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1. WO2019106572 - COMPOSITION POUR TRAITER ET PRÉVENIR LE DIABÈTE SUCRÉ DE TYPE II ET LA MALADIE D'ALZHEIMER

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[ EN ]

COMPOSITION FOR TREATING AND PREVENTING

DIABETES MELLITUS TYPE II AND ALZHEIMER’S DISEASE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62/591,394, filed November 28, 2017, the entire contents of which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

A. Field of the Invention

[0002] The present invention relates to formulations containing a compound and mixtures of compounds capable of preventing and treating diabetes mellitus type II and Alzheimer’s disease.

B. Description of Related Art

[0003] Misfolding, aggregation and accumulation of diverse proteins in different organs is the causative agent of several diseases collectively known as protein misfolding disorders (PMDs). There are over 30 known PMDs. Among these PMDs are diseases associated with the formation of amyloid fibers and oligomers, collectively known as amyloidogenic diseases. Amyloid fibers and oligomers occur when soluble polypeptides or proteins aggregate to form insoluble amyloid fibers, with spines consisting of many-stranded b-pleated sheets (Virchow R.; Glenner et ah). These fibers and oligomers can forms clumps in cells and create plaques that result in toxicity to the surrounding environment.

[0004] Currently, over 25 amyloid-forming proteins have been identified and associated with serious diseases, including amyloid-b peptide (Ab) with Alzheimer’s disease (AD), islet amyloid polypeptide (IAPP) with diabetes mellitus type II (T2DM), and prion protein (PrP) with the spongiform encephalopathies (Eisenberg et ah, Mukheijee et ah). Interestingly, combined Ab and IAPP aggregation have been shown to exacerbate pathologies of both AD and T2DM, potentially linking the pathologies of these diseases (Wijesekara et ah).

[0005] One of these diseases, diabetes mellitus type II, is a dangerous, global problem that is becoming increasingly prevalent. Diabetes is a chronic disease that occurs when there is a deficiency of insulin, either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Over time diabetes can lead to serious damage to many of the body's systems, especially the nerves and blood vessels, and if left untreated, it can be fatal.

[0006] The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. Diabetes mellitus type II is responsible for 90 to 95% of all diabetes cases. Over the same time span, diabetes has risen in adults over the age of 18 from 4.7% to 8.5%, nearly a doubling in prevalence (WHO Global Report on Diabetes). In 2012 diabetes was the direct cause of 1.5 million deaths, and high blood glucose was the cause of another 2.2 million deaths. The WHO projects that diabetes will be the 7th leading cause of death in 2030 (Mathers et al.).

[0007] There are many theories about what causes T2DM, but one of the most widely accepted is the toxic oligomer hypothesis (Haataja et al.). This hypothesis states that protein hormones within the pancreas can produce toxic oligomers (amyloids) that kill pancreatic cells. In T2DM, toxic aggregates of islet amyloid polypeptide (IAPP or amylin), a 37-residue peptide hormone secreted from b-cells, are involved in the death of insulin-producing islet b-cells (Cooper et al.; Westermark et al.). There are no clinically approved inhibitors of IAPP toxicity. While there are current treatments available to manage T2DM, there are none that treat the underlying mechanism of disease (Cimmaruta et al.). A drug that could prevent, or even reverse type II diabetes is urgently needed.

SUMMARY OF THE INVENTION

[0008] The present invention provides a solution to the current problems facing treatment and prevention of diabetes mellitus type II and Alzheimer’s disease. Specifically, it is shown herein that a compound found in turmeric ( Curcuma longd) and derivatives thereof are capable of preventing and treating diabetes mellitus type II and Alzheimer’s disease. In addition, the inventors believe that using the compounds of the present invention with one or more additional anti-diabetes agents or anti-Alzheimer’s disease agents will enhance the ability of the combination to prevent and treat diabetes and/or Alzheimer’s disease.

[0009] In one aspect, disclosed is a composition containing a compound of Formula II.


Formula II

where Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R3, R4, Rs are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms.

[0010] The alkyl group can include any branched and/or straight chain group. Non-limiting examples of alkyl groups include methyl, ethyl, or propyl. The aryl group can include a phenyl moiety and derivatives thereof. A non-limiting example of a phenyl derivative can include ortho, metha, or para, tolyl groups (C7H7), dimethyl benzyl groups (C9H9), or the like. The group substituted for hydrogen in the substituted groups can include heteroatoms. The heteroatoms can include oxygen, nitrogen or phosphorous. In some embodiments, the heteroatoms are oxygen.

[0011] In some instances, Ri and R7 are the same. In some instances, R2 and Rx are the same. In some instances, Ri and R7 are the same and R2 and Rs are the same. In some instances, Ri and R7 are the same and are methyl or acetyl. In some instances, R2 and Rx are the same and are methyl or acetyl. In some instances, Ri, R2, R7, and Rx are independently either methyl or acetyl ,Ri and R7 are the same, and R2 and Rx are the same. In some instances, Ri, R2, R7, and R8 are independently either methyl or acetyl, Ri and R7 are the same, R2 and Rx are the same, and at least one of Ri and R7 or R2 and Rs are acetyl. In some instances, R6 is a disubstituted hydrocarbon ring having 6 carbon atoms. In some instances, R6 is a disubstituted aromatic hydrocarbon ring having 6 carbon atoms. In some instances, R6 is a disubstituted hydrocarbon ring having 6 carbon atoms wherein all of the carbon atoms of the carbon ring are singly bonded. In some instances, R6 is a disubstituted hydrocarbon ring having 6 carbon atoms and is either aromatic or all of the carbon atoms of the carbon ring are singly bonded. In some instances, R3, R4, Rs are independently H, =0, or OH. In some instances, R3, R4, Rs are independently H, =0, or OH and at least one of R3, R4, Rs are =0 or OH. In some instances, Ri, R2, R7, and Rx are independently either methyl or acetyl, Ri and R7 are the same, R2 and Rx are the same, at least one of Ri and R7 or R2 and Rx are acetyl, R6 is a disubstituted hydrocarbon ring having 6 carbon atoms and is either aromatic or all of the carbon atoms of the carbon ring are singly bonded, R3, R4, Rs are independently H, =0, or OH, and at least one of R3, R4, Rs are =0 or OH.

[0012] In some instances the compound of Formula II is the compound of Formula I


Formula I

or salts thereof.

[0013] In some instances the compound of Formula II is the compound of Formula III


Formula III

or salts thereof.

[0014] In some instances the compound of Formula II is the compound of Formula IV


Formula IV

or salts thereof.

[0015] In some instances the compound of Formula II is the compound of Formula V


Formula V

or salts thereof.

[0016] In some instances the compound of Formula II is the compound of Formula VI


Formula VI

or salts thereof.

[0017] In some instances, the composition contains any two or more of the compounds disclosed herein in the composition.

[0018] In some instances, the composition contains a pharmaceutically acceptable carrier. In some instances, the pharmaceutically acceptable carrier can be a naturally or a non-naturally occurring compound or structure. In some instances, the composition further contains a preservative, stabilizer, bulking agent, and/or excipient. In some instances, the preservative, stabilizer, bulking agent, and/or excipient can be a naturally or a non-naturally occurring compound or composition. In some instances, the composition is a pharmaceutical composition. In some instances, the composition is coated with a polymer. In some instances, the polymer is a naturally or a non-naturally occurring polymer. In another aspect, the composition may further comprise one or more ingredients described herein. For example, the composition may comprise one or more additional ingredients selected from one or more pH adjusters, structuring agents, and inorganic salts.

[0019] In some instances, the composition is formulated for oral administration. In some instances, the composition is one or more of a lozenge, a powder, a tablet, a delayed release capsule, a quick release capsule, a gel-cap, a gelatin, a liquid solution, and/or a dissolvable film. In some instances, the composition is formulated for topical application, intravenous administration, subcutaneous administration, intramuscular administration, and/or intranasal delivery. In some instances, the composition comprises 12 to 100% by weight of the compound. In some instances, the composition comprises 15 to 99.9% by weight of the compound. In some instances, the composition comprises 30 to 99.9%, 40 to 99.9%, 50 to 99.9%, 60 to 99.9%, 70 to 99.9%, 80 to 99.9%, 90 to 99.9%, 95 to 99.9%, or 97 to 99.9%, or any range therein by weight of the compound. In some instances, the composition contains a dose of the compound. In some instances, a dose is 1 pg to 10 gram of the compound. In some instances, the composition contains a sub-dose of the compound. In some instances, the composition contains 0.1 mg to 3 g, 1 mg to 1 g, 1 mg to 500 mg, 1 to 300 mg, 1 to 100 mg, 1 to 10 mg, 1 mg, 2 mg, 3 mg, or 4 mg of the compound, or any range therein.

[0020] In one aspect, the composition contains at least one second anti-diabetes agent. In some instances, the composition does not comprise a second anti-diabetes agent. In some instances, the at least one second anti-diabetes agent is an anti-diabetes mellitus type II agent. In some instances, the at least one second anti-diabetes mellitus type II agent is metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, pioglitazone, sitagliptin, saxagliptin, linagliptin, acarbose, miglitol, colesevelam, insulin, or salts thereof, or any combination thereof.

[0021] In another aspect, the compound is synthetically obtained. In some instances, the compound of Formula III is synthetically obtained by the reaction outlined in Reaction Scheme I, disclosed below. In some instances, the compound of Formula IV is synthetically obtained by the reaction outlined in Reaction Scheme II, disclosed below. In some instances, the compound of Formula V is synthetically obtained by the reaction outlined in Reaction Scheme III, disclosed below. In some instances, the compound of Formula VI is synthetically obtained by the reaction outlined in Reaction Scheme IV, disclosed below. In some instances, the compound of Formula I is synthetically obtained by the reaction outlined in Reaction Scheme V, disclosed below.

[0022] In yet another aspect, the compound is obtained from an organism. In some instances, the compound is obtained from turmeric ( Curcuma longd). In some instances the compound of Formula I is obtained from turmeric.

[0023] Also disclosed is a method of treating and/or preventing diabetes mellitus in a subject, the method comprises administering any one of the compositions of the present invention to the subject. In some instances, the method treats and/or prevents diabetes mellitus type II. Further, herein is disclosed a method of administering any one of the compositions of the present invention to a subject by administering any one of the compositions of the present invention to the subject. In a particular instance, the subject has been diagnosed with diabetes mellitus. In a particular instance, the subject has been diagnosed with diabetes mellitus type II. In a particular instance, the subject has metabolic syndrome. In a particular instance, the subject has pre-diabetes. In some instances, a mixture of any two or more of the compounds contained herein is administered to the subject.

[0024] Disclosed herein is a method of reducing aggregation of islet amyloid polypeptide, the method comprising contacting islet amyloid polypeptide with any one of the compounds and/or compositions of the present invention. In some instances, the method reduces the amount of pre-existing aggregation of islet amyloid polypeptide. In some instances, the method reduces the amount of aggregation of islet amyloid polypeptides in comparison to the amount of aggregation that would have occurred without contacting the islet amyloid polypeptide with the compound. In some instances, a mixture of any two or more of the compounds disclosed herein contacts the islet amyloid polypeptide. In some instances, the islet amyloid polypeptide is contacted by administering any one or more of the compounds and/or compositions disclosed herein to a subject. In some instances, the subject has diabetes mellitus type II. In some instances, the subject has metabolic syndrome. In some instances, the subject has prediabetes. In some instances, the subject is at risk for diabetes mellitus type II, metabolic syndrome, and/or prediabetes.

[0025] In some aspects of any of the methods described herein, a subject is administered a total sum of between 0.001 mg and 10 g of the compound during a 24 hour period. In some instances, the subject is administered a total sum of between 0.1 and 1,500 mg, 1 and 1,500 mg, 5 and 1,000 mg, 10 and 500 mg, or any range therein, of the compound during a 24 hour period.

[0026] In some aspects of any of the methods described herein, the subject is administered any one of the compositions disclosed herein at least once a day. In some instances, the subject is administered any one of the compositions disclosed more than once a day. In some instances, the subject is administered any one of the compositions disclosed herein twice a day. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least five days. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least ten days. In some aspects, the subject is administered any one of the compositions disclosed herein at least daily for two weeks, a month, two months, three months, six months, a year, two years, or more. In some aspects, the subject is administered any one of the compositions disclosed herein daily for at least fourteen days. In some aspects, the subject is administered any one of the compositions disclosed herein daily for two weeks, a month, two months, three months, six months, a year, two years, or more. In some aspects, the subject is administered any one of the compositions disclosed herein daily for the rest of the subject’s life. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least six days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least ten days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for at least fourteen days. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for two weeks, a month, two months, three months, six months, a year, two years, or more. In some aspects, the subject is administered any one of the compositions disclosed herein every other day for the rest of the subject’s life.

[0027] In some aspects of the invention, the composition may further comprise one or more nutraceutical and/or pharmaceutically acceptable carriers or diluents. These carriers/diluents can be adjuvants, excipients, or vehicles such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrance, antibacterial agents, antifungal agents, lubricating agents, vitamins, polymers, siloxane containing compounds, essential oils, structuring agents, and dispensing agents. Each carrier is acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. In some aspects of the invention, the carrier can include at least one hydrophilic polymeric compound selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a carbohydrate carrier, talc, lactose, mannitol, glucose, water, gelatin, a protein-derived compound, polyvinyl pyrrolidone, magnesium stearate, and any combination

thereof. Non-limiting examples of diluents/carriers are identified throughout this specification and are incorporated into this section by reference. The amounts of such ingredients can range from 0.0001% to 99.9% by weight or volume of the composition, or any integer or range in between as disclosed in other sections of this specification, which are incorporated into this paragraph by reference.

[0028] The composition can be stored for one month, 6 months, 12 months, 18 months, or 24 months at room temperature. In some aspects of the invention, the composition is formulated as a powder, a tablet, a gel-cap, a bead, an edible tablet, a dissolvable film, a liquid capable of being dispersed through the air, a gelatin, a lotion, a transdermal patch, or a liquid solution for oral administration. In some aspects of the invention, the formulated composition can be comprised in a solid nanoparticle, a lipid-containing nanoparticle, a lipid-based carrier, a sealed conduit, a straw, sealed bag, or any combination thereof. In other aspects of the invention, the composition can be formulated for administration by injection.

[0029] Kits that include the compositions of the present invention are also contemplated. In certain embodiments, the composition is comprised in a container. The container can be a bottle, dispenser, package, or a straw. The container can dispense a predetermined amount of the composition. In certain aspects, the compositions are dispensed as a pill, a tablet, a capsule, a transdermal patch, an edible chew, a cream, a lotion, a gel, spray, mist, dollop, a powder, or a liquid. The container can include indicia on its surface. The indicia can be a word, an abbreviation, a picture, or a symbol.

[0030] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0031] Also contemplated is a product that includes the composition of the present invention. In non-limiting aspects, the product can be a nutraceutical product. The nutraceutical product can be those described in other sections of this specification or those known to a person of skill in the art. In other non-limiting aspects, the product can be a pharmaceutical product. The pharmaceutical and/or nutraceutical product can be those described in other sections of this specification or those known to a person of skill in the art. Non-limiting examples of products include a pill, a tablet, an edible chew, a capsule, a cream, a lotion, a gel, a spray, a mist, a dissolving film, a transdermal patch, or a liquid, etc.

[0032] Also disclosed are the following Embodiments 1 to 46 of the present invention. Embodiment 1 is a composition comprising: the compound of Formula II and/or a salt thereof


Formula II

where: Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R3, R4, Rs are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms. Embodiment 2 is the composition of Embodiment 1, wherein the composition comprises 15 to 99.9% by weight of the compound of Formula II. Embodiment 3 is the composition of any of Embodiments 1 to 2, wherein the composition does not comprise a second anti-diabetes agent. Embodiment 4 is the composition of any one of Embodiments 1 to 2, wherein the composition further comprises at least one second anti-diabetes agent. Embodiment 5 is the composition of Embodiment 4, wherein the at least one second anti diabetes agent is an anti-diabetes mellitus type II agent. Embodiment 6 is the composition of Embodiment 5, wherein the anti-diabetes mellitus type II agent is metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, pioglitazone, sitagliptin, saxagliptin, linagliptin, acarbose, miglitol, colesevelam, insulin, or salts thereof, or any combination thereof. Embodiment 7 is the composition of any one of Embodiments 1 to 6, wherein the composition is formulated for oral administration. Embodiment 8 is the composition of Embodiment 7, wherein the composition is one or more of a lozenge, a powder, a tablet, a gel-cap, a delayed release capsule, a quick release capsule, a gelatin, a liquid solution, and/or a dissolvable film. Embodiment 9 is the composition of any one of Embodiments 1 to 8, wherein the composition is formulated for topical application, intravenous administration, subcutaneous administration, intramuscular administration, and/or intranasal delivery. Embodiment 10 is the composition of any one of Embodiments 1 to 8, wherein the compound of Formula II is the compound of Formula I


Formula I

and/or a salt thereof. Embodiment 11 is the composition of any one of Embodiments 1 to 8, wherein the compound of Formula II is the compound of Formula III


Formula III

and/or a salt thereof. Embodiment 12 is the composition of any one of Embodiments 1 to 8, wherein the compound of Formula II is the compound of Formula IV


Formula IV

and/or a salt thereof. Embodiment 13 is the composition of any one of Embodiments 1 to 8, wherein the compound of Formula II is the compound of Formula V


Formula V

and/or a salt thereof. Embodiment 14 is the composition of any one of Embodiments 1 to 8, wherein the compound of Formula II is the compound of Formula VI


Formula VI

and/or a salt thereof. Embodiment 15 is a method of treating a subject with diabetes mellitus type II or at risk of diabetes mellitus type II, the method comprising administering to the subject a compound of Formula II and/or a salt thereof


Formula II

where: Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R3, R4, Rs are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms. Embodiment 16 is the method of Embodiment 15, wherein the subject has diabetes mellitus type II. Embodiment 17 is the method of Embodiment 15, wherein the subject has metabolic syndrome and/or pre-diabetes. Embodiment 18 is the method of any one of Embodiments 15 to 17, wherein the subject is administered a total sum of between 0.1 and 10,000 mg, preferably between 1 and 1,500 mg, between 5 and 1,000 mg, or between 10 and 500 mg of the compound of Formula II during a 24 hour period. Embodiment 19 is the method of any one of Embodiments 15 to 18, wherein the composition is administered at least once a day for at least five days. Embodiment 20 is the method of any one of Embodiments 15 to 19, wherein the compound of Formula II that is administered to the subject is the compound of Formula I


Formula I

and/or a salt thereof. Embodiment 21 is the method of any one of Embodiments 15 to 19, wherein the compound of Formula II that is administered to the subject is the compound of Formula III


Formula III

and/or a salt thereof. Embodiment 22 is the method of any one of Embodiments 15 to 19, wherein the compound of Formula II that is administered to the subject is the compound of Formula IV


Formula IV

and/or a salt thereof. Embodiment 23 is the method of any one of Embodiments 15 to 19, wherein the compound of Formula II that is administered to the subject is the compound of Formula V


Formula V

and/or a salt thereof. Embodiment 24 is the method of any one of Embodiments 15 to 19, wherein the compound of Formula II that is administered to the subject is the compound of Formula VI


Formula VI

and/or a salt thereof. Embodiment 25 is a method of preventing diabetes mellitus type II in a subject, the method comprising administering to the subject a compound of Formula II and/or a salt thereof


Formula II

where: Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R3, R4, Rs are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms, wherein diabetes mellitus type II is prevented in the subject. Embodiment 26 is the method of Embodiment 25, wherein the subject has metabolic syndrome. Embodiment 27 is the method of Embodiment 25, wherein the subject has pre-diabetes. Embodiment 28 is the method of any one of Embodiments 25 to 27, wherein the subject is administered a total sum of between 0.1 and 10,000 mg, preferably between 1 and 1,500 mg, between 5 and 1,000 mg, or between 10 and 500 mg of the compound of Formula II during a 24 hour period. Embodiment 29 is the method of any one of Embodiments 25 to 28, wherein the composition is administered at least once a day for at least five days. Embodiment 30 is the method of any one of Embodiments 25 to 29, wherein the compound of Formula II that is administered to the subject is the compound of Formula III


Formula I

and/or a salt thereof. Embodiment 31 is the method of any one of Embodiments 25 to 29, wherein the compound of Formula II that is administered to the subject is the compound of Formula III


Formula III

and/or a salt thereof. Embodiment 32 is the method of any one of Embodiments 25 to 29, wherein the compound of Formula II that is administered to the subject is the compound of Formula IV


Formula IV

and/or a salt thereof. Embodiment 33 is the method of any one of Embodiments 25 to 29, wherein the compound of Formula II that is administered to the subject is the compound of Formula V


Formula V

and/or a salt thereof. Embodiment 34 is the method of any one of Embodiments 25 to 29, wherein the compound of Formula II that is administered to the subject is the compound of Formula VI


Formula VI

and/or a salt thereof. Embodiment 35 is a method of reducing aggregation of islet amyloid polypeptide, the method comprising contacting islet amyloid polypeptide with a compound of Formula II and/or a salt thereof


Formula II

where: Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group; R3, R4, Rs are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms, wherein aggregation of islet amyloid polypeptide is reduced. Embodiment 36 is the method of Embodiment 35, wherein the compound of Formula II is administered to a subject. Embodiment 37 is the method of Embodiment 36, wherein the subject has diabetes mellitus type II. Embodiment 38 is the method of Embodiment 36, wherein the subject has metabolic syndrome. Embodiment 39 is the method of Embodiment 36, wherein the subject has pre-diabetes. Embodiment 40 is the method of any one of Embodiments 36 to 39, wherein the subject is administered a total sum of between 0.1 and 10,000 mg, preferably between 1 and 1,500 mg, between 5 and 1,000 mg, or between 10 and 500 mg of the compound of formula II during a 24 hour period. Embodiment 41 is the method of any one of Embodiments 36 to 40, wherein the composition is administered at least once a day for at least five days. Embodiment 42 is the method of any one of Embodiments 35 to 41, wherein the compound of Formula II that contacts islet amyloid polypeptide is the compound of Formula III


Formula I

and/or a salt thereof. Embodiment 43 is the method of any one of Embodiments 35 to 41, wherein the compound of Formula II that contacts islet amyloid polypeptide is the compound of Formula III


Formula III

and/or a salt thereof. Embodiment 44 is the method of any one of Embodiments 35 to 41, wherein the compound of Formula II that contacts islet amyloid polypeptide is the compound of Formula IV


Formula IV

and/or a salt thereof. Embodiment 45 is the method of any one of Embodiments 35 to 41, wherein the compound of Formula II that contacts islet amyloid polypeptide is the compound of Formula V


Formula V

and/or a salt thereof. Embodiment 46 is the method of any one of Embodiments 35 to 41, wherein the compound of Formula II that contacts islet amyloid polypeptide is the compound of Formula VI


Formula VI

and/or a salt thereof.

[0033] “Therapeutic agent” encompasses the compounds specifically claimed herein. It also encompasses such compounds together with nutraceutical and/or pharmaceutically

acceptable salts thereof. Useful salts are known to those skilled in the art and include salts with inorganic acids, organic acids, inorganic bases, or organic bases. Therapeutic agents useful in the present invention are those compounds that affect a desired, beneficial, and often pharmacological, effect upon administration to a human or an animal, whether alone or in combination with other nutraceutical and/or pharmaceutical excipients or inert ingredients.

[0034] The term“accurate mass” refers to a measured mass of a molecule experimentally determined for an ion of known charge. The units for accurate mass include atomic mass units (amu) and milli unified atomic mass units (mmu). The term“molecular weight” refers to the average weight of the molecule with all of the different isotopic compositions present in a compound but weighted for their natural abundance.

[0035] The term“relative abundance” refers to the abundance of a compound of interest relative to the abundance of a reference compound. In particular aspects, relative abundance is the raw intensity of a mass spectrometry peak for the compound of interest over the raw intensity of a mass spectrometry peak for a reference compound. In one non-limiting instance, the mass spectrometry peaks can be obtained by the use of DART-TOF mass spectrometry. In another particular aspect, the reference compound is a compound that is spiked, or doped, into a sample containing the compound of interest. In yet another particular aspect, the reference compound is a compound that does not exist in the sample previous to its addition to the sample for determining relative abundance. In another particular aspect, the reference compound can be salicylic acid.

[0036] Accurate mass and relative abundances described herein are based on experiments using particular instruments and particular settings and can change from instrument to instrument. There is variability in each measurement. Thus, the accurate mass and relative abundances are defined as being close to as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be within 20%, preferably 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. In one non-limiting embodiment, the accurate mass has an error of within +/- 20 mmu, preferably 10 mmu, more preferably within 5 mmu, and most preferably within 1 mmu. In one non-limiting embodiment, the relative abundance has an error of +/- 20%, preferably 10%, preferably within 5%, and more preferably within 1%, and most preferably within 0.5%.

[0037] The term“substantially” and its variations are defined as being largely but not necessarily wholly what is specified as understood by one of ordinary skill in the art, and in one non-limiting embodiment substantially refers to ranges within 10%, within 5%, within 1%, or within 0.5%.

[0038] “Patient,”“subject,” or“individual” refers to a mammal ( e.g ., human, primate, dog, cat, bovine, ovine, porcine, equine, mouse, rat, hamster, rabbit, or guinea pig). In particular aspects, the patient, subject, or individual is a human.

[0039] “Inhibiting” or“reducing” or any variation of these terms includes any measurable decrease or complete inhibition to achieve a desired result.

[0040] “Effective” or “effect” or any variation of these terms means adequate to accomplish a desired, expected, or intended result.

[0041] “Treating” or“treat” or any variation of these terms includes any measurable improvement in a disease, condition, or symptom that is being treated or is associated with the disease, condition, or symptom being treated.

[0042] “Preventing” or“prevent” or any variation of these terms means to slow, stop, or reverse progression toward a result. The prevention may be any slowing of the progression toward the result.

[0043] “Analogue” and“analog,” when referring to a compound, refers to a modified compound wherein one or more atoms have been substituted by other atoms, or wherein one or more atoms have been deleted from the compound, or wherein one or more atoms have been added to the compound, or any combination of such modifications. Such addition, deletion or substitution of atoms can take place at any point, or multiple points, along the primary structure comprising the compound.

[0044] “Derivative,” in relation to a parent compound, refers to a chemically modified parent compound or an analogue thereof, wherein at least one substituent is not present in the parent compound or an analogue thereof. One such non-limiting example is a parent compound which has been covalently modified. Typical modifications are amides, carbohydrates, alkyl groups, acyl groups, esters, pegylations and the like.

[0045] A“therapeutically equivalent” compound is one that has essentially the same effect in the treatment of a disease or condition as one or more other compounds. A compound that is therapeutically equivalent may or may not be chemically equivalent, bioequivalent, or generically equivalent.

[0046] “Parenteral injection” refers to the administration of small molecule drugs via injection under or through one or more layers of skin or mucus membranes of an animal, such as a human.

[0047] “Bioavailability” refers to the extent to which the therapeutic agent is absorbed from the formulation.

[0048] “Systemic,” with respect to delivery or administration of a therapeutic agent to a subject, indicates that the therapeutic agent is detectable at a biologically significant level in the blood plasma of the subject.

[0049] Controlled release” refers to the release of the therapeutic agent at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic concentrations over a period of time of about one hour or longer, preferably 12 hours or longer.

[0050] “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering a drug compound of the present invention to a mammal such as an animal or human.

[0051] “Nutraceutical acceptable carrier” refers to a nutraceutical acceptable solvent, suspending agent or vehicle for delivering a compound of the present invention to a mammal such as an animal or human.

[0052] “Pharmaceutically acceptable” ingredient, excipient or component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.

[0053] “Nutraceutical acceptable” ingredient, excipient or component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.

[0054] The term“about” or“approximately” or“substantially unchanged” are defined as being close to as understood by one of ordinary skill in the art, and in one non-limiting embodiment the terms are defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. Further,“substantially non-aqueous” refers to less than 5%, 4%, 3%, 2%, 1%, or less by weight or volume of water.

[0055] The use of the word“a” or“an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean“one,” but it is also consistent with the meaning of“one or more,”“at least one,” and“one or more than one.”

[0056] As used in this specification and claim(s), the words“comprising” (and any form of comprising, such as“comprise” and“comprises”),“having” (and any form of having, such as“have” and“has”),“including” (and any form of including, such as“includes” and “include”) or“containing” (and any form of containing, such as“contains” and“contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0057] The compositions and methods for their use can“comprise,”“consist essentially of,” or“consist of’ any of the ingredients or steps disclosed throughout the specification. With respect to the transitional phase“consisting essentially of,” in one non-limiting aspect, a basic and novel characteristic of the compounds, compositions, and methods disclosed in this specification includes the ability to treat or prevent diabetes mellitus type II.

[0058] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the examples, while indicating specific embodiments of the invention, are given by way of illustration only. Additionally, it is contemplated that changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0060] FIG. 1. An expanded DART- Accu- TOF mass spectrum region between 445 and 460 amu showing binding of the compound of Formula I to b-amyloid fibrils in vitro (m/z [M+H]+ = 450.261). Inset: candidate molecular formula for the compound of Formula I.

[0061] FIG. 2. Pharmacokinetic properties of the compound of Formula I.

[0062] FIGS. 3A-3B. Molecular model of the natural structural conformation of Abi-42.

A and B show two different perspectives of the oligomer formation model.

[0063] FIG. 4. Molecular model of the interaction between Ab i-42 monomers and the compound of Formula I.

[0064] FIG. 5. Molecular model of the interaction between the compound of Formula I and the islet amyloid polypeptide (IAPP). The compound of Formula I is represented in solid gray.

DETAILED DESCRIPTION

[0065] The inventors have surprisingly shown that a compound that can be found in turmeric ( Curcuma longa), and derivatives thereof, can prevent and treat diabetes mellitus type II and Alzheimer’s disease. In addition, the inventors believe that using the compound of the present invention with one or more additional anti-diabetes and/or anti -Alzheimer’s disease agents will enhance the ability of the combined compounds to treat and prevent diabetes mellitus type II and Alzheimer’ s disease. Without wishing to be bound by theory, it is believed that the compound and compositions disclosed herein are capable of blocking the aggregation of disease related peptides such as islet amyloid polypeptide. Further, it is expected that the compounds disclosed herein will have synergistic effect with other anti-diabetes mellitus type II agents and anti- Alzheimer’ s disease agents for prevention and treatment of diabetes and/or Alzheimer’s disease.

A. Active Compounds

[0066] Extracts of turmeric have shown promising properties for the treatment of

Alzheimer’s disease (Shytle et al., 2009, Shytle et al., 2012). The detrimental effects of Alzheimer’s disease is caused at least in part by formation of amyloid fibers of amyloid-b peptide (Ab). Similarities between different amyloidogenic diseases are noted. For example, studies have shown that the Ab-amyloids in AD and the IAPP-amyloids in diabetes mellitus

type II (T2DM) share many structural, formation and functional features (Kayed et al., DeToma et al.). In both, different fibril morphologies possess different underlying molecular structures and the cytotoxicity features of the fibrils are reflective of the mechanisms by which the fibrils grow (Petkova et al.; Jeong et al.; Akter et al.). Also, the number of therapeutic options for AD and T2DM are severely limited.

[0067] Disclosed herein is a newly identified small molecule of Formula I, with an exact mass of 450.261 g/mole, that has been identified in turmeric that inhibits the formation of amyloid aggregates, fibrils, and plaques, including islet amyloid polypeptide.


Formula I

[0068] The compound of formula I has been demonstrated to have a strong, dose-dependent, and irreversible interaction with the b-amyloid peptide (Ab), a component of AD senile plaques. This interaction was confirmed and validated by molecular modeling. In addition, a strong interaction was found between this compound and the islet amyloid polypeptide (IAPP), a protein involved in diabetes mellitus type II pathogenesis. The interaction with IAPP was also confirmed by molecular modeling studies. The studies predict that the interaction with amyloid peptides can inhibit the formation of the toxic amyloid aggregates thought to cause a number of diseases such as diabetes mellitus type II and Alzheimer’s disease. It is further predicted that animal models will confirm the activity of this compound in treating and/or preventing diabetes mellitus type II. Pharmokinetic studies have shown that this compound is rapidly absorbed into the human blood stream after oral administration, making it a promising drug candidate.

[0069] Derivatives of the compound of Formula I, such as the compound of Formula II, III, IV, V, and VI have also been synthesized and are likewise expected to inhibit amyloid aggregation, such as aggregation of b-amyloid peptide (Ab) and islet amyloid polypeptide (IAPP). Accordingly, these compounds are also expected to treat and/or prevent diseases associated with amyloid aggregation, such as Alzheimer’s and diabetes mellitus type II.

[0070] Derivatives of the compound of Formula I include the compounds of Formula II, III, IV, V, VI, and salts thereof.


Formula II

where:

Ri, R2, R7, and Rx are each independently hydrogen, alkyl, or -COR9, where R9 is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group;

R3, R4, R5 are each independently H, =0, or OR10 where Rio is hydrogen, an alkyl group, a substituted alkyl group, aryl group, or a substitute aryl group; and

R6 is a disubstituted hydrocarbon ring having at least 6 carbon atoms.


Formula V


Formula VI

[0071] In some aspects of the invention, the compound and derivatives and analogues can be made through known synthetic methods. In some aspects of the invention, the compound can be synthetically obtained by producing the compound according to methods known to one of skill in the art in chemical synthesis. In one instance, the compound is synthesized through organic chemistry methods.

[0072] In some instances, the compound of Formula III is synthetically obtained by the reaction of Reaction Scheme I, wherein curcumin (1) is tosylated with TsCl and the double bonds are hydrogenated/reduced using Pd/C in ethyl acetate at 55 psig to give a mixture of compounds 4, 5, and 6. Refluxing lithium aluminum hydride reduces the remaining alkyl and carbonyl double bonds to give the dihydroxy compound 6. Deprotection of the tosyl groups using magnesium, followed by acetylation of the phenolic groups gives compound 7 (the compound of Formula III).



Reaction Scheme I.

[0073] In some instances, the compound of Formula IV is synthetically obtained by the reaction of Reaction Scheme II, wherein compounds 8 and 9 can be coupled in the presence of Et0Ac/B203 and tributyl borate at 40°C to give compound 10. Compound 10 is tosylated with TsCl and the double bonds are hydrogenated/reduced using Pd/C in ethyl to give a mixture of compounds 13, 14, and 15. Refluxing lithium aluminum hydride reduces the remaining alkyl and carbonyl double bonds to give the dihydroxy compound 15. Deprotection of the tosyl groups using magnesium, followed by acetylation of the phenolic groups gives compound 16 (compound of Formula IV).



Reaction Scheme II.

[0074] In some instances, the compound of Formula V is synthetically obtained by the reaction of Reaction Scheme III, wherein compound 17 can be combined with compound 18 following a Grignard reaction to provide the ketone 19. The silyl protecting groups (-TBDMS) can be removed using tetra-butylammonium fluoride (TBAF) and acetyl groups can be added using acetyl chloride in pyridine to give compound 20. Sodium borohydride (NaBH4) will reduce the ketone to a secondary alcohol without affecting the protecting groups to give compound 21 (compound of Formula V).



Reaction Scheme III.

[0075] In some instances, the compound of Formula VI is synthetically obtained by the reaction of Reaction Scheme IV, wherein compound 22 can be coupled to compound 23 using an Aldol condensation reaction to give the ketone 24. Palladium catalyst can be used to reduce the C-H double bonds to give compound 25, and again, TBAF and AcCl in pyridine can be used to exchange the TBDMS protecting groups with the desired acetyl protecting groups providing compound 26 (compound of Formula VI).



Reaction Scheme IV.

[0076] In some instances, the compound of Formula I is synthetically obtained by the reaction of Reaction Scheme V, wherein sodium borohydride (NaBH4) will reduce the ketone of compound 26 (compound of Formula VI, non-limiting synthetic pathway in Reaction Scheme IV) to a secondary alcohol without affecting the protecting groups to give compound 27 (compound of Formula I).


Reaction Scheme V.

[0077] In some aspects of the invention, the compound of Formula I can be isolated from extracts of an organism such as fruits, plants, animals, fungi, bacteria, and/or archaea. Non-limiting examples of suitable plants include turmeric. The compound can be extracted from the organism using known extraction methods, such as contacting the extract with CO2, contacting the extract with H2O, or any combination of EtOFfFhO, and/or with any method utilizing polymer separating the extract. A non-limiting example of a polymer used for polymer separation includes ADS 5 polymer (Nankai University, China).

B. Additional Anti-Diabetes Agents

[0078] In some aspects, one or more anti-diabetes agents can be combined with the compounds disclosed herein. In some instances, anti-diabetes agents can decrease the amount of glucose released from the liver, stimulate the release of insulin, sensitize the body to insulin, decrease the amount of glucose made in the body, increase the production of insulin, slow the absorption of carbohydrates, lower blood glucose, or provide insulin. Anti- diabetes agents include those that are combination drugs and single drugs. In one embodiment, the compositions disclosed herein further includes at least one additional anti-diabetes agent.

[0079] Anti- diabetes agents are compounds or compositions that are used to decrease the effects of diabetes, reduce the symptoms of diabetes, prevent diabetes, or address the underlying cause(s) of diabetes. Non-limiting examples of anti-diabetes agents include metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, pioglitazone, sitagliptin, saxagliptin, linagliptin, acarbose, miglitol, colesevelam, insulin, or salts thereof, or any combination thereof. In one embodiment, the compositions disclosed herein further includes at least one additional anti-diabetes agent.

C. Amounts of Ingredients

[0080] It is contemplated that the compositions of the present invention can include any amount of the ingredients discussed in this specification. The compositions can also include any number of combinations of additional ingredients described throughout this specification

(e.g., stabilizers, fillers, pharmaceutically and/or nutraceutical acceptable salts, and/or additional pharmaceutical and/or nutraceutical ingredients). The concentrations of the any ingredient within the compositions can vary. In non-limiting embodiments, for example, the compositions can comprise, consisting essentially of, or consist of, in their final form, for example, at least about 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%,

0.0008%, 0.0009%, 0.0010%, 0.0011%, 0.0012%, 0.0013%, 0.0014%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%, 0.0020%, 0.0021%, 0.0022%, 0.0023%, 0.0024%, 0.0025%, 0.0026%, 0.0027%, 0.0028%, 0.0029%, 0.0030%, 0.0031%, 0.0032%, 0.0033%, 0.0034%, 0.0035%, 0.0036%, 0.0037%, 0.0038%, 0.0039%, 0.0040%, 0.0041%, 0.0042%, 0.0043%, 0.0044%, 0.0045%, 0.0046%, 0.0047%, 0.0048%, 0.0049%, 0.0050%, 0.0051%, 0.0052%, 0.0053%, 0.0054%, 0.0055%, 0.0056%, 0.0057%, 0.0058%, 0.0059%, 0.0060%, 0.0061%, 0.0062%, 0.0063%, 0.0064%, 0.0065%, 0.0066%, 0.0067%, 0.0068%, 0.0069%, 0.0070%, 0.0071%, 0.0072%, 0.0073%, 0.0074%, 0.0075%, 0.0076%, 0.0077%, 0.0078%, 0.0079%, 0.0080%, 0.0081%, 0.0082%, 0.0083%, 0.0084%, 0.0085%, 0.0086%, 0.0087%, 0.0088%, 0.0089%, 0.0090%, 0.0091%, 0.0092%, 0.0093%, 0.0094%, 0.0095%, 0.0096%, 0.0097%, 0.0098%, 0.0099%, 0.0100%, 0.0200%, 0.0250%, 0.0275%, 0.0300%, 0.0325%, 0.0350%, 0.0375%, 0.0400%, 0.0425%, 0.0450%, 0.0475%, 0.0500%, 0.0525%, 0.0550%, 0.0575%, 0.0600%, 0.0625%, 0.0650%, 0.0675%, 0.0700%, 0.0725%, 0.0750%, 0.0775%, 0.0800%, 0.0825%, 0.0850%, 0.0875%, 0.0900%, 0.0925%, 0.0950%, 0.0975%, 0.1000%, 0.1250%, 0.1500%, 0.1750%, 0.2000%, 0.2250%, 0.2500%, 0.2750%, 0.3000%, 0.3250%, 0.3500%, 0.3750%, 0.4000%, 0.4250%, 0.4500%, 0.4750%, 0.5000%, 0.5250%, 0.0550%, 0.5750%,

0.6000%, 0.6250%, 0.6500%, 0.6750%, 0.7000%, 0.7250%, 0.7500%, 0.7750%, 0.8000%, 0.8250%, 0.8500%, 0.8750%, 0.9000%, 0.9250%, 0.9500%, 0.9750%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%,

2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%,

4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%,

5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%,

6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%,

8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%,

9.7%, 9.8%, 9.9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% or any range derivable therein, of at least one of the ingredients that are mentioned throughout the specification and claims. In non-limiting aspects, the percentage can be calculated by weight or volume of the total composition or relative abundance. A person of ordinary skill in the art would understand that the concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given composition.

D. Additional Components

[0081] The compound of the present invention can be formulated into any suitable composition form for administration to a human or non-human animal patient.

[0082] The composition may consist of the claimed compound or compounds alone or may include the compound or compounds and any suitable additional component, such as one or more pharmaceutically and/or nutraceuti cal acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

1. Excipients

[0083] Excipients employed in the compositions of the present invention can be solids, semi-solids, liquids or combinations thereof. Preferably, the excipients are solids. Compositions of the invention containing excipients can be prepared by any known technique

that comprises, for example, admixing an excipient with the claimed compounds. A pharmaceutical composition of the invention contains a desired amount of the claimed compounds per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, or any other form reasonably adapted for such administration. If intended for parenteral administration, it can be in the form, for example, of a suspension or transdermal patch. If intended for rectal administration, it can be in the form, for example, of a suppository. Presently preferred are oral dosage forms that are discrete dose units each containing a predetermined amount of the claimed compounds such as tablets or capsules.

2. Carriers / Diluents

[0084] Suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CELUTAB™and EMDEX™), mannitol, sorbitol, xylitol, dextrose (e.g., CERELOSE™ 2000) and dextrose monohydrate, dibasic calcium phosphate dihydrate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, granular calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, celluloses including microcrystalline cellulose, food grade sources of alpha- and amorphous cellulose (e.g., RexcelJ), powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC), calcium carbonate, glycine, clay, bentonite, block co-polymers, polyvinylpyrrolidone, and the like. Such carriers or diluents, if present, constitute in total about 5% to about 99.999%, about 10% to about 85%, and 20% to about 80%, of the total weight of the composition. The carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.

3. Disintegrant

[0085] Compositions of the invention optionally can include one or more pharmaceutically and/or nutraceutical acceptable disintegrants as excipients, particularly for tablet formulations. Suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate and pregelatinized corn starches, clays, celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium, alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums. Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the total weight of the composition.

4. Binders

[0086] The compositions of the present invention can include binding agents or adhesives particularly for tablet formulations. Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Such binding agents may also prevent or inhibit crystallization or recrystallization of a co-crystal of the present invention once the salt has been dissolved in a solution. Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; tragacanth, sucrose, gelatin, glucose, starches such as, but not limited to, pregelatinized starches, celluloses such as, but not limited to, methylcellulose and carmellose sodium, alginic acid and salts of alginic acid; magnesium aluminum silicate, PEG, guar gum, polysaccharide acids, bentonites, povidone, polymethacrylates, HPMC, hydroxypropylcellulose, and ethylcellulose. Such binding agents and/or adhesives, if present, constitute in total about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about 1% to about 10%, of the total weight of the pharmaceutical composition. Many of the binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, can be included in pharmaceutical compositions of the present invention. Polyvinylpyrrolidones is an non-limiting example of a binder used for slow release tablets. Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer. Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance.

5. Wetting Agents

[0087] Wetting agents can be used in the compositions of the present invention. Wetting agent can be selected to maintain the crystal in close association with water, a condition that may improve bioavailability of the composition. Such wetting agents can also be useful in solubilizing or increasing the solubility of crystals. Surfactants can be used as wetting agents. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and di glycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80, propylene glycol fatty acid esters, for example propylene glycol laurate, sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, constitute in total about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5%, of the total weight of the pharmaceutical composition.

6. Lubricants

[0088] Lubricants can be included in the compositions of the present invention. Suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behenate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils, colloidal silica, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, PEG (e.g., CARBOWAX™ 4000 and CARBOWAX™ 6000 of the Dow Chemical Company), sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, preferably about 0.2% to about 8%, and more preferably about 0.25% to about 5%, of the total weight of the composition.

7. Other Agents

[0089] Surfactant, emulsifier, or effervescent agents can be used in the compositions. Emulsifying agents can be used to help solubilize the ingredients within a soft gelatin capsule. Non-limiting examples of the surfactant, emulsifier, or effervescent agent include D-sorbitol, ethanol, carrageenan, carboxyvinyl polymer, carmellose sodium, guar gum, glycerol, glycerol fatty acid ester, cholesterol, white beeswax, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, stearyl alcohol, stearic acid, polyoxyl 40 stearate, sorbitan sesquioleate, cetanol, gelatin, sorbitan fatty acid ester, talc, sorbitan trioleate, paraffin, potato starch, hydroxypropyl cellulose, propylene glycol, propylene glycol fatty acid ester, pectin, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, octyldodecyl myristate, methyl cellulose, sorbitan monooleate, glycerol monostearate, sorbitan monopalmitate, sorbitan monolaurate, lauryl dimethylamine oxide solution, sodium lauryl sulfate, lauromacrogol, dry sodium carbonate, tartaric acid, sodium hydroxide, purified soybean lecithin, soybean lecithin, potassium carbonate, sodium hydrogen carbonate, medium-chain triglyceride, citric anhydride, cotton seed oil-soybean oil mixture, and liquid paraffin.

E. Vehicles

[0090] Various delivery systems are known in the art and can be used to administer a therapeutic agent or composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis and the like. Methods of administration include, but are not limited to, parenteral, intra-arterial, intramuscular, intravenous, intranasal, and oral routes. The compositions can be provided in the form of tablets, lozenges, granules, capsules, pills, ampoule, suppositories or aerosol form. The compositions can also be provided in the form of suspensions, solutions, and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.

F. Formulation and Administration

[0091] The composition may, for example, be a pharmaceutical composition (medicament), and over the counter composition (OTC), a nutraceutical, etc. Compositions according to the present invention include formulations suitable for oral or parenteral routes.

Non-limiting examples of specific routes include intradermal, subcutaneous, intramuscular, intravenous, local injection, rectal, intranasal inhalation, insufflation, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art. Such methods include the step of bringing into association the active ingredient (or ingredients) with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a suitable carrier, such as liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Formulations of the subject invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, or as an oil-in-water liquid emulsion, water-in-oil liquid emulsion, or as a supplement within an aqueous solution, for example, a tea. The active ingredient can also be presented as bolus, electuary, or paste. Useful injectable preparations include sterile suspensions, solutions or emulsions of the compound compositions in aqueous or oily vehicles. The compositions can also contain formulating agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, and can contain added preservatives. Alternatively, the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the compound compositions can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0092] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth, pastilles that include the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia, mouthwashes that include the active ingredient in a suitable liquid carrier, and chocolate comprising the active ingredients.

[0093] Formulations suitable for topical administration according to the subject invention can be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. Alternatively, a formulation can comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active ingredients, and optionally one or more excipients or diluents. Topical formulations preferably comprise compounds that facilitate absorption of the active ingredients through the skin and into the bloodstream.

[0094] Formulations suitable for intranasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid for intranasal administration, such as by the non-limiting examples of a nebulizer, include aqueous or oily solutions of the agent. Formulations preferably can include compounds that facilitate absorption of the active ingredients through the skin and into the bloodstream.

[0095] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations can be presented in unit-dose or multi-dose or multi-dose sealed containers, such as for example, ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0096] Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically and/or nutraceutical acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.

[0097] For buccal administration, the compositions can take the form of the non-limiting examples of tablets or lozenges formulated in a conventional manner.

[0098] For rectal and vaginal routes of administration, the compound compositions can be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0099] For nasal administration or administration by inhalation or insufflation, the compound compositions can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0100] For prolonged delivery, the compound compositions can be formulated as a depot preparation for administration by implantation or intramuscular injection. The compound compositions can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch, which slowly releases the compound compositions for percutaneous absorption, can be used. To this end, permeation enhancers can be used to facilitate transdermal penetration of the compound compositions. Suitable transdermal patches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336, 168; U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164, 189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No. 5,087,240; U.S. Pat. No. 5,008, 110; and U.S. Pat. No. 4,921,475.

[0101] Alternatively, other delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the compound compositions. Certain organic solvents such as dimethylsulfoxide (DMSO) can also be employed, although usually at the cost of greater toxicity.

[0102] It should be understood that in addition to the ingredients particularly mentioned above, the formulations useful in the present invention can include other agents conventional in the art regarding the type of formulation in question. For example, formulations suitable for oral administration can include such further agents as sweeteners, thickeners, and flavoring agents. It also is intended that the agents, compositions, and methods of this invention be combined with other suitable compositions and therapies.

G. Other Pharmaceutical and/or Nutraceutical Agents

[0103] Pharmaceutical, OTC, and/or nutraceutical formulations of the invention can be administered simultaneously or sequentially with other drugs or biologically active agents. Examples include, but are not limited to, antioxidants, free radical scavenging agents, analgesics, anesthetics, anorectals, antihistamines, anti-inflammatory agents including non steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antimicrobials, anti cancer actives, antineoplastics, biologically active proteins and peptides, enzymes, hemostatics, steroids including hormones and corticosteroids, etc.

H. Therapeutic Methods And Dosage

[0104] Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose, or an appropriate fraction thereof, of an agent. Therapeutic amounts can be empirically determined and will vary with the pathology being treated, the subject being treated, and the efficacy and toxicity of the agent. Similarly, suitable dosage formulations and methods of administering the agents can be readily determined by those of ordinary skill in the art.

[0105] In some embodiments, a therapeutic method of the present invention can include treating a disease, condition, or disorder by administering to a subject having such disease or condition a stable formulation as described herein in an amount effective to treat the disease, condition, or disorder. In some embodiments, the subject is administered a stable formulation comprising the compounds claimed herein. The disease, condition, or disorder can be caused by diabetes, such as diabetes mellitus type II. Further, the disease, condition, or disorder can be diabetes, diabetes mellitus type II, metabolic syndrome, and/or pre-diabetes and related diseases, conditions, and disorders. For prophylactic administration, the composition can be administered to a patient at risk of developing one of the previously described conditions. [0106] The amount of composition administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art. In some aspects of the invention, total dosage amounts of a compound composition will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg of patient/day to about 100 mg/kg patient/day, but may be higher or lower, depending upon, among other factors, the activity of the components, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds can be administered once per week, several times per week (e.g., every other day), once per day, or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

I. Secondary and Combination Treatments

[0107] Certain embodiments provide for the administration or application of one or more secondary or additional forms of therapies or preventative interventions. The type of therapy is dependent upon the type of disease that is being treated or prevented. The secondary form of therapy may be administration of one or more secondary pharmacological agents that can be applied in the treatment or prevention of diabetes.

[0108] If the secondary or additional therapy is a pharmacological agent, it may be administered prior to, concurrently, or following administration of any one or a combination of the compounds disclosed herein, such as compounds of Formula II. The interval between administration of the compound and the secondary or additional therapy may be any interval as determined by those of ordinary skill in the art. For example, the compound and the secondary or additional therapy may be administered simultaneously, or the interval between treatments may be minutes to weeks. In embodiments where the agents are separately administered, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that each therapeutic agent would still be able to exert an advantageously combined effect on the subject. For example, the interval between therapeutic agents may be about 12 h to about 24 h of each other and, more preferably, within about 6 hours to about 12 h of each other. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. In some embodiments, the timing of administration of a secondary therapeutic agent is determined based on the response of the subject to the compound.

[0109] Examples of secondary treatments useful with methods disclosed herein are: anti diabetes agents, agents that decrease the amount of glucose released from the liver, stimulate the release of insulin, sensitize the body to insulin, decrease the amount of glucose made in the body, increase the production of insulin, slow the absorption of carbohydrates, lowers blood glucose, or provide insulin, such as but not limited to metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, pioglitazone, sitagliptin, saxagliptin, linagliptin, acarbose, miglitol, colesevelam, insulin, or salts thereof, or any combination thereof. Further, secondary treatments can include treatments for the symptoms of diabetes or the complications caused by diabetes. Secondary treatments can also include dietary supplements such as vitamins C, E and D, calcium, zinc, selenium, curcumin, folate, bioflavonoids, resveratrol, and plant extracts.

J. DART-TOF Mass Spectrometry

[0110] In a non-limiting example, the compounds of the present invention can be identified using Direct Analysis in Real Time (DART) Time of Flight/Mass Spectrometry (TOF/MS). Specifically, a JEOL DART™ AccuTOF-mass spectrometer from Jeol EISA of Peabody, MA (JMS-T100LC) can be used. Accurate mass can be determined by subtracting the mass of a proton (1.007825 amu) from the measured mass of the ions produced from the sample. The mass of compounds may be determined in a sample by directly introducing the sample to the ion stream by means of a Dip-IT sampler and a Dip-IT sampler holder (IONSENSE™). While no sample preparation is required for a simple analysis with the DART, a chemical doped/spiked solution can be used for quantitation relative to a known quantity. As a non limiting example, salicylic acid is not present in turmeric and can therefore be used to create a quantitative chemical profile of the bioactive molecules. The settings for the DART ion source can be the following:

Gas: He

Flow: 2.52 LPM @ 50 PSI

Temperature: 250 C

Needle Voltage: 3000V

Grid Electrode Voltage: 250V

Discharge Electrode Voltage: 400V

[0111] The settings for the JEOL AccuTOF MS can be the following:

Peaks Voltage: 1000V

Orifice 1 Temperature: 120 C

Detector Voltage: 2600V

Reflectron Voltage: 990.0V

[0112] Samples can be analyzed in six replicates by DART-TOF MS. These six replicates can be analyzed to create a single, averaged, filtered, and statistically significant DART fingerprint of the sample. This processed fingerprint can then be used to determine the presence of the markers by comparison of masses. A simple mass comparison can be sufficient to determine the presence of a target compound in any extract or mixture of chemicals.

[0113] All MS have a mass tolerance - a range of acceptable reported masses surrounding the predicted [M+H] or [M-H] value. For the AccuTOF, that mass tolerance is less than 20 millimass units (mmu) (predicted mass +/-10 mmu). Given the same sample and ion source, other TOF-MS may have a higher or lower mass tolerance.

[0114] In another non-limiting example, the compounds of the present invention can be determined by DART TOF/MS by using a JEOL DART™ AccuTOF-mass spectrometer from Jeol EISA of Peabody, MA (JMS-T100LC) executed in the positive ion mode ([M+H]+) using the following settings for the DART ion source:

Gas: He

Flow: 3.98 L/min

Needle voltage: 3500 V

Temperature: 300 °C

Electrode 1 Voltage: 150 V

Electrode 2 Voltage: 250 V,

[0115] The settings for the JEOL AccuTOF MS can be the following:

Peaks Voltage: 1000V

Orifice 1 Voltage: 20 V

Ring Lens Voltage: 5 V

Orifice 2 Voltage: 5 V

Detector Voltage: 2550V

[0116] Calibrations can be performed internally with each sample using a 10% (weight/volume) solution of PEG 600 from Ultra Chemical of North Kingston, RI that provided mass markers throughout the required mass range of 100-1000 amu. Calibration tolerances can be held to 5 mmu. Samples can be introduced into the DART He plasma using the closed end of a borosilicate glass melting point capillary tube until a signal is achieved in the total-ion chromatogram (TIC). The next sample can then be introduced when the TIC returned baseline levels.

K. Kits

[0117] In another aspect of the present invention, kits for treating or preventing a disease, condition or disorder as described herein. For instance, compositions of the present invention can be included in a kit. A kit can include a container. Containers can include a bottle, a metal tube, a laminate tube, a plastic tube, a dispenser, a straw, a pressurized container, a barrier container, a package, a compartment, or other types of containers such as injection or blow-molded plastic containers into which the dispersions or compositions or desired bottles, dispensers, or packages are retained. The kit and/or container can include indicia on its surface. The indicia, for example, can be a word, a phrase, an abbreviation, a picture, or a symbol.

[0118] The containers can dispense a predetermined amount of the composition. In other embodiments, the container can be squeezed ( e.g ., metal, laminate, or plastic tube) to dispense a desired amount of the composition. The composition can be dispensed as a spray, an aerosol, a liquid, a fluid, a semi-solid, or a solid. In a preferred embodiment, the composition is dispensed as a tablet or lozenge. The containers can have spray, pump, or squeeze mechanisms. A kit can also include instructions for employing the kit components as well the use of any other compositions included in the container. Instructions can include an explanation of how to apply, use, and maintain the compositions. The compositions can, if desired, be presented in a pack or dispenser device, which can contain one or more unit dosage forms containing the compound compositions. The pack can, for example, comprise metal or plastic foil, such as a

blister pack. The pack or dispenser device can be accompanied by instructions for administration.

EXAMPLES

[0119] The present invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

EXAMPLE 1

(IDENTIFICATION OF COMPOUND OF FORMULA I AND DERIVATIVES THEREOF)

[0120] The compound of Formula I, with a chemical formula of C25H39O7, was identified as a compound in an extract of turmeric that bound to Abi-42 after ultrafiltration and washing (to remove any unbound chemistries). A DART - Accu - TOF mass spectrometer was used to analyze the bound compounds and the proprietary software programs and databases with the DART-TOF-MS were used to determine the molecular formula of the compound of Formula I. FIG. 1 shows an expanded DART- Accu- TOF mass spectrum region between 445 and 460 amu where binding of a compound possessing an exact mass of 450.261 amu to Ab in vitro was detected. Based on this molecular formula, the compound of Formula I and derivatives thereof were synthesized.

[0121] Briefly, 20 pg mL 1 of a turmeric derived extract in 50 mM Tris buffer, pH 7.4, 1% (v/v) DMSO was incubated with 50 pM b-amyloid (1-42) peptides at 37°C for 120 hours. The mixture was then ultra-filtered using a 100 KDa molecular weight Amicon cut-off filter (Millipore, Billerica, MA), centrifuged at 10,000 rpm for 5 min at 37°C. To remove any remaining chemicals not bound to the amyloid aggregates, the b-amyloid (1-42) were washed 4 times with 500 pL 50 mM Tris (pH = 7.4) 1.0% (v/v) DMSO and centrifuged under the same conditions for an additional 5 min. The samples were then analyzed by DART TOF-MS to identify those chemical species bound to b-amyloid (1-42) peptide aggregates.

[0122] The JEOL DART™ Accu-TOF mass spectrometer (JMS-T 100LC; Jeol USA, Peabody, MA) used for chemical analysis required no sample preparation and yielded masses with accuracies to 0.0001 mass units. For positive ion mode (DART+), the needle voltage was set to 3500V, heating element to 300°C, electrode 1 to 150V, electrode 2 to 250V, and helium gas flow to 2.52 liters per minute. For the mass spectrometer, the following settings were loaded: orifice 1 set to 10V, ring lens voltage set to 5V, and orifice 2 set to 5V. The peak voltage was set to 1000V in order to give peak resolution beginning at 100 m/z. The microchannel plate detector (MCP) voltage was set at 2600V. Calibrations were performed internally with each sample using a 10% (w/v) solution of PEG that provided mass markers throughout the required mass range 100-1000 m/z. Calibration tolerances were held to 5 mmu.

[0123] Molecular formulas and chemical structures were identified and confirmed by elemental composition and isotope matching programs in the Jeol MassCenterMain Suite software (MassCenter Main, Version 1.3.0.0; JEOL ETSA Inc. : Peabody, MA, ETSA, Copyright 2001-2004). In addition, molecular formulas and structure identifications were searched against the NIST/NIH/EPA Mass Spec Database (S. Stein, Y. Mirokhin, D. Tchekhovskoi, G. Mallard, A. Mikaia, V. Zaikin, J. Little, D. Zhu, C. Clifton and D. Sparkman, 2005. The NIST mass spectral search program for the NIST/EPA/NIH mass spectral library - Version 2.0d. National Institute of Standards and Technology, Gaithersburg, MD), the Dictionary of Natural Products (Chapman & Hall: Dictionary of Natural Products on DVD - Version 16:2. CRC Press, Boca Raton, FL, 2008), and the Chemical Abstract Services structure search (http://chembiofmder.cambridgesoft.com/).

EXAMPLE 2

(SAFETY AND PHARMACOKINETICS)

[0124] The safety and pharmacokinetic of the compound of Formula I was determined by prediction software and through administration to five human subjects. ADMET -Predictor software was used to predict the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of the compound of Formula I. Based on the software calculations, the compound of Formula I was predicted to be absorbed in the lower intestine, will likely pass through the blood brain barrier, and will have low interactions with Cytochrome P450 (data not shown). ETsing similar molecular modeling tools, it was determined that the derivatives of Formula I, such as the compound of Formula III, IV, V, and VI, are not mutagenic, based on AMES mutagenicity predictions, and they have a predicted rat oral LDso of >300 mg kg 1. Further, the compound of Formula I, when ingested by five human subjects, was found in the bloodstream (serum) within 120 minutes and remained in the blood up to 360 minutes post- ingestion. The compound was not detected at 480 minutes (6 hours) after ingestion. See FIG. 2. This data indicates that the compounds are safe and are bioavailable.

[0125] Briefly, for the software predictions of safety, ADMET PREDICTOR™ software was used to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compound of Formula I, III, IV, V, and VI.

[0126] For the pharmacokinetics, five healthy consenting female adults ranging in age from 23 to 57, who had diets free of flavonoids and any nonsteroidal anti-inflammatory drugs (NSAIDs), participated in the pharmacokinetics study. A single 200 mg dose, of a mixture containing the compound of Formula I, was administered as a capsule with water. Blood samples were collected at several time intervals between 0 and 480 minutes after the capsule was ingested. Blood samples were centrifuged to remove cells and the serum fraction was collected and frozen. The blood samples were not treated with heparin to avoid any analytical interference. Serum samples were prepared for DART TOF-MS analysis by extraction with an equal volume of neat ethanol (USP) to minimize background of proteins, peptides, and polysaccharides present in serum. The ethanol extract was centrifuged for 10 minutes at 4°C, the supernatant was removed, concentrated to 200 pL volume, and 50 pL of an internal standard was added.

EXAMPLE 3

(INHIBITION OF BETA-AMYLOID AND IAPP AGGREGATION)

[0127] Mixtures containing compounds of the present invention inhibited IAPP amyloid aggregation ranging between 1 and 12 pg/mL. Using the biological activity of these mixtures as well as proprietary methodology for identifying bioactive chemicals in vitro , the predicted IC50 values for the inhibition of IAPP (1-40) amyloid aggregation by the compound of Formula I is between 0.01 and 10 pM.

[0128] Mixtures containing the compound of Formula I inhibited b-amyloid aggregation ranging between 2 and 10 pg/mL. Using the biological activity of these mixtures as well as proprietary methodology for identifying bioactive chemicals in vitro, the predicted IC50 values for the inhibition of b-amyloid aggregation by the compound of Formula I is between 0.2 and 4 pM.

[0129] Briefly, the presence of IAPP amyloid aggregates or A b1-42 fibers was monitored in solution by thioflavin T fluorescence. Triplicate 15 PL samples of IAPP or A b1-42 (25 mM, 95pg/mL) in 50 mM Tris-HCl buffer (pH 7.4) were removed after incubation of the peptide solution in the presence or absence of compositions containing compounds from turmeric extracts, including the compound of Formula I, or curcuminoid standards (curcumin (Cur), dimethoxycurcumin (DMC), bisdem ethoxy curcumin (BDCM), and tetrahydrocurcumin (THC)) at concentrations from 0 to 30 pg/mL for up to 120 hours at 37°C. The peptide solutions were each added to 100 pL of 10 mM Thioflavin T in 50 mM glycine/NaOH buffer (pH 9.0) in a black-walled 96-well plate and incubated for 30 minutes at 25°C. The characteristic change in fluorescence was monitored (Ex450nm and Em 482 nm) following binding of thioflavin T to the IAPP amyloid aggregates or A b1-42 amyloid fibers by using a Molecular Devices SPECTRAmax GEMINI plate reader. Triplicate samples were scanned three times before and immediately after the addition of the peptide solutions.

EXAMPLE 4

(MODELING OF BETA- AMYLOID AND IAPP BINDING)

[0130] Abi-42 has been implicated directly in Alzheimer’s disease (AD) through the formation of abnormal, but stable aggregates. Several studies point to the importance of the region spanning from amino acids 10 to 35 for aggregation (Sato et al., Hilbich et al.). Not to be bound by theory, it is believed that Phei9 and Phe2o are important for the early aggregation steps and that Phe4 and Met35 interact in the oligomers (FIG. 3 A and 3B). In this model, the Abi -42 monomers start aggregating into oligomers, interlocking the helices and stabilizing the stacking through the interaction of Phei9 and Phe2o with Hisn and Hisi4. This conformation would also allow for the interaction between Phe4 and Met35 that was previously reported (Sato et al.). The monomers stack in a head-to-toe fashion and the quaternary structure formed is stabilized by the interactions between the phenylalanines and the histidines. FIG. 3 shows the Phei9 and Phe2o residues and the Hisn and His i4 residues in black.

[0131] In silico molecular modeling of molecular binding has been used to predict inhibitors of protein aggregation and to virtually screen potential drug candidates (Patel et al., Zou et al., and Montane et al.). FIG. 4 shows a predicted model on how the compound of Formula I would bind to Abi-42 monomers. A hydrogen bond between Tyno and the compound of Formula I can be seen which would allow the compound of Formula I to surround Hisn and Hisi4 effectively preventing Phei9 and Phe2o from binding and forming oligomers. The

compound of Formula I binding to these residues will also disrupt stabilizing intermolecular interactions of the Abi-42 oligomers, thus preventing aggregation.

[0132] Aggregation of IAPP into amyloid deposits is implicated in diabetes mellitus type II (T2DM) pathogenesis, as are Ab amyloid deposits in AD. Molecular modeling of the compound of Formula I revealed a strong interaction with the islet amyloid polypeptide or IAPP(i -40) (FIG. 5), analogous to that found between the compound of Formula I and Abi-42 monomers. Specifically, the compound of Formula I interacted with Asparagine2i, Asparagine22, Phenylalanine23, Glycine24, and Isoleucine26 of IAPP(i-40), the amino acids likely responsible for IAPP fibril formation in T2DM patients. Such interactions could block or prevent IAPP(i-40) b-sheet formation, and hence aggregation.

[0133] The compound of Formula I, identified from a turmeric derived mixture, binds to b-amyloid and IAPP peptides preventing aggregation. The compound has methoxy groups on either end of the molecule and its 3-dimensional minimized energy structure is not linear, but folded in such a way as to allow the acetyl groups, as well as the hydroxyl group on the hydrocarbon linker to stick out into space. Not to be bound by theory, the interactions between the acetyl groups and the backbone hydroxyl group could be interacting with the binding sites on the b-amyloid polymers leading to direct, irreversible binding. Another possibility, again due to the 3-dimensional minimized energy structure, is that the acetyl and methoxy head groups on either end of the compound of Formula I could create a“pocket” that encloses the leading end of the b-amyloid polymers preventing further aggregation.

[0134] A recent publication that examined the atomic structures of fibrillar segments of human IAPP (hlAPP), suggested that tightly mated b-sheets are important for cytotoxicity (Krotee et ak). Interestingly they found that the most critical stretch of amino acids of hlAPP responsible for formation of these cytotoxic b-sheets are between positions 19 to 29. The results disclosed herein are closely aligned with this finding as all the amino acid residues of hlAPP predicted to interact with the compound of Formula I and the analogs thereof and prevent amyloid formation are found within this region (Asp ?!, Asp22, Phen 23, G!y24, and Iso26).

[0135] The ability of the compound of Formula I to bind to and prevent b -amyloid fibrils and IAPP from aggregating represents a dramatic leap in the understanding of the mode-of-action of the chemical constituents of turmeric and represents the compound of Formula I as a lead compound for Alzheimer’s disease and diabetes mellitus type II pharmaceutical

development. Further, the structural similarity between the compound of Formula I and its derivatives, such as the compounds of Formula II, III, IV, V, and VI, provide an expectation that the derivatives will also have anti -aggregation and anti-diabetic properties. The structural similarities can include the non-linearity of the 3 -dimensional minimized energy structures that place the acetyl groups as well as the oxygen containing hydroxyl or ketone groups on the hydrocarbon linker as sticking out into space. The structural similarities can also include that the 3 -dimensional minimized energy structure will create a“pocket” because of the placement of the acetyl and methoxy head groups on either end of the compounds.

[0136] The strong association between IAPP aggregation and development of T2DM highlights the need to find new therapeutics to block IAPP mediated toxicity. Several epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients with T2DM, highlighting a possible common mechanism involved in these amyloidogenic diseases (Mittal et al.). A recent study has suggested that misfolded IAPP produced in T2DM potentiates AD pathology by cross-seeding Ab, providing a molecular explanation for the link between these diseases (Moreno-Gonzales et al.). Building on these findings, it is expected that the compound of Formula II, such as the compounds of Formulas I, III, IV, V, and VI will have an anti-amyloid effect for the treatment of diabetes mellitus type II and are promising therapeutic candidates.

EXAMPLE 5

(IN VIVO TESTING OF TREATMENT AND PREVENTION OF DIABETES MELLITUS TYPE II)

[0137] Transgenic mice that over express hlAPP have been described as an animal model for T2DM (Janson et al., Verehere et al ). The male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with hlAPP aggregation, selective beta-cell death, and impaired insulin secretion. This animal model will be very useful for testing, in vivo, the efficacy of the compounds disclosed herein. It is expected that administration of the compounds of Formula II, such as compounds of the Formulas I, III, IV, V, and VI will inhibit hlAPP aggregation and prevent and/or treat diabetes mellitus type II.

EXAMPLE 6

(SYNERGY)

[0138] Because of the predicted method of action of the compounds disclosed herein, it is believed that the compound(s) will act synergistically with other anti-diabetes compounds that act through a separate mechanism. To determine synergism with other compounds/compositions, the compounds disclosed herein can be tested in combination with one or more anti-diabetes treatments and or drugs. The anti-diabetes agents can include one or more anti-diabetes drugs. Combination studies can show competitive, additive, or synergistic interactions for treatment and/or prevention of diabetes, cell viability, cellular toxicity, side effects, etc. of the combination in cell culture, animal studies, human studies, etc. Non-limiting examples of studies can include those described above and herein as well as those known to one of skill in the art. As a non-limiting example, the combination of the compound of Formula I and metformin may be tested. As a non-limiting example, the combination of Formula I and metformin is expected to show synergistic activity against at least diabetes mellitus type II.

[0139] A non-limiting example of a combination assay that can be performed to determine the competitive, additive, or synergistic interactions of a combination can utilize an interaction matrix commonly used to look at drug interactions and synergy. In one instance, the interaction matrix is used in a prevention and/or treatment study of diabetes mellitus type II in cell culture. Briefly, the experiment can have 25 samples: 4 with a first test compound/composition (such as the compound of Formula I) alone, 4 with a second test compound/composition (such as metformin) alone, 1 with no chemistries, and the remaining 16 can be combinations of the first and second test compounds/compositions. 1 :4 dilutions of the first test compound/composition from a starting concentration (such as 1.0 pg/ml for the compound of Formula I) and 1 :4 dilutions of the second test compound/composition from a starting concentration (such as 1.0 pg/ml for metformin) can be tested. The induction of diabetes like symptoms in the cell culture can occur in the constant presence of the inhibitory compounds. In this way, the experiment simulates a patient developing diabetes while on prophylactic treatment and tests prevention of development of diabetes by the first test compound/composition alone, the second test compound/composition alone, and the combination of the two at a range of concentrations. The data can be analyzed with the methodology of Berenbaum to determine competitive, additive, or synergistic interactions. (Berenbaum 1977).

[0140] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method

described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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