Biguanide Compositions and Methods of Treating Metabolic Disorders

• US 20130095140A1
• Filed: 07/11/2012
• Published: 04/18/2013
• Est. Priority Date: 01/07/2011
• Status: Active Grant

• Current Assignee: Anji Pharmaceuticals, Inc.
• Original Assignee: Elcelyx Therapeutics, Inc.
• Inventors: Baron, Alain D., Fineman, Mark S., Beeley, Nigel R. A.
• Granted Patent: US 8,796,338 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2086 : Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 : containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2846 : Poly(meth)acrylates
• CPC Class Codes: A61K 9/2853 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07C 279/26 : X and Y being nitrogen atoms, i.e. biguanides
• CPC Class Codes: C07D 207/06 : with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 249/14 : Nitrogen atoms
• CPC Class Codes: C07D 251/10 : having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 251/18 : with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 255/02 : not condensed with other rings
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/66 : Nitrogen atoms
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

Provided herein are methods for treating certain conditions, including diabetes, obesity, and other metabolic diseases, disorders or conditions by administrating a composition comprising a biguanide or related heterocyclic compound, e.g., metformin. Also provided herein are biguanide or related heterocyclic compound compositions, and methods for the preparation thereof for use in the methods of the present invention. Also provided herein are compositions comprising metformin and salts thereof and methods of use.

Claims

1. A composition comprising a biguanide or related heterocyclic compound of structural Formula I,

2. A composition according to claim 1, wherein

R₂, R₃, R₄, R₅, R₆ and R₇ are independently selected from H, methyl, ethyl, propyl or isopropyl;

and

R₁ is selected from;

H,

C₁ to C₁₂ straight chain or branched chain alkyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkenyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkynyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₃ to C₇ cycloalkyl, C₂ to C₆ heterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N,

C₄ to C₁₂ alkylcycloalkyl,

C₃ to C₁₁ alkylheterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N and wherein N is present in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,

phenyl, substituted phenyl, naphthyl, substituted naphthyl,

alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl,

pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, thiazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted.

17. The composition according to any one of claims 1, 4, 7, 10, 13 and 16 wherein the biguanide or related heterocyclic compound comprises an asymmetric center or centers and forms a composition of a racemic mixture, a diastereoisomeric mixture, a single enantiomer, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers thereof, etc.

18. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, wherein the biguanide or related heterocyclic compound comprises one or more double bonds, wherein the compound is a cis/trans, E/Z mixture or an E or Z geometric isomer thereof.

19. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, wherein the biguanide or related heterocyclic compound is a salt selected from hydrochloride, hydrobromide, acetate, propionate, butyrate, sulfate, hydrogen sulfate, sulfite, carbonate, hydrogen carbonate, phosphate, phosphinate, oxalate, hemi-oxalate, malonate, hemi-malonate, fumarate, hemi-fumarate, maleate, hemi-maleate, citrate, hemi-citrate, tartrate, hemi-tartrate, aspartate and glutamate.

20. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, wherein the biguanide or related heterocyclic compound is formulated as a composition comprising the components A, B, and C, wherein:

A is the protonated form of a natural or unnatural amino acid;

B is the dianion of an acid; and

C is the protonated form of the biguanide or related heterocyclic compound.

21. The composition according to claim 20, wherein

A is the protonated form of a natural amino acid selected from alanine, aspartic acid, asparagine, arginine, glycine, glutamine, glutamic acid lysine, phenylalanine, tyrosine, serine, threonine, tryptophan, leucine, isoleucine, histidine, methionine, proline, cysteine, and cystine;

and

B is the dianion of an acid selected from oxalic, malonic, citric, maleic, fumaric, tartaric, aspartic, and glutamic acid.

C is the protonated form of the biguanide or related heterocyclic compound.

23. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, further comprising a DPP-IV inhibitor.

24. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, further comprising an anti-obesity or anti-diabetes agent.

26. A method of inducing feelings of happiness, well-being or contentment in subjects comprising administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16.

27. A method of treating a condition selected from metabolic syndrome, diabetes type I, diabetes type II, obesity, binge eating, undesired food cravings, food addiction, a desire to reduce food intake or to lose weight or maintain weight loss, desire to maintain healthy weight, desire to maintain normal blood glucose metabolism, anorexia, pre-diabetes, glucose intolerance, gestational diabetes mellitus (GDM), impaired fasting glycemia (IFG), post-prandial hyperglycemia, accelerated gastric emptying, dumping syndrome, delayed gastric emptying, dyslipidemia, post-prandial dyslipidemia, hyperlipidemia, hypertriglyceridemia, post-prandial hypertriglyceridemia, insulin resistance, bone loss disorders, osteopenia, osteoporosis, muscle wasting disease, muscle degenerative disorders, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), immune disorders of the gut, celiac disease, bowel irregularity, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn'"'"'s disease, short bowel syndrome, peripheral neuropathy and diabetic neuropathy in a subject comprising administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16.

28. A method of treating a condition selected from sadness, stress, grief, anxiety, anxiety disorder (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder or social anxiety disorder or a mood disorder (e.g., depression, bipolar disorder, dysthymic disorder and cyclothymic disorder) comprising administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16.

29. A method according to claim 27, wherein the condition is diabetes.

30. A method according to claim 27, wherein the condition is obesity.

31. A method according to claim 27, wherein the subject has undergone bariatric surgery.

32. A method according to claim 27, further comprising administration of a drug for diabetes or obesity.

33. A method of treating a defect in energy homeostasis in a subject comprising administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16.

40. A method of increasing circulating GLP-1 concentration in a subject by administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16 to the subject.

41. A method of increasing circulating PYY concentration in a subject by administering a composition according to any one of claims 1, 4, 7, 10, 13 and 16 to the subject.

61. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, wherein said composition is adapted to minimize the circulating plasma concentration below about 5 μ

g/mL, 4 μ

g/mL, 3 μ

g/mL, 2 μ

g/mL, 1 μ

g/mL, 0.5 μ

g/mL or 0.25 μ

g/mL.

62. The composition according to any one of claims 1, 4, 7, 10, 13 and 16, wherein said composition is adapted to provide 60%, 50%, 40%, 30%, or 20% less relative bioavailability of the compound compared to an immediate release composition having the same amount of the compound.

3. (canceled)

4. A composition comprising a biguanide or related heterocyclic compound of

5. A composition according to claim 4, wherein:

R₂, R₃, R₄ and R₅ are independently selected from H, methyl, ethyl, propyl or isopropyl; and

R₁ is selected from;

H,

C₁ to C₁₂ straight chain or branched chain alkyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkenyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkynyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₃ to C₇ cycloalkyl, C₂ to C₆ heterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N,

C₄ to C₁₂ alkylcycloalkyl,

C₃ to C₁₁ alkylheterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N and wherein N is present in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,

phenyl, substituted phenyl, naphthyl, substituted naphthyl,

alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl,

pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, thiazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted.

6. (canceled)

7. A composition comprising a biguanide or related heterocyclic compound of structural Formula II,

8. The composition according to claim 7, wherein:

R₂, R₃, and R₄ are independently selected from H, methyl, ethyl, propyl or isopropyl;

R₅ is selected from H, CH₃, lower alkyl, NH₂, NHCH₃, N(CH₃)₂, NH-alkyl, N(alkyl)₂; and

R₁ is selected from;

H,

C₁ to C₁₂ straight chain or branched chain alkyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkenyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkynyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₃ to C₇ cycloalkyl, C₂ to C₆ heterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N,

C₄ to C₁₂ alkylcycloalkyl,

C₃ to C₁₁ alkylheterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N and wherein N is present in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,

phenyl, substituted phenyl, naphthyl, substituted naphthyl,

alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl,

pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, thiazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted.

9. (canceled)

10. A composition comprising a biguanide or related heterocyclic compound of structural Formula III,

11. The composition according to claim 10, wherein:

R₂, R₃, R₄, R₅, R₆ and R₇ are independently selected from H, methyl, ethyl, propyl or isopropyl; and

R₁ is selected from;

H,

C₁ to C₁₂ straight chain or branched chain alkyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkenyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkynyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₃ to C₇ cycloalkyl, C₂ to C₆ heterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N,

C₄ to C₁₂ alkylcycloalkyl,

C₃ to C₁₁ alkylheterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N and wherein N is present in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,

aryl, phenyl, substituted phenyl, naphthyl, substituted naphthyl,

alkylaryl, alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl,

heteroaryl, pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, thiazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted,

alkylheteroaryl, pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted.

12. (canceled)

13. A composition comprising a biguanide or related heterocyclic compound of structural Formula IV,

14. The composition according to claim 13, wherein:

R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are independently selected from H or methyl; and

R₁ is selected from;

H,

C₁ to C₁₂ straight chain or branched chain alkyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkenyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₁ to C₁₂ straight chain or branched chain alkynyl optionally hetero substituted with oxygen, silicon, sulphur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH₂, NH-alkyl,

C₃ to C₇ cycloalkyl, C₂ to C₆ heterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N,

C₄ to C₁₂ alkylcycloalkyl,

C₃ to C₁₁ alkylheterocycloalkyl, where the heterocycle comprises one or two hetero atoms selected from O, S, or N and wherein N is present in the heterocyclic ring, the nitrogen atom may be in the form of an amide, carbamate or urea,

phenyl, substituted phenyl, naphthyl, substituted naphthyl,

alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl,

pyridyl, furanyl, thiophenyl, pyrrollyl, oxazolyl, isoxazolyl, thiazolyl, diazolyl, pyrazolyl, triazolyl all of which are optionally substituted.

15. (canceled)

16. A composition comprising metformin or salt thereof wherein the composition is adapted to reduce the average bioavailability of the compound, release a therapeutically effective amount of the compound to one or more regions of the intestine of a subject, or a combination thereof.

25. (canceled)

34. (canceled)

35. (canceled)

36. (canceled)

37. (canceled)

38. (canceled)

39. (canceled)

42. (canceled)

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

47. (canceled)

48. (canceled)

49. (canceled)

50. (canceled)

51. (canceled)

52. (canceled)

53. A pharmaceutical dosage form comprising

(a) a pH 6.5 enterically coated immediate release component comprising metformin hydrochloride and a pharmaceutically acceptable excipient;

and

b) a pH 6.5 enterically coated extended release component comprising metformin hydrochloride and a pharmaceutically acceptable excipient; and

wherein the metformin hydrochloride has reduced average bioavailability.

54. A pharmaceutical dosage form according to claim 53, wherein the average systemic bioavailability is less than the average systemic bioavailability of an immediate release metformin formulation having an equivalent amount of metformin.

55. A pharmaceutical dosage form according to claim 53, wherein the average bioavailability is less than 15%.

56. A pharmaceutical dosage form according to claim 53, wherein the proportion of metformin hydrochloride in the immediate release component to the metformin hydrochloride in the extended release component is about 20/80, 30/70, 35/65, 40/60, 45/55 or 50/50.

57. A pharmaceutical dosage form according to claim 53, wherein the dosage form further comprises a DPP-IV inhibitor in (a), (b) or both.

58. A pharmaceutical dosage form according to claim 53, wherein the dosage form further comprises (c) an immediate release component comprising metformin hydrochloride.

60. A pharmaceutical dosage form according to claim 58, wherein the combined amount of metformin hydrochloride is less than 400 mg.