Biguanide Compositions and Methods of Treating Metabolic Disorders

A composition comprising a biguanide or related heterocyclic compound of

• wherein:
• R1, R2, R3, R4, and R5 are independently selected from:
• H, OH,
• O-Rx, wherein Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;
• optionally substituted alkyl;
• cycloalkyl;
• alkylcycloalkyl;
• heterocycloalkyl;
• alkylheterocycloalkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted aryl;
• optionally substituted alkylaryl;
• optionally substituted heteroaryl;
• optionally substituted alkylheteroaryl;
• and
• or R1 and R2 may together form a 3 to 8 membered heterocyclic ring, including the nitrogen atoms to which they are attached;
• or R4 and R5 may together form a ring selected from the group aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl, including the nitrogen atoms to which they are attached;
• 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.

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

• wherein:
• R1, R2, R4, and R5, are independently selected from:
• H, OH,
• O-Rx, wherein Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;
• optionally substituted alkyl;
• cycloalkyl;
• alkylcycloalkyl;
• heterocycloalkyl;
• alkylheterocycloalkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted aryl;
• optionally substituted alkylaryl;
• optionally substituted heteroaryl;
• optionally substituted alkylheteroaryl;
• and
• or R1 and R2 may together form a 3 to 8 membered heterocyclic ring, including the nitrogen atoms to which they are attached;
• or R4 and R5 may together form a ring selected from the group aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl, including the nitrogen atoms to which they are attached;
• R8 is selected from:
• H;
• optionally substituted alkynyl;
• cycloaklyl;
• alkylcycloalkyl;
• heterocycloalkyl;
• alkylheterocycloalkyl;
• optionally substituted aryl;
• optionally substituted alkylaryl (e.g., alkylphenyl, alkylsubstituted phenyl, alkylnaphthyl, alkylsubstituted naphthyl);
• optionally substituted heteroaryl;
• optionally substituted alkylheteroaryl;
• and —NRaRb
• wherein Ra and Rb are independently selected from:
• H;
• optionally substituted alkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• cycloalkyl;
• alkylcycloalkyl;
• heterocyclalkyl;
• alkylheterocycloalkyl;
• optionally substituted aryl, optionally substituted alkylary, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl;
• 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.

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

• wherein:
• R1, R2, R3, R4, R5, R9, and R10, are independently selected from:
• H, OH,
• O-Rx, wherein Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;
• optionally substituted alkyl;
• cycloalkyl;
• alkylcycloalkyl;
• heterocycloalkyl;
• alkylheterocycloalkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted aryl;
• optionally substituted alkylaryl;
• optionally substituted heteroaryl;
• optionally substituted alkylheteroaryl;
• and
• or R1 and R2 may together form a 3 to 8 membered heterocyclic ring, including the nitrogen atoms to which they are attached;
• or R4 and R5 may together form a ring selected from the group aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl, including the nitrogen atoms to which they are attached;
• 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.

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

• wherein:
• wherein R3, R4, R5, R6, R7, R8 and R9 are independently selected from H, methyl, ethyl, propyl or isopropyl;
• and wherein R1 and R2, and are independently selected from:
• H;
• optionally substituted alkyl;
• cycloalkyl;
• alkylcycloalkyl;
• heterocycloalkyl;
• alkylheterocycloalkyl;
• optionally substituted alkenyl;
• optionally substituted alkynyl;
• optionally substituted aryl;
• optionally substituted alkylaryl;
• optionally substituted heteroaryl;
• optionally substituted alkylheteroaryl;
• and
• or R1 and R2 may together form a 3 to 8 membered heterocyclic ring, including the nitrogen atoms to which they are attached
• 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.

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.