WO2005056536A1 - Antidiabetic agents which exhibit activity against ppar - Google Patents

Antidiabetic agents which exhibit activity against ppar Download PDF

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Publication number
WO2005056536A1
WO2005056536A1 PCT/IB2004/003861 IB2004003861W WO2005056536A1 WO 2005056536 A1 WO2005056536 A1 WO 2005056536A1 IB 2004003861 W IB2004003861 W IB 2004003861W WO 2005056536 A1 WO2005056536 A1 WO 2005056536A1
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compound
formula
benzoylphenylamino
alkyl
prop
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PCT/IB2004/003861
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French (fr)
Inventor
Mohammad Salman
Jitendra A. Sattigeri
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Ranbaxy Laboratories Limited
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Publication of WO2005056536A1 publication Critical patent/WO2005056536A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to alkanoic acids and their derivatives which exhibit activity against PPARs, and hence can be used as antidiabetic compounds.
  • Compounds disclosed herein can be used as peroxisome proliferation activated receptor (PPAR) activator.
  • Such compounds can be used as therapeutic agents for the treatment of diseases and conditions mediated through any ofthe isoforms of PPAR, diabetes and diabetes- associated complications, and treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity.
  • Processes for the preparation ofthe disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are also provided.
  • Type II insulin-resistant diabetes mellitus also known as non insulin-dependent diabetes mellitus
  • Type II diabetes is a complex metabolic disorder and is characterized by hyperglycemia. This results from contribution of impaired insulin secretion from pancreas and insulin resistance mainly in muscle and liver.
  • Insulin-resistant individuals in addition to being hyperglycemic, exhibit a variety of closely related clinical indications, which include obesity, hypertension, dyslipidemia, premature atherosclerosis. In fact, 80% of diabetic mortality arises from ' atherosclerotic cardiovascular disease (ASCVD).
  • ASCVD atherosclerotic cardiovascular disease
  • Uncontrolled hyperglycemia can further lead to late stage complications such as nephropathy, neuropathy and retinopathy.
  • Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise.
  • several pharmacological agents are also available as hypoglycemic agents including insulin secretagogues - sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide) which increase insulin secretion from pancreatic cells; biguanides (for example, metformin) which lower hepatic glucose production; and ⁇ -glucosidase inhibitors (for example, acarbose) which delays intestinal absorption of carbohydrate.
  • insulin secretagogues - sulphonyl ureas for example, glimeperide
  • non sulphonyl ureas for example, repaglinide
  • biguanides for example, metformin
  • PPAR Peroxisome-Proliferator-Activated Receptor
  • PPAR are ligand activated transcription factors (members of nuclear receptor family), which offer promising therapeutic approaches to Type II diabetes mellitus.
  • PPAR exists in three subtype forms, ⁇ , ⁇ , ⁇ and ⁇ .
  • PPAR ⁇ is abundantly expressed in adipose tissues.
  • Direct activation of PPAR ⁇ leads to induction of adipocyte genes, such as for fatty acid transporter 1, which in turn contributes to lowering of triglycerides and free fatty acid (FFA) levels.
  • FFA free fatty acid
  • FFA is a potential mediator of insulin resistance
  • lowering of FFA levels contributes to efficacy of PPAR ⁇ activation in increasing insulin sensitivity and consequently glucose uptake in skeletal muscle cell.
  • Glitazones (for example, rosiglitazone and pioglitazone) belong to this class of drug and are now proven insulin sensitisers (Moller, D.E., Nature, 2001, 414(6865), 821-827).
  • WO 03/018553 discloses compounds, pharmaceutical compositions containing such compounds, processes for preparing such compounds, and their use as antidiabetic agents.
  • WO 02/100813 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as antidiabetic agents.
  • WO 02/16331 discloses oxazolyl-arylpropionic acid derivatives and their use as PPAR agonists.
  • WO 01/55085 discloses propionic acid derivatives, which are described as useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator- Activated Receptors (PPAR).
  • PPAR Peroxisome Proliferator- Activated Receptors
  • WO 00/23425 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as antidiabetic agents.
  • WO 00/63161 discloses certain 1,4-disubstituted phenyl derivatives that are described as acting as agonists to PPAR- ⁇ receptors.
  • WO 99/08501 discloses ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids, which are described as having antiobesity and hypocholesterolemic properties.
  • WO 97/31907 discloses substituted 4-hydroxy-phenylalkanoic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment and or prophylaxis of hyperglycemia, dyslipidemia, and is of particular use in the treatment of Type II diabetes.
  • WO 94/01420 discloses certain heterocyclic compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • 6,274,608 discloses compounds, their preparation and use in the treatment of condition mediated by nuclear receptors, in particular the Retinoid X Receptor (RXR) and the Peroxisome Proliferator- Activated Receptor (PPAR) families. Such conditions include diabetes and obesity.
  • RXR Retinoid X Receptor
  • PPAR Peroxisome Proliferator- Activated Receptor
  • Such conditions include diabetes and obesity.
  • U.S Patent No. 6,054,453 discloses ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids, compositions containing them, and their use as hypohpidemic and antihyperglycemic agents.
  • U.S. Patent No. 6,214,820 discloses compounds which are described as useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
  • PPAR Peroxisome Proliferator-Activated Recept
  • U.S. Patent No. 6,258,850 discloses 3-aryl-2-hydroxypropionic acid derivatives, process and intermediates for their manufacture, pharmaceutical preparations containing them and the use ofthe compounds in clinical conditions associated with insulin resistance.
  • U.S. Patent No. 6,297,580 discloses substituted 4-hydroxy-phenyl alkanoic acid derivatives described as having agonist activity to PPAR. Summary ofthe Invention Particular alkanoic acids and their derivatives exhibiting activity against PPARs and hence can be used as antidiabetic compounds, and processes for the synthesis of these compounds are disclosed. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, N-oxides or metabolites of these compounds having the same type of activity are also provided.
  • compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which can be used for the treatment of diseases and conditions mediated through any of the isoforms of peroxisome proliferation activated receptor (PPAR), treatment of diabetes mellitus and the disease or condition mediated through insulin resistance are also provided.
  • PPAR peroxisome proliferation activated receptor
  • A can represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl, or heterocycle;
  • X can represent
  • R can represent hydrogen or alkyl
  • B can represent aryl, heterocycle
  • Y can represent (CH 2 ) m , wherein m represents an integer 1 to 3;
  • Ri can represent hydrogen or alkyl
  • R ⁇ can represent OR 2 or NR 2 R , wherein R 2 and R 3 are independently selected from hydrogen, alkyl, or together represent cycloalkyl;
  • R 4 can represent
  • R 5 can represent alkyl; and D and E can be independently selected from optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, optional substituent(s) is/are selected from halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NReR 7 , -CONR ⁇ , -CH 2 R 6 R 7 , -COOR 7 , -OCH 2 R 7 or - CH 2 OR 7 , wherein R5 and R 7 are independently selected from hydrogen, alkyl and aryl.
  • D and E can be independently selected from optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, optional substituent(s) is/are selected from halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NReR 7 , -CONR ⁇ , -CH
  • a third aspect there are provided methods for the treatment of mammals suffering from diseases or conditions in which insulin resistance is the central pathophysiological mechanism.
  • diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, psoriasis or obesity.
  • processes for preparing compounds disclosed herein there are provided processes for preparing compounds disclosed herein.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • acyl and “acyloxy” refer to COR 8 and OCOR 8 wherein R 8 represents alkyl or aryl.
  • alkoxy refers to O-R 8 wherein R 8 represents alkyl or aryl.
  • thioalkyl refers to -S-R 8 wherein R 8 refers to alkyl or aryl.
  • cycloalkoxy refers to O-R 9 wherein R 9 represents cycloalkyl or cycloalkenyl.
  • haloalkyl refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen.
  • the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring.
  • the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydro furanyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, piperazinyl, benzoxazinyl, benzthiazinyl, benzimidazolyl, carbazolyl, indolyl, phenoxazinyl, and phenothiazinyl, and the like.
  • the heterocyclic substitute for B includes
  • the aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from halogen, hydroxy, nitro, mercapto, cyano, alkyl, aryl, haloalkyl, alkoxy, haloalkoxy, thioalkyl, cycloalkoxy, -NR ⁇ R ? , -CONR ⁇ R ? , - COOR 7 , -OCOR 7 , -COR 7 , -NHSO 2 R 7 and -SO 2 NHR 7 , wherein R 6 and R 7 are independently selected from hydrogen, alkyl and aryl.
  • the term "polymorphs" includes all crystalline form for compounds described herein.
  • solvates may form solvates with water (for example, hydrate, hemihydrate or sesquihydrate) or organic solvents. Such solvates are also encompassed within the scope of this invention.
  • pharmaceutically acceptable salts denotes salts ofthe free acid, which substantially possess the desired pharmacological activity ofthe free acid.
  • Suitable pharmaceutically acceptable salts may be prepared from inorganic or organic base. Examples of inorganic base include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc hydroxides, and the like.
  • Organic bases include, but are not limited to, primary, secondary and tertiary amines, cyclic amines, N,N'- dibenzylethylenediamine, chloroprocame, choline, diethanolamine, ethylenediamine, and procaine and the like.
  • the salt fo ⁇ ns may differ from compounds described herein with regard to certain physical properties such as solubility in polar solvent, but the salts are otherwise equivalent for purposes disclosed herein.
  • the compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist.
  • the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme I. Scheme I
  • reaction of a compound of Formula II with triflic anhydride to give a compound of Formula III can be carried out in a solvent, for example, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, benzene or toluene.
  • a solvent for example, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, benzene or toluene.
  • the reaction of a compound of Formula II with a triflic reagent, for example, triflic anhydride can be carried out in the presence of an organic base, for example, pyridine, 4-dimethylaminopyridine or triethylamine.
  • reaction of a compound of Formula III with a compound of Formula IV to give a compound of Formula V can be carried out in a solvent, for example toluene, acetonitrile, dimethylformamide or dimethyl sulfoxide.
  • a solvent for example toluene, acetonitrile, dimethylformamide or dimethyl sulfoxide.
  • the reaction of a compound of Formula III with a compound of Formula IV can be carried out in the presence of an organic base, for example diethylamine, triethylamine, diisopropylamine, pyridine or 4- dimethylamino pyridine.
  • the reaction of a compound of Formula III with a compound of Formula IV can be carried out in the presence of a metallic reagent, for example, copper (I) iodide, triphenylphosphine and a palladium catalyst such as palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) propionate, tetra kis(triphenylphosphine) palladium (0), tris(dibenzylidineacetone) palladium (0) and bis(triphenylphosphine) palladium (II) chloride.
  • a metallic reagent for example, copper (I) iodide, triphenylphosphine and a palladium catalyst such as palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) propionate, tetra kis(triphenylphosphine) palladium
  • the hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in a solvent, for example, tetrahydrofuran, methanol, ethanol or acetonitrile.
  • the hydrolysis of a compound of Formula V to give a compound of Fo ⁇ nula VI can be earned out in the presence of an inorganic base, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction of a compound of Formula VI with an amine of Formula HNR 2 R 3 to give a compound of Formula VII can be carried out by conventional methods known in the prior art.
  • compositions comprising, as an active ingredient, at least one ofthe disclosed compound or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent.
  • Compounds disclosed herein may be administered to humans or animals for treatment by any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramascular, intranasal) routes of administration.
  • the pharmaceutical compositions disclosed herein comprise a pharmaceutically effective amount of a compound ofthe present invention formulated together with one or more pharmaceutically acceptable earners.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating materials or formulations of any type.
  • Solid form preparations for oral administration include capsules, tablets, pills, powders, granules, sachets and suppositories.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipients or carrier such as sodium citrate, dicalcium phosphate; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia; disintegrating agents such as agar-agar, calcium carbonate, alginic acid, certain silicates and sodium carbonate; absorption acceptors such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate; adsorbents such as kaolin; Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof.
  • pharmaceutically acceptable excipients or carrier such as sodium citrate, dicalcium phosphate
  • binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia
  • disintegrating agents such as agar
  • the dosage form may also comprise buffering agents.
  • the solid preparations of tablets, capsules, pills, granules can be prepared with coatings and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.
  • Liquid form preparations of oral administration include pharmaceutically acceptable emulsions, solution, suspensions, syrup and elixir.
  • the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (such as cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, and fatty acid esters of Sorbitan and mixture thereof.
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (such as cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, and fatty acid esters
  • the oral composition can also include adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • injectible preparations such as sterile injection or aqueous solution may be formulated according to the art using suitable dispersing or wetting and suspending agent.
  • suitable dispersing or wetting and suspending agent are water, Ringer's solutions, and isotonic sodium chloride.
  • the fonn illations disclosed herein may be formulated so as to provide quick, sustained, or delayed release ofthe active ingredient after administration to the patient by employing procedures well known to the art. Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspects ofthe disclosure, and do not constrain the scope ofthe present invention as defined by the claims. Examples
  • Example 1 General Procedure Step 1 : Preparation of Compound of Formula III To a solution of compound of Formula II (1 equiv) in dichloromethane (0.1-1.0 M) was added pyridine (3 equiv). The reaction mixture was cooled further down to -78 °C and triflic anhydride (1.5 equiv) was added dropwise. Stirring was continued at -78 °C for 30 minutes further, at the end of which the reaction temperature was allowed to warm to an ambient temperature. The reaction mixture was neutralized with aqueous hydrochloric acid and the organic phase was extracted into dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated and residue purified on silica column using ethyl acetate and hexane to afford the title compound.
  • Step 2 Preparation of Compound of Formula IV
  • dimethylformamide and sodium hydride 1.2 equiv
  • the suspension was cooled to 0 °C and a solution of heterocycle in dimethylformamide (0.1-1.0 M) was added slowly.
  • the ice bath was removed and the stirring continued at an ambient temperature for 1 hour.
  • the resulting clear solution was cooled down to 0 °C, and propargyl bromide (1 equiv.) added slowly.
  • the reaction mixture was allowed to warm to an ambient temperature. After completion of reaction, the reaction mixture was diluted in water and organ ics extracted with ethyl acetate.
  • Step 3 Preparation of Compound of Formula V A mixture of bis(triphenylphosphine) palladium (II) chloride (0.05 equiv), copper (I) iodide (0.1 equiv), a compound of Formula III (1.0 equiv, from step 1), triethylamine (3-7 equiv) and triphenylphosphine (1.0 equiv) in dimethylformamide was sti ⁇ ed at 80 °C.
  • Step 4 Preparation of Compound of Formula VI
  • a solution of a compound of Fo ⁇ nula V (1 equiv, from step 3) in tetrahydrofuran and water (3:1) was treated with a solution of lithium hydroxide in water (1.5 equiv).
  • the resulting solution was sti ⁇ ed at an ambient temperature.
  • the pH ofthe reaction mixture was adjusted to 6.0-7.0 using an aqueous solution of hydrochloric acid and the organic phase was extracted with ethyl acetate.
  • the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator.
  • the residue was purified by silica gel column chromatography to yield the title compound.
  • reaction is then quenched and the product is extracted with ethyl acetate.
  • organic layer is washed with water, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator.
  • the residue is purified on silica gel column to yield the title compound.
  • Example 2 Functional and Binding Assay Coactivator-dependent receptor ligand assays (CARLA) for PPAR ⁇ / ⁇ / ⁇ in a homogeneous time resolved- fluorescence resonance energy transfer (TR-FRET) format.
  • CARLA coactivator-dependent receptor ligand assays
  • TR-FRET time resolved- fluorescence resonance energy transfer
  • Compounds disclosed herein have EC 50 values as determined by the following assay.
  • the functional and binding assays for the PPAR ⁇ , PPAR ⁇ and PPAR ⁇ are a variation ofthe coactivator-dependent receptor ligand assay (CARLA) (Krey G, Braissant O, L'Horset F, Kalkhoven E, Pe ⁇ oud M, Parker MG and Wahli W.
  • All assays include 3 nM ofthe glutathione-S-transferase (GST) fusion proteins of either the liPPAR ⁇ ligand binding domain (LBD) (amino acids 167- 468) (GST- hPPAR ⁇ LBD), GST-hPPAR ⁇ LBD (amino acids 139-442) or GST-hPPAR ⁇ LBD (amino acids 175-476); 3 nM Eu-labelled anti-GST antibody (Wallac); 30 nM biotinylated steroid receptor coactivator-1 (SRC-1) pep tide (an N- terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS, derived from amino acids 676-700 of SRC-1); and 10 nM streptavidin-labelled allophycocyanin (APC; Prozyme).
  • LBD liPPAR ⁇ ligand binding domain
  • GST-hPPAR ⁇ LBD amino acids 139-442
  • the binding of a ligand to a PPAR LBD alters the conformation ofthe LBD and permits the biotinylated SRC-1 peptide to bind. This brings the Eu-labelled anti-GST antibody and the strepavidin-labelled APC in close proximity, thereby facilitating fluorescence energy transfer.
  • the biotinylated SRC-1 peptide is prepared by standard solid-phase peptide synthetic methods.
  • the GST-PPAR LBDs were expressed in pGEX vectors (Amersham Pharmacia) in the E. co ⁇ strain BL21(DE3) using standard expression conditions at 18 °C. In some cases, the GST-PPAR LBDs are co-expressed with groESL.
  • the GST fusion proteins are purified on glutathione sepharose affinity columns (Amersham Pharmacia) using the method described by the manufacturer.
  • the assay buffer contains 50 mM Tris pH 7.4, 50 mM KC1, 0.1% BSA, and 1 mM DTT.
  • the assay is carried out in black half area 96-well plates in a final volume of 25 ⁇ L. After mixing all components, the reaction mixture sat for 3 hours at room temperature before reading the TR-FRET signal on a Wallac Victor 2 plate reader (measuring the ratio of signals at 665 nm and 620 nm).
  • EC 50 values are estimated with the Excel add-in program XLFit (ID Business Solutions, Guildford, Surrey, UK) utilizing a 4-parameter logistic equation. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope ofthe present invention.

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Abstract

The present invention relates to alkanoic acids and their derivatives which exhibit activity against PPARs, and hence can be used as antidiabetic compounds. Compounds disclosed herein can be used as peroxisome proliferation activated receptor (PPAR) activator. Such compounds can be used as therapeutic agents for the treatment of diseases and conditions mediated through any of the isoforms of PPAR, diabetes and diabetes-associated complications, and treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity. Processes for the preparation of the disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are also provided.

Description

ANTIDIABETIC AGENTS WHICH EXHIBIT ACTIVITY AGAINST PPAR
Field ofthe Invention The present invention relates to alkanoic acids and their derivatives which exhibit activity against PPARs, and hence can be used as antidiabetic compounds. Compounds disclosed herein can be used as peroxisome proliferation activated receptor (PPAR) activator. Such compounds can be used as therapeutic agents for the treatment of diseases and conditions mediated through any ofthe isoforms of PPAR, diabetes and diabetes- associated complications, and treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity. Processes for the preparation ofthe disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are also provided. Background ofthe Invention Type II insulin-resistant diabetes mellitus [also known as non insulin-dependent diabetes mellitus] afflicts an estimated 6% ofthe adult population in western society and is expected to continue to grow at a rate of 6% per annum worldwide. Type II diabetes is a complex metabolic disorder and is characterized by hyperglycemia. This results from contribution of impaired insulin secretion from pancreas and insulin resistance mainly in muscle and liver. Insulin-resistant individuals in addition to being hyperglycemic, exhibit a variety of closely related clinical indications, which include obesity, hypertension, dyslipidemia, premature atherosclerosis. In fact, 80% of diabetic mortality arises from ' atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late stage complications such as nephropathy, neuropathy and retinopathy. Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise. Presently, several pharmacological agents are also available as hypoglycemic agents including insulin secretagogues - sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide) which increase insulin secretion from pancreatic cells; biguanides (for example, metformin) which lower hepatic glucose production; and α-glucosidase inhibitors (for example, acarbose) which delays intestinal absorption of carbohydrate. PPAR (Peroxisome-Proliferator-Activated Receptor) are ligand activated transcription factors (members of nuclear receptor family), which offer promising therapeutic approaches to Type II diabetes mellitus. PPAR exists in three subtype forms, α, β, γ and δ. PPAR γ is abundantly expressed in adipose tissues. Direct activation of PPAR γ leads to induction of adipocyte genes, such as for fatty acid transporter 1, which in turn contributes to lowering of triglycerides and free fatty acid (FFA) levels. As FFA is a potential mediator of insulin resistance, lowering of FFA levels contributes to efficacy of PPAR γ activation in increasing insulin sensitivity and consequently glucose uptake in skeletal muscle cell. Glitazones (for example, rosiglitazone and pioglitazone) belong to this class of drug and are now proven insulin sensitisers (Moller, D.E., Nature, 2001, 414(6865), 821-827). WO 03/018553 discloses compounds, pharmaceutical compositions containing such compounds, processes for preparing such compounds, and their use as antidiabetic agents. WO 02/100813 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as antidiabetic agents. WO 02/16331 discloses oxazolyl-arylpropionic acid derivatives and their use as PPAR agonists. WO 01/55085 discloses propionic acid derivatives, which are described as useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator- Activated Receptors (PPAR). WO 00/23425 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as antidiabetic agents. WO 00/63161 discloses certain 1,4-disubstituted phenyl derivatives that are described as acting as agonists to PPAR-γ receptors. WO 99/08501 discloses β-aryl-α-oxysubstituted alkylcarboxylic acids,, which are described as having antiobesity and hypocholesterolemic properties. WO 97/31907 discloses substituted 4-hydroxy-phenylalkanoic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment and or prophylaxis of hyperglycemia, dyslipidemia, and is of particular use in the treatment of Type II diabetes. WO 94/01420 discloses certain heterocyclic compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine. U.S. Patent No. 6,274,608 discloses compounds, their preparation and use in the treatment of condition mediated by nuclear receptors, in particular the Retinoid X Receptor (RXR) and the Peroxisome Proliferator- Activated Receptor (PPAR) families. Such conditions include diabetes and obesity. U.S Patent No. 6,054,453 discloses β-aryl-α-oxysubstituted alkylcarboxylic acids, compositions containing them, and their use as hypohpidemic and antihyperglycemic agents. U.S. Patent No. 6,214,820 discloses compounds which are described as useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR). U.S. Patent No. 6,258,850 discloses 3-aryl-2-hydroxypropionic acid derivatives, process and intermediates for their manufacture, pharmaceutical preparations containing them and the use ofthe compounds in clinical conditions associated with insulin resistance. U.S. Patent No. 6,297,580 discloses substituted 4-hydroxy-phenyl alkanoic acid derivatives described as having agonist activity to PPAR. Summary ofthe Invention Particular alkanoic acids and their derivatives exhibiting activity against PPARs and hence can be used as antidiabetic compounds, and processes for the synthesis of these compounds are disclosed. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, N-oxides or metabolites of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which can be used for the treatment of diseases and conditions mediated through any of the isoforms of peroxisome proliferation activated receptor (PPAR), treatment of diabetes mellitus and the disease or condition mediated through insulin resistance, are also provided. Other aspects will be set forth in accompanying description which follows and in the part will be apparent from the description or may be learnt by the practice ofthe invention. In accordance with one aspect, there is provided compounds having the structure of Formula I,
Figure imgf000005_0001
Formula I its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N-oxides, polymorphs or metabolites wherein
A can represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl, or heterocycle;
X can represent
-(CH2)nθ/(CH2)n f "N(Q* Qr -(CH2)/
wherein n is an integer 0 to 3, R can represent hydrogen or alkyl;
B can represent aryl, heterocycle;
Y can represent (CH2)m, wherein m represents an integer 1 to 3;
Ri can represent hydrogen or alkyl;
Rό can represent OR2 or NR2R , wherein R2 and R3 are independently selected from hydrogen, alkyl, or together represent cycloalkyl; and
R4 can represent
Figure imgf000005_0002
wherein R5 can represent alkyl; and D and E can be independently selected from optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, optional substituent(s) is/are selected from halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NReR7, -CONR^, -CH2 R6R7, -COOR7, -OCH2R7 or - CH2OR7, wherein R5 and R7 are independently selected from hydrogen, alkyl and aryl. In accordance with a second aspect, there are provided methods for the treatment of mammals suffering from diabetes and diabetes-associated complications. In accordance with a third aspect, there are provided methods for the treatment of mammals suffering from diseases or conditions in which insulin resistance is the central pathophysiological mechanism. In accordance with a fourth aspect, there are provided methods for the treatment of mammals suffering from diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, psoriasis or obesity. In accordance with a fifth aspect, there are provided processes for preparing compounds disclosed herein. The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq>, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRfRq {wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO2R6 (wherein Rό is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C(=O)NRfRq, -OC(=O) NRfRq , -NHC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2Rό,
(wherein P^ are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa- {wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier), SO2R6 (where Re is as defined earlier), or -C(=O)NRfRq (wherein Rf and Rq are as defined earlier)} . Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CF3, cyano, and -SO2Rό (where R is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above. The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC (=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, or SO2R6 (wherein R are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -NRfRq, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) and -SO2R6( where R6 is same as defined earlier). The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=O)Rf, -NRfRq, -NHC(=O)NRfRq , -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), or -SO2Rό (wherein R6 is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq , -C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano, or -SO2R6 (where Re is same as defined earlier). The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -NHC(=O)NRfRq, -NHC(=O)Rf, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SO2-Rό (wherein Rό is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq , -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano or -SO2R6 (where R6 is same as defined earlier). As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. As used herein, the terms "acyl" and "acyloxy" refer to COR8 and OCOR8 wherein R8 represents alkyl or aryl. As used herein, the term "alkoxy" refers to O-R8 wherein R8 represents alkyl or aryl. As used herein, the term "thioalkyl" refers to -S-R8 wherein R8 refers to alkyl or aryl. As used herein, the term "cycloalkoxy" refers to O-R9 wherein R9 represents cycloalkyl or cycloalkenyl. As used herein, the term "haloalkyl" refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen. The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORe (wherein Re is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq , -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), -SO2Rό (wherein Re is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. The aryl substituted for group B includes
Figure imgf000009_0001
The term 'heterocyclyl," unless otherwise specified, refers to a non- aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)Rf, -O-C(=O)ORf> -C(=O)NRfRq, SO2Re, -O-C(=O)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein Re, Rf and Rq are as defined earlier) or guanidine. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydro furanyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, piperazinyl, benzoxazinyl, benzthiazinyl, benzimidazolyl, carbazolyl, indolyl, phenoxazinyl, and phenothiazinyl, and the like. The heterocyclic substitute for B includes
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
The aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from halogen, hydroxy, nitro, mercapto, cyano, alkyl, aryl, haloalkyl, alkoxy, haloalkoxy, thioalkyl, cycloalkoxy, -NRβR?, -CONRόR?, - COOR7, -OCOR7, -COR7, -NHSO2R7 and -SO2NHR7, wherein R6 and R7 are independently selected from hydrogen, alkyl and aryl. The term "polymorphs" includes all crystalline form for compounds described herein. In addition, some ofthe compounds described herein may form solvates with water (for example, hydrate, hemihydrate or sesquihydrate) or organic solvents. Such solvates are also encompassed within the scope of this invention. The phrase "pharmaceutically acceptable salts" denotes salts ofthe free acid, which substantially possess the desired pharmacological activity ofthe free acid. Suitable pharmaceutically acceptable salts may be prepared from inorganic or organic base. Examples of inorganic base include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc hydroxides, and the like. Organic bases include, but are not limited to, primary, secondary and tertiary amines, cyclic amines, N,N'- dibenzylethylenediamine, chloroprocame, choline, diethanolamine, ethylenediamine, and procaine and the like. The salt foπns may differ from compounds described herein with regard to certain physical properties such as solubility in polar solvent, but the salts are otherwise equivalent for purposes disclosed herein. Detailed Description ofthe Invention The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme I. Scheme I
Figure imgf000011_0001
Formula II Formula III Formula V (Formula I, wherein R6 is OR2)
Figure imgf000011_0002
Formula VI (Formula I, wherein Rg is NR2R3) Formula VI (Formula I, wherein Rg is OH) Compounds of Formula VII can be prepared according to Scheme I. Thus, a compound of Foπnula II (J Med. Chem., 41, 5020-5036 (1998)) is reacted with a tnflic reagent, for example, triflic anhydride, to give a compound of Formula III (wherein B, Y, Ri, R2 and R3 are the same as defined earlier), which is treated with a compound of Formula IV to give a compound of Formula V (Formula I, wherein R is OR2 and A, X and R2 are the same as defined earlier), which is hydrolysed to give a compound of Formula VI (Formula I, wherein R is OH), which is finally subjected to reaction with an amine of Formula HNR2R3 to give a compound of Formula VII (Foπnula I, wherein R6 is NR2R3 and R2 and R are the same as defined earlier). The reaction of a compound of Formula II with triflic anhydride to give a compound of Formula III can be carried out in a solvent, for example, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, benzene or toluene. The reaction of a compound of Formula II with a triflic reagent, for example, triflic anhydride can be carried out in the presence of an organic base, for example, pyridine, 4-dimethylaminopyridine or triethylamine. The reaction of a compound of Formula III with a compound of Formula IV to give a compound of Formula V can be carried out in a solvent, for example toluene, acetonitrile, dimethylformamide or dimethyl sulfoxide. The reaction of a compound of Formula III with a compound of Formula IV can be carried out in the presence of an organic base, for example diethylamine, triethylamine, diisopropylamine, pyridine or 4- dimethylamino pyridine. The reaction of a compound of Formula III with a compound of Formula IV can be carried out in the presence of a metallic reagent, for example, copper (I) iodide, triphenylphosphine and a palladium catalyst such as palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) propionate, tetra kis(triphenylphosphine) palladium (0), tris(dibenzylidineacetone) palladium (0) and bis(triphenylphosphine) palladium (II) chloride. The hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in a solvent, for example, tetrahydrofuran, methanol, ethanol or acetonitrile. The hydrolysis of a compound of Formula V to give a compound of Foπnula VI can be earned out in the presence of an inorganic base, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction of a compound of Formula VI with an amine of Formula HNR2R3 to give a compound of Formula VII can be carried out by conventional methods known in the prior art. In the above scheme, where specific bases, solvents, catalysts, etc., are mentioned it is be understood that other bases, solvents, catalysts, etc., known to those skilled in the art may be used. Similarly the reaction temperature, duration, and other reaction conditions may be adjusted as desired. An illustrative list of particular compounds disclosed herein are listed below (also shown in Table I):
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-phenyl-5-methyloxazol-4- yl)methoxy}prop-l-ynyl]phenyl propionic acid ethyl ester (Compound No. 1) -(2S)-2 - (2 -B enzoylphenylamino)-3 - [4- { 3 -phenoxazin- 10-yl } prop- 1 -ynyl] phenyl propionic acid ethyl ester (Compound No. 2) -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(N-(l-methylbenzimidazol-2-yl)-N- methyla ino)}prop-l-ynyl]phenyl propionic acid ethyl ester (Compound No. 3) -(2S)-2-(2-Benzoylρhenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzthiazin-4-yl)}prop- l-ynyl]phenyl propionic acid ethyl ester (Compound No. 4) -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4-benzoxazin-4- yl)}prop-l -ynyl]phenyl propionic acid ethyl ester (Compound No. 5) -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-((N-benzoxazol-2-yl)-N- methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester (Compound No. 6)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(indolin-l-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester (Compound No. 7) -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzoxazin-4-yl)}prop- l-ynyl]phenyl propionic acid ethyl ester (Compound No. 8)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-(5-ethylpyridin-2-yl-ethoxy)}prop-l- ynyl] phenyl propionic acid ethyl ester (Compound No. 9)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4-dihydroquinazolin- 3 -yl) } prop - 1 - ynyl] phenyl propionic acid ethyl ester (Compound No . 10)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-N-pyridin-2-yl-N- methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester (Compound No. 11)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-chlorobenzimidazol-l-yl)prop-l- ynyll]phenyl propionic acid (Compound No. 12) -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(carbazol-9-yl}prop-l-ynyl]phenyl propionic acid (Compound No. 13)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4-benzthiazin-4- yl)}prop-l-ynyl]phenyl propionic acid (Compound No. 14)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzoxazin-4-yl)}prop- l-ynyl]phenyl propionic acid (Compound No. 15)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(N-benzoxazol-2-yl)-N- methylamino}prop-l-ynyl]phenyl propionic acid (Compound No. 16)
-(2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(2-phenyl-4-methyl imidazol- 1 - yl)}prop-l-ynyl]phenyl propionic acid (Compound No. 17) -(2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(3-oxo-2H-l ,4-benzthiazin-4-yl)}prop- l-ynyl]phenyl propionic acid (Compound No. 18)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-phenoxazin-10-yl}prop-l-ynyl]phenyl propionic acid (Compound No. 19)
-(2S)-2 - (2 -B enzoylphenylamino)-3 - [4- { 3 -(indolin- 1 -yl } prop- 1 -yl]phenyl propionic acid (Compound No. 20)
-(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4-dihydroquinazolin- 3-yl)prop-l-ynyl]phenyl propionic acid (Compound No. 21) Table I
Figure imgf000014_0001
Formula I
(wherein B- , Y— CH2, Ri— H, e~ OR2 , j—
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000015_0001
In another aspect, pharmaceutical compositions are disclosed comprising, as an active ingredient, at least one ofthe disclosed compound or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent. Compounds disclosed herein may be administered to humans or animals for treatment by any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramascular, intranasal) routes of administration. The pharmaceutical compositions disclosed herein comprise a pharmaceutically effective amount of a compound ofthe present invention formulated together with one or more pharmaceutically acceptable earners. The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating materials or formulations of any type. Solid form preparations for oral administration include capsules, tablets, pills, powders, granules, sachets and suppositories. For solid form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipients or carrier such as sodium citrate, dicalcium phosphate; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia; disintegrating agents such as agar-agar, calcium carbonate, alginic acid, certain silicates and sodium carbonate; absorption acceptors such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate; adsorbents such as kaolin; Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof. In the case of capsules, tablets, pills, the dosage form may also comprise buffering agents. The solid preparations of tablets, capsules, pills, granules can be prepared with coatings and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art. Liquid form preparations of oral administration include pharmaceutically acceptable emulsions, solution, suspensions, syrup and elixir. For liquid preparations, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (such as cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, and fatty acid esters of Sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents. Injectible preparations such as sterile injection or aqueous solution may be formulated according to the art using suitable dispersing or wetting and suspending agent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solutions, and isotonic sodium chloride. The fonn illations disclosed herein may be formulated so as to provide quick, sustained, or delayed release ofthe active ingredient after administration to the patient by employing procedures well known to the art. Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspects ofthe disclosure, and do not constrain the scope ofthe present invention as defined by the claims. Examples
Example 1 : General Procedure Step 1 : Preparation of Compound of Formula III To a solution of compound of Formula II (1 equiv) in dichloromethane (0.1-1.0 M) was added pyridine (3 equiv). The reaction mixture was cooled further down to -78 °C and triflic anhydride (1.5 equiv) was added dropwise. Stirring was continued at -78 °C for 30 minutes further, at the end of which the reaction temperature was allowed to warm to an ambient temperature. The reaction mixture was neutralized with aqueous hydrochloric acid and the organic phase was extracted into dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated and residue purified on silica column using ethyl acetate and hexane to afford the title compound.
Step 2: Preparation of Compound of Formula IV In a 3 -neck round-bottom flask fitted with nitrogen gas inlet, guard tube and septum was placed dimethylformamide and sodium hydride (1.2 equiv). The suspension was cooled to 0 °C and a solution of heterocycle in dimethylformamide (0.1-1.0 M) was added slowly. The ice bath was removed and the stirring continued at an ambient temperature for 1 hour. The resulting clear solution was cooled down to 0 °C, and propargyl bromide (1 equiv.) added slowly. The reaction mixture was allowed to warm to an ambient temperature. After completion of reaction, the reaction mixture was diluted in water and organ ics extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated with a rotary evaporator. The residue was purified by column chromatography (Silica gel, 100-200 mesh). Step 3: Preparation of Compound of Formula V A mixture of bis(triphenylphosphine) palladium (II) chloride (0.05 equiv), copper (I) iodide (0.1 equiv), a compound of Formula III (1.0 equiv, from step 1), triethylamine (3-7 equiv) and triphenylphosphine (1.0 equiv) in dimethylformamide was stiπed at 80 °C. A solution of a compound of Formula IV (1.2 equiv, from step 2) in dimethylformamide was added to reaction mixture. The reaction mixture was poured into ice-cold water and the product was extracted into dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulphate, concentrated over rotavapor, and the residue was puri ied by silica gel column chromatography using ethyl acetate and hexane to afford the title compound. The following compounds of Formula V were prepared according to the general procedure above: Compound No. 1 : (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-ρhenyl-5- methyloxazol-4-yl)methoxy}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ vc ion mode): m/z 599 (M++l)
Compound No. 2: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-phenoxazin-10- yl}prop-l-ynyl]phenyl propionic acid ethyl ester. MS (+ ve ion mode): m/z 593 (M++l) Compound No. 3 : (2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(N-(l-methyl benzimidazol-2-yl)-N-methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 571 (M++l)
Compound No. 4: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4- benzthiazin-4-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ vc ion mode): m z 575 (M*+l)
Compound No. 5: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4- benzoxazin-4-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 545 (M++l)
Compound No. 6: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-((N-benzoxazol-2-yl)- N-methyl amino)} prop- l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 558 (M++l) Compound No. 7: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(indolin-l-yl)}prop-l- ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 529 (M++l)
Compound No. 8: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4- benzoxazin-4-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 559 (M++l) Compound No. 9: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-(5-ethylpyridin-2- yl-ethoxy)}prop-l-ynyl] phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 561 (M++l).
Compound No. 10: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4- dihydroquinazolin-3-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 570 (M++l)
Compound No. 11: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-N-pyridin-2-yl-N- methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester MS (+ ve ion mode): m/z 518 (M++l)
Step 4: Preparation of Compound of Formula VI A solution of a compound of Foπnula V (1 equiv, from step 3) in tetrahydrofuran and water (3:1) was treated with a solution of lithium hydroxide in water (1.5 equiv). The resulting solution was stiπed at an ambient temperature. The pH ofthe reaction mixture was adjusted to 6.0-7.0 using an aqueous solution of hydrochloric acid and the organic phase was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was purified by silica gel column chromatography to yield the title compound. The following compounds of Formula VI were prepared using the general procedure above: Compound No. 12: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2- chlorobenzimidazol-1-yl) prop-1-ynyll] phenyl propionic acid MS (+ ve ion mode): m/z 534 (M++l). Compound No. 13: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(carbazol-9-yl}prop- l-ynyl]phenyl propionic acid
MS (+ vc ion mode): m/z 549 (M++l).
Compound No. 14: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4- benzthιazm-4-yl)}prop-l-ynyl]phenyl propionic acid
MS (+ vc ion mode): m/z 533 (M++l).
Compound No. 15: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4- benzoxazm-4-yl)}prop-l-ynyl]phenyl propionic acid
MS (+ vc ion mode): m/z 531 (M++l).
Compound No. 16: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(N-benzoxazol-2-yl)- N-methylamino} prop- 1 -ynyl]phenyl propionic acid
MS (+ vc ion mode): m/z 530 (M++l)
Compound No. 17: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-phenyl-4-methyl imidazol-l-yl)}prop-l-ynyl]phenyl propionic acid MS (+ ve ton mode): m/z 540 (M++l)
Compound No. 18: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4- benzthιazm-4-yl)}prop-l-ynyl]phenyl propionic acid
MS (+ ve ion mode): m/z 547 (M++l)
Compound No. 19: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-phenoxazin-10- yl}prop-l-ynyl]phenyl propionic acid
MS (+ ve ion mode): m/z 565 (M++l)
Compound No. 20: (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(indolin-l-yl}proρ-l- yl]phenyl propionic acid.
MS (+ve ion mode): m/z 501 (M++l)
Compound No. 21 : (2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4- dihydroquιnazolin-3-yl)ρrop-l-ynyl]phenyl propionic acid
MS (+ve ion mode): m/z 542 (M++l) Step 5: Preparation of Compound of Formula VII To a solution of compound of Formula VI (1 equiv, from step 4) and triethylamine (2 equiv.) in tetrahydrofuran is slowly added oxalyl chloride (1.3 equiv) at 0 °C. The resulting solution was stiπed at 0 °C for further 15 min. followed by at ambient temperature for 15 min. Amine of Formula HNR2R3 (1.1 equiv.) is then added at 0 °C and the reaction stiπed at ambient temperature till the completion of reaction. The reaction is then quenched and the product is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue is purified on silica gel column to yield the title compound.
Example 2: Functional and Binding Assay Coactivator-dependent receptor ligand assays (CARLA) for PPARα/δ/γ in a homogeneous time resolved- fluorescence resonance energy transfer (TR-FRET) format. Compounds disclosed herein have EC50 values as determined by the following assay. The functional and binding assays for the PPARα, PPARδ and PPARγ are a variation ofthe coactivator-dependent receptor ligand assay (CARLA) (Krey G, Braissant O, L'Horset F, Kalkhoven E, Peπoud M, Parker MG and Wahli W. Fatty acids, eicosanoids, and hypohpidemic agents identified as ligands of peroxisome proliferator- activated receptors by coactivator-dependent receptor ligand assay. (1997) Molecular Endocrinology. 11 :779-791). The present CARLA assays use a TR-FRET detection method previously reviewed (Hemmila I. LANCE: Homogeneous assay platform for HTS. (1999) J. Biomol. Screening 4:303-307; Mathis G. HTRF Technology. (1999) J. Biomol. Screening 4:309-313). All assays include 3 nM ofthe glutathione-S-transferase (GST) fusion proteins of either the liPPARα ligand binding domain (LBD) (amino acids 167- 468) (GST- hPPARα LBD), GST-hPPARδ LBD (amino acids 139-442) or GST-hPPARγ LBD (amino acids 175-476); 3 nM Eu-labelled anti-GST antibody (Wallac); 30 nM biotinylated steroid receptor coactivator-1 (SRC-1) pep tide (an N- terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS, derived from amino acids 676-700 of SRC-1); and 10 nM streptavidin-labelled allophycocyanin (APC; Prozyme). The binding of a ligand to a PPAR LBD alters the conformation ofthe LBD and permits the biotinylated SRC-1 peptide to bind. This brings the Eu-labelled anti-GST antibody and the strepavidin-labelled APC in close proximity, thereby facilitating fluorescence energy transfer. The biotinylated SRC-1 peptide is prepared by standard solid-phase peptide synthetic methods. The GST-PPAR LBDs were expressed in pGEX vectors (Amersham Pharmacia) in the E. co\\ strain BL21(DE3) using standard expression conditions at 18 °C. In some cases, the GST-PPAR LBDs are co-expressed with groESL. The GST fusion proteins are purified on glutathione sepharose affinity columns (Amersham Pharmacia) using the method described by the manufacturer. The assay buffer contains 50 mM Tris pH 7.4, 50 mM KC1, 0.1% BSA, and 1 mM DTT. The assay is carried out in black half area 96-well plates in a final volume of 25 μL. After mixing all components, the reaction mixture sat for 3 hours at room temperature before reading the TR-FRET signal on a Wallac Victor 2 plate reader (measuring the ratio of signals at 665 nm and 620 nm). EC50 values are estimated with the Excel add-in program XLFit (ID Business Solutions, Guildford, Surrey, UK) utilizing a 4-parameter logistic equation. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope ofthe present invention.

Claims

We claim
1. A compound having the structure of Formula I,
Figure imgf000023_0001
Formula I its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N-oxides, polymorphs or metabolites, wherein
A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl, or heterocycle;
X represents
Figure imgf000023_0002
wherein n is an integer 0 to 3, R represents hydrogen or alkyl;
B represents aryl, or heterocycle;
Y represents (CH2)m wherein m represents an integer 1 to 3;
R[ represents hydrogen or alkyl;
Re represents OR2 or NR2R3 wherein R2 and R3 are independently hydrogen, alkyl, or together represent cycloalkyl;
Rt represents
Figure imgf000023_0003
wherein R5 represents alkyl; and
D and E are independently optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, wherein the optional substituent is selected from halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NReR7, -CONR^Ry, -CH2NReR7, -COOR7, -OCH2R7 or -CH2OR7 wherein Re and R7 are independently hydrogen, alkyl or aryl.
2. The compound of claim 1, wherein A is optionally substituted monocyclic heterocycle wherein the optional substituent is alkyl, aryl or halogen.
3. The compound of claim 1, wherein A is
Figure imgf000024_0001
4. The compound of claim 1, wherein A is optionally substituted bicyclic heterocycle wherein the optional substituent is selected from the group comprising of alkyl, aryl or halogen.
5. The compound of claim 1, wherein A is:
Figure imgf000024_0002
6. The compound of claim 1, wherein A is aromatic ring fused with non-aromatic ring wherein one or more carbon atom of non-aromatic ring is replaced by carbonyl.
7. The compound of claim 1, wherein A is:
Figure imgf000024_0003
8. The compound of claim 1, wherein A is tricyclic heterocycle.
9. The compound of claim 1, wherein A is:
Figure imgf000024_0004
10. The compound of claim 1, wherein X is:
Figure imgf000025_0001
11. The compound of claim 1 , wherein R2 is alkyl.
12. The compound of claim 1, wherein R2 is ethyl.
13. The compound of claim 1, wherein Y and Ri are respectively methylene and hydrogen.
14. The compound of claim 1, wherein R is
H 0
15. The compound of claim 1, wherein Rj is
Figure imgf000025_0002
16. The compound of claim 1, wherein B is aryl.
17. The compound of claim 1, wherein B is phenyl.
18. A compound selected from: -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-phenyl-5-methyloxazol-4- yl)methoxy}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-phenoxazin-10-yl}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(N-(l-methylbenzimidazol-2-yl)-N- methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzthiazin-4-yl)}prop- l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4-benzoxazin-4- yl)}prop- 1 -ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-((N-benzoxazol-2-yl)-N- methylamino)}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(indolin-l-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzoxazin-4-yl)}prop- l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-(5-ethylpyridin-2-yl-ethoxy)}prop-l- ynyl] phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4-dihydroquinazolin- 3-yl)}prop-l-ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(2-N-pyridin-2-yl-N- methylamino) } prop- 1 -ynyl]phenyl propionic acid ethyl ester, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-chlorobenzimidazol-l-yl)prop-l- ynyll]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(carbazol-9-yl}prop-l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2,3-dihydro-l,4-benzthiazin-4- yl) } prop - 1 - ynyl] phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzoxazin-4-yl)}prop- l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(N-benzoxazol-2-yl)-N- methylamino}prop-l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4- {3-(2-phenyl-4-methyl imidazol- 1 - yl)}prop-l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(3-oxo-2H-l,4-benzthiazin-4-yl)}proρ- l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-phenoxazin-10-yl}prop-l-ynyl]phenyl propionic acid, -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(indolin-l-yl}prop-l-yl]phenyl propionic acid or -(2S)-2-(2-Benzoylphenylamino)-3-[4-{3-(2-methyl-4-oxo-2,4-dihydroquinazolin- 3-yl)prop-l-ynyl]phenyl propionic acid, or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N-oxides, polymorphs or metabolites.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the preceding claims together with pharmaceutically acceptable carriers, excipients or diluents.
20. A method of treating mammal suffering from diabetes and diabetes association complication, comprising administering to the mammal, a therapeutically effective amount of a compound of claim 1.
21. A method of treating mammal suffering from the diseases and conditions mediated through insulin resistance and impaired insulin secretion, comprising administering to the mammal, a therapeutically effective amount of a compound of claim 1.
22. A method of treating mammal suffering from the diseases or conditions selected from the group comprising of Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors, for improving cognitive functions in dementia, psoriasis and obesity, comprising administering to the mammal, a therapeutically effective amount of a compound of claim 1.
23. A method of treating mammal suffering from diabetes and diabetes associated complication, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutically composition according to claim 19.
24. A method of treating mammal suffering from the diseases and conditions mediated through insulin resistance or impaired insulin secretion, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition according to claim 19.
25. A method of treating mammal suffering from disease or condition selected from the group comprising of Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors, for improving cognitive functions in dementia, psoriasis and obesity, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition according to claim 19.
26. A process of preparing a compound having the structure of Formula V,
Figure imgf000028_0001
Formula V (Formula I, wherein R6 is OR )
its pharmaceutically acceptable salts, phannaceutically acceptable solvates, enantiomers, N-oxides, polymorphs or metabolites, wherein
A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl, or heterocycle;
X represents
Figure imgf000028_0002
wherein n is an integer 0 to 3, R represents hydrogen or alkyl;
B represents aryl, or heterocycle;
Y represents (CH2)m wherein m represents an integer 1 to 3;
Ri represents hydrogen or alkyl;
R» represents
Figure imgf000028_0003
wherein R5 represents alkyl; and
D and E are independently selected from optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, optional substituent is halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NReR?, -CONR6R7, -CH2NRόR7, -COOR7, -OCH2R7 or -CH2OR7 wherein R and R7 are independently hydrogen, alkyl or aryl,
which method comprises reacting a compound of Formula II with triflic anhydride
Figure imgf000029_0001
Formula II to give a compound of Formula III (wherein B, Y, Rls R2 and R3 are the same as defined earlier), and
Figure imgf000029_0002
Formula HI
treating the compound of Formula III with a compound of Formula IV A H Formula IV to give a compound of Formula V ((Formula I, wherein R6 is OR2 and A, X and R2 are the same as defined earlier).
27. The process of claim 26, wherein the reaction of a compound of Formula II with triflic anhydride to give a compound of Formula III is carried out in a suitable solvent selected from the group comprising of dichloromethane, chloroform, acetonitrile, benzene, toluene and tetrahydrofuran.
28. The process of claim 27, wherein the reaction is carried out in dichloromethane.
29. The process of claim 26, wherein the reaction of a compound of Formula II with triflic anhydride to give a compound of Formula III is carried out in the presence of an organic base selected from pyridine, 4-dimethylaminopyridine and triethylamine.
30. The process of claim 29, wherein the reaction is carried out in the presence of pyridine.
31. The process of claim 26, wherein the reaction of a compound of Formula III with a compound of Formula IV to give a compound of Formula V is carried out in a suitable solvent selected from toluene, acetonitrile, dimethylformamide and dimethyl sulfoxide.
32. The process of claim 31 , wherein the reaction is carried out in dimethylformamide.
33. The process of claim 26, wherein the reaction of a compound of Formula III with a compound of Foπu la IV is carried out in the presence of an organic base selected from diethylamine, triethylamine, diisopropylamine, pyridine and 4-dimethylamino pyridine.
34. The process of claim 33, wherein the reaction is carried out in the presence of triethylamine.
35. The process of claim 26, wherein the reaction of a compound of Formula III with a compound of Formula IV is caπied out in the presence of copper (I) iodide, triphenylphosphine and a palladium catalyst selected from palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) propionate, tetra kis(triphenylphosphine) palladium (0), tris(dibenzylidineacetone) palladium (0) and bis(triphenylphosphine) palladium (II) chloride.
36. The process of claim 35, wherein the reaction is carried out in the presence of bis(triphenylphosphine) palladium (II) chloride.
37. A process of preparing a compound having the structure of Formula VI,
Figure imgf000030_0001
Formula VI (Formula I, wherein R6 is OH)
its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, N-oxides, polymorphs or metabolites wherein A represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acyloxy, aryl, or heterocycle;
X represents R -(CH^O /^ (CH2)n , _I N(CΉH2)Λπ or — / (CHu2) wherein n is an integer 0 to 3, R represents hydrogen or alkyl;
B represents aryl, or heterocycle;
Y represents (CH2)m wherein m represents an integer 1 to 3;
Ri represents hydrogen or alkyl;
R4 represents
Figure imgf000031_0001
wherein R5 represents alkyl; and
D and E are independently selected from optionally substituted phenyl, naphthyl, thienyl, pyridinyl, thiazolyl, optional substituent(s) is/are selected from halogen, alkyl, haloalkyl, alkoxy, thioalkyl, -NR6R7, -CONR6R7, -CH2NR6R7, -COOR7, -OCH2R7 or -CH2OR7 wherein R and R7 are independently selected from hydrogen, alkyl and aryl,
which method comprises hydro lyzing a compound of Formula V
Figure imgf000031_0002
Formula V (Formula I, wherein R6 is OR2)
to give a compound of Formula VI (Foπnula I, wherein R^ is OH and wherein A, X, B, Y, R] and R are the same as defined earlier).
38. The process of claim 37, wherein the hydrolysis of a compound of Formula V to give a compound of Foπnula VI is carried out in a solvent selected from tetrahydrofuran, methanol, ethanol and acetonitrile.
39. The process of claim 38, wherein the hydrolysis is carried out in tetrahydrofuran.
40. The process of claim 37, wherein the hydrolysis of a compound of Formula V to give a compound o f Formula VI is carried out in the presence of an inorganic base selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.
41. The process of claim 40, wherein the hydrolysis is caπied out in the presence of lithium hydroxide.
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JP2016166182A (en) * 2010-02-02 2016-09-15 アーガシナ インコーポレイテッド Phenylalanine derivative as nonpeptide glp-1 receptor regulator and application thereof

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WO2002092084A1 (en) * 2001-05-15 2002-11-21 F. Hoffmann-La Roche Ag Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes
WO2003011834A1 (en) * 2001-07-30 2003-02-13 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
WO2003084535A1 (en) * 2002-04-05 2003-10-16 Warner-Lambert Company Llc Antidiabetic agents

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2002092084A1 (en) * 2001-05-15 2002-11-21 F. Hoffmann-La Roche Ag Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes
WO2003011834A1 (en) * 2001-07-30 2003-02-13 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
WO2003084535A1 (en) * 2002-04-05 2003-10-16 Warner-Lambert Company Llc Antidiabetic agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016166182A (en) * 2010-02-02 2016-09-15 アーガシナ インコーポレイテッド Phenylalanine derivative as nonpeptide glp-1 receptor regulator and application thereof

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