CREATINE SUGAR AMIDES AND SALTS THEREOF

Related Applications

[0001] The present application is related to and claims benefit of priority to U.S. Provisional Application Number: 61/059,938 entitled "Salts of Creatine Imino Sugar Amides" filed June 9, 2008, the disclosure of which is hereby fully incorporated by reference; and 61/057,539, U.S. Provisional Application Number: 61/057,521, U.S. Provisional Application Number: 61/057,509, U.S. Provisional Application Number: 61/057,489, and U.S. Provisional Application Number: 61/057,469, all of which were filed May 30, 2008; and U.S. Application Number: 12/229,979, and U.S. Application Number 12/229,955 both of which were filed August 28, 2008, the disclosures of which are all hereby fully incorporated by reference.

Field of the Invention

[0002] The present invention relates to structures and methods for producing creatine imino sugar amides and salts thereof. Specifically, the present invention relates to compounds comprising an imino sugar bound to creatine, via an amide linkage, and formed salts thereof that are particularly well suited for oral and parenteral use.

Background of the Invention

[0003] Creatine is a naturally occurring amino acid that is derived from the amino acids; glycine, arginine and methionine. Although it is ingested from meats and fish, the human body also synthesizes its own creatine. About 65% of creatine is stored in the musculature of mammals in the form of phosphocreatine (creatine bound to a phosphate molecule), and utilized mostly as a source of energy for muscle. Oral supplementation of creatine has been shown to increase creatine concentration in muscle, and also enables an increase in the resynthesis of phosphocreatine, resulting in a rapid replenishment of ATP within the first two minutes of the start of exercise.

[0004] The beneficial effects of creatine supplementation with regard to skeletal muscle are apparently not restricted to the role of creatine in energy metabolism. Creatine supplementation in combination with strength training results in specific, measurable physiological changes in skeletal muscle compared to strength training alone. For example, creatine supplementation amplifies the strength training-induced increase of human skeletal satellite cells as well as the number of myonuclei in human skeletal muscle fibers. Satellite cells, stem cells of adult muscle, are normally in a quiescent state and become activated to

fulfill roles of routine maintenance, repair and hypertrophy. Postnatal muscle growth involves both myofiber hypertrophy and increased numbers of myonuclei - the source of which are satellite cells.

[0005] Imino sugars constitute a major class of naturally occurring molecules that have important and diverse biological functions. Imino sugars may be pentose, hexose or heptose sugars where at least one oxygen-containing group is replaced by a nitrogen-containing group. These imino sugars are useful in pharmacology, since they have been found to play major roles in the selective inhibition of various enzymatic functions. [0006] Many have attempted to address issues such as stability, solubility, and bioavailability of creatine and imino sugars, independently, through the use of salts, esters, and amides. However, compounds of an imino sugar and a creatine bound via an amide bond are not known. It is commonly understood that hydrolysis of amides is more difficult to accomplish than the hydrolysis of esters. Therefore, an amide of creatine and an imino sugar would be more stable in solution than the related ester. Summary of the Invention

[0007] In the present invention, compounds and methods of production are disclosed, wherein the compounds comprise an imino sugar bound to creatine, via an amide linkage, and having a structure corresponding to Formula 1 :

Formula 1

where R, = H, OH, or CH ₂ OH;

R ₂ = H, OH, CH ₃ or CH ₂ OH; and n = 0, 1 or 2.

[0008] An additional aspect of the present invention discloses a method for producing the compound corresponding to Formula 1.

[0009] In a further aspect of the present invention, the compound corresponding to Formula 1 may be combined with one or more pharmaceutically acceptable carriers to form a nutritional composition, which can be orally administered to a subject.

[0010] In an additional aspect of the present invention, creatine imino sugar amide salts, methods for their production, and solid compositions comprising said creatine imino sugar amide salts, are disclosed. Specifically, the creatine imino sugar amide salts comprise an acceptable inorganic or organic acid and a creatine imino sugar amide. [0011] An additional aspect of the present invention discloses a method for producing creatine imino sugar amide salts.

[0012] In a further aspect of the present invention, the creatine imino sugar amide salts may be combined with one or more pharmaceutically acceptable carriers to form a nutritional composition, which can be administered to a subject.

Detailed Description of the Invention

[0013] In the following description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced without these specific details. [0014] The present invention relates to compounds of creatine imino sugar amides, salts thereof, and their routes of syntheses. Specific benefits are conferred by the creatine portion of the compound in addition to, and separate from, the imino sugar substituent. Additionally, the present invention provides for combinations of creatine imino sugar amides and inorganic or organic acid, which are free of physiologically unsafe additives. Furthermore, the present invention is particularly well suited for use in tablets, capsules, powders, granules, powdered beverage mixes and other forms known in the art of dietary supplements. [0015] As used herein, 'creatine' refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N- (aminoiminomethyl)-N-glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N- Methyl-N-guanylglycine. Additionally, as used herein, 'creatine' also includes derivatives of creatine such as esters and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

[0016] As used herein, 'deoxynojirimycin' refers to the chemical (2i?,3i?,4i?,55)-2- (hydroxymethyl)-3,4,5-piperideinetriol, (CAS Registry No. 19130-96-2), also known as D-5- amino- 1 ,5-dideoxyglucopyranose, l,5-dideoxy-l,5-imino-D-glucitol, (2i?,37?,4./?,5iS ^r )-2- hydroxymethyl-3,4,5-trihydroxypiperidine, or moranoline. Additionally, as used herein, 'deoxynojirimycin' also includes derivatives of deoxynojirimycin such as esters and salts.

[0017] As used herein, 'deoxygalactonojirimycin' refers to the chemical 2- (hydroxymethyl)piperidine-3,4,5-triol, (CAS Registry No. 75172-81-5), also known as 1,5- dideoxy-l,5-imino-D-galactitol, or galactostatin. Additionally, as used here, 'deoxygalactonojirimycin' also includes derivatives of deoxygalactonojirimycin such as esters and salts.

[0018] As used herein, 'deoxymannojirimycin' refers to the chemical (2R,3R,4R,5R)-2- (hydroxymethyl)piperidine-3,4,5-triol, (CAS Registry No. 73465-43-7), also known as 1,5- dideoxy-l,5-imino-D-mannitol. Additionally, as used here, 'deoxymannojirimycin' also includes derivatives of deoxymannojirimycin such as esters and salts. [0019] As used herein, 'homomannojirimycin' refers to the chemical (2R,3R,5R,6R)-2,6- bis(hydroxymethyl)ρiperidine-3,4,5-triol, (CAS Registry No. 127995-29-3). Additionally, as used here, 'homomannojirimycin' also includes derivatives of homomannojirimycin such as esters and salts.

[0020] As used herein, 'homonojirimycin' refers to the chemical (2R,3R,5S,6R)-2,6- bis(hydroxymethyl)piperidine-3,4,5-triol, (CAS Registry No. 119557-99-2). Additionally, as used here, 'homonojirimycin' also includes derivatives of homonojirimycin such as esters and salts.

[0021] As used herein, the term 'subject' refers to mammals and non-mammals. Mammals refers to any member of the mammalia class including, but not limited to, humans; non- human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. [0022] As used herein, 'citric acid' refers to the chemical 2-hydroxy-l,2,3-propane- tricarboxylic acid, (CAS Registry No. 77-92-9), also known as, β-hydroxytricarboxylic acid . Additionally, as used herein, 'citric acid' also includes derivatives of citrate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

[0023] As used herein, 'maleic acid' refers to the chemical (Z)-butenedioic acid, (CAS registry No. 1 10-16-7), also known as toxilic acid, cis- 1 ,2-ethylenedicarboxylic acid.

Additionally, as used herein, 'maleic acid' also includes derivatives of maleic acid such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

[0024] As used herein, 'malic acid' refers to the chemical 1 -Hydroxy- 1,2- ethanedicarboxylic acid, (CAS Registry No. 6915-15-17), also known as, hydroxybutanedioic acid, hydroxysuccinic acid, malate, or 2-hydroxybutanedioate. Additionally, as used herein, 'malic acid' also includes derivatives of malate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

[0025] As used herein, 'fumaric acid' refers to the chemical (£)-2-butenedioic acid, (CAS Registry No. 1 10-17-8), also known as, frαo^-l,2-ethylenedicarboxylic acid, allomaleic acid, and boletic acid. Additionally, as used herein, 'fumaric acid' also includes derivatives of fumarate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

[0026] As used herein, the term Organic acid' refers to organic compounds which contain carboxylic acids (-C(O)OH). Typical examples of organic acids include, but are not limited to; malic acid, fumaric acid, citric acid, orotic acid, lactic acid, pyruvic acid, and tartaric acid. [0027] As used here, the term "acceptable oral dosage form' would be known by one of skill in the art to include, for example, powder beverage mixes, liquid beverages, ready-to-eat bars, capsules, liquid capsules, tablets, capleta, dietary gels, soft-gel™ caplets, and gel-caps. [0028] As used here, the term 'parenteral' refers to methods of administration of nutrients to that region outside of the digestive tract. Examples of parenteral routes of administration include, but are not limited to, subcutaneous, intramuscular or intravenous injection, and nasopharyngeal, mucosal or transdermal absorption.

[0029] As used herein, the term 'pharmaceutically-acceptable salt' refers to acid-addition salts of creatine imino sugar amides with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifiuoroacetic, citric, maleic, malic, or fumaric acid. [0030] The term 'pharmaceutically acceptable carrier' is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be 'acceptable' in the sense of being compatible with the subject composition and its components and not injurious to the individual to which it is administered. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as

peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (1 1) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; and (15) other non-toxic compatible substances employed in pharmaceutical formulations, and combinations thereof.

[0031] As used herein, the term 'nutritional composition' includes dietary supplements, diet supplements, nutritional supplements, supplemental compositions and supplemental dietary compositions or those similarly envisioned and termed compositions not belonging to the conventional definition of pharmaceutical interventions as is known in the art. Furthermore, 'nutritional compositions' as disclosed herein belong to category of compositions having at least one physiological function when administered to a subject by conventional routes of administration. [0032] Alternatively, formulations and nutritional compositions belonging to the present invention may be considered to be nutraceuticals. As used herein, the term 'nutraceutical' is recognized and used in the art to describe a specific chemical compound or combination of compounds found in, organic matter for example, which may prevent, ameliorate or otherwise confer benefits against an undesirable condition. As is known in the art, the term 'nutraceutical' is used to refer any substance that is a food, a part of food, or an extract of food which is suitable for consumption by an individual and providing physiological benefit which may be medical or health-related. Furthermore, the term has been used to refer to a product isolated, extracted or purified from foods or naturally-derived material suitable for consumption by an individual and usually sold in medicinal forms, such as caplets, tablets, capsules, soft-gel™ caplets, gel-caps and the like, not associated with food. [0033] According to the present invention, the compounds disclosed herein comprise imino sugars bound to creatine. Furthermore, the imino sugars and creatine are bound by an amide linkage and have a structure according to Formula 1. The aforementioned compounds can be prepared, for example, according to the reaction as set forth for the purposes of the description in Scheme 1 below:

Scheme 1

Step 3:

6 1

R ₁ = H, OH Or CH ₂ OH,

R ₂ = H, OH, CH ₃ Or CH ₂ OH, and n = O, 1 or 2

[0034] As an example in Scheme 1 , Step 1 , creatine (2) is dissolved in water and an excess of sodium bicarbonate (NaHCO ₃ ) is added with stirring and then cooled in an ice- water bath. The resultant solution is cooled in an ice-water bath and di-tert-butyl carbonate (3), also known as boc anhydride, is added as a solution in/>-dioxane (also cooled). The mixture is then stirred at about 0 ⁰ C for about one hour and allowed to warm to room temperature (-23 ⁰ C) for between 2-4 hours. Water is added to the mixture and the aqueous layer is extracted twice with ethyl acetate. The resultant organic layer is then back extracted twice with a saturated sodium bicarbonate solution. The combined aqueous layers are acidified to a pH of 1 with 10% HCl and then extracted three times with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resultant protected creatine (4) would be of sufficient purity to be used in subsequent steps. It should be noted at this step that any amino protecting group, as would be known to one of skill in the art, could be used in place of boc anhydride. Examples of amino protecting groups include, but are not limited to: 9-fluorenylmethyl carbamate, di-/er/-butyl carbonate, benzyl

carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine, benzylideneamine, p- toluenesulfonamide, most preferably, di-tert-buty\ carbonate.

[0035] Step 2 describes the combining of an imino sugar (5) and the protected creatine (4). The two substrates, 5 and 4, are stirred in DCM and submersed in an ice-water bath to bring to the temperature of the reaction to about 0 ⁰ C. After cooling, a solution of dicyclohexylcarbodiimine (DCC) and DCM is added to the mixture of 5 and 4 with vigorous stirring; the DCC acts to activate the carboxylic acid of the protected creatine in situ. Following the addition of the DCC the reaction is allowed to warm to room temperature (-23 ⁰ C) with constant agitation. Stirring is maintained overnight (between about 8 and about 10 hours). The mixture is then filtered through Celite ^® in order to remove any by-products and unreacted materials. The filtrate is then concentrated under reduced pressure and purified by flash chromatography through a silica gel packed column to yield the bis-boc-protected creatine imino sugar amide (6). [0036] In the preferred embodiment of the present invention, deoxynojirimycin is the imino sugar used. However any imino sugar, as is known by one of skill in the art, may be utilized to synthesize a creatine imino sugar amide according to the method disclosed herein. [0037] Step 3 describes the removal of the two boc protecting groups from the guanidine group of 6, via acidification. The bis-boc-protected creatine imino sugar amide (6) is dissolved in a trifluoroacetic acid:H ₂ θ (1 :1) mixture. The reaction is stirred at room temperature for between about 1.5 and about 3.5 hours. After the reaction is complete the mixture is concentrated under reduced pressure and then purified by flash chromatography through a silica gel packed column to yield the target amide, creatine imino sugar amide (1). [0038] According to an additional embodiment, the creatine imino sugar amide of the present invention may be formulated into nutritional compositions that may be consumed in any form. For instance, the dosage form of the nutritional compositions may be provided as, e.g. a powder beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid capsule, a tablet, a caplet, or as a dietary gel. The preferred dosage forms of the present invention are provided as a powder beverage mix. [0039] Furthermore, the dosage form of the nutritional composition may be provided in accordance with customary processing techniques for herbal and nutritional compositions in any of the forms mentioned above. Additionally, the nutritional composition, comprising the creatine imino sugar amide may contain any appropriate number and type of pharmaceutically acceptable carriers, as is well known in the art.

[0040] Compounds of an imino sugar and a creatine bound via an amide bond offer increased resistance to the cyclization of creatine while in solution. It is commonly understood that hydrolysis of amides is more difficult to accomplish than the hydrolysis of esters. While amides of creatine and an imino sugar would be more stable in solution than related esters, the salts of these amides of creatine and an imino sugar would offer the further advantage of enhanced nutritional and/or therapeutical efficacy due to increased solubility. [0041] According an aspect of the present invention, creatine imino sugar amides combined with an inorganic or organic acid to form a creatine imino sugar amide salts are disclosed. The creatine imino sugar amide salts can be prepared according to the details set forth in the description below.

[0042] In one step of the process, a creatine imino sugar amide is dissolved in an excess of hot lower alcohol. The lower alcohol is considered to be hot, as would be known by one of ordinary skill in the art. Preferably the lower alcohol is considered to be hot when heated to a temperature about 5°C below the boiling point of the corresponding lower alcohol. [0043] In various embodiments of the present invention, the creatine imino sugar amide may be selected, for example, from the group including of 1 -methyl- l-(2-oxo-2- ((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-l -yl)ethyl) guanidine, also known as creatine deoxynojirimycin amide; l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5- trihydroxy-2-(hydroxymethyl)piperidin-l-yl)ethyl)guanidine, also known as creatine deoxygalactonojirimycin amide; l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2- (hydroxymethyl)piperidin-l-yl)ethyl)guanidine, also known as creatine deoxymannojirimycin amide; l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine, also known as creatine homomannojirimycin amide; and l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy- 2,6-bis(hydroxymethyl) piperidin-l-yl)ethyl)guanidine, also known as creatine homonojirimycin amide. However, it should be noted that a creatine imino sugar amine may be made with any imino sugar as would be known by one of skill in the art, and would be acceptable for use in the present invention. [0044] Additionally, in various embodiments of the present invention, the lower alcohol preferably is selected from the group consisting of methanol, ethanol, propanol, and isopropanol. These lower alcohols may be used singly or in admixture containing two or more alcohols.

[0045] In another step of the process, the inorganic or organic acid is dissolved in an excess of hot lower alcohol. The lower alcohol is considered to be hot, as would be known by one

of ordinary skill in the art. Preferably the lower alcohol is considered to be hot when heated to a temperature about 5°C below the boiling point of the corresponding lower alcohol. [0046] In various embodiments of the present invention, the inorganic or organic acid preferably is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, trifluoroacetic acid, citric acid, maleic acid, malic acid and fumaric acid.

[0047] The order in which the creatine imino sugar amide and the inorganic or organic acid are dissolved is not critical. Both solutions prepared above are then mixed together and heated to about the boiling point of the corresponding lower alcohol. If there are solids still present after heating, the combined solution is filtered while hot to remove any unreacted starting materials. The combined solution is then allowed to cool to room temperature, covered and refrigerated or cooled until crystallization occurs, preferably for between about 24 to about 48 hours. The resultant solid is filtered under vacuum and washed with ice cold lower alcohol, yielding the creatine imino sugar amide salt. [0048] In larger scale preparations of the present invention, diethyl ether can be added until the cloud point, as would be known to one of skill in the art, is reached after the mixture is cooled to room temperature, after which the solution is refrigerated or cooled to allow crystallization to complete. This will facilitate greater precipitation of the product thus yielding more of the creatine imino sugar amide salt, which would be desired in industrial settings. [0049] Creatine imino sugar amide salts are used advantageously alone or with additional active ingredients, such as, trace elements, vitamins, mineral substances, or other amino acids as well as, optionally, excipients usually used for the preparation of the respective forms of administration. The forms of administration include, particularly, all varieties of tablets, both those that are swallowed without being chewed, and tablets to be chewed or dissolved in the mouth of an individual, as well as those that are dissolved in a liquid before being ingested by an individual. The tablet forms include uncoated tablets, one-layer or multilayer or encased forms or effervescent tablets. Further preferred forms of administration are capsules of hard and soft gelatin, the latter being particularly suitable to include a liquid core. Additionally, creatine imino sugar amide salts can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated.

[0050] Creatine imino sugar amide salts of the present invention may, for example include: 1. 1 -methyl- 1 -(2-oxo-2-((2R, 3 R,4R, 5 S)-3 ,4, 5 -trihydroxy-2-(hydroxymethyl)piperidin- 1 - yl)ethyl)guanidine hydrochloride;

2. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine hydrobromide;

3. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine sulfate; 4. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine hemisulfate;

5. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine 2,2,2-trifluoroacetate;

6. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xy-methyl)piperidin- 1 -yl)ethyl)guanidine-2-hydroxypropane- 1 ,2,3-tricarboxylate;

7. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxy-methyl )piperidin- 1 -yl)ethyl)guanidine-hemi(2-hydroxypropane- 1 ,2,3-tricarboxylate);

8. tris(l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-( hydroxy- methyl)piperidin- 1 -yl)ethyl)guanidine)-2-hydroxypropane- 1 ,2,3-tricarboxylate; 9. l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine maleate;

10. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin- 1 -yl)ethyl)guanidine hemimaleate;

1 1. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) ρiperidin- l-yl)ethyl)guanidine malate;

12. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin- l-yl)ethyl)guanidine hemimalate;

13. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin- 1 -yl)ethyl)guanidine fumarate; 14. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)p iperidin-

1 -yl)ethyl)guanidine hemifumarate;

15. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine hydrochloride;

16. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxy- methyl)piperidin-l- yl)ethyl)guanidine hydrobromide;

17. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxy- methyl)piperidin-l- yl)ethyl)guanidine sulfate;

18. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine hemisulfate;

19. 1 -methyl- l-(2-oxo-2-((3 S,4R,5S)-3, 4,5-trihydroxy-2-(hydroxymethyl)piperidin-l- yl)ethyl)guanidine 2,2,2-trifluoroacetate;

20. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxy- methyl)piperidin-l- yl)ethyl)guanidine-2-hydroxypropane- 1 ,2,3-tricarboxylate; 21. 1 -methyl- 1 -(2-oxo-2-((3 S,4R,5S)-3,4,5-trihydroxy-2-(hydroxy-methyl)piperidin-l - yl)ethyl)guanidine-hemi(2-hydroxypropane- 1 ,2,3 -tricarboxylate);

22. tris(l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hyd roxy-methyl)piperidin- 1 -yl)ethyl)guanidine)-2-hydroxypropane-l ,2,3-tricarboxylate;

23. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine maleate;

24. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine hemimaleate;

25. 1 -methyl- 1 -(2-oxo-2-((3 S,4R,5 S)-3 ,4,5-trihydroxy-2-(hydroxymethyl)piperidin- 1 - yl)ethyl)guanidine malate; 26. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine hemimalate;

27. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine fumarate;

28. l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine hemifumarate;

29. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)ρiperidin- 1 -yl)ethyl)guanidine hydrochloride;

30. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin- 1 -yl)ethyl)guanidine hydrobromide; 31. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl)p iperidin-

1 -yl)ethyl)guanidine sulfate;

32. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)ρiperidin- 1 -yl)ethyl)guanidine hemisulfate;

33. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl) ρiperidin- 1 -yl)ethyl)guanidine 2,2,2-trifluoroacetate;

34. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxy-methyl) piperidin- 1 -yl)ethyl)guanidine-2-hydroxypropane- 1 ,2,3-tricarboxylate;

35. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xy-methyl)piperidin- 1 -yl)ethyl)guanidine-hemi(2-hydroxypropane- 1 ,2,3-tricarboxylate);

36. tris(l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-( hydroxy- methyl)piperidin- 1 -yl)ethyl)guanidine)-2-hydroxypropane- 1 ,2,3 -tricarboxylate;

37. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin- 1 -yl)ethyl)guanidine maleate; 38. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-

1 -yl)ethyl)guanidine hemimaleate;

39. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin- 1 -yl)ethyl)guanidine malate;

40. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin- l-yl)ethyl)guanidine hemimalate;

41. l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin- 1 -yl)ethyl)guanidine fumarate;

42. 1 -methyl- l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin- 1 -yl)ethyl)guanidine hemifumarate; 43. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hydrochloride;

44. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hydrobromide;

45. 1 -methyl- l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine sulfate;

46. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine hemisulfate;

47. 1 -methyl- l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine 2,2,2-trifluoroacetate; 48. 1 -methyl- 1 -(2-oxo-2-((2R,3R,5R,6R)-3 , 4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine-2-hydroxypr opane- 1,2,3 - tricarboxylate;

49. 1 -methyl- 1 -(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine-hemi(2-hydr oxypropane-l,2,3- tricarboxylate);

50. tris(l -methyl- l-(2-oxo-2-((2R,3R,5R,6R)-3, 4,5 -trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine)-2-hydroxyp ropane- 1,2,3- tricarboxylate;

51. 1 -methyl- 1 -(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine maleate; 52. 1 -methyl- l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemimaleate; 53. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l -yl)ethyl)guanidine malate;

54. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemimalate;

55. l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine fumarate;

56. 1 -methyl- 1 -(2-oxo-2-((2R,3R,5R,6R)-3 , 4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemifumarate;

57. 1 -methyl- l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hydrochloride; 58. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hydrobromide;

59. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine sulfate;

60. l-memyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemisulfate;

61. 1 -methyl- l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine 2,2,2-trifluoroacetate;

62. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l -yl)ethyl)guanidine 2-hydroxypropane- 1 ,2,3- tricarboxylate;

63. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine hemi(2-hydroxypropane-l,2,3- tricarboxylate);

64. tris(l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy- 2,6- bis(hydroxymethyl)piperidin-l -yl)ethyl)guanidine) 2-hydroxypropane- 1 ,2,3- tricarboxylate;

65. 1 -methyl- 1 -(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l -yl)ethyl)guanidine maleate;

66. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l -yl)ethyl)guanidine hemimaleate;

67. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine malate; 68. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemimalate;

69. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin-l-yl)ethyl)guanidine fumarate; and

70. l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine hemifumarate.

[0051] The non-limiting examples given above provide examples of creatine imino sugar amides salts which are within the present invention. One of skill in the art may readily envision various other salts within the scope of the present invention, considering the examples with reference to the specification herein provided. [0052] The following non-limiting example illustrates feasible synthesis of various creatine imino sugar amides and salts thereof. One of skill in the art may readily envision various other combinations within the scope of the present invention, considering the example with reference to the specification herein provided. [0053] Also provided below is a method for producing creatine imino sugar amide salts of the present invention. Provided with the present specification, those of skill in the art will readily appreciate that certain modifications and variations may be made in the process of "scaling-up" the reaction to manufacture larger batches of creatine imino sugar amide salts which may be required or useful for commercial uses and supply requirements. Other methods of synthesis may also be apparent to those of skill in the art. [0054] Furthermore, it would be known by one of skill in the art that varying the stoichiometric ratios of the various creatine imino sugar amides to the inorganic or organic acids will results in various salts. For example using equimolar ratios of creatine deoxynojirimycin amide and malic acid will lead to creatine deoxynojirimycin amide malate, whereas using 2 molar equivalents of creatine deoxynojirimycin amide for every 1 molar equivalent of malic acid will lead to creatine deoxynojirimycin amide hemimalate.

Examples Example 1 l-methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine

[0055] In a round bottomed flask, equipped with a magnetic stirrer, 7.87 g (O.OόOmol) of creatine is dissolved in 200 mL of water and 10.08 g (0.120mol) of sodium bicarbonate is added with stirring. The solution is then cooled to about about 0 ⁰ C in an ice-water bath. To the cooled solution is added a cooled solution of 31.10 ml (0.150mol) of di-tert-butyl dicarbonate dissolved in 150 mL of/>-dioxane. The mixture is then stirred at about 0 ⁰ C in an ice-water bath for an hour, after which the ice bath is removed and the solution is allowed to warm to room temperature (~23°C). After stirring at room temperature for an additional 2 hours, the mixture is diluted with 150 mL of water and transferred to a 1-L separatory funnel, where the aqueous layer is extracted sequentially with one 300 mL and one 150 mL portions of ethyl acetate. The resultant organic layer is then back extracted sequentially one 150 mL and one 75 mL portions of saturated sodium bicarbonate solution. The combined aqueous portions are then slowly acidified to a pH of 1, in a 1-L separatory funnel, with 10% HCl, and then extracted with three 100 mL ethyl acetate portions. The organic layers are then combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The resultant 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid would be sufficiently pure to use in subsequent steps.

[0056] A dry, 2-necked round bottomed flask, equipped with a magnetic stirrer and a dropping funnel containing a solution of 10.83 g (0.0525mol) of N,N'- dicyclohexylcarbodiimide (DCC) dissolved in 125 mL of DCM, is charged with 16.57g (0.050mol) of 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid, 8.97 g (0.055mol) of deoxynojirimycin, and 10OmL of DCM (all of which is under an argon atmosphere). The resultant mixture is stirred in an ice-water bath to cool the solution to a temperature of about 0 ⁰ C. Following cooling, the solution of DCC from the dropping funnel

is added and the reaction is allowed to warm to room temperature and then to stir overnight. The mixture is then filtered through a Celite ^® plug and the filtrate is purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield the bis-boc protected creatine deoxynojirimycin amide, tert-butyl (tert-butoxycarbonylarmno)(methyl(2-oxo-2- ((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin- 1 -yl)ethyl)amino)methylene- carbamate.

[0057] In a dry, round bottomed flask, equipped with a magnetic stirrer, 19.06 g (0.040mol) of tert-butyl (tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3R,4R,5S)-3,4 ,5-trihydroxy-2- (hydroxymethyl)piperidin-l-yl)ethyl)amino) methylenecarbamate is dissolved in 250 mL of a trifluoroacetic acid:H2O (1 :1) mixture. The resultant mixture is stirred for 1.5 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine deoxynojirimycin amide, 1- methyl-l-(2-oxo-2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxy methyl)piperidin-l- yl)ethyl)guanidine. Example 2 l-methyl-l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxym ethyl)piperidin-l- yl)ethyl)guanidine

[0058] In a round bottomed flask, equipped with a magnetic stirrer, 6.50 g (0.050mol) of creatine is dissolved in 175 mL of water and 8.40 g (O.lOmol) of sodium bicarbonate is added with stirring. The solution is then cooled to about 0 ⁰ C in an ice-water bath. To the cooled solution is added a cooled solution of 28.72 ml (O. lOmol) of di-tert-butyl dicarbonate dissolved in 125 mL of/?-dioxane. The mixture is then stirred at O ⁰ C in an ice-water bath for an hour, after which the ice-water bath is removed and the solution is allowed to warm to room temperature (-23 ⁰ C). After stirring at room temperature for an additional 2 hours, the mixture is diluted with 150 mL of water and transferred to a 1-L separatory funnel, where the aqueous layer is extracted sequentially with one 300 mL and one 150 mL portions of ethyl acetate. The resultant organic layer is then back extracted sequentially one 150 mL and one 75 mL portions of saturated sodium bicarbonate solution. The combined aqueous portions

are then slowly acidified to a pH of 1, in a 1 -L separatory funnel, with 10% HCl, and then extracted with three 100 mL ethyl acetate portions. The organic layers are then combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The resultant 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid would be sufficiently pure to use in subsequent steps.

[0059] A dry, 2-necked round bottomed flask, equipped with a magnetic stirrer and a dropping funnel containing a solution of 8.66 g (0.042mol) of λ^iV'-dicyclohexylcarbodiimide (DCC) dissolved in 100 mL of DCM, is charged with 13.25 g (0.040mol) of 2-(2,3-bis(tert- butoxycarbonyl)-l-methylguanidino)acetic acid, 7.18 g (0.044mol) of deoxygalactonojirimycin, and 75 mL of DCM (all of which is under an argon atmosphere). The resultant mixture is stirred in an ice-water bath to cool the solution to a temperature of about 0 ⁰ C. Following cooling, the solution of DCC from the dropping funnel is added and the reaction is allowed to warm to room temperature and then to stir overnight. The mixture is then filtered through a Celite ^® plug and the filtrate is purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield the bis-boc protected creatine deoxygalactonojirimycin amide, tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((3S,4R, 5S)-3,4,5-trihydroxy-2- (hydroxymethyl)piperidin- 1 -yl)ethyl)amino) methyl enecarbamate.

[0060] In a dry, round bottomed flask, equipped with a magnetic stirrer, 23.81 g (0.050mol) of tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((3S,4R, 5S)-3,4,5-trihydroxy-2- (hydroxymethyl)piperidin-l-yl)ethyl)amino) methylenecarbamate is dissolved in 275 mL of a trifluoroacetic acid:H2O (1 :1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 2/3) to yield the creatine deoxygalactonojirimycin amide, 1 -methyl- l-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy -2-(hydroxymethyl)piperidin-l- yl)ethyl)guanidine. Example 3 l-methyl-l-(2-oxo-2-((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydro xymethyl)piperidin-l- yl)ethyl)guanidine

[0061] In a round bottomed flask, equipped with a magnetic stirrer, 9.17 g (0.070mol) of creatine is dissolved in 300 mL of water and 1 1.76 g (0.140mol) of sodium bicarbonate is added with stirring. The solution is then cooled to about 0 ⁰ C in an ice-water bath. To the cooled solution is added a cooled solution of 40.20 ml (0.175mol) of di-tert-butyl dicarbonate dissolved in 175 mL of />-dioxane. The mixture is then stirred at about 0 ⁰ C in an ice-water bath for an hour, after which the ice-water bath is removed and the solution is allowed to warm to room temperature (-23 ⁰ C). After stirring at room temperature for an additional 3 hours, the mixture is diluted with 250 mL of water and transferred to a 2-L separatory funnel, where the aqueous layer is extracted sequentially with one 300 mL and one 150 mL portions of ethyl acetate. The resultant organic layer is then back extracted sequentially one 150 mL and one 75 mL portions of saturated sodium bicarbonate solution. The combined aqueous portions are then slowly acidified to a pH of 1, in a 2-L separatory funnel, with 10% HCl, and then extracted with three 100 mL ethyl acetate portions. The organic layers are then combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The resultant 2-(2,3 -bis(tert-butoxycarbonyl)- 1 -methyl-guanidino)acetic acid would be sufficiently pure to use in subsequent steps.

[0062] A dry, 2-necked round bottomed flask, equipped with a magnetic stirrer and a dropping funnel containing a solution of 13.00 g (0.063mol) of N,N'- dicyclohexylcarbodiimide (DCC) dissolved in 150 mL of DCM, is charged with 19.88 g (0.060mol) of 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid, 10.77 g

(0.066mol) of deoxymannojirimycin, and 15OmL of DCM (all of which is under an argon atmosphere). The resultant mixture is stirred in an ice-water bath to cool the solution to a temperature of about 0 ⁰ C. Following cooling, the solution of DCC from the dropping funnel is added and the reaction is allowed to warm to room temperature and then to stir overnight. The mixture is then filtered through a Celite ^® plug and the filtrate is purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield the bis-boc protected creatine deoxymannojirimycin amide, tert-butyl (tert-butoxycarbonylamino)(methyl(2-oxo-2- ((2R,3R,4R,5R)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-l -yl)ethyl)amino) methy lenecarbamate . [0063] In a dry, round bottomed flask, equipped with a magnetic stirrer, 30.96 g (0.065mol) of tert-butyl (tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3R,4R,5R)-3,4 ,5-trihydroxy-2- (hydroxymethyl)piperidin-l-yl)ethyl)amino) methylenecarbamate is dissolved in 325 mL of a trifluoroacetic acid:H2O (1 :1) mixture. The resultant mixture is stirred for 3 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash

chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine deoxymannojirimycin amide, l-methyl-l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine. Example 4 l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis( hydroxymethyl)piperidin-l- yl)ethyl)guanidine

[0064] In a round bottomed flask, equipped with a magnetic stirrer, 3.93 g (0.030mol) of creatine is dissolved in 150 mL of water and 5.04 g (O.OόOmol) of sodium bicarbonate is added with stirring. The solution is then cooled to about 0 ⁰ C in an ice-water bath. To the cooled solution is added a cooled solution of 17.24 mL (0.075mol) of di-tert-butyl dicarbonate dissolved in 100 mL of/?-dioxane. The mixture is then stirred at about O ⁰ C in an ice-water bath for an hour, after which the ice-water bath is removed and the solution is allowed to warm to room temperature (~23°C). After stirring at room temperature for an additional hour, the mixture is diluted with 125 mL of water and transferred to a 1-L separatory funnel, where the aqueous layer is extracted sequentially with one 200 mL and one 75 mL portions of ethyl acetate. The resultant organic layer is then back extracted sequentially one 100 mL and one 50 mL portions of saturated sodium bicarbonate solution. The combined aqueous portions are then slowly acidified to a pH of 1 , in a 1 -L separatory funnel, with 10% HCl, and then extracted with three 75 mL ethyl acetate portions. The organic layers are then combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The resultant 2-(2,3-bis(tert-butoxycarbonyl)-l -methyl - guanidino)acetic acid would be sufficiently pure to use in subsequent steps. [0065] A dry, 2-necked round bottomed flask, equipped with a magnetic stirrer and a dropping funnel containing a solution of 6.50 g (0.0315mol) of ./V ₅ TV- dicyclohexylcarbodiimide (DCC) dissolved in 80 mL of DCM, is charged with 9.94 g (0.030mol) of 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid, 6.38 g (0.033mol) of homomannojirimycin, and 10OmL of DCM (all of which is under an argon atmosphere). The resultant mixture is stirred in an ice-water bath to cool the solution to a

temperature of about 0 ⁰ C. Following cooling, the solution of DCC from the dropping funnel is added and the reaction is allowed to warm to room temperature and then to stir overnight. The mixture is then filtered through a Celite ^® plug and the filtrate is purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield the bis-boc protected creatine homomannojirimycin amide, tert-butyl (tert-butoxycarbonylamino)(methyl(2-oxo-2- ((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)piperi din-l- yl)ethyl)amino)methylene-carbamate.

[0066] In a dry, round bottomed flask, equipped with a magnetic stirrer, 10.12 g (0.020mol) oftert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3 R,5R,6R)-3,4,5-trihydroxy- 2,6-bis(hydroxymethyl)piperidin-l-yl)ethyl) amino)methylenecarbamate is dissolved in 150 mL of a trifluoroacetic acid:H2O (1 : 1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine homomannojirimycin amide, l-methyl-l-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine. Example 5

1 -methyl- l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6-bis(hydrox ymethyl)piperidin-

1 -yl)ethyl)guanidine H H [0067] In a round bottomed flask, equipped with a magnetic stirrer, 7.87 g (0.060mol) of creatine is dissolved in 200 mL of water and 10.08 g (0.120mol) of sodium bicarbonate is added with stirring. The solution is then cooled to about 0 ⁰ C in an ice-water bath. To the cooled solution is added a cooled solution of 31.10 ml (0.150mol) of di-tert-butyl dicarbonate dissolved in 150 mL ofp-dioxane. The mixture is then stirred at about 0 ⁰ C in an ice-water bath for an hour, after which the ice-water bath is removed and the solution is allowed to warm to room temperature (-23 ⁰ C). After stirring at room temperature for an additional 2 hours, the mixture is diluted with 150 mL of water and transferred to a 1-L separatory funnel, where the aqueous layer is extracted sequentially with one 300 mL and one 150 mL portions of ethyl acetate. The resultant organic layer is then back extracted sequentially one 150 mL

and one 75 mL portions of saturated sodium bicarbonate solution. The combined aqueous portions are then slowly acidified to a pH of 1, in a 1 -L separatory funnel, with 10% HCl, and then extracted with three 100 mL ethyl acetate portions. The organic layers are then combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The resultant 2-(2,3-bis(tert-butoxycarbonyl)-l-methyl-guanidino)acetic acid would be sufficiently pure to use in subsequent steps.

[0068] A dry, 2-necked round bottomed flask, equipped with a magnetic stirrer and a dropping funnel containing a solution of 10.83 g (0.0525mol) of TV ₅ JV'- dicyclohexylcarbodiimide (DCC) dissolved in 60 mL of DCM, is charged with 16.57 g (0.050mol) of 2-(2,3-bis(tert-butoxycarbonyl)-l-methylguanidino)acetic acid, 10.62 g (0.055mol) of homonojirimycin, and 10OmL of DCM (all of which is under an argon atmosphere). The resultant mixture is stirred in an ice- water bath to cool the solution to a temperature of about 0 ⁰ C. Following cooling, the solution of DCC from the dropping funnel is added and the reaction is allowed to warm to room temperature and then to stir overnight. The mixture is then filtered through a Celite ^® plug and the filtrate is purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield the bis-boc protected creatine homonojirimycin amide, tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2- ((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)pip eridin-l- yl)ethyl)amino)methylene-carbamate. [0069] In a dry, round bottomed flask, equipped with a magnetic stirrer, 20.62 g (0.040mol) oftert-butyl (tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3R,4S,5S,6R)- 3,4,5- trihydroxy-2,6-bis(hydroxymethyl)piperidin-l -yl)ethyl) amino)methylenecarbamate is dissolved in 250 mL of a trifluoroacetic acid:H2O (1 :1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine homonojirimycin amide, 1 -methyl- l-(2-oxo-2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-2,6- bis(hydroxymethyl)piperidin- 1 -yl)ethyl)guanidine. Example 5 [0070] 552.58 g (2 mol) of creatine deoxynojirimycin amide is dissolved into 40OmL of hot ethanol, solution 1. Concurrently, 134.09 g (1 mol) of malic acid is dissolved in 20OmL of hot ethanol, solution 2. Solution 2 is added to solution 1 with stirring and the resultant combined solution is heated to the boiling point. If there are solids still present the combined solution is filtered at this temperature to remove unreacted starting materials. The combined solution is then allowed to cool to room temperature and then covered and refrigerated to

allow crystallization to complete; about 24 hours. The resultant crystals are filtered under vacuum and washed with ice cold ethanol, yielding the creatine deoxynojirimycin amide hemimalate. Example 6 [0071] 552.58 g (2 mol) of creatine deoxygalactonojirimycin amide is dissolved into 40OmL of hot propanol, solution 1. Concurrently, 116.07 g (1 mol) of fumaric acid is dissolved in 20OmL of hot propanol, solution 2. Solution 2 is added to solution 1 with stirring and the resultant combined solution is heated to the boiling point. If there are solids still present the combined solution is filtered at this temperature to remove unreacted starting materials. The combined solution is then allowed to cool to room temperature and refrigerated to allow crystallization to complete; about 24 hours. The resultant crystals are filtered under vacuum and washed with ice cold ethanol, yielding the creatine deoxygalactonojirimycin amide hemifumarate. Example 7 [0072] 828.27 g (3 mol) of creatine deoxymannojirimycin amide is dissolved into 60OmL of hot isopropanol, solution 1. Concurrently, 192.12 g (1 mol) of citric acid is dissolved in 30OmL of hot isopropanol, solution 2. Solution 2 is added to solution 1 with stirring and the resultant combined solution is heated to the boiling point. If there are solids still present the combined solution is filtered at this temperature to remove unreacted starting materials. The combined solution is then allowed to cool to room temperature and refrigerated to allow crystallization to complete; about 24 hours. The resultant crystals are filtered under vacuum and washed with ice cold ethanol, yielding the tris(creatine deoxymannojirimycin amide) citrate.

Extensions and Alternatives [00731 In the foregoing specification, the invention has been described with respect to specific embodiments thereof; however, it will be evident to one skilled in the art that various modifications and changes may be made thereto without departing from the scope of the invention.

[0074] All publications which are cited herein are hereby specifically incorporated by reference into the disclosure for the teachings for which they are cited.