COMPOSITIONS AND METHODS OF USE FOR TREATING OR PREVENTING LIPID RELATED DISORDERS

• US 20090054450A1
• Filed: 06/17/2008
• Published: 02/26/2009
• Est. Priority Date: 06/19/2007
• Status: Abandoned Application

• Current Assignee: Ironwood Pharmaceuticals, Inc.
• Original Assignee: Ironwood Pharmaceuticals, Inc.
• Inventors: TALLEY, John Jeffrey, CALI, Brian, CURRIE, Mark G.
• Application Number:
  US12/140,637
• Publication Number:
  US 20090054450A1
• Time in Patent Office: Days
• US Class Current: 514/252.190
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07C 203/04 having nitrate groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 235/30 the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2602/28 Hydrogenated naphthalenes
• CPC Class Codes: C07C 279/12 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 279/14 being further substituted by carboxyl groups
• CPC Class Codes: C07C 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07C 281/16 Compounds containing any of the groups , e.g. aminoguanidine
• CPC Class Codes: C07C 291/02 containing nitrogen-oxide bonds
• CPC Class Codes: C07C 69/712 the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07D 207/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 209/24 with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 257/06 with nitrogen atoms directly attached to the ring carbon atom
• CPC Class Codes: C07D 263/28 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

Disclosed herein are novel compositions and methods for treating or preventing a variety of disorders and conditions associated with lipid metabolism. The methods generally include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more fibric acid or statin derivative compositions alone or in combination with one or more lipid altering agents and/or PDE inhibitors.

Claims

1-149. -149. (canceled)

150. A compound represented by the structure (I)

wherein

R¹ is chosen from H and halogen;

R² is chosen from H, halogen, cycloalkyl substituted with from 1 to 3 halogens, COR³, and (CH₂)_mNHOR³;

R³ is phenyl substituted with from one to three halogen groups;

Z is chosen from O and (CH₂)_nO;

X is chosen from direct bond, O, NH, and an amino acid residue;

R⁴ is chosen from OH, NO, NO₂, an amino acid residue, a fabric acid residue, a guanidine residue, a tetrazolyl residue, an agmatine residue, an amino-containing compound residue;

a lower alkyl group terminating in ONO, (ONO₂)_p, or guanidine;

a resveratrol residue; and

an imidazoline receptor agonist residue; and

m, n, and p are independently chosen from 1 to 3.

151. A compound according to claim 150 represented by the structure (II):

152. The compound according to claim 151, wherein X is O and R⁴ is a lower alkyl terminating in (ONO₂)_p, and p=1.

153. The compound according to claim 152, chosen from the following structures:

154. The compound according to claim 151, wherein X is NH and R⁴ is OH.

155. A composition for the prevention and/or treatment of lipid related disorders, said composition comprising:

(1) a pharmaceutically acceptable carrier and (2) a therapeutically effective amount of a compound represented by the structure (I)

wherein

R¹ is chosen from H and halogen;

R² is chosen from H, halogen, cycloalkyl substituted with from 1 to 3 halogens, COR³, or (CH₂)_mNHOR³;

R³ is phenyl substituted with from one to three halogen groups;

Z is chosen from O or (CH₂)_nO;

X is chosen from a direct bond, O, NH, or an amino acid residue;

R⁴ is chosen from OH, NO, NO₂, an amino acid residue, a fabric acid residue, a guanidine residue, a tetrazolyl residue, an agmatine residue, an amino-containing compound residue;

a lower alkyl group terminating in ONO, (ONO₂)_p, or guanidine;

a resveratrol residue;

or an imidazoline receptor agonist residue; and

m, n, and p are independently chosen from 1 to 3.

156. The composition according to claim 155 comprising a compound represented by the structure (II)

157. The composition according to claim 156, wherein said compound (II) is chosen from the following structures:

158. The composition according to claim 156, wherein said compound (II) is chosen from the following structures:

159. The composition according to claim 156, wherein said compound (II) is chosen from the following structures:

wherein R¹⁰ is C₁-C₆ acyl.

160. The composition according to claim 159, wherein said compound (II) is represented by the following structure:

161. The composition according to claim 156, wherein said compound (II) is chosen from the following structures:

wherein R¹¹ is C₁-C₆ alkyl.

162. The composition according to claim 161, wherein said compound (II) is represented by the following structure:

163. The composition according to claim 155 further comprising at least one lipid altering agent.

164. The composition according to claim 163, wherein said lipid altering agent is chosen from among:

statins, fibrates, cholesterol-ester-transfer-protein (CETP) inhibitors, squalene synthase inhibitors, microsomal-triglyceride-transfer-protein (MTTP) inhibitors, cholesterol absorption inhibitors, soluble guanylate cyclase modulators, bile acid sequestrants, thyroid receptor agonists, LXR modulators, or antisense inhibitors of apoB-100 or C-reactive protein.

165. The composition according to claim 155 further comprising a therapeutically effective amount of at least one phosphodiesterase inhibitor.

166. A kit for treating a lipid metabolism disorder comprising, in one or more containers, a therapeutically effective amount of the composition according to claim 155, together with a label or packaging insert containing instructions for use.

167. A method for treating or preventing a lipid metabolism disorder, said method comprising:

administering to a patient in need thereof a therapeutically effective amount of a composition comprising a compound represented by the structure (I)

wherein

R¹ is chosen from H and halogen;

R² is chosen from H, halogen, cycloalkyl substituted with from 1 to 3 halogens, COR³, or (CH₂)_mNHOR³;

R³ is phenyl substituted with from one to three halogen groups;

Z is chosen from O or (CH₂)_nO;

X is chosen from a direct bond, O, NH, or an amino acid residue;

R⁴ is chosen from OH, NO, NO₂, an amino acid residue, a fabric acid residue, a guanidine residue, a tetrazolyl residue, an agmatine residue, an amino-containing compound residue;

a lower alkyl group terminating in ONO, (ONO₂)_p, or guanidine;

a resveratrol residue;

or an imidazoline receptor agonist residue; and

m, n, and p are independently chosen from 1 to 3.

168. The method according to claim 167 wherein said composition comprises a compound represented by the structure (II)

169. The method according to claim 167, wherein said lipid metabolism disorder is chosen from:

dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, or fatty liver disease.

170. The method according to claim 167, wherein said patient is diabetic.

171. The method according to claim 167, wherein said method is effective in said patient for:

(i) lowering glycosylated hemoglobin levels (HbA_1C);

(ii) lowering fasting plasma glucose (FPG) levels;

(iii) lowering peak and 2-hour post-prandial glucose (PPG) levels;

(iv) improving insulin sensitivity or reducing insulin resistance;

(v) increasing insulin secretion;

or (vi) reducing the risk of developing diabetes-associated complications.