阅读说明：本技术 双胍组合物和治疗代谢性病症的方法 (Biguanide compositions and methods of treating metabolic disorders ) 是由 A.D.贝伦 M.S.芬曼 N.R.A.比利 于 2012-07-11 设计创作，主要内容包括：双胍组合物和治疗代谢性病症的方法。本文提供了用于通过施用包含双胍或相关杂环化合物例如二甲双胍的组合物来治疗包括糖尿病、肥胖症的某些病状和其它代谢性疾病、病症或病状的方法。本文还提供了双胍或相关杂环化合物组合物以及用于制备它们以用于在本发明的方法中使用的方法。本文还提供了包含二甲双胍及其盐的组合物以及使用方法。(Biguanide compositions and methods of treating metabolic disorders. Provided herein are methods for treating certain conditions, including diabetes, obesity, and other metabolic diseases, disorders, or conditions by administering compositions comprising biguanides or related heterocyclic compounds, such as metformin. Also provided herein are biguanide or related heterocyclic compound compositions and methods for preparing them for use in the methods of the present invention. Also provided herein are compositions comprising metformin and salts thereof and methods of use.)

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

wherein:

R₁、R₂、R₃、R₄、R₅、R₆and R₇Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and

or R₆And R₇May be linked together to form a bond, thereby together forming a ring containing the nitrogen atom to which they are attached;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

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 the subject, or a combination thereof.

2. The composition of claim 1, wherein

R₂、R₃、R₄、R₅、R₆And R₇Independently selected from H, methyl, ethyl, propyl or isopropyl; and

R₁selected from:

H；

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂A linear or branched alkyl group;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkynyl;

C₃to C₇Cycloalkyl radical, C₂To C₆Heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

C₄to C₁₂An alkyl cycloalkyl group;

C₃to C₁₁Alkyl heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S, or N and wherein N is present in the heterocycle, the nitrogen atom may be in the form of an amide, a carbamate, or a urea;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

3. The composition of claim 1, wherein the compound having formula I is selected from the following structures:

4. a composition comprising a biguanide or related heterocyclic compound of formula IA,

wherein:

R₁、R₂、R₃、R₄and R₅Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl, and piperidinyl;

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 the subject, or a combination thereof.

5. The composition of claim 4, wherein:

R₂、R₃、R₄and R₅Independently selected from H, methyl, ethyl, propyl or isoPropyl; and

R₁selected from:

H；

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂A linear or branched alkyl group;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkynyl;

C₃to C₇Cycloalkyl radical, C₂To C₆Heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

C₄to C₁₂An alkyl cycloalkyl group;

C₃to C₁₁Alkyl heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S, or N and wherein N is present in the heterocycle, the nitrogen atom may be in the form of an amide, a carbamate, or a urea;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

6. The composition of claim 4, wherein the compound having formula IA is selected from the following structures:

7. a composition comprising a biguanide or related heterocyclic compound of formula II,

wherein:

R₁、R₂、R₄and R₅Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl, and piperidinyl;

R₈selected from:

h; optionally substituted alkynyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted aryl; optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and-NR_aR_b

Wherein R is_aAnd R_bIndependently selected from:

h; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted aryl, optionally substituted alkylaryl, 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 the subject, or a combination thereof.

8. The composition of claim 7, wherein:

R₂、R₃and R₄Independently selected from H, methyl, ethyl, propyl or isopropyl;

R₅selected from H, CH₃Lower alkyl, NH₂、NHCH₃、N(CH₃)₂NH-alkyl, N (alkyl)₂(ii) a And

R₁selected from:

H；

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂A linear or branched alkyl group;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl;

optionally hetero-substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkynyl;

C₃to C₇Cycloalkyl radical, C₂To C₆Heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

C₄to C₁₂An alkyl cycloalkyl group;

C₃to C₁₁Alkyl heterocycloalkyl, wherein the heterocycle contains one or two heteroatoms selected from O, S, or N and wherein N is present in the heterocycle, the nitrogen atom may be in the form of an amide, a carbamate, or a urea;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

9. The composition of claim 7, wherein the compound having formula II is selected from the following structures:

10. a composition comprising a biguanide or related heterocyclic compound of formula III,

wherein:

R₁、R₂、R₃、R₄、R₅、R₉and R₁₀Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl, and piperidinyl;

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 the subject, or a combination thereof.

Technical Field

The present invention generally relates to compositions for targeted administration of biguanides or related heterocyclic compounds to a subject, for example in a method of treating a metabolic disorder.

Background

Despite the extensive efforts long-standing to develop effective treatments for diabetes, metabolic syndrome, obesity, overweight and related metabolic conditions, the number of people worldwide suffering from these conditions is rapidly increasing. These pathologies result in a number of medical complications, a reduction in quality of life, a reduction in longevity, a loss of work efficiency, a strain on the medical system, and a burden on the medical insurance provider (which translates into increased costs for all). In addition, it is desirable to maintain health (including healthy body weight and healthy blood glucose levels).

Type II diabetes treatment in use or development is designed to lower blood glucose levels. They include mimetics of GLP-1 (glucagon-like peptide-1), a hormone that plays a critical role in regulating insulin, glucose and hunger. An example of a mimetic is the GLP-1 receptor agonist Exenatide (Exenatide)

And the GLP-1 analogue Liraglutide (Liraglutide). Other drugs inhibit DPP-IV, which is an enzyme that rapidly degrades endogenous GLP-1. Exenatide is a GLP-1 receptor agonist that is more slowly degraded by DPP-IV. The GLP-1 analogue liraglutide is attached to the albumin-binding fatty acid molecule and reduces the rate of GLP-1 release and its degradation. (see, e.g., Nicolucci et al, 2008, "inclusion-based therapeutics: a new potential treatment of a to overhead linkage involvement in type 2 diabetes," Acta biomedical 79 (3): 184-91 and U.S. Pat. No.5,424,286, "Exendin-3 and Exendin-4 polypeptides, and pharmacological interactions comprising same")

Biguanides (Metformin) are antihyperglycemic agents that improve glucose tolerance in patients with type II diabetes by lowering both basal and postprandial blood glucose. The pharmacological mechanism of action is different from other classes of oral antihyperglycemic drugs. Metformin reduces intrahepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. However, metformin is reported to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal function impairment. For example, in patients with known or suspected impaired renal function (such as those of advanced age), metformin administration requires intensive dose monitoring and titration to prevent the potentially fatal metabolic complication of lactic acidosis. Patients with concomitant cardiovascular or hepatic disease, sepsis and hypoxia also increase the risk of lactic acidosis. Thus, for some patient groups, metformin remains an unavailable and/or dangerous treatment due to its side effects.

Until recently, obesity treatment included two FDA-approved drugs. Orlistat (Orlistat)

The intestinal fat absorption is reduced by inhibiting pancreatic lipase. Sibutramine (Sibutramine) withdrawn from the European and US marketsBy suppressing spiritAppetite is reduced by inactivation of the transmitters norepinephrine, 5-hydroxytryptamine, and dopamine. These drugs have reported unwanted side effects, including effects on blood pressure. (see, e.g., "description medicines for the Treatment of Obesity," NIH publication No.07-4191, month 12 2007). Surgical treatments including gastric bypass surgery and gastric banding are available, but only in extreme cases. These procedures can be dangerous and, furthermore, may not be an appropriate option for patients with more moderate weight loss goals.

Summary of The Invention

Provided herein are compositions having at least one biguanide or related heterocyclic compound, including metformin, and methods of treatment using the same.

In some embodiments, the compositions herein are adapted to minimize the systemic bioavailability of the compound, e.g., reduce the average systemic bioavailability of the biguanide compared to compositions formulated for immediate release with an equivalent amount of the compound. In some embodiments, the compositions described herein may be suitable for release to the upper or small intestine, the lower or large intestine, or both. The composition is administered enterally by any known method including oral administration. In some embodiments, the compositions described herein comprise a biguanide or related heterocyclic compound suitable for releasing a therapeutically effective amount of the biguanide or related heterocyclic compound across the stomach.

In certain embodiments, the biguanide or related heterocyclic compound is selected from a compound having structural formula I,

wherein:

r1, R2, R3, R4, R5, R6, and R7 are independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and is

Or R6 and R7 may be joined together to form a bond, thereby together forming a ring containing the nitrogen atom to which they are attached;

or R1 and R2 may together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R4 and R5 may together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In some embodiments of the present invention, the substrate is,

O-Rx is selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments of the present invention, the substrate may be,

r2, R3, R4, R5, R6 and R7 are independently selected from H, methyl, ethyl, propyl or isopropyl; and is

R1 is selected from:

H；

c1 to C12 straight or branched chain alkyl optionally substituted with oxygen, silicon, sulfur, hetero-or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkenyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkynyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c3 to C7 cycloalkyl, C2 to C6 heterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

c4 to C12 alkylcycloalkyl;

c3 to C11 alkylheterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N and wherein N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate or urea form;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

In certain embodiments, the biguanide or related heterocyclic compound is selected from a compound of formula IA,

wherein:

r1, R2, R3, R4, and R5 are independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and is

Or R1 and R2 may together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R4 and R5 may together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In some embodiments of the present invention, the substrate is,

O-Rx is selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments of the present invention, the substrate may be,

r2, R3, R4 and R5 are independently selected from H, methyl, ethyl, propyl or isopropyl; and is

R1 is selected from:

H；

c1 to C12 straight or branched chain alkyl optionally substituted with oxygen, silicon, sulfur, hetero-or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkenyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkynyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c3 to C7 cycloalkyl, C2 to C6 heterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

c4 to C12 alkylcycloalkyl;

c3 to C11 alkylheterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N and wherein N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate or urea form;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

In other embodiments, the biguanide or related heterocyclic compound is selected from a compound having the structural formula II,

wherein:

r1, R2, R4, and R5 are independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and is

Or R1 and R2 may together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R4 and R5 may together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl, and piperidinyl;

r8 is selected from:

h; optionally substituted alkynyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted aryl; optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted 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; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, and optionally substituted alkylheteroaryl.

In some embodiments of the present invention, the substrate is,

O-Rx is selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments of the present invention, the substrate may be,

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 is

R1 is selected from:

H；

c1 to C12 straight or branched chain alkyl optionally substituted with oxygen, silicon, sulfur, hetero-or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkenyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkynyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c3 to C7 cycloalkyl, C2 to C6 heterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

c4 to C12 alkylcycloalkyl;

c3 to C11 alkylheterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N and wherein N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate or urea form;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

In some embodiments, the biguanide or related heterocyclic compound is selected from a compound having structural formula III,

wherein:

r1, R2, R3, R4, R5, R9, and R10 are independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and is

Or R1 and R2 may together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R4 and R5 may together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In some embodiments of the present invention, the substrate is,

O-Rx is selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In some embodiments of the present invention, the substrate is,

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 or branched chain alkyl optionally substituted with oxygen, silicon, sulfur, hetero-or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkenyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkynyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c3 to C7 cycloalkyl, C2 to C6 heterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

c4 to C12 alkylcycloalkyl;

c3 to C11 alkylheterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N and wherein N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate or urea form;

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

alkylaryl, alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

heteroaryl, pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted;

alkyl heteroaryl, pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

In some embodiments, the biguanide or related heterocyclic compound is selected from a compound having 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 are independently selected from:

h; optionally substituted alkyl; a cycloalkyl group; an alkyl cycloalkyl group; a heterocycloalkyl group; an alkyl heterocycloalkyl group; optionally substituted alkenyl; optionally substituted alkynyl;

optionally substituted aryl; optionally substituted alkylaryl; optionally substituted heteroaryl; optionally substituted alkylheteroaryl; and is

Or R1 and R2 may together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached.

In one embodiment of the process of the present invention,

O-Rx is selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In a further embodiment of the process of the present invention,

r2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from H or methyl; and is

R1 is selected from:

H；

c1 to C12 straight or branched chain alkyl optionally substituted with oxygen, silicon, sulfur, hetero-or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkenyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c1 to C12 straight or branched alkynyl optionally substituted with oxygen, silicon, sulfur hetero or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl;

c3 to C7 cycloalkyl, C2 to C6 heterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N;

c4 to C12 alkylcycloalkyl;

c3 to C11 alkylheterocycloalkyl wherein the heterocycle contains one or two heteroatoms selected from O, S or N and wherein N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate or urea form;

phenyl, substituted phenyl, naphthyl, substituted naphthyl;

alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl;

pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted.

In some embodiments, the biguanide or related heterocyclic compound is metformin or a salt thereof. In another embodiment, the biguanide or related heterocyclic compound is metformin hydrochloride.

In the compositions and methods disclosed herein, the biguanides or related heterocyclic compounds may contain one or more asymmetric centers and form compositions of racemic mixtures, diastereomeric mixtures, individual enantiomers, diastereomers of enantiomers, meso compounds, pure epimers or mixtures of epimers thereof, and the like. In other embodiments, the biguanide or related heterocyclic compound comprises one or more double bonds, wherein the compound is cis/trans, an E/Z mixture, or an E or Z geometric isomer thereof. The biguanide or related heterocyclic compound may be a salt selected from: hydrochloride, hydrobromide, acetate, propionate, butyrate, sulfate, bisulfate, sulfite, carbonate, bicarbonate, phosphate, phosphinate, oxalate, hemi-oxalate, malonate, hemi-malonate, fumarate, hemi-fumarate, maleate, hemi-maleate, citrate, hemi-citrate, tartrate, hemi-tartrate, aspartate, and glutamate.

In the methods disclosed herein, the biguanide or related heterocyclic compound may be formulated as a composition containing components A, B, and C, wherein:

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

b is a divalent anion of an acid; and is

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

In some embodiments of the present invention, the substrate is,

a is a 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 is

B is a divalent anion of an acid selected from: oxalic acid, malonic acid, citric acid, maleic acid, fumaric acid, tartaric acid, aspartic acid, and glutamic acid.

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

In other embodiments, the therapeutically effective amount of biguanide or related heterocyclic compound, e.g., metformin or a salt thereof, is from about 1mg to about 2000 mg. In other embodiments, the therapeutically effective amount of metformin or a salt thereof is from about 10mg to about 1500 mg. In a further embodiment, the therapeutically effective amount of biguanide or related heterocyclic compound, e.g., metformin or a salt thereof, is from about 50mg to about 1000 mg. In a further embodiment, the therapeutically effective amount of biguanide or related heterocyclic compound, e.g., metformin or a salt thereof, is from about 100mg to about 500 mg.

In preferred embodiments, the compositions described herein are suitable for reducing or minimizing the systemic bioavailability of the compound, e.g., minimizing the circulating plasma concentration of the biguanide compound in a patient and/or reducing the average systemic bioavailability of the compound, e.g., when compared to an immediate release composition having an equivalent amount of the compound. In some embodiments, the circulating plasma concentration that is minimized in a subject having normal or impaired renal function is less than 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 0.24 μ g/mL. In other embodiments, a suitable combination of compounds has a relative bioavailability of 70%, 60%, 50%, 40%, 30%, 20%, or 10% relative to an immediate release composition having the same amount of the compound.

In some embodiments, the compositions herein are suitable for the delivery of a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

In some embodiments, the composition is suitable for release in the duodenum, jejunum, ileum, caecum, colon, and/or rectum. In other embodiments, the composition is suitable for release in the jejunum, ileum, caecum, colon and/or rectum. In some embodiments, the composition is formulated for release in the lower intestine. In further embodiments, the composition is formulated for release in the upper intestine. In still further embodiments, the composition is formulated to release in the upper and lower intestines.

In one embodiment, the composition begins to release the biguanide or related heterocyclic compound about 75 minutes, about 105 to about 135 minutes, about 165 to about 195 minutes, or about 225 to about 255 minutes, or a combination of times thereof, following oral administration to a subject.

In other embodiments, the composition begins to release the biguanide or related heterocyclic compound at about pH 5.0, about pH 5.5, about pH6.0, about pH6.5, about pH 7.0, or a combination thereof following oral administration to a subject.

Also provided herein are compositions comprising a biguanide or related heterocyclic compound, the composition further comprising one or more chemosensory receptor ligands selected from the group consisting of: a sweet taste receptor ligand, an umami taste receptor ligand, a fat receptor ligand, a bile acid receptor ligand, a bitter taste receptor ligand, or any combination thereof. In some embodiments, the composition further comprises a sweet taste receptor ligand. In other embodiments, the composition further comprises an umami receptor ligand. In other embodiments, the composition further comprises a sweet taste receptor ligand and an umami taste receptor ligand.

Sweet receptor ligands include glucose, sucralose, aspartame, stevioside, rebaudioside, Neotame (Neotame), acesulfame-K, and saccharin. Umami receptor ligands include glutamate, glutamine, acetylglycine or aspartame. Fat receptor ligands include linoleic acid, oleic acid, palmitate, oleoylethanolamide, mixed fatty acid emulsions, omega-3 fatty acids, and N-acylphosphatidylethanolamine (NAPE). Acid acceptor ligands include citric acid and hydroxycitric acid. Bile acids include deoxycholic acid, taurocholic acid and chenodeoxycholic acid. In certain embodiments, the chemosensory receptor ligand is non-metabolic. In certain embodiments, the chemosensory receptor ligand is an agonist. In certain embodiments, the chemosensory receptor ligand is an enhancer.

Accordingly, also provided herein is a composition comprising a biguanide or related heterocyclic compound, said composition further comprising a chemosensory receptor enhancer selected from the group consisting of: sweet taste receptor potentiators, bitter taste receptor potentiators, umami taste receptor potentiators, fat receptor potentiators, sour taste receptor potentiators, and bile acid receptor potentiators. In certain embodiments, the sensory receptor enhancer is an umami receptor enhancer that enhances the effect of food on umami receptors in the intestine.

The compositions described herein may be formulated with an enteric coating. In another aspect, the compositions described herein can be formulated with a modified release system. In yet another aspect, the compositions described herein can be formulated with a timed release system. In another aspect, the compositions described herein can be formulated with modified release and enteric coatings. In yet another aspect, the compositions described herein can be formulated with a timed release system and an enteric coating.

Provided herein is a method of treating certain conditions in a subject, the method comprising administering to the subject a composition comprising a biguanide or related heterocyclic compound described herein.

In one aspect, the method comprises administering to the subject at least one biguanide or related heterocyclic compound comprising a compound selected from any of the compounds described herein, and wherein the composition is adapted to minimize the systemic bioavailability of the compound and/or release a therapeutically effective amount of the biguanide or related heterocyclic compound to one or more regions of the intestine.

In preferred embodiments, the administration results in a reduced or minimized systemic bioavailability of the compound, e.g., a minimized circulating plasma concentration of the biguanide compound and/or a reduced average systemic bioavailability of the compound in a patient, when compared to an immediate release composition having an equivalent amount of the compound. In some embodiments, the circulating plasma concentration that is minimized in a subject having normal or impaired renal function is less than 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. In other embodiments, the compound has a relative bioavailability that is less than 60%, 50%, 40%, 30%, or 20% as compared to an immediate release composition having an equivalent amount of the compound.

Provided herein is a method of treating certain conditions by administering to the lower intestine of a subject a composition having at least one biguanide or related heterocyclic compound. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the upper intestine of a subject. In yet another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the upper and lower intestines of a subject. In some cases, the biguanide or related heterocyclic compound in the upper and lower intestines is the same biguanide or related heterocyclic compound. In some cases, the biguanides or related heterocyclic compounds in the upper and lower intestines are different.

Provided herein is a method of treating certain conditions by administering to the duodenum, jejunum, ileum, caecum, colon, and/or rectum a composition having at least one biguanide or related heterocyclic compound. In other embodiments, a composition comprising at least one biguanide or related heterocyclic compound is administered to the duodenum of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the jejunum of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the ileum of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the cecum of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the colon of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the rectum of a subject. In another embodiment, a composition comprising at least one biguanide or related heterocyclic compound is administered to the duodenum, jejunum, ileum, caecum, colon and/or rectum of a subject.

Provided herein is a method of treating certain conditions by administering one or more biguanide or related heterocyclic compound compositions that begin release at about 75 minutes, 105 to about 135 minutes, about 165 to about 195 minutes, about 225 to about 255 minutes, or a combination of times thereof after oral administration to a subject.

Provided herein is a method of treating certain conditions by administering one or more biguanide or related heterocyclic compound compositions beginning at about 120 minutes, about 180 minutes, about 240 minutes, or a combination thereof after oral administration to a subject. In one embodiment, the composition begins to release about 120 minutes after administration to the subject. In one embodiment, the composition begins to release about 180 minutes after administration to a subject. In one embodiment, the composition begins to release about 240 minutes after administration to a subject. In one embodiment, the composition begins to release about 120 minutes, about 180 minutes, and about 240 minutes after oral administration to a subject.

In certain embodiments, the one or more biguanide or related heterocyclic compound compositions begin to release at about pH 5.5, about pH6.0, about pH6.5, and/or about pH 7.0.

In certain embodiments, the biguanide or related heterocyclic compound composition begins release at two different pH ranges, wherein the two pH ranges are selected from the group consisting of about pH 5.0 to about pH6.0, about pH6.0 to about pH 7.0, and about pH 7.0 to about pH 8.0.

Provided herein are methods of modulating the circulating concentration of one or more hormones, including but not limited to GLP-1, GLP-2, GIP, gastrointestinal hormone, PYY, CCK, active glucagon (glycitin), insulin, glucagon, ghrelin, amylin, insulin, C-peptide, and uroacilin, by administering to a subject a composition comprising at least one biguanide or related heterocyclic compound described herein. Provided herein are methods of modulating hormonal properties of the lower intestine of a subject by administering to the lower intestine a composition having at least one biguanide or related heterocyclic compound. In one embodiment, the hormonal property is a property of GLP-1, a gastrointestinal hormone, and PYY.

Provided herein are methods of modulating hormonal properties of the upper intestine by administering to the upper intestine of a subject a composition having at least one biguanide or related heterocyclic compound. In one embodiment, the hormonal characteristic is a characteristic of GLP-1, GLP-2, gastrointestinal hormone, PYY, GIP, C-peptide, glucagon, insulin, CCK, or any combination thereof.

Further provided herein are methods of sensitizing lower intestine chemosensory receptors by stimulating bitter taste receptors in the upper intestine with a biguanide or related heterocyclic compound.

Provided herein are methods of treating certain conditions with the biguanide or related heterocyclic compound compositions described herein. These conditions include metabolic syndrome, type I diabetes, type II diabetes, obesity, binge eating, undesired overeating, food addiction, a need to reduce food intake or to reduce body weight or to maintain body weight loss, a need to maintain healthy body weight, a need to maintain normoglycemic metabolism, anorexia, pre-diabetes, glucose intolerance, Gestational Diabetes Mellitus (GDM), Impaired Fasting Glucose (IFG), postprandial hyperglycemia, accelerated gastric emptying, dumping syndrome, delayed gastric emptying, dyslipidemia, post-prandial dyslipidemia, hyperlipidemia, hypertriglyceridemia, post-hypertriglyceridemia, insulin resistance, bone loss disorders, osteopenia, osteoporosis, muscle wasting disorders, muscle degenerative disorders, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), Intestinal immune disorders (e.g., celiac disease), bowel irregularity (bowelirregularity), Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) including, for example, ulcerative colitis, Crohn's disease, short bowel syndrome, and peripheral neuropathy (e.g., diabetic neuropathy). In some embodiments, the condition is obesity. In certain embodiments, the condition is diabetes. In additional embodiments, the subject has undergone bariatric surgery. In other embodiments, the methods provided herein further comprise administering a medicament for diabetes or obesity.

In certain embodiments, these conditions include depression, stress, sadness, anxiety disorders (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, or social anxiety disorder, or mood disorders (e.g., depression, bipolar disorder, dysthymic disorder, and cyclothymic disorder).

In addition, the compositions described herein may be used for the dietary management of the conditions listed above.

Also provided herein are methods for treating a disease, disorder, or deficiency of energy balance in a subject, comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for treating overweight in a subject, the methods comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for treating obesity in a subject comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for reducing food intake in a subject comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for treating type II diabetes in a subject, comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for maintaining healthy body weight in a subject comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for treating pre-diabetes in a subject comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for increasing GLP-1 concentration in a subject comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

Also provided herein are methods for increasing a PYY concentration in a subject, comprising administering a composition described herein. In one aspect, the compositions are suitable for delivering a therapeutically effective amount of a biguanide or related heterocyclic compound to one or more regions of the intestine.

In some embodiments of the methods provided herein, prior to administration of the composition, the subject is pre-screened for endogenous chemosensory receptor levels and types for modulating the amount of the composition administered.

The methods disclosed herein may also further comprise administering a DPP-IV inhibitor, a chemosensory receptor ligand (e.g., a sweet receptor ligand, a bitter receptor ligand, an umami receptor ligand, an sour receptor ligand, a fat receptor ligand, or a bile acid receptor ligand, or a combination thereof, a chemosensory receptor antagonist (e.g., lactitol), a chemosensory receptor enhancer), an anti-obesity agent, or an anti-diabetic agent.

Also provided herein are pharmaceutical dosage forms comprising: (a) a pH6.5 enteric coated immediate release component comprising metformin hydrochloride and a pharmaceutically acceptable excipient; and (b) a pH6.5 enteric coated extended release component comprising metformin hydrochloride and a pharmaceutically acceptable excipient; and wherein the total amount of metformin from both components is less than 400mg and wherein the metformin has a subtherapeutic plasma AUC and a subtherapeutic plasma Cmax.

In some embodiments, the ratio of metformin hydrochloride in the immediate release component to metformin hydrochloride in the delayed release component is about 20/80, 30/70, 35/65, 40/60, 45/55, or 50/50. In other embodiments, the dosage form exhibits a dissolution release profile of metformin hydrochloride in an amount of 80% to 100% after 75 minutes of oral administration.

In some embodiments, the plasma AUC and plasma Cmax resulting from administration of the dosage form is 50% or less than the plasma AUC and Cmax resulting from administration of a single dose of 500mg of glumeteza.

In some embodiments, the dosage form in (a), (b), or both further comprises a DPP-IV inhibitor. In other embodiments, the dosage form further comprises an anti-diabetic agent or an anti-obesity agent.

In some embodiments, the dosage form further comprises (c) an immediate release component comprising metformin hydrochloride. In some cases, (c) the immediate release component has an enteric coating at pH 5.0. In some cases, the total amount of metformin from components (a) to (c) is less than 600 mg.

In some embodiments, the excipient in the extended release component is selected from the group consisting of: ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, xanthan gum, sodium alginate, polysorbate-80, and mixtures thereof.

In some embodiments, the total amount of metformin hydrochloride is about 250 mg.

In some embodiments, the dosage form is a bilayer tablet. In other embodiments, the dosage form is a capsule having two components as encapsulated mini-tablets.

Also provided herein are pharmaceutical dosage forms comprising: (a) a pH6.5 enteric coated immediate release component comprising metformin hydrochloride and a pharmaceutically acceptable excipient; and (b) an enteric coated extended release component, ph6.5, comprising metformin hydrochloride and a pharmaceutically acceptable excipient; and wherein the metformin hydrochloride has a reduced average systemic bioavailability.

In some embodiments, the average systemic bioavailability is less than the average systemic bioavailability of an immediate release metformin formulation having an equivalent amount of metformin. In other embodiments, the average systemic bioavailability is less than 15%.

In some embodiments, the total amount of metformin hydrochloride is less than 400 mg.

Is incorporated by reference

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of Drawings

Figure 1 shows the design of the study described in example 5.

Figure 2 shows events during the treatment period of the study described in example 5.

Figure 3 shows plasma concentrations (x-axis; ng/mL) of Metformin (●) and sustained release Metformin (Re-Metformin) (■) as a function of time (y-axis; min) after ingestion of t-240 and after a meal of t-0 min.

Figure 4A shows PYY plasma concentrations (x-axis; pg/mL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after metformin (●) or extended release metformin (■) ingestion and after a meal at T-0 min figure 4B shows active GLP-1 plasma concentrations (x-axis; GLP-1A pmol/L) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after metformin (●) or extended release metformin (■) ingestion and after a meal at T-0 min ingestion figure 4C shows the percentage increase of GLP-1 plasma concentrations (x-axis; GLP-1A pmol/L) as a function of time (y-axis; GLP-1A pmol/L) in subjects at baseline (□, ○) or after metformin (●) or extended release metformin (■) ingestion and after a meal at T-0 min in subjects as a function of time (y-axis; total GLP-1 pmol/L) versus AUC 4C for the graph.

Fig. 5A shows the glucose plasma concentration (x-axis; mg/dL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after metformin (●) or extended release metformin (■) ingestion and after a meal at t-0 min fig. 5B shows the insulin plasma concentration (x-axis; pmol/L) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after metformin (●) or extended release metformin (■) ingestion and after a meal at t-0 min the percentage decrease in Abs AUC is relative to baseline values for fig. 5A-5B.

Figure 6 is a graph showing the area under the PYY curve (x-axis; log-transformed) as a function of the area under the metformin curve (ng/mL min) after ingestion of metformin (●) or extended release metformin (■).

Figure 7A shows plasma concentrations (x-axis; ng/mL) of metformin (●) and extended release metformin (■) as a function of time (y-axis; min) after ingestion of t-240 and after a meal of t-0 min figure 7B shows PYY plasma concentrations (x-axis; pg/mL) as a function of time (y-axis; min) in subjects at baseline (□, ○) or after ingestion of metformin (●) or extended release metformin (■) and after a meal of t-0 min.

Figure 8 is a flow chart of a 12-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the safety and efficacy of twice-daily administration of extended release metformin in subjects with type 2 diabetes.

Detailed Description

The present invention relates to methods and compositions for treating certain conditions (e.g., metabolic conditions, including obesity and diabetes) using biguanides or related heterocyclic compounds or a combination of biguanides or related heterocyclic compounds. One or more biguanides or related heterocyclic compounds regulate the synthesis, secretion and/or storage of hormones, such as GLP-1, GLP-2, gastrointestinal hormones, PYY, GIP, insulin, C-peptide, active glucagon, amylin, ghrelin, uroguanin and/or CCK, which are key regulators of energy and metabolic processes, such as glucose metabolism.

These embodiments described herein additionally encompass targeted administration of biguanides or related heterocyclic compounds to specific sites throughout the intestine. Enteroendocrine cells such as L cells, K cells, and I cells, each secreting a different set of metabolic hormones in response to chemosensory stimulation, are present throughout the length of the intestine. The concentration and ratio of these enteroendocrine cell types is different in different intestinal segments, and as noted above, the various cell types have different metabolic hormone expression profiles. Targeted administration of the compositions of the present invention to specific segments of the intestine, for example, by using formulations designed for release within one or more desired segments of the intestine, provides another level of control over the action of such compositions (e.g., modulation of hormones involved in metabolism).

These embodiments described herein thus include novel methods of modulating the secretion of metabolic hormones to treat certain conditions, for example, by using biguanides or related heterocyclic compounds to activate via enteroendocrine chemosensory receptors. Embodiments further include the ability to select combination therapies suitable for specific needs of individuals with varying hormonal properties.

Biguanides or related heterocyclic compounds may be used in combination with one or more chemosensory receptor ligands to modulate hormonal properties in an individual. Exemplary chemosensory receptor ligands and their use in modulating hormonal properties are described, for example, in U.S. application publication No.: 20100267643, 20110065660, and 20120094942; and PCT application publication nos. wo2010123930, WO2011133180, WO2012054523, WO2012054526, WO2012054527, WO2012054528, and WO2012054530, each of which is incorporated herein by reference in its entirety.

Embodiments described herein include compositions and methods for modulating the concentration of circulating enteroendocrine cytokines including, but not limited to, GLP-1, GLP-2, GIP, gastrointestinal hormones, PYY, CCK, active glucagon, insulin, glucagon, C-peptide, ghrelin, amylin, urocanin, and the like, such compositions and methods comprising administering at least one biguanide or related heterocyclic compound to a subject to treat certain conditions. Hormone modulation can be achieved by administering a composition comprising a biguanide or related heterocyclic compound to act on a bitter taste receptor.

In particular embodiments, the combination of a biguanide or related heterocyclic compound with one or more agonists of sweet, umami, bitter, free fatty acids and bile acid receptors will stimulate the simultaneous release of important hormones and neural signals from enteroendocrine cells and thus aid in the assimilation and processing of dietary nutrients. In further embodiments, the combination of a biguanide or related heterocyclic compound and one or more agonists of sweet, umami, bitter, free fatty acids and bile acid receptors inhibits ghrelin synthesis, activity or effect or post-translational modification thereof (ghrelin octanoyl acyltransferase activity or GOAT) and/or ghrelin secretion or release.

Biguanides and related heterocyclic compounds

The compositions and methods disclosed herein relate to biguanides and related heterocyclic compounds. By way of background, metformin is one of the simplest structural variants of a class of compounds known as biguanides. From a structural perspective, metformin resembles a pharmacophore or fragment of a chemical structure with greater biological activity. The parent biguanide structures and structures of metformin, phenformin, buformin, proguanil, imeglimin and their enantiomers are shown below.

Without intending to be limited by theory, although the geometry of metformin and related open chain biguanides is not fully understood in the context of their interaction with biological targets, the geometry is intended to be limited to the cis and trans forms shown below.

Furthermore, without intending to be limited by theory, these two forms represent low energy forms of the structure with an intrinsic energy barrier to key bond rotation that allows the cis and trans forms to be converted to each other. X-ray crystal studies of metformin dinitrate show a "cis" structure that is a favorable conformer in the solid phase. Fridrichov a M,

I. N ě mec i.1, 1-Dimethyl-biguanidinium (2+) dintrate. actacrytallogr sec E Struct Rep online.2012 1 month 1; 68(Pt 1): o18-9. electronic publication 2011 12, 3. A group of related structural dihydrotriazines, for example the compound known as Imeglimin (currently in the late clinical evaluation phase of Poxel pharmaceuticals) have an immobilizationThe "cis" conformation within its structure, as shown below:

in one disclosed aspect, biguanides and related heterocyclic compounds are provided, including those containing elements that cause conformational immobilization or solidification of a "cis" biguanide, as shown below, with metformin variants of each exemplary structural type. More specifically, the relationship between the metformin series [ herein represented by formula (I) ], the triazole series [ herein represented by formula (IA) ], the triazine series [ herein represented by formula (II) ], the dihydrotriazine series [ herein represented by formula (III) ] and the 7-membered ring series [ herein represented by formula (IV) ] is shown.

In one embodiment, compounds having formula I may be used in combination with the disclosed compositions and methods.

Wherein:

R₁、R₂、R₃、R₄、R₅、R₆and R₇Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two members selected from O, C,Hetero atoms of S or N, including C₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl);

optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and is

Or R₆And R₇May be linked together to form a bond, thereby together forming a ring containing the nitrogen atom to which they are attached;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In certain embodiments, O-Rx may be selected from: O-C1 to C8 straight or branched chain alkyl; O-C3 to C7 cycloalkyl; O-C4 to C8 alkylcycloalkyl; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH2, NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.

In certain embodiments, R3, R6, and R7; or R3, R4, R5 and R7; or R3, R4, R5 and R7; or R3, R4, R5, R6 and R7; or each of R2, R3, R4, R5, R6 and R7 is independently selected from:

H. methyl, ethyl, propyl or isopropyl;

and the remaining substituent groups R₁、R₂、R₄And R₅(ii) a Or R₁、R₂And R₆(ii) a Or R₁、R₂And R₆(ii) a Or R₁And R₂(ii) a Or R₁Each of which is independently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl)Radical); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

Exemplary compounds having formula I and substituents R1, R2, R3, R4, R5, R6, and R7 are shown below. However, other combinations of selection of substituents R1, R2, R3, R4, R5, R6, and R7 are envisioned.

In other embodiments of compounds having formula I, R₆And R₇Taken together to form a bond to form a ring containing the nitrogen atom to which they are attached, thereby providing triazole compounds having formula IA, which can be used in conjunction with the disclosed compositions and methods. Unless otherwise indicated, the substituent definitions are the same as those provided with reference to formula I.

Wherein:

R₁、R₂、R₃、R₄and R₅Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); ring (C)Alkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl);

optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and is

Or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In certain embodiments, O-Rx may be selected from: O-C₁To C₈A linear or branched alkyl group; O-C₃To C₇A cycloalkyl group; O-C₄To C₈An alkyl cycloalkyl group; an O-acyl group; an O-ester;and an O-thioester.

In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.

In certain embodiments, R₃(ii) a Or R₃And R₄(ii) a Or R₃、R₄And R₅(ii) a Or R₂、R₃、R₄And R₅Each of which is independently selected from:

H. methyl, ethyl, propyl or isopropyl;

and the remaining substituent groups: r₁、R₂、R₄And R₅(ii) a Or R₁、R₂And R₅(ii) a Or R₁And R₂(ii) a Or R₁And R₂(ii) a Or R₁Each of which is independently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where N is present in the heterocycleWhen in (1), the nitrogen atom may be in the form of an amide, carbamate, or urea); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

Exemplary compounds and substituents R having formula IA₁、R₂、R₃、R₄And R₅As shown below. However, substituents R are foreseen₁、R₂、R₃、R₄And R₅Other combinations of selections of (a).

In other embodiments, triazine compounds having formula II can be used in conjunction with the disclosed compositions and methods. Unless otherwise indicated, the substituent definitions are the same as those provided with reference to formula I.

Wherein:

R₁、R₂、R₄and R₅Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl);

optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and is

Or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl, and piperidinyl;

R₈selected from:

h; optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and-NR_aR_b

Wherein R is_aAnd R_bIndependently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocyclic ringsAlkyl groups); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl), optionally substituted alkylaryl (e.g., alkylphenyl, alkyl substituted phenyl, alkylnaphthyl, alkyl substituted naphthyl), optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted), and optionally substituted alkylheteroaryl.

In certain embodiments, O-Rx may be selected from: O-C₁To C₈A linear or branched alkyl group; O-C₃To C₇A cycloalkyl group; O-C₄To C₈An alkyl cycloalkyl group; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.

In certain embodiments, R₈Can be selected from H; lower alkyl, including CH₃；NH₂(ii) a NH-alkyl, N (alkyl)₂Including NHCH₃、N(CH₃)₂. In certain aspects, if desired, with R₈In these particular selected combinations of (1), R₁、R₂、R₄And R₅(ii) a Or R₂、R₄And R₅(ii) a Or R₄And R₅(ii) a Or R₅Each of which may be independently selected from:

H. methyl, ethyl, propyl or isopropyl;

and the remaining substituents: r₁(ii) a Or R₁And R₂(ii) a Or R₁、R₂And R₅Each of which is independently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

Exemplary Compounds and substituents R having formula II₁、R₂、R₄、R₅And R₈As shown below. However, substituents R are foreseen₁、R₂、R₄、R₅And R₈Other combinations of selections of (a).

In other embodiments, the dihydrotriazine compounds having formula III can be used in conjunction with the disclosed compositions and methods. Unless otherwise indicated, the substituent definitions are the same as those provided with reference to formula I.

Wherein:

R₁、R₂、R₃、R₄、R₅、R₉and R₁₀Independently selected from:

H、OH；

O-Rx, where Rx is alkyl, cycloalkyl, alkylcycloalkyl, acyl, ester, thioester;

optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight chainOr a branched alkenyl group); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally substituted with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl);

optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

In certain embodiments, O-Rx may be selected from: O-C₁To C₈A linear or branched alkyl group; O-C₃To C₇A cycloalkyl group; O-C₄To C₈An alkyl cycloalkyl group; an O-acyl group; an O-ester; and an O-thioester.

In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.

In certain aspects, R₃Or R₃、R₄、R₅And R₁₀(ii) a Or R₃、R₄、R₅、R₉And R₁₀(ii) a Or R₂、R₃、R₄、R₅、R₉And R₁₀Each of which may be independently selected from:

H. methyl, ethyl, propyl or isopropyl;

and the remaining substituent groups: r₁、R₂、R₄、R₅、R₉And R₁₀(ii) a Or R₁、R₂And R₉(ii) a Or R₁And R₂(ii) a Or R₁Each of which is independently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached;

or R₄And R₅May together form a ring containing the nitrogen atom to which they are attached selected from the group consisting of: aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidinyl.

Exemplary Compounds and substituents R having formula III₁、R₂、R₃、R₄、R₅、R₉And R₁₀As shown below. However, substituents R are foreseen₁、R₂、R₃、R₄、R₅、R₉And R₁₀Other combinations of selections of (a).

In other embodiments, compounds of the 7-membered ring series having formula IV can be used in conjunction with the disclosed compositions and methods. Unless otherwise indicated, the substituent definitions are the same as those provided with reference to formula I.

Wherein:

wherein R is₃、R₄、R₅、R₆、R₇、R₈And R₉Independently selected from H, methyl, ethyl, propyl or isopropyl;

and wherein R₁And R₂Independently selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., hetero thereinThe ring containing one or two hetero atoms selected from O, S or N, including C₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g. optionally substituted by oxygen, silicon, sulphur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl);

optionally substituted aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); optionally substituted alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); optionally substituted heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); optionally substituted alkylheteroaryl; and

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached.

In other embodiments, optional substituents may include, for example, OH, O-alkyl, SH, S-alkyl, NH₂NH-alkyl. In addition, alkyl, alkenyl, alkynyl, and the like can be substituted with oxygen, silicon, sulfur, and the like to form heteroalkyl, heteroalkenyl, heteroalkynyl, and the like.

In certain aspects, R₂、R₃、R₄、R₅、R₁₁、R₁₂、R₁₃And R₁₄Each of which is independently selected from:

H. methyl, ethyl, propyl or isopropyl;

and R is₁Selected from:

h; optionally substituted alkyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched chain alkyl); optionally substituted alkenyl (e.g. optionally substituted by oxygen, silicon, sulfur or optionally OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkenyl); optionally substituted alkynyl (e.g., optionally substituted with oxygen, silicon, sulfur or optionally with OH, O-alkyl, SH, S-alkyl, NH)₂NH-alkyl-substituted C₁To C₁₂Straight or branched alkynyl); cycloalkyl (e.g. C)₃To C₇Cycloalkyl groups); alkylcycloalkyl (e.g. C)₄To C₁₂Alkyl cycloalkyl); heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₂To C₆Heterocycloalkyl); alkyl heterocycloalkyl (e.g., where the heterocycle contains one or two heteroatoms selected from O, S or N, including C)₃To C₁₁Alkyl heterocycloalkyl, and includes where when N is present in the heterocycle, the nitrogen atom may be in the amide, carbamate, or urea form); aryl (e.g., phenyl, substituted phenyl, naphthyl, substituted naphthyl); alkylaryl (e.g., alkylphenyl, alkyl-substituted phenyl, alkylnaphthyl, alkyl-substituted naphthyl); heteroaryl (e.g., pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, triazolyl, all of which are optionally substituted); an alkyl heteroaryl group;

or R₁And R₂May together form a 3-to 8-membered heterocyclic ring containing the nitrogen atom to which they are attached.

Exemplary Compounds and substituents R having formula IV₁、R₂、R₃、R₄、R₅、R₁₁、R₁₂、R₁₃And R₁₄As shown below. However, substituents R are foreseen₁、R₂、R₃、R₄、R₅、R₁₁、R₁₂、R₁₃And R₁₄Other combinations of selections of (a).

In certain embodiments, the compounds of formula I, IA, II, III, or IV may contain one or more asymmetric centers and may be in the form of compositions of racemic mixtures, diastereomeric mixtures, individual enantiomers, diastereomeric mixtures of enantiomers, meso compounds, pure epimers, or mixtures of epimers thereof, and the like. Furthermore, compounds having formula I, IA, II, III or IV may have one or more double bonds and may be in the form of cis/trans, E/Z mixtures or E or Z geometric isomers thereof.

The compounds having formulae I, IA, II, III and IV may also be prepared in salt form, for example pharmaceutically acceptable salts, including suitable acid forms, for example in the form of a salt selected from: hydrochloride, hydrobromide, acetate, propionate, butyrate, sulfate, bisulfate, sulfite, carbonate, bicarbonate, phosphate, phosphinate, oxalate, hemi-oxalate, malonate, hemi-malonate, fumarate, hemi-fumarate, maleate, hemi-maleate, citrate, hemi-citrate, tartrate, hemi-tartrate, aspartate, glutamate and the like.

In one embodiment, the disclosed compounds can be prepared as a three component salt form comprising component A, B and C, wherein:

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

b is a divalent anion of an acid; and is

C is a protonated form of a compound having formula I, IA, II, III, or IV.

In certain aspects, a stoichiometric amount of A, B, and C may be included, wherein:

a is a 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, or cystine;

b is a divalent anion of an acid selected from: oxalic acid, malonic acid, citric acid, maleic acid, fumaric acid, tartaric acid, aspartic acid, glutamic acid, and the like; and is

C is a protonated form of a compound having formula I, IA, II, III, or IV.

Synthesis of Compounds

The compounds described herein can be synthesized using standard synthetic techniques known to those skilled in the art, or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions provided herein may be varied according to the practice and knowledge of those skilled in the art.

Starting materials for the synthesis of the compounds described herein are available from commercial sources, such as Aldrich Chemical Co, (Milwaukee, Wis.), Sigma Chemical Co, (st. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and materials known to those skilled in the art, as described, for example, in the following references: march, ADVANCED ORGANIC CHEMISTRY 4 th edition (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th edition, volumes A and B (Plenum2000, 2001); and Green and Wuts, technical GROUPS IN ORGANIC SYNTHESIS 3 rd edition (Wiley1999) (all of which are incorporated herein by reference IN their entirety). General methods for preparing compounds as disclosed herein can be derived from reactions known in the art, and the reactions can be modified by using appropriate reagents and conditions, as recognized by the skilled artisan, for the introduction of various moieties found in the formulae provided herein.

Additional biguanide or related heterocyclic compounds and methods and protocols for the synthesis of the compounds described herein are found in U.S. application No.12/593,479 (published as u.s.2010/0130498); U.S. application serial No.12/593,398 (published as u.s.2010/0184796); U.S. patent nos. 7,829,299; U.S. application serial No.11/578,013 (published as u.s.2010/0056621); U.S. patent nos. 7,416,867; U.S. application Ser. No.11/455,693 (published as U.S. 2007/0037212); U.S. application serial No.13/059,730 (published as u.s.2011/0143376); U.S. application serial No.12/996,670 (published as u.s.2011/0311991); U.S. patent nos. 7,811,788; U.S. application Ser. No.11/182,942 (published as U.S. 2006/0019346); U.S. application serial No.12/993,542 (published as u.s.2011/0086138); U.S. application serial No.12/373,235 (published as u.s.2010/0055209); international application No. PCT/IL2007/000454 (published as WO 2007/116404); U.S. application Ser. No.10/472,056 (published as U.S. 2004/0138189); U.S. patent nos. 5,891,919; U.S. patent nos. 6,376,657; U.S. application Ser. No.11/554,982 (published as U.S. 2007/0104805); U.S. application serial No.11/926,745 (published as u.s.2008/0108604); international application No. pct/CA2009/001688 (published as WO 2010/060198); U.S. application serial No.12/735,557 (published as u.s.2010/0330205); international application No. PCT/CA2007/001066 (published as WO 2008/000063); U.S. application Ser. No.11/438,204 (published as U.S. 2006/0269617); U.S. application Ser. No.10/563,713 (published as U.S. 2006/0172020); U.S. application Ser. No.10/902,352 (published as U.S. 2006/0024335); U.S. application Ser. No.10/538,038 (published as U.S. 2006/0275765); U.S. application serial No.11/555,617 (published as u.s.2008/0187936); U.S. application serial No.12/739,264 (published as u.s.2010/0316736); U.S. application serial No.12/215,609 (published as u.s.2009/0042813); U.S. application serial No.11/893,088 (published as u.s.2008/0050499); U.S. patent nos. 7,807,204; U.S. application serial No.11/811,166 (published as u.s.2008/0003268); U.S. patent nos. 6,376,657; international application No. pct/US2011/041183 (published as WO 2011/163183); international application No. pct/EP2011/059814 (published as WO 2011/157692); U.S. application serial No.12/790,292 (published as u.s.2011/0293753); international application No. pct/JP2009/071700 (published as WO 2010/076879); U.S. application serial No.13/032,530 (published as u.s.2011/0217394); international application No. pct/EP2011/000110 (published as WO 2011/085979); international application No. pct/US2010/058467 (published as WO 2011/068814); U.S. application serial No.13/060,996 (published as u.s.2011/0152361); U.S. application Ser. No.12/09,253 (published as U.S. 201I/0124609); U.S. application serial No.12/687,962 (published as u.s.2011/0119499); and international application No. pct/EP2010/004623 (published as WO 2011/012298); each of which is incorporated herein by reference in its entirety.

Other known biguanides and related compounds include:

chlorhexidine, a compound with antibacterial properties:

enbo cycloguanide, a compound with antimalarial properties:

polyhexamethylene biguanide, a compound with antibacterial properties:

a compound designated JPC-2067-B, which is known as a Toxoplasma gondii (Toxoplasma Gondi) inhibitor:

these and other biguanides and related heterocyclic compounds are envisioned to be within the scope of the present disclosure. In other embodiments, the biguanide and related heterocyclic compound is metformin or a salt thereof.

Metformin

Metformin has a lower bioavailability in terms of circulating blood concentrations relative to many other orally administered drugs. For example, metformin is reported to have a mean systemic bioavailability of 30% to 60%, while many comparable small molecules have a bioavailability greater than 60%. See, for example, Tucker et al, "Metformin kinetics in healthcare and in properties with diabetes mellitis" Br.J.Clin.Pharmacol.1981, 12(2) -. Administration of metformin has been reported to increase the release of GLP-1 from L cells located in the intestine. However, GLP-1 release from L cells (and activation of enteroendocrine cells) is triggered by luminal signaling on the epithelial aspect of the intestine. There are no known examples of blood borne or circulatory signals that can activate enteroendocrine cells to release their hormone content. Thus, it is contemplated that metformin does not act through its presence in the plasma circulation itself. Metformin may cause activation of enteroendocrine cells (e.g., by binding to bitter receptors on L cells or other enteroendocrine cells) by interaction with luminal or epithelial aspects of L cells, including release of GLP-1 from L cells.

Minimizing systemic exposure

In certain embodiments, provided herein are compositions of biguanides or related heterocyclic compounds (e.g., metformin or salts thereof) suitable for minimizing the systemic bioavailability of the compounds, e.g., by delivering the compounds to the intestine. In some embodiments, compositions of biguanides or related heterocyclic compounds (e.g., metformin or salts thereof) suitable for delivery to enteroendocrine cells described herein minimize metformin plasma absorption in a subject. In other embodiments, the composition of biguanide or related heterocyclic compound (e.g., metformin or a salt thereof) minimizes plasma Cmax and/or AUC levels. In other embodiments, the compositions of biguanides or related heterocyclic compounds (e.g., metformin or salts thereof) have negligible plasma absorption, Cmax and/or AUC levels of metformin. In other embodiments, the Cmax and/or AUC levels of the biguanide or related heterocyclic compound (e.g., metformin or a salt thereof) compared to the Cmax and/or AUC of a reported known formulation of the compound are those previously considered subtherapeutic Cmax and/or AUC for the composition.

In preferred embodiments, the compositions disclosed herein are suitable for reducing or minimizing the systemic bioavailability of the compound, e.g., minimizing the circulating plasma concentration of the biguanide compound in a patient and/or reducing the average systemic bioavailability of the compound when compared to an immediate release composition having an equivalent amount of the compound. In some embodiments, the circulating plasma concentration that is minimized in a subject having normal or impaired renal function is less than 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. In other embodiments, useful compounds provide a relative bioavailability of 70%, 60%, 50%, 40%, 30%, or 20% of a smaller compound relative to an immediate release composition having an equivalent amount of the compound.

Negligible or subtherapeutic plasma Cmax and/or AUC levels of Metformin include reported Cmax and/or AUC levels of 50%, 40%, 30%, 20%, and 10% of known Metformin formulations (e.g., glumeteza, glucophe XR, RIOMET, fortame, OBIMET, glutormin, dienben, DIABEX, diformin IR, Metformin SR, etc.). For example, extended release metformin formulation GLUMETZA is known to have mean Cmax values of 473 + -145 ng/mL, 868 + -223 ng/mL, 1171 + -297 ng/mL, and 1630 + -399 ng/mL for single doses of 500mg, 1000mg, 500mg, and 2500mg, respectively. With respect to AUC, the mean values of GLUMETZA were 3501. + -. 796 ng. hr/mL, 6705. + -. 1918 ng. hr/mL, 9299. + -. 2833 ng. hr/mL, and 14161. + -. 4432 ng. hr/mL for 500mg, 1000mg, 1500mg, and 2500mg single doses (GLUMETZA product label), respectively.

In further embodiments, the composition of metformin or a salt thereof has a reduced average systemic bioavailability. In some embodiments, the reduced average systemic bioavailability is a lower average systemic bioavailability relative to an immediate release metformin formulation with an equivalent amount of metformin (relative bioavailability). In other embodiments, the reduced average systemic bioavailability is the average systemic bioavailability, e.g., when the relative bioavailability is less than 40%, 30%, less than 25%, less than 15%, less than 10%, and less than 5%. In some cases, the average systemic bioavailability is less than 15%.

To achieve these effects, delivery of metformin is designed for modified release, for example, to remain in the gastrointestinal tract and/or to release a metformin dose in an amount that minimizes plasma absorption. Delivery of metformin to one or more regions of the intestine is by any known method, including, for example, oral, rectal, nasogastric tube, parenteral injection (e.g., intraluminal enteral injection). In some cases, the delivery is oral. Oral delivery of metformin compositions is described in the modified release formulation section and includes timed release systems, enteric coating and pH dependent systems, gastric retention systems, floatation systems, bioadhesive systems, swelling systems and the like. In some embodiments, the metformin compositions described herein utilize a multi-component system, wherein the metformin is delivered to several locations of the gastrointestinal tract after administration, such as the duodenum, jejunum, ileum, lower intestine, or combinations thereof. For example, metformin compositions may be delivered to the small intestine by the use of immediate release and timed or delayed (enteric) release components. The multicomponent system of the metformin composition may be in unit dosage form, such as a bi-or tri-or multi-layer tablet or multiparticulate form, such as an encapsulated mini-tablet, or as separate dosage forms, such as separate tablets taken together or periodically.

In some embodiments, a composition of metformin or a salt thereof suitable for delivery to one or more regions of the intestine comprises two components for delivery of metformin, wherein the first component is immediate release and the second component is immediate release or timed release covered by an enteric coating. The second component is released after the desired pH has started due to the enteric coating. Contemplated phs include about pH 5.0, about pH 5.5, about pH6.0, about pH6.5, and about pH 7.0. After the desired pH has started, the second component begins to release. The second component comprises immediate release of metformin within about 15 minutes, about 20 minutes, about 25 minutes or about 30 minutes after the desired pH is initiated, while the second component comprises timed, extended or slow release over an extended period of time, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours or about 8 hours. In some embodiments, the exemplary two-component metformin delivery system may be a bilayer tablet. Three, four, and additional components are contemplated within the embodiments. For example, the third or fourth component may comprise a gastric retentive component or a component that specifically delivers and releases metformin to the lower intestine.

For compositions comprising metformin or a salt thereof, the dosage of metformin may range from about 1mg to about 2000mg, about 10mg to about 1500mg, about 50mg to about 1000mg, or about 100mg or about 500mg per day. In some cases, the dose of metformin or a salt thereof is about 2000mg, about 1500mg, about 1000mg, about 800mg, about 600mg, about 500mg, about 400mg, about 300mg, about 250mg, about 200mg, about 150mg, about 100mg, about 75mg, about 50mg, about 25mg, about 10mg, or about 1mg per day. In some embodiments, the dose of metformin or a salt thereof is less than 400 mg. In some embodiments, the dose of metformin or a salt thereof is 250 mg.

Salts of metformin include, but are not limited to, the hydrochloride, phosphate, sulfate, hydrobromide, salicylate, maleate, benzoate, succinate, ethanesulfonate, fumarate, glycolate, pamoate, orotate, acetate, isobutyrate, acetylsalicylate, nicotinate, adamantine, zinc chlorophyllin, carboxylate, benzoate, dichloroacetate, theophylline-7-acetate, clofibrate, tartrate, oxalate, tannate, and hydroxy acid salts. In some cases, the metformin salt is metformin hydrochloride.

In some embodiments, a composition of metformin or a salt thereof suitable for delivery into one or more regions of the intestine is administered or combined with another agent such as an anti-obesity agent and/or an anti-diabetic agent as described herein. Important agents for combination with the metformin compositions described herein include DPP-IV inhibitors (e.g., sitagliptin, saxagliptin, berberine, vildagliptin, linagliptin, alogliptin, etc.), thiazolidinediones (e.g., pioglitazone, rivoglitazone, rosiglitazone, troglitazone, etc.), sulfonylureas (e.g., glipizide, glibenclamide), glibenclamide (glibenclamide), glibenclamide, glipizide, gliquidone, glimepiride, gliclazide, hexetimide, sulbutide, chlorpyride, gliclazide, etc.), gliclazide (gliclazide), gliclazide, etc.), gliclazide, PPAR, gliclazide, etc.

In other embodiments, the chemosensory receptor modulator is administered with a biguanide or related heterocyclic compound to alter or alter the activity of the receptor against the compound. In further embodiments, the chemosensory receptor potentiator is administered with a biguanide or related heterocyclic compound to enhance, potentiate, or augment the effect of the compound. In certain instances, a modulator and/or enhancer is administered prior to administration of a compound to enhance, enhance or increase the effect of the compound. In other cases, modulators and/or enhancers are administered with a compound to enhance, potentiate, or increase the effect of the compound.

Modulators and enhancers may be specific for one chemoreceptor type and/or multiple chemoreceptor types. Specific chemical receptor modulators and enhancers may include, but are not limited to, umami receptor modulators and enhancers, sweet taste receptor modulators and enhancers, bitter taste receptor modulators and enhancers, fat receptor modulators and enhancers, bile acid receptor modulators and enhancers, sour taste receptor modulators and enhancers, and the like.

In some embodiments, the bitter taste receptor enhancer is selected from enhancer compounds described herein or known in the art. Bitter taste receptor enhancers include, but are not limited to, sub-bitter (sub-bitter) amounts of sweet taste receptor ligands, i.e., amounts that do not elicit a bitter taste response. In some embodiments, the bitter taste receptor potentiator is a silver salt. Silver salts include silver acetate and silver lactate.

Combination of

The biguanides or related heterocyclic compounds may be administered alone or in combination with one another. The dosage of each biguanide or related heterocyclic compound can be determined by methods known in the art. The maximum response dose and the maximum tolerated dose can be determined by animal and human protocols as described herein. Additional relative doses expressed as a percentage of the maximal response or maximal tolerated dose are readily available by the regimen.

In one exemplary dose response experiment, biguanides or related heterocyclic compounds are administered individually in animal models (rat models of diabetes or obesity) to determine the optimal dose of each biguanide or related heterocyclic compound. Biguanides or related heterocyclic compounds are administered alone in increasing amounts (mg/kg/min), wherein each subject is administered a set of mg/kg/min doses and the doses are maintained at this set of levels for a defined period of time. Blood samples are collected at frequent intervals (e.g., every 1 minute, 2 minutes, or 5 minutes) throughout the time period and hormone concentrations are determined. The hormones assayed include CCK, GIP, GLP-1, gastrointestinal hormone, PYY, insulin, C-peptide, and GLP-2. 50% maximal response dose and 50% maximal tolerated dose were determined for each biguanide or related heterocyclic compound.

In some embodiments, at least one biguanide or related heterocyclic compound is administered at a concentration of 50% of the maximal response dose. In other embodiments, at least one biguanide or related heterocyclic compound is administered at a concentration of 50% of the maximum tolerated dose. The biguanide or related heterocyclic compound may be administered as 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the maximal response or maximal tolerated dose (including all integers).

The biguanide or related combination of heterocyclic compounds may be administered in a single composition or in multiple compositions. The multiple compositions may be administered simultaneously or at different times. The compositions can be administered in different delivery forms (i.e., tablets, powders, capsules, gels, liquids, nutritional supplements, edible food preparations (e.g., medical foods, bars, gels, sprays (sprinkle), chewing gums (gum), lozenges, candies, liquids, etc.), as well as any combination of these forms.

In one non-limiting example, a tablet containing at least one biguanide or related heterocyclic compound is administered concurrently with another tablet containing at least one biguanide or related heterocyclic compound to provide the desired dosage. In another example, two tablets are administered at different times. In another non-limiting example, a tablet containing the desired combination of one or more biguanides or related heterocyclic compounds is administered to provide a full dose. Any combination of delivery form, composition, and time of delivery is contemplated herein.

The ingredients of the compositions provided by the present invention may vary with respect to both the individual ingredients and the relative proportions of the ingredients. In embodiments, the relative proportions of the ingredients are optimized to produce the desired synergistic activity from the drug combination. For example, in a composition comprising two ingredients (e.g., two biguanides or related heterocyclic compounds, or, as another non-limiting example, a biguanide or related heterocyclic compound and a chemosensory receptor ligand) or a method comprising administering the two ingredients, the ingredients may be present in the following ratios: about, for example, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 10, 1: 15, 1: 20, 1: 25, 1: 30, 1: 35, 1: 40, 1: 45, 1: 50, 1: 60, 1: 70, 1: 80, 1: 90, 1: 100, 1: 200. 1: 300, 1: 400, 1: 500, 1: 1000, etc. In a composition comprising three components (e.g., two biguanides or related heterocyclic compounds and a metabolic chemosensory receptor ligand) or a method comprising administering the three components, the components may be present in the following ratios: for example, about 1: 1, 2: 1, 3: 1, 3: 1, 3: 2, 3: 2, 3: 2: 1, 4: 1, 4: 1, 4: 2, 4: 2, 4: 2: 3, 4: 3, 4: 3, 4: 2: 1, 5: 1, 5: 1, 5: 2: 1, 5: 3: 2, 5: 3: 4, 5: 2, 5: 3, 5: 4, 10: 1, 10: 1, and the like.

When more than one biguanide or related heterocyclic compound is used in combination with at least one other chemosensory receptor ligand or compound, it is understood that a combination treatment regimen includes a treatment regimen in which administration of one compound is commenced before, during or after treatment with the second or further agent in the combination and continued until any time during treatment with any other agent in the combination or after termination of treatment with any other agent. Treatment regimens also include those in which the agents used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination therapy includes starting and stopping at different times to help clinically manage the patient's regular treatment.

Indications of

Contemplated conditions for treatment using the compositions and methods of embodiments herein are metabolic syndrome, type I diabetes, type II diabetes, obesity, binge eating, undesired overeating, food addiction, a need to reduce food intake or to lose weight or to maintain weight loss, a need to maintain healthy weight, a need to maintain euglycemic metabolism, anorexia, pre-diabetes, glucose intolerance, Gestational Diabetes Mellitus (GDM), Impaired Fasting Glucose (IFG), postprandial hyperglycemia, accelerated gastric emptying (dumping syndrome), delayed gastric emptying, dyslipidemia, postprandial dyslipidemia, hyperlipidemia, hypertriglyceridemia, post-hypertriglyceridemia, insulin resistance, bone loss disorders, osteopenia, osteoporosis, muscle wasting disorders, muscle degenerative disorders, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFL), fatty liver disease(s), and combinations thereof, Non-alcoholic steatohepatitis (NASH), intestinal immune disorders (e.g., celiac disease), bowel irregularity, Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) including, for example, ulcerative colitis, crohn's disease, and short bowel syndrome, peripheral neuropathy (e.g., diabetic neuropathy). In certain embodiments, the methods comprise treating a subject having depression, stress, sadness, anxiety disorder (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, or social anxiety disorder), or mood disorder (e.g., depression, bipolar disorder, dysthymic disorder, and cyclothymic disorder) by administering a composition comprising a biguanide or related heterocyclic compound provided herein. In certain embodiments, the methods comprise methods of eliciting a sense of well-being, or satisfaction in a subject by administering a composition comprising a biguanide or related heterocyclic composition provided herein.

In addition, the compositions and methods described herein may be used for the dietary management of the conditions listed above. In some embodiments, the compositions and methods provided herein are indicated for the treatment, prevention, and or maintenance of a metabolic disorder, disease, or deficiency. A metabolic disorder, disease, or deficiency may include a disorder, disease, or deficiency in energy balance and a disorder, disease, or deficiency in fuel balance.

In certain embodiments, the compositions and methods provided herein are indicated for the treatment, prevention and or maintenance of disorders, diseases and deficiencies associated with energy balance. Energy balance generally involves signal pathways, molecules and hormones related to food intake and energy expenditure. Conditions, diseases and deficiencies associated with energy balance include, but are not limited to, type I diabetes, type II diabetes, pre-diabetes, Impaired Fasting Glucose (IFG), impaired postprandial glucose, and gestational diabetes. In some cases, the compositions and methods provided herein are indicated for the treatment, prevention, and or maintenance of type I diabetes or type II diabetes.

In certain embodiments, the compositions and methods provided herein are indicated for the treatment, prevention and or maintenance of conditions, diseases and deficiencies associated with fuel balance. Conditions, diseases and deficiencies associated with fuel balance include, but are not limited to, nonalcoholic fatty liver disease (NAFL), nonalcoholic steatohepatitis (NASH), hyperlipidemia, post-hypertriglyceridemia, insulin resistance, and polycystic ovary syndrome (PCOS).

Embodiments also provide compositions and methods useful for treating the following conditions: in such conditions, increased insulin secretion or control of glucose concentration resulting from modulation of enteroendocrine cytokines (e.g., GLP-1 or GIP) is advantageous. These conditions include, but are not limited to, metabolic syndrome, type 1 diabetes, type II diabetes, gestational diabetes, glucose intolerance, and related conditions (including those in which the patient suffers from glucose intolerance).