80.08 grams of N-(3-aminopropyl)diethanolamine and 200 milliliters of deionized water. To this mixture was added 3.18 grams of K 2 CO3 and the resulting solution was cooled to less than 5° C with an ice bath. 130 milliliters of dichloromethane with vigorous stirring. This was followed by the addition of 45.0 milliliters of acryloylchloride (about 1.1 equivalents relative to amine) in 50 milliliters of dichloromethane.
• a 50% aqueous solution of KOH was prepared by dissolving 20.58 grams of KOH (about 0.74 equivalents with respect to amine) in 25 milliliters of deionized water. About half of the acryloylchloride solution over 30 to 45 minutes until the pH between 7 and 8. The KOH solution and acryloylchloride solution were then added dropwise simultaneously, keeping the pH between 8 and 9. The reaction was stined overnight and allowed to warm to room temperature. The next day, the aqueous layer was separated from the organic layer, which was discarded.
• the material was dialyzed (molecular weight cut off 3.5 K) over 24 hours with a water change after 16 hours.
• the purified polymer was then dried in a forced air oven at 50° C for 30 hours. An orange and tacky film was obtained and was then redissolved in 300 milliliters of methanol. The solvent was removed in vacuo to yield an oil, which was then precipitated into 3 liters of ether. The gummy mass was then vacuum dried at about 35° C to 40° C for 16 hours.
• the final yield of (17) was 50 grams of a grindable, yellow solid (50% recovery).
• Example 13 Polymers of the Present Invention Inhibit Lipase Activity In Vitro An in vitro assay of pancreatic lipase activity was used to measure the efficacy of lipase inhibitory compounds. Porcine pancreatic lipase (23 units/milliliters) was incubated for 4 hours at 37° C with 72 mM triglyceride (as an olive oil/gum arabic emulsion) in 5.5 milliliters of a 300 mM BES buffer, pH 7.0, containing 10 mM CaCl 2 , 109 mM NaCl, and 8 mM sodium taurocholate.
• 72 mM triglyceride as an olive oil/gum arabic emulsion
• the reaction was stopped by acidification with HCI and the lipids were extracted by the disclosed in Folch, et al, J. Biol. Chem. 226:497 (1957) prior to analysis by HPLC.
• An aliquot of the chloroform layer was evaporated and reconstituted in hexane, and the sample was analyzed on a Waters Alliance 2690 HPLC with a Sedex 55 Evaporative Light Scattering detector utilizing a YMC PVA Sil 3 x 50 millimeter column.
• the mobile phase consisted of hexane and methyl t-butyl ether delivered in a linear gradient at a flow rate of 0.5 milliliters/minute.
• Example 14 Polymers of the Present Invention Inhibit Lipolysis In Vivo Compounds were evaluated in rats to determine their in vivo potency in inhibiting fat absorption through lipase inhibition. Rats were acclimated to the facility for approximately 1 week in individual wire-bottom cages and provided a standard chow diet and water ad libitum. Rats were then randomly assigned to groups of 4. They were gavaged at (7-8AM) with 4 milliliters olive oil emulsified with gum arabic, with or without drug following an 18 hour fast. Test compounds were dissolved in DMSO or deionized water. Drug solutions were mixed thoroughly in the olive oil emulsion just prior to administration.
• the milligrams of intestinal contents that was extracted and the total number of milligrams collected were recorded.
• the milligrams/milliliters values obtained from the HPLC analysis were entered.
• the individual lipid components were calculated and expressed as total milligrams recovered.
• Dose units are expressed as the milligrams of drug per gram of oil administered to each rat.
• the ED 50 's were determined by extrapolating the dose value at half the maximum obtainable triglyceride recoverable in the assay. The results are shown in the Table. As can be seen, the polymers are effective in inhibiting lipolysis in vivo.

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• 2002
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