WO2015173813A1 - Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes - Google Patents

Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes Download PDF

Info

Publication number
WO2015173813A1
WO2015173813A1 PCT/IL2015/050499 IL2015050499W WO2015173813A1 WO 2015173813 A1 WO2015173813 A1 WO 2015173813A1 IL 2015050499 W IL2015050499 W IL 2015050499W WO 2015173813 A1 WO2015173813 A1 WO 2015173813A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenylpropanamide
propan
hydroxyphenyl
hydroxypropoxy
pharmaceutical composition
Prior art date
Application number
PCT/IL2015/050499
Other languages
French (fr)
Inventor
Eliahu Kaplan
Original Assignee
Novaremed Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novaremed Ltd. filed Critical Novaremed Ltd.
Publication of WO2015173813A1 publication Critical patent/WO2015173813A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide for the treatment of type II diabetes and/or other medical conditions associated with therewith.
  • Diabetes mellitus is considered as a worldwide epidemic.
  • the International Diabetes Federation's most recent estimates indicate that 8.3% of adults - 382 million people - have diabetes, and the number of people with this disease is set to rise beyond 592 million in less than 25 years.
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Type I diabetes is considered as an autoimmune disease, results from an immune destruction of the ⁇ -cells of the pancreas. Although the exact cause is unknown, evidence suggests that both genetic predisposition and environmental factors, such as viral infection, are involved.
  • the prevalent treatment for type I diabetes is administration of exogenous insulin.
  • Type II diabetes accounts for about 90% of those with diabetes. Unlike type I diabetes, this is a metabolic disease which is characterized by hyperglycemia (high blood glucose levels) due to insulin resistance and insulin deficiency. Several risk factors have been associated with type II diabetes, including obesity, advancing age, genetic susceptibility, high blood pressure, and life style patterns (such as physical inactivity, smoking and alcohol). Type II diabetes progresses through three stages of the disease. The first stage is known as a "pre-diabetic" state and involves hyperinsulinemia and "primary" insulin resistance. In this phase, cells no longer respond properly to insulin, the pancreas compensates for this resistance by producing more insulin. The insulin responsiveness in this stage is sufficient to maintain normal glucose tolerance or partially impaired glucose tolerance.
  • insulin resistance worsens such that blood glucose levels abnormally rise after a meal despite elevated insulin levels (this condition is known as "postprandial hyperglycemia").
  • postprandial hyperglycemia this condition is known as "postprandial hyperglycemia”
  • insulin resistance does not change, however, the elevated glucose levels further damage ⁇ -cells, thereby drastically reducing insulin secretion and causing overt diabetes. This is made evident by "fasting hyperglycemia", in which glucose levels are high most of the time.
  • fasting hyperglycemia in which glucose levels are high most of the time.
  • the mechanism of insulin resistance is not fully understood. However, several observations have suggested that insulin resistance is due, at least in part, to inhibition of the insulin receptor.
  • insulin-receptor function Deficiencies of insulin-receptor function might lead to decrease in the insulin-stimulated activities which include, for example, insulin receptor autophosphorylation and insulin receptor- mediated kinase activities (such as tyrosine kinase).
  • insulin receptor autophosphorylation and insulin receptor- mediated kinase activities (such as tyrosine kinase).
  • insulin receptor- mediated kinase activities such as tyrosine kinase
  • N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide is disclosed in U.S. 7,642,290 for the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection.
  • U.S. 7,674,829 discloses the stereoisomers of (S)N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide in the treatment of AIDS and other viral diseases.
  • U.S.2011/0086910 discloses the use of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the treatment or prevention of pain.
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide (formula I) for the treatment of type II diabetes and related medical conditions.
  • the present invention relates to the use of substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, or substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, or combination thereof, for the treatment of type II diabetes and/or a medical condition associated with this disease.
  • the present invention is based in part on the unexpected discovery that the (S,S) and (S,R) diastereomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide, namely N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)- 1 -(4-hydroxyphenyl)- 3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide both individually induce cellular intake of glucose, in vitro.
  • N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide have the ability to mimic the metabolic insulin action through independent activation of insulin receptor. This may be accomplished by the activation of the tyrosine kinase Lyn with either one or both of the compounds of the present invention.
  • the activated kinase phosphorylates the insulin receptor substrate 1 (IRS-1), which triggers several signaling pathways that are involved in the regulation of glucose production, transportation, and cellular utilization.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent for use in the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
  • the N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
  • said N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and a combination thereof.
  • the N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
  • the N-(l- (4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide.
  • the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-
  • the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-
  • the composition is in the form of a capsule, tablet, granule, powder, solution or suspension.
  • the pharmaceutical composition is in a form suitable for intravenous, intramuscular, oral, sublingual, buccal, parenteral, intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal administration.
  • the present invention contemplates a method for treating type II diabetes and/or a medical condition associated with type II diabetes in a subject in need thereof, comprising the step of administering to said subject a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent.
  • said treating comprises any one or more of alleviating, preventing, delaying the onset, attenuating the progression of type II diabetes or conditions associated with this disease and achieving a beneficial therapeutic effect for a sustained period of time.
  • the medical condition associated with type II diabetes is selected from the group consisting of hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease), vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke, peripheral vascular disease, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
  • neuropathy nerve damage
  • nephropathy kidney disease
  • vision disorders e.g., retinopathy, glaucoma, cataract and corneal disease
  • macrovascular complications including heart disease, stroke, peripheral vascular disease, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
  • the subject is a mammal, preferably a human.
  • the present invention relates to the use of a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described herein, for the manufacture of a medicament for treating type II diabetes and/or a medical condition associated with type II diabetes.
  • Figs. 1A-1D show Oil-Red stained human subcutaneous pre-adipocytes (A xlO; B x20) and human subcutaneous differentiated adipocytes (C xlO; D x20).
  • Figs. 2A-2B are bar charts representing the glucose uptake level in adipocytes, in vitro, in the presence of different concentrations of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide (Fig. 2A; (S,S); relative to insulin performance) and N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide (Fig. 2B; (S,R); relative to insulin performance).
  • the two left columns depict control experiments, in which cultures were treated with 100 nM insulin or 10 ⁇ of Rosiglitazone.
  • the present invention relates to pharmaceutical compositions comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide for use in the treatment of type II diabetes and/or related medical conditions, e.g., hyperglycemia, insulin resistance and impaired glucose tolerance, among others.
  • type II diabetes and/or related medical conditions e.g., hyperglycemia, insulin resistance and impaired glucose tolerance, among others.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent for use in the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
  • the N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
  • said N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and a combination thereof.
  • the N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
  • the N-(l- (4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide.
  • the composition of the invention comprises a combination of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)- 1 -(4-hydroxyphenyl)- 3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Enantiomers have identical chemical and physical properties except for their ability to rotate plane- polarized light (+/-) by equal amounts but in opposite directions.
  • Diastereomers refers to stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of one another.
  • Diastereomers are characterized by differences in physical properties (e.g., melting points, boiling points and spectral properties) and by some differences in chemical behavior towards achiral as well as chiral reagents.
  • the terms "diastereomers” and “diastereoisomer” as used herein, are interchangeable.
  • All stereoisomers of the compound of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the compound can exist in enantiomeric and/or diastereomeric forms or in mixtures thereof.
  • the present invention intends to the use of any enantiomerically or diastereomerically enriched mixtures (i.e., mixtures enriched for one enantiomer or diastereomer), substantially pure enantiomers or diastereomers, or any mixtures thereof.
  • the chiral centers can be designated as R or S.
  • the compound of the invention may be present as a salt.
  • salt encompasses both basic and acid addition salts, including but not limited to phosphate, dihydrogen phosphate, hydrogen phosphate and phosphonate salts, and include salts formed with organic and inorganic anions and cations. Furthermore, the term includes salts that form by standard acid-base reactions of basic groups and organic or inorganic acids.
  • Such acids include hydrochloric, hydrofluoric, hydrobromic, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, D-camphoric, phthalic, tartaric, salicyclic, methanesulfonic, benzenesulfonic, p- toluenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • Additional salts of the compound described herein may be prepared by reacting the parent molecule with a suitable base, e.g., NaOH or KOH to yield the corresponding alkali metal salts, e.g., the sodium or potassium salts.
  • a suitable base e.g., NaOH or KOH
  • Additional basic addition salts include ammonium salts (NH/t + ), substituted ammonium salts, Li, Ca, Mg, salts, and the like.
  • the compound of the invention may be present as a hydrate.
  • hydrate refers to a solvate wherein the solvent molecule is water.
  • Solvate contemplates a physical association of the compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation.
  • substantially pure generally refers to the presence of at least about 80% of a single stereoisomer, preferably at least about 90% more preferably at least about 95% or 97% and most preferably at least about 98% or 99% of a single stereoisomer.
  • the compositions of the invention comprise substantially pure N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide.
  • the substantially pure stereoisomer comprises at least about 80% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 20% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 90% by weight of N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, and less than about 10% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 5% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 97% by weight of N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, and less than about 3% of other stereoisomeric forms of the compound. According to yet other preferred embodiments, the substantially pure stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 2% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 99% by weight of N-((S)-1- (4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 1 % of other stereoisomeric forms of the compound.
  • compositions of the invention comprise substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide.
  • the substantially pure stereoisomer comprises at least about 80% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 20% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 90% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 10% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 5% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 97% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 3% of other stereoisomeric forms of the compound. According to yet other preferred embodiments, the substantially pure stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 2% of other stereoisomeric forms of the compound.
  • the substantially pure stereoisomer comprises at least about 99% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 1 % of other stereoisomeric forms of the compound.
  • compositions of the invention comprise a mixture of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
  • the stereoisomer comprises at least about 80% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or N- ((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a combination thereof, and less than about 20% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 5% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 97% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 3% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 2% of other stereoisomeric forms of the compound.
  • the stereoisomer comprises at least about 99% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 1% of other stereoisomeric forms of the compound.
  • the at least one other stereoisomer is selected from the group consisting of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- 1 -(4-hydroxyphenyl)-3- ((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((R)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((R)- l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or combination thereof.
  • WO 2013/084238 discloses a stereochemically controlled synthesis of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide. The prevailing racemization was overcome by controlling the reaction temperature and the order of adding the raw materials.
  • WO 2013/084238 also demonstrates a method of separation of the two diastereomers prepared as a mixture in the traditional synthesis (described for example, in US 2011/0086910), by a supercritical fluid chromatography (SFC) on RegisPackTM, a polysaccharide coated chiral column.
  • SFC supercritical fluid chromatography
  • RegisPackTM a polysaccharide coated chiral column
  • the present invention provides a method for treating type II diabetes and/or a medical condition associated with type II diabetes in a subject in need thereof, comprising the step of administering to said subject a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent.
  • treating and “treatment”, as used herein are interchangeable and refer to any one or more of delaying the onset of, retarding or reversing the progress of, alleviating or preventing either type II diabetes or one or more medical conditions associated with of such disease, and achieving a beneficial therapeutic effect preferably for a sustained or prolonged period of time.
  • treating and “treatment”, as used herein are interchangeable and refer to any one or more of delaying the onset of, retarding or reversing the progress of, alleviating or preventing either type II diabetes or one or more medical conditions associated with of such disease, and achieving a beneficial therapeutic effect preferably for a sustained or prolonged period of time.
  • the medical condition associated with type II diabetes is selected from the group consisting of glucose and insulin metabolism deficiencies, diabetic complications and metabolic disorders.
  • Non limiting examples of medical conditions associated with type II diabetes include hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease) and vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke and peripheral vascular disease (which can lead to ulcers, gangrene and amputation) among others.
  • neuropathy nerve damage
  • nephropathy kidney disease
  • vision disorders e.g., retinopathy, glaucoma, cataract and corneal disease
  • macrovascular complications including heart disease, stroke and peripheral vascular disease (which can lead to ulcers, gangrene and amputation) among others.
  • Type II diabetes Other medical conditions associated with type II diabetes, include but are not limited to, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
  • administering refers to bringing in contact with a compound of the present invention. Administration can be accomplished to cells or tissue cultures, or to living organisms, for example humans.
  • the subject is a mammal, preferably a human.
  • the present invention relates to the use of a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described herein, in the manufacture of a medicament for treating type II diabetes and/or a medical condition associated with type II diabetes.
  • the method of treatment of the invention may be in parallel to, prior to, or following additional method of treatment.
  • the composition of the present invention may be administered to a subject in need as a prodrug.
  • the prodrug often offers advantages such as delayed release, solubility, and/or tissue compatibility.
  • the term "prodrug”, as used herein, refers to the compound of the present invention that when administered generates the biologically active "drug'Vcomposition as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s).
  • the prodrug and derivatives thereof may be prepared by methods and techniques known to those of skill in the art.
  • the present invention further provides the administration of the pharmaceutical compositions of the present invention in combination with at least one additional antidiabetic medication.
  • the combination therapy may be administered to the subject undergoing treatment simultaneously or sequentially in any order, at a time interval determined by a skilled artisan.
  • Non-limiting examples of anti-diabetic medication include insulin, secretagogues (such as sulfonylureas and nonsulfonylurea secretagogues), alpha-glucosidase inhibitors, biguanides, meglitinides, and thiazolidinediones, sensitizers (such as biguanides and thiazolidinediones), peptide analogs (such as injectable incretin mimetics and injectable Amylin analogues), among others.
  • secretagogues such as sulfonylureas and nonsulfonylurea secretagogues
  • alpha-glucosidase inhibitors biguanides, meglitinides, and thiazolidinediones
  • sensitizers such as biguanides and thiazolidinediones
  • peptide analogs such as injectable incretin mimetics and injectable Amylin analogues
  • Non-limiting examples of known anti-diabetic drugs include Metformin, rosiglitazone (Avandia), pioglitazone (Actos), tolbutamide (Orinase),acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide (Diabinese), Second-generation agents, glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), glimepiride (Amaryl), gliclazide (Diamicron), repaglinide (Prandin), nateglinide (Starlix), miglitol (Glyset), acarbose (Precose/Glucobay), Exenatide, Liraglutide, vildagliptin (Galvus), sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta) among
  • the pharmaceutical composition of the present invention can be formulated for administration by a variety of routes selected from the group consisting of intravenous, intramuscular, oral, sublingual, buccal, parenteral, , intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal among others.
  • routes selected from the group consisting of intravenous, intramuscular, oral, sublingual, buccal, parenteral, , intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal among others.
  • routes selected from the group consisting of intravenous, intramuscular, oral, sublingual, buccal, parenteral, , intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal among others.
  • composition is prepared in a manner well known in the pharmaceutical art and comprise as the active ingredient one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described hereinabove, and a pharmaceutically acceptable excipient and/or carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.
  • composition of the invention is suitable for use in a variety of drug delivery systems as detailed hereinbelow.
  • Pharmaceutically acceptable carriers suitable for use in the present invention may be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed. (1985).
  • the active ingredient is usually mixed with a carrier and/or excipient, which may be a solid, semi-solid, or liquid material.
  • a carrier and/or excipient which may be a solid, semi-solid, or liquid material.
  • the composition is preferably suited for oral administration, in which case it may be in the form of a tablet, pill, pellet, chewable tablet, capsule, granule, powder, lozenge, sachet, cachet, elixir, suspension, transdermal patch, dispersion, emulsion, solution, syrup, intranasal spray, aerosol (as a solid or in a liquid medium), ointment (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsule, suppositorie, sterile injectable solution and sterile packaged powder among other.
  • the compound of the present invention may be added to a person's diet by mixing them with food or drink.
  • the carrier may be any of those conventionally used. The choice of carrier will be determined by the particular method used to administer the pharmaceutical composition. Some examples of suitable carriers include lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose. Other pharmaceutical carriers may be sterile liquids, such as water, alcohols (e.g., ethanol) and lipid carriers such as oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), phospholipids (e.g.
  • lecithin polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • the formulations may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents, surfactants, emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavoring agents, colorants, buffering agents (e.g., acetates, citrates or phosphates), disintegrating agents, moistening agents and agents for the adjustment of tonicity such as sodium chloride. Fatty acids may also be included.
  • Alternative formulations include immediate-release formulations, slow-release formulations, controlled-release formulations, sustained-release formulations, extended-release formulations, delayed-release formulations and the like, as are known in the art. Each possibility is a separate embodiment of the invention.
  • the amount of the active ingredient that will be effective in the treatment of type II diabetes will depend on the severity of the disease, and may be determined by standard non-clinical or clinical techniques.
  • the precise dose to be employed in the formulation will also depend on the route of administration, the seriousness of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • a preferred dosage will be within the range of 0.01-1000 mg/kg of body weight, more preferably, about 0.1 mg/kg to about 100 mg/kg and even more preferably about 1 mg/kg to about 10 mg/kg.
  • Applicable methods for determining an appropriate dose and dosing schedule for administration of the present invention are known in the art and are described, for example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Brunton. L., Chabner B., and Knollman B., McGraw-Hill (2006), and in Remington: The Science and Practice of Pharmacy, Troy D. B., and Beringer P., Lippencott Williams & Wilkins (2003)
  • Example 1 The effect of N- «S)-l-(4-hydroxyphenyl)-3- «S)-2- hvdroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)-l-(4- hvdroxyphenyl)-3-((R)-2-hvdroxypropoxy)propan-2-yl)-3-phenylpropanamide on glucose uptake in vitro
  • N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide were provided by Novaremed. Each compound was dissolved in DMSO (10 mM stock solution) and stored at -20°C until use.
  • Human Subcutaneous Preadipocytes isolated from human subcutaneous fat tissues were purchased from Innoprot. The cells were cultured in preadipocyte medium in 96 well plates in a humidified atmosphere of 5% CO2 at 37 °C. After confluence, the cells were incubated in differentiation medium for two days. The medium was then changed to Dulbecco's Modified Eagle medium (DMEM), a medium containing 10 ⁇ g/ml insulin, for another two days. The cells were allowed to differentiate for six days before glucose uptake experiments. As shown in Figure 1 , pre- adipocytes (Fig. 1A; xlO and Fig. IB; x20) and differentiated adipocytes (Fig. 1C; xlO and Fig.
  • DMEM Dulbecco's Modified Eagle medium
  • Control cultures were treated with 100 nM insulin or 10 ⁇ of Rosiglitazone (RGT), a PPARy agonist. After incubation, free 2-NBDG was washed out from the cultures and the remaining fluorescence monolayer in the cell was measured with a Tecan-GENios fluorescence reader (Tecan). Excitation wavelength was set to 460 nm and an emission wavelength to 540 nm. Values of 2-NBDG incorporation in the absence of insulin were subtracted from those obtained with 100 nM insulin to establish 100% of specific 2-NBDG uptake.
  • RTT Rosiglitazone
  • Figures 2A-B demonstrate that both compounds induced glucose uptake in a biphasic manner.
  • N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide may be therapeutically advantageous over N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide (Fig. 2A) as with merely 0.25 ⁇ of the former a substantial glucose uptake was achieved, while a similar effect was obtained with about 100 ⁇ of the later.

Landscapes

  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to pharmaceutical composition comprising one or more stereoisomers of N-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide for the the treatment of type II diabetes and/or other medical conditions associated with this disease.

Description

PHARMACEUTICAL COMPOSITION COMPRISING STEREOISOMERS OF N-(l-(4-HYDROXYPHENYL)-3-(2-HYDROXYPROPOXY)PROPAN-2-YL)-3- PHENYLPROPANAMIDE FOR THE PREVENTION AND TREATMENT
OF TYPE II DIABETES
FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide for the treatment of type II diabetes and/or other medical conditions associated with therewith.
BACKGROUND OF THE INVENTION
Diabetes mellitus is considered as a worldwide epidemic. The International Diabetes Federation's most recent estimates indicate that 8.3% of adults - 382 million people - have diabetes, and the number of people with this disease is set to rise beyond 592 million in less than 25 years.
There are two main clinical forms of diabetes, each with a different pathogenesis: type I, insulin dependent diabetes mellitus (IDDM) and type II, non-insulin dependent diabetes mellitus (NIDDM).
Type I diabetes is considered as an autoimmune disease, results from an immune destruction of the β-cells of the pancreas. Although the exact cause is unknown, evidence suggests that both genetic predisposition and environmental factors, such as viral infection, are involved. The prevalent treatment for type I diabetes is administration of exogenous insulin.
Type II diabetes accounts for about 90% of those with diabetes. Unlike type I diabetes, this is a metabolic disease which is characterized by hyperglycemia (high blood glucose levels) due to insulin resistance and insulin deficiency. Several risk factors have been associated with type II diabetes, including obesity, advancing age, genetic susceptibility, high blood pressure, and life style patterns (such as physical inactivity, smoking and alcohol). Type II diabetes progresses through three stages of the disease. The first stage is known as a "pre-diabetic" state and involves hyperinsulinemia and "primary" insulin resistance. In this phase, cells no longer respond properly to insulin, the pancreas compensates for this resistance by producing more insulin. The insulin responsiveness in this stage is sufficient to maintain normal glucose tolerance or partially impaired glucose tolerance. In the second stage, insulin resistance worsens such that blood glucose levels abnormally rise after a meal despite elevated insulin levels (this condition is known as "postprandial hyperglycemia"). In the third or late phase of type II diabetes, insulin resistance does not change, however, the elevated glucose levels further damage β-cells, thereby drastically reducing insulin secretion and causing overt diabetes. This is made evident by "fasting hyperglycemia", in which glucose levels are high most of the time. The mechanism of insulin resistance is not fully understood. However, several observations have suggested that insulin resistance is due, at least in part, to inhibition of the insulin receptor. Deficiencies of insulin-receptor function might lead to decrease in the insulin-stimulated activities which include, for example, insulin receptor autophosphorylation and insulin receptor- mediated kinase activities (such as tyrosine kinase). Thus, although the receptor can bind insulin, the normal insulin-mediated transduction signals are not transmitted.
The compound N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide is disclosed in U.S. 7,642,290 for the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection.
U.S. 7,674,829 discloses the stereoisomers of (S)N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide in the treatment of AIDS and other viral diseases.
U.S.2011/0086910 discloses the use of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the treatment or prevention of pain.
These stereoisomers of (S)N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide are further disclosed in U.S. 2014/0039060 for treating cell proliferative disorders, more specifically Syk tyrosine kinase-mediated disorders.
Isolated stereoisomers of (S,S) and (S,R), are disclosed in WO 2013/084238, in particular the use of the stereoisomer N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is disclosed for the treatment or prevention of pain. There is a need for an effective anti-diabetic drug to treat the disease and other medical conditions associated with type II diabetes. Ideally, this therapeutic agent should mimic the ordinary insulin metabolic action with minimal adverse side effects.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical composition comprising stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide (formula I) for the treatment of type II diabetes and related medical conditions.
Figure imgf000004_0001
In one embodiment, the present invention relates to the use of substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, or substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, or combination thereof, for the treatment of type II diabetes and/or a medical condition associated with this disease.
The present invention is based in part on the unexpected discovery that the (S,S) and (S,R) diastereomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide, namely N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)- 1 -(4-hydroxyphenyl)- 3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide both individually induce cellular intake of glucose, in vitro.
Without wishing to be limited by any particular theory or mechanism of action, it is hypothesized that N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide have the ability to mimic the metabolic insulin action through independent activation of insulin receptor. This may be accomplished by the activation of the tyrosine kinase Lyn with either one or both of the compounds of the present invention. The activated kinase phosphorylates the insulin receptor substrate 1 (IRS-1), which triggers several signaling pathways that are involved in the regulation of glucose production, transportation, and cellular utilization.
According to one aspect, the present invention provides a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent for use in the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
According to some embodiments, the N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
According to further embodiments, said N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and a combination thereof.
In one embodiment, the N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide. In another embodiment, the N-(l- (4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide.
In one embodiment, the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound. In another embodiment, the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-
2- yl)-3-phenylpropanamide or a combination thereof, and less than about 5% of other stereoisomeric forms of the compound.
In one currently preferred embodiment, the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-
3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a combination thereof, and less than about 2% of other stereoisomeric forms of the compound.
According to some embodiments, the composition is in the form of a capsule, tablet, granule, powder, solution or suspension.
According to some embodiments, the pharmaceutical composition is in a form suitable for intravenous, intramuscular, oral, sublingual, buccal, parenteral, intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal administration.
According to another aspect, the present invention contemplates a method for treating type II diabetes and/or a medical condition associated with type II diabetes in a subject in need thereof, comprising the step of administering to said subject a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent.
According to some embodiments, said treating comprises any one or more of alleviating, preventing, delaying the onset, attenuating the progression of type II diabetes or conditions associated with this disease and achieving a beneficial therapeutic effect for a sustained period of time.
According to some embodiments, the medical condition associated with type II diabetes is selected from the group consisting of hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease), vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke, peripheral vascular disease, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
According to some embodiments, the subject is a mammal, preferably a human. In another aspect, the present invention relates to the use of a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described herein, for the manufacture of a medicament for treating type II diabetes and/or a medical condition associated with type II diabetes.
The present invention will be more fully understood from the following figures and detailed description of the preferred embodiments thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figs. 1A-1D show Oil-Red stained human subcutaneous pre-adipocytes (A xlO; B x20) and human subcutaneous differentiated adipocytes (C xlO; D x20).
Figs. 2A-2B are bar charts representing the glucose uptake level in adipocytes, in vitro, in the presence of different concentrations of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide (Fig. 2A; (S,S); relative to insulin performance) and N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2- yl)-3 -phenylpropanamide (Fig. 2B; (S,R); relative to insulin performance). In both charts the two left columns depict control experiments, in which cultures were treated with 100 nM insulin or 10 μΜ of Rosiglitazone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide for use in the treatment of type II diabetes and/or related medical conditions, e.g., hyperglycemia, insulin resistance and impaired glucose tolerance, among others.
According to some embodiments, the present invention provides a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent for use in the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
According to some embodiments, the N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
According to some embodiments, said N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and a combination thereof.
The stereoisomers N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)- 1 -(4-hydroxyphenyl)- 3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide are represented by formula (II) and formula (III), respectively:
Figure imgf000008_0001
(Π)
Figure imgf000008_0002
(III)
In one embodiment, the N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide. In another embodiment, the N-(l- (4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide. In another embodiment, the composition of the invention comprises a combination of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)- 1 -(4-hydroxyphenyl)- 3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
Chemical Definitions
The term "stereoisomers" as used herein, refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. In particular, "enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Enantiomers have identical chemical and physical properties except for their ability to rotate plane- polarized light (+/-) by equal amounts but in opposite directions. "Diastereomers", on the other hand, refers to stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of one another. Diastereomers are characterized by differences in physical properties (e.g., melting points, boiling points and spectral properties) and by some differences in chemical behavior towards achiral as well as chiral reagents. The terms "diastereomers" and "diastereoisomer" as used herein, are interchangeable.
Stereochemical definitions used herein generally follow McGraw-Hill Dictionary of Chemical Terms, S. P. Parker, Ed., McGraw-Hill Book Company, New York (1984) and Stereochemistry of Organic Compounds, Eliel, E. L. and Wilen, S. H., John Wiley & Sons, Inc., New York (1994).
All stereoisomers of the compound of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compound can exist in enantiomeric and/or diastereomeric forms or in mixtures thereof. The present invention intends to the use of any enantiomerically or diastereomerically enriched mixtures (i.e., mixtures enriched for one enantiomer or diastereomer), substantially pure enantiomers or diastereomers, or any mixtures thereof. The chiral centers can be designated as R or S.
The compound of the invention may be present as a salt. The term "salt" encompasses both basic and acid addition salts, including but not limited to phosphate, dihydrogen phosphate, hydrogen phosphate and phosphonate salts, and include salts formed with organic and inorganic anions and cations. Furthermore, the term includes salts that form by standard acid-base reactions of basic groups and organic or inorganic acids. Such acids include hydrochloric, hydrofluoric, hydrobromic, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, D-camphoric, phthalic, tartaric, salicyclic, methanesulfonic, benzenesulfonic, p- toluenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids. Additional salts of the compound described herein may be prepared by reacting the parent molecule with a suitable base, e.g., NaOH or KOH to yield the corresponding alkali metal salts, e.g., the sodium or potassium salts. Additional basic addition salts include ammonium salts (NH/t+), substituted ammonium salts, Li, Ca, Mg, salts, and the like.
The compound of the invention may be present as a hydrate. The term "hydrate" refers to a solvate wherein the solvent molecule is water. The term "Solvate" contemplates a physical association of the compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation.
As used herein, the term "substantially pure" generally refers to the presence of at least about 80% of a single stereoisomer, preferably at least about 90% more preferably at least about 95% or 97% and most preferably at least about 98% or 99% of a single stereoisomer.
According to some embodiments, the compositions of the invention comprise substantially pure N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide. According to some specific embodiments, the substantially pure stereoisomer comprises at least about 80% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 20% of other stereoisomeric forms of the compound. According to other embodiments, the substantially pure stereoisomer comprises at least about 90% by weight of N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, and less than about 10% of other stereoisomeric forms of the compound. According to currently preferred embodiments, the substantially pure stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 5% of other stereoisomeric forms of the compound. According to other preferred embodiments, the substantially pure stereoisomer comprises at least about 97% by weight of N-((S)- 1 -(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, and less than about 3% of other stereoisomeric forms of the compound. According to yet other preferred embodiments, the substantially pure stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 2% of other stereoisomeric forms of the compound. According other preferred embodiments, the substantially pure stereoisomer comprises at least about 99% by weight of N-((S)-1- (4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 1 % of other stereoisomeric forms of the compound.
According to other embodiments, the compositions of the invention comprise substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)- 3-phenylpropanamide. According to some specific embodiments, the substantially pure stereoisomer comprises at least about 80% by weight of N-((S)-l-(4-hydroxyphenyl)-3- ((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 20% of other stereoisomeric forms of the compound. According to other embodiments, the substantially pure stereoisomer comprises at least about 90% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 10% of other stereoisomeric forms of the compound. According to currently preferred embodiments, the substantially pure stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 5% of other stereoisomeric forms of the compound. According to other preferred embodiments, the substantially pure stereoisomer comprises at least about 97% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 3% of other stereoisomeric forms of the compound. According to yet other preferred embodiments, the substantially pure stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 2% of other stereoisomeric forms of the compound. According to other preferred embodiments, the substantially pure stereoisomer comprises at least about 99% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, and less than about 1 % of other stereoisomeric forms of the compound.
According to yet other embodiments, the compositions of the invention comprise a mixture of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.According to some embodiments, the stereoisomer comprises at least about 80% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or N- ((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a combination thereof, and less than about 20% of other stereoisomeric forms of the compound.
According to some embodiments, the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound.
According to some embodiments, the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 5% of other stereoisomeric forms of the compound.
According to some embodiments, the stereoisomer comprises at least about 97% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 3% of other stereoisomeric forms of the compound.
According to some embodiments, the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 2% of other stereoisomeric forms of the compound.
According to some embodiments, the stereoisomer comprises at least about 99% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide or a combination thereof, and less than about 1% of other stereoisomeric forms of the compound.
According to some embodiments the at least one other stereoisomer is selected from the group consisting of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- 1 -(4-hydroxyphenyl)-3- ((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((R)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((R)- l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or combination thereof.
Methods to obtain stereochemically purity compounds, such as classical separation techniques and stereochemically controlled synthesis are well known in the art (see e.g., Enantiomers, Racemates and Resolutions, Jacques J., Collet A. and Wilen S. H., John Wiley & Sons, Inc., New York (1981)). WO 2013/084238 for example, discloses a stereochemically controlled synthesis of N-((S)-l-(4-hydroxyphenyl)-3- ((S)-2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide. The prevailing racemization was overcome by controlling the reaction temperature and the order of adding the raw materials. WO 2013/084238 also demonstrates a method of separation of the two diastereomers prepared as a mixture in the traditional synthesis (described for example, in US 2011/0086910), by a supercritical fluid chromatography (SFC) on RegisPack™, a polysaccharide coated chiral column. The contents of WO 2013/084238 are hereby incorporated by reference in their entirety. Therapeutic Use
According to some embodiments, the present invention provides a method for treating type II diabetes and/or a medical condition associated with type II diabetes in a subject in need thereof, comprising the step of administering to said subject a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent.
The terms "treating" and "treatment", as used herein are interchangeable and refer to any one or more of delaying the onset of, retarding or reversing the progress of, alleviating or preventing either type II diabetes or one or more medical conditions associated with of such disease, and achieving a beneficial therapeutic effect preferably for a sustained or prolonged period of time. Each possibility is a separate embodiment of the invention.
According to some embodiments, the medical condition associated with type II diabetes is selected from the group consisting of glucose and insulin metabolism deficiencies, diabetic complications and metabolic disorders.
Non limiting examples of medical conditions associated with type II diabetes include hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease) and vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke and peripheral vascular disease (which can lead to ulcers, gangrene and amputation) among others. Each possibility is a separate embodiment of the invention.
Other medical conditions associated with type II diabetes, include but are not limited to, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
As used herein, the term "administering" refers to bringing in contact with a compound of the present invention. Administration can be accomplished to cells or tissue cultures, or to living organisms, for example humans.
According to some embodiments, the subject is a mammal, preferably a human. According to some embodiments, the present invention relates to the use of a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described herein, in the manufacture of a medicament for treating type II diabetes and/or a medical condition associated with type II diabetes.
The method of treatment of the invention may be in parallel to, prior to, or following additional method of treatment.
According to some embodiments, the composition of the present invention may be administered to a subject in need as a prodrug. The prodrug often offers advantages such as delayed release, solubility, and/or tissue compatibility. The term "prodrug", as used herein, refers to the compound of the present invention that when administered generates the biologically active "drug'Vcomposition as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). The prodrug and derivatives thereof may be prepared by methods and techniques known to those of skill in the art.
The present invention further provides the administration of the pharmaceutical compositions of the present invention in combination with at least one additional antidiabetic medication. The combination therapy may be administered to the subject undergoing treatment simultaneously or sequentially in any order, at a time interval determined by a skilled artisan.
Non-limiting examples of anti-diabetic medication include insulin, secretagogues (such as sulfonylureas and nonsulfonylurea secretagogues), alpha-glucosidase inhibitors, biguanides, meglitinides, and thiazolidinediones, sensitizers (such as biguanides and thiazolidinediones), peptide analogs (such as injectable incretin mimetics and injectable Amylin analogues), among others. Each possibility represents a separate embodiment of the invention.
Non-limiting examples of known anti-diabetic drugs include Metformin, rosiglitazone (Avandia), pioglitazone (Actos), tolbutamide (Orinase),acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide (Diabinese), Second-generation agents, glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), glimepiride (Amaryl), gliclazide (Diamicron), repaglinide (Prandin), nateglinide (Starlix), miglitol (Glyset), acarbose (Precose/Glucobay), Exenatide, Liraglutide, vildagliptin (Galvus), sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta) among others. Each possibility represents a separate embodiment of the invention.
Pharmaceutical Composition
According to some embodiments, the pharmaceutical composition of the present invention can be formulated for administration by a variety of routes selected from the group consisting of intravenous, intramuscular, oral, sublingual, buccal, parenteral, , intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal among others. Each possibility is a separate embodiment of the invention.
Such composition is prepared in a manner well known in the pharmaceutical art and comprise as the active ingredient one or more stereoisomers of N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide as described hereinabove, and a pharmaceutically acceptable excipient and/or carrier. The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.
The pharmaceutical composition of the invention is suitable for use in a variety of drug delivery systems as detailed hereinbelow. Pharmaceutically acceptable carriers suitable for use in the present invention may be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed. (1985).
During the preparation of the pharmaceutical composition according to the present invention the active ingredient is usually mixed with a carrier and/or excipient, which may be a solid, semi-solid, or liquid material. The composition is preferably suited for oral administration, in which case it may be in the form of a tablet, pill, pellet, chewable tablet, capsule, granule, powder, lozenge, sachet, cachet, elixir, suspension, transdermal patch, dispersion, emulsion, solution, syrup, intranasal spray, aerosol (as a solid or in a liquid medium), ointment (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsule, suppositorie, sterile injectable solution and sterile packaged powder among other. Each possibility is a separate embodiment of the invention. In another embodiment, the compound of the present invention may be added to a person's diet by mixing them with food or drink.
The carrier may be any of those conventionally used. The choice of carrier will be determined by the particular method used to administer the pharmaceutical composition. Some examples of suitable carriers include lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose. Other pharmaceutical carriers may be sterile liquids, such as water, alcohols (e.g., ethanol) and lipid carriers such as oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), phospholipids (e.g. lecithin), polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
The formulations may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents, surfactants, emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavoring agents, colorants, buffering agents (e.g., acetates, citrates or phosphates), disintegrating agents, moistening agents and agents for the adjustment of tonicity such as sodium chloride. Fatty acids may also be included.
Alternative formulations include immediate-release formulations, slow-release formulations, controlled-release formulations, sustained-release formulations, extended-release formulations, delayed-release formulations and the like, as are known in the art. Each possibility is a separate embodiment of the invention.
The amount of the active ingredient that will be effective in the treatment of type II diabetes will depend on the severity of the disease, and may be determined by standard non-clinical or clinical techniques. The precise dose to be employed in the formulation will also depend on the route of administration, the seriousness of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances. A preferred dosage will be within the range of 0.01-1000 mg/kg of body weight, more preferably, about 0.1 mg/kg to about 100 mg/kg and even more preferably about 1 mg/kg to about 10 mg/kg. Applicable methods for determining an appropriate dose and dosing schedule for administration of the present invention are known in the art and are described, for example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Brunton. L., Chabner B., and Knollman B., McGraw-Hill (2006), and in Remington: The Science and Practice of Pharmacy, Troy D. B., and Beringer P., Lippencott Williams & Wilkins (2003).
The examples hereinbelow are presented in order to more fully illustrate some embodiments of the invention. They should, in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art may readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.
EXAMPLES
Example 1: The effect of N-«S)-l-(4-hydroxyphenyl)-3-«S)-2- hvdroxypropoxy)propan-2-yl)-3-phenylpropanamide and N-((S)-l-(4- hvdroxyphenyl)-3-((R)-2-hvdroxypropoxy)propan-2-yl)-3-phenylpropanamide on glucose uptake in vitro
The effects of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide on glucose uptake was determined in vitro using human subcutaneous adipocytes.
N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide and N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide were provided by Novaremed. Each compound was dissolved in DMSO (10 mM stock solution) and stored at -20°C until use.
Human Subcutaneous Preadipocytes (HP A), isolated from human subcutaneous fat tissues were purchased from Innoprot. The cells were cultured in preadipocyte medium in 96 well plates in a humidified atmosphere of 5% CO2 at 37 °C. After confluence, the cells were incubated in differentiation medium for two days. The medium was then changed to Dulbecco's Modified Eagle medium (DMEM), a medium containing 10 μg/ml insulin, for another two days. The cells were allowed to differentiate for six days before glucose uptake experiments. As shown in Figure 1 , pre- adipocytes (Fig. 1A; xlO and Fig. IB; x20) and differentiated adipocytes (Fig. 1C; xlO and Fig. ID; x20), stained with Oil-Red. The mature adipocytes were incubated for two h with PBS at 37 °C to deplete them from glucose. Following incubation for 60 min with PBS containing 80 mM of 2-[N-(7-nitrobenz-2-oxa-l, 3-diazol-4-yl) amino] -2- deoxy-D -glucose (2-NBDG; a fluorescent glucose analog) and different concentrations of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan- 2-yl)-3-phenylpropanamide. Control cultures were treated with 100 nM insulin or 10 μΜ of Rosiglitazone (RGT), a PPARy agonist. After incubation, free 2-NBDG was washed out from the cultures and the remaining fluorescence monolayer in the cell was measured with a Tecan-GENios fluorescence reader (Tecan). Excitation wavelength was set to 460 nm and an emission wavelength to 540 nm. Values of 2-NBDG incorporation in the absence of insulin were subtracted from those obtained with 100 nM insulin to establish 100% of specific 2-NBDG uptake.
Figures 2A-B demonstrate that both compounds induced glucose uptake in a biphasic manner. However, N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide (Fig. 2B) may be therapeutically advantageous over N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2- yl)-3-phenylpropanamide (Fig. 2A) as with merely 0.25 μΜ of the former a substantial glucose uptake was achieved, while a similar effect was obtained with about 100 μΜ of the later.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

Claims

A pharmaceutical composition comprising one or more stereoisomers of N- (l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent, for use in the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
The pharmaceutical composition according to claim 1, wherein the N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
The pharmaceutical composition according to claim 2, wherein the N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide, N-((S)- 1 -(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide and a combination thereof.
The pharmaceutical composition according to claim 3, wherein the N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
The pharmaceutical composition according to claim 3, wherein the N-(l-(4- hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide.
The pharmaceutical composition according to claim 2, wherein the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound.
7. The pharmaceutical composition according to claim 6, wherein the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a combination thereof, and less than about 5% of other stereoisomeric forms of the compound.
8. The pharmaceutical composition according to claim 7, wherein the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4- hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or N-((S)-l-(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a combination thereof, and less than about 2% of other stereoisomeric forms of the compound.
9. The pharmaceutical composition according to claim 1, wherein the medical condition associated with type II diabetes is selected from the group consisting of hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease), vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke, peripheral vascular disease, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
10. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a capsule, tablet, granule, powder, solution or suspension.
11. The pharmaceutical composition according to claim 1 , in a form suitable for intravenous, intramuscular, oral, sublingual, buccal, parenteral, , intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal administration.
12. A method for treating type II diabetes and/or a medical condition associated with type II diabetes in a subject in need thereof, comprising the step of administering to said subject a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent.
13. The method according to claim 12, wherein the N-(l-(4-hydroxyphenyl)-3- (2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is in the form of a substantially pure stereoisomer or a combination of stereoisomers.
14. The method according to claim 13, wherein the N-(l-(4-hydroxyphenyl)-3- (2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is selected from N- ((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide, N-((S)- 1 -(4-hydroxyphenyl)-3-((R)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide and a combination thereof.
15. The method according to claim 14, wherein the N-(l-(4-hydroxyphenyl)-3- (2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((S)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide.
16. The method according to claim 14, wherein the N-(l-(4-hydroxyphenyl)-3- (2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide is substantially pure N-((S)-l-(4-hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide.
17. The method according to claim 13, wherein the stereoisomer comprises at least about 90% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a combination thereof, and less than about 10% of other stereoisomeric forms of the compound.
18. The method according to claim 17, wherein the stereoisomer comprises at least about 95% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a combination thereof, and less than about 5% of other stereoisomeric forms of the compound.
19. The method according to claim 18, wherein the stereoisomer comprises at least about 98% by weight of N-((S)-l-(4-hydroxyphenyl)-3-((S)-2- hydroxypropoxy)propan-2-yl)-3-phenylpropanamide or N-((S)-l-(4- hydroxyphenyl)-3-((R)-2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a combination thereof, and less than about 2% of other stereoisomeric forms of the compound.
20. The method according to claim 12, wherein treating comprises at least one of alleviating, preventing, delaying the onset, attenuating the progression of type II diabetes and/or medical condition associated with type II diabetes and achieving a beneficial therapeutic effect.
21. The method according to claim 12, wherein the subject is a mammal.
22. The method according to claim 21, wherein the subject is human.
23. The method according to claim 12, wherein the pharmaceutical composition is administered in a route of administration selected from the group consisting of intravenous, intramuscular, oral, sublingual, buccal, parenteral, intramuscular, inhalation, intraperitoneal, nasal, subcutaneous, topical, intradermal or transdermal.
24. The method according to claim 12, wherein the medical condition associated with type II diabetes is selected from the group consisting of hyperglycemia, insulin resistance, impaired glucose tolerance, fatty liver, metabolic syndrome X, obesity, cancer, microvascular complications including neuropathy (nerve damage), nephropathy (kidney disease), vision disorders (e.g., retinopathy, glaucoma, cataract and corneal disease), macrovascular complications including heart disease, stroke, peripheral vascular disease, infections, metabolic difficulties, impotence, autonomic neuropathy and pregnancy complications.
25. Use of a pharmaceutical composition comprising one or more stereoisomers of N-(l-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3- phenylpropanamide or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent, for the manufacture of a medicament for the treatment of type II diabetes and/or a medical condition associated with type II diabetes.
PCT/IL2015/050499 2014-05-14 2015-05-12 Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes WO2015173813A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201461992922P 2014-05-14 2014-05-14
US61/992,922 2014-05-14

Publications (1)

Publication Number Publication Date
WO2015173813A1 true WO2015173813A1 (en) 2015-11-19

Family

ID=54479404

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2015/050499 WO2015173813A1 (en) 2014-05-14 2015-05-12 Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes

Country Status (1)

Country Link
WO (1) WO2015173813A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3939578A1 (en) * 2020-07-13 2022-01-19 Novaremed Ltd. Compounds for treatment or prevention of an infection resulting from a coronavirus and/or a coronavirus-induced disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004031129A2 (en) * 2002-10-03 2004-04-15 New Era Biotech, Ltd. Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection
WO2013042005A1 (en) * 2011-09-21 2013-03-28 Novaremed Ltd N- substituted benzenepropanamide and benzenepropenamide for use in the prevention or the treatment of affective disorders
WO2013084238A1 (en) * 2011-12-08 2013-06-13 Novaremed Ltd. Isolated stereoisomeric forms of (s) 2-n (3-o-(propan 2-ol) -1-propyl-4-hydroxybenzene) -3-phenylpropylamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004031129A2 (en) * 2002-10-03 2004-04-15 New Era Biotech, Ltd. Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection
WO2013042005A1 (en) * 2011-09-21 2013-03-28 Novaremed Ltd N- substituted benzenepropanamide and benzenepropenamide for use in the prevention or the treatment of affective disorders
WO2013084238A1 (en) * 2011-12-08 2013-06-13 Novaremed Ltd. Isolated stereoisomeric forms of (s) 2-n (3-o-(propan 2-ol) -1-propyl-4-hydroxybenzene) -3-phenylpropylamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3939578A1 (en) * 2020-07-13 2022-01-19 Novaremed Ltd. Compounds for treatment or prevention of an infection resulting from a coronavirus and/or a coronavirus-induced disease

Similar Documents

Publication Publication Date Title
EP2275108B1 (en) Pharmaceutical preparation comprising dpp-iv inhibitor and other diabetes therapeutic agent in concomitant or combined form
US20090324701A1 (en) Compositions containing (s)-bethanechol and their use in the treatment of insulin resistance, type 2 diabetes, glucose intolerance and related disorders
US11034691B2 (en) Sphinogosine-1 -phosphate receptor modulators for treatment of cardiopulmonary disorders
WO2012067111A1 (en) PKC-ε ACTIVATOR
US8440678B2 (en) Pharmaceutical composition
TW201206443A (en) Treatment of Type 2 diabetes
CN115348863A (en) Treatment of type 2 diabetes or obesity or excess body weight with 2- [ (4- {6- [ (4-cyano-2-fluorobenzyl) oxy ] pyridin-2-yl } piperidin-1-yl) methyl ] -1- [ (2S) -oxetan-2-ylmethyl ] -1H-benzimidazole-6-carboxylic acid or a pharmaceutically salt thereof
TW202308620A (en) Pharmaceutical composition comprising gpr40 agonist and sglt-2 inhibitor and preparation thereof
WO2015173813A1 (en) Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes
US9649294B2 (en) Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
WO2023129595A1 (en) Obicetrapib and sglt2 inhibitor combination
US9468669B2 (en) Methods to treat dysregulated blood glucose disorders
US20210206773A1 (en) Drug for treating disorders of corneal epithelium
JP2010516716A (en) Use of catecholamines and related compounds as angiogenesis inhibitors
EP3996704A1 (en) Combination therapy of gpr119 agonists and dpp-4 inhibitors
CA3102407A1 (en) Method of administering a therapeutically effective amount of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
CA3102584A1 (en) Use of 5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]benzyl]-1,3-thiazolidine-2,4-dione and its salts
TWI842924B (en) Pharmaceutical combination and pharmaceutical kit of gpr119 agonists and dpp-4 inhibitors
RU2818562C2 (en) Combined therapy with gpr119 agonists and dpp-4 inhibitors
US20160166578A1 (en) Method for treating type i and type ii diabetes
US20240009195A1 (en) Novel uses
US20230414621A1 (en) No-pde5 inhibitor for use in treating dry age-related macular degeneration, geographic atrophy and glaucoma-associated neurodegeneration

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15792863

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15792863

Country of ref document: EP

Kind code of ref document: A1