WO2012025811A1 - Composés indolylpyrimidines en tant que modulateurs de gpr119 - Google Patents

Composés indolylpyrimidines en tant que modulateurs de gpr119 Download PDF

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Publication number
WO2012025811A1
WO2012025811A1 PCT/IB2011/001916 IB2011001916W WO2012025811A1 WO 2012025811 A1 WO2012025811 A1 WO 2012025811A1 IB 2011001916 W IB2011001916 W IB 2011001916W WO 2012025811 A1 WO2012025811 A1 WO 2012025811A1
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oxy
pyrimidin
methylsulfonyl
indol
alkyl
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PCT/IB2011/001916
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English (en)
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Rajesh Thotapally
Ashok Bhau Pathak
Bhavana Shrirang Kardile
Milind Dattatraya Sindkhedkar
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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Publication of WO2012025811A1 publication Critical patent/WO2012025811A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the invention relates to substituted heterocyclic compounds and their stereoisomers or pharmaceutically acceptable salts thereof.
  • the invention also relates to a process for the preparation of the compounds of invention.
  • the invention also relates to methods of treating, preventing and/or managing diseases, disorders, syndromes or conditions associated with the modulation of the GPR119 receptor.
  • the invention also relates to combination therapy for treating, preventing and/or managing diseases, and disorders associated with the modulation ofGPRl 19 receptors.
  • Type I diabetes also referred to as insulin dependent diabetes mellitus
  • Type II also referred to as non-insulin dependent diabetes mellitus
  • Type I diabetes is an autoimmune disease wherein there is an extensive loss of the insulin producing ⁇ -cells of the pancreas. The resulting insulin deficiency leads to hyperglycemia (abnormally high glucose levels in the blood).
  • Type II diabetes mellitus develops as a result of non-responsiveness of muscle, fat and liver cells to insulin. This phenomenon is referred to as insulin resistance and could arise due to a reduced number of insulin receptors on the surface of these cells, or a defective insulin-mediated signaling, or a combination of both.
  • Chronic Type II diabetes leads to pancreatic ⁇ -cell dysfunction. Surprisingly, there is no cure for diabetes.
  • the current treatments focus on disease management, by controlling blood glucose levels and delaying complications that arise due to hyperglycemia.
  • Treatments that target insulin resistance include metformin and TZDs (Thiazolidinediones), and those that stimulate insulin secretion, such as sulfonylureas and GLP-1 agonists.
  • GLP-1 agonists stimulate insulin secretion only in the presence of glucose, but it is not orally bioavailable and has to be given intravenously.
  • DPP-IV inhibitors work by increasing the levels of GLP-1 which in turn leads to insulin secretion.
  • GPR119 G protein-coupled receptor
  • GPCRs G protein-coupled receptor
  • GPR119 activation by endogenous ligands leads to an increase in the intracellular concentrations of cAMP, which subsequently leads to increased secretion of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP-1).
  • GIP glucose-dependent insulinotropic peptide
  • GLP-1 glucagon-like peptide
  • GPR119 is reported to be involved in various diseases in addition to Type 2 diabetes. These include but are not limited to obesity (Overton HA, et al, British Journal of Pharmacology (2008) 153 S76-S81) and osteoporosis (WO2007/ 120689 A2).
  • the agonists of GPR119 receptors are useful as therapeutic agents for treating or preventing a condition modulated by PYY(peptide YY), such as a condition modulated by stimulation of NPY Y2 receptor (Y2R).
  • Conditions modulated by PYY include but are not limited to bone-related conditions, metabolic disorders, angiogenesis-related conditions, ischemia-related conditions, convulsive disorders, malabsorptive disorders, cancers, and inflammatory disorders.
  • PCT application WO 2009/126245 Al discloses GPR119 receptors to be involved in inflammation, inflammatory bowel disease and atherosclerosis.
  • Obesity is a condition in which individuals have high body mass index (BMI). Overweight conditions and obesity are closely linked to Type 2 diabetes, heart disease, increased cholesterol, dislipidemia, high blood pressure, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, strokes, gallstones, cholecystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea, respiratory problems, certain forms of cancers (endometrial, breast, prostate and colon) and psychological disorders (e.g., depression, eating disorder, low self-esteem).
  • BMI body mass index
  • Osteoporosis is characterized by the loss of bone mass and the deterioration of skeletal structure leading to decreased bone strength. Patients have an enhanced risk of fractures. Osteoporosis leads to morbidity, mortality and decreased quality of life. Osteoporotic fractures therefore cause substantial mortality, morbidity, and economic cost. With an ageing population, the number of osteoporotic fractures and their costs will at least double in the next 50 years unless effective preventive strategies are developed. (Cole et al., Curr. Rheum. Reports (2008); 10; 92-96; Reginster, Bone (2006) 38:S4-S9); Boonen, Curr. Med. Res. Opin. (2008); 24; 1781-1788).
  • Atherosclerosis is a condition involving inflammation, lipid accumulation, cell death (necrosis) and fibrosis. Foam cell formation results from monocyte infiltration and cholesterol deposition in the subendothelial space. Complications of atherosclerosis lead to myocardial infarction and stroke. Atherosclerosis is one of the major causes of death in many countries (Ruggeri, Nat. Med. (2002); 8; 1227-1234; Li, Nat. Med. (2002); 8; 1234-1242).
  • IBD Inflammatory bowel disease
  • the invention provides compounds having the structure of Formula
  • Wi, W 2 , W 3 and W 4 are each independently selected from CR 3 and N;
  • Z is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl, heterocyclyl, -(CH 2 ) q C(0)OR a , -C(0)R a , C(0)(CH 2 ) q NR a Rb, -S(0) 2 Ra, and -S(0) 2 NRaR b ;
  • Ri, R 2j and R4 are each independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, -ORa, and -NRaRj,;
  • R 3 is selected from hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cyano, hydroxylamino, -OR a , -NR a Rb, -
  • Ra and Rb are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heterocyclyl; or
  • Ra and Rb are joined together with the nitrogen atom to which they are attached to form a heterocyclyl ring;
  • R 5 is selected from hydrogen, halo, cyano, alkyl, haloalkyl, cycloalkyl, -OR a , C(0)OR a , -C(0)R a , -C(0)NR a R b , and -N(R a )C(0)R b ;
  • R6, R 7 , Re, and R 9 are each and independently selected from the group consisting of hydrogen, halo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cylcoalkyl, aryl, heteroaryl, heterocyclyl, cyano, -ORa, haloalkyl, -C(0)OR a , -OC(0)R a , -C(0)NR a R b , -N(R a )C(0)R b , - S(0)pR a , -S(0) 2 NR a R b , and -N(R a )S(0) p R b ; wherein any two of R , R 7 , Rg, and R 9 may be present on same or different carbon atom; or
  • any two of R 5 , R6, R 7 , R 8 , R and Z are joined together to form a cycloalkyl or heterocyclyl ring; wherein the heterocyclyl ring may be consisting of any one or more hetero atoms selected from N, O and S;
  • X is selected from the group consisting of -0(CH 2 ) q -, -(CH 2 ) q O-, and -S(0) p ;
  • 'm' and 'n' are each independently selected from 0, 1 and 2;
  • 'p' is selected from 0, 1 and 2;
  • R x , R y and R z are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, , heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl; or pharmaceutically acceptable salt thereof.
  • Ri, R 2 , R3, R4, R7, Re and Z are as defined herein above.
  • Ri, R 2 , R3, R4, R 7 and Z are as defined herein above.
  • R6, R 7 , Rs, and R 9 are hydrogen, hydroxyalkyl, -C(0)OR a ; wherein any two of R ⁇ , R 7 , Re, and R 9 may be present on the same or different carbon atom; and wherein R a is alkyl.
  • any two of R 5 , R ⁇ R7, R 8 , R9 and Z are joined together to form a cycloalkyl or heterocyclyl ring; wherein the heterocyclyl ring may consist of any one or more hetero atoms selected from N, O and S.
  • any two of R 5 , R6, R 7 , Rs, R 9 and Z are joined together to form a saturated pyran ring.
  • W b W 2 , W 3 and W 4 are CR 3 ;
  • Z is heteroaryl, -C(0)0-alkyl, -C(0)-alkyl, or - C(0)CF 3 ;
  • X is O or -CH 2 0-; or Ri, R 2; and R4 are hydrogen, alkyl or alkoxy;
  • R 5 , R 7 , Rs, and R 9 are hydrogen.
  • a pharmaceutical composition comprising at least one compound of Formula (I) and one or more pharmaceutically acceptable excipient such as a carrier or diluents.
  • the pharmaceutical composition comprises a therapeutically affective amount of at least one compound of Formula (I).
  • a pharmaceutical composition comprising a compound of Formula (I) for treating, preventing, and/or managing diseases or syndromes or disorders associated with the modulation of the GPR119 receptor.
  • the compounds of Formula (I) may be used either alone or in combination with one or more therapeutically active agents described herein for treating, preventing, managing diseases, disorders, syndromes or conditions associated with the modulation of the GPR119 receptor.
  • the invention further provides methods of treating, preventing, and/or managing diseases, disorders, syndromes or conditions associated with the modulation of the GPR1 19 receptor.
  • the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of Formula (I) or its stereoisomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or diluents for treating, preventing, managing diseases, disorders, syndromes or conditions associated with the modulation of the GPR119 receptor.
  • halogen or halo means fluorine, chlorine, bromine, or iodine.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t- butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbon radical containing at least one carbon- carbon triple bond, and having 2 to about 10 carbon atoms.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a monocyclic or bicyclic nonaromatic carbocyclic radical containing at least one double bond and having from 3 to 10 ring members, and refers in particular cyclobutenyl, cyclopentenyl or cyclohexenyl radicals. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl, as defined herein, that is substituted by one or more halogen groups as defined herein.
  • the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodine, bromine, chlorine or fluorine substituent.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen groups.
  • a polyhaloalkyl is substituted with up to 12, 10, 8, 6, 4, 3, or 2 halogen groups.
  • Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms.
  • hydroxylamino refers to one of the hydrogen atoms in an amino group replaced with a hydroxyl group for example -NH-OH.
  • hydroxyalkyl refers to an alkyl, as defined herein, that is substituted by one or more hydroxy groups.
  • the hydroxyalkyl can be monohydroxyalkyl or dihydroxyalkyl.
  • Non-limiting examples of hydroxyalkyl include 2- hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, and the like.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above, directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H4C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quatemized; also, unless otherwise constrained by the definition, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepiny
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, ind
  • heteroaryl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • substituted refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety.
  • May optionally be substituted means that the moiety or group may or may not be substituted.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • treating or “treatment” of a state, diseases, disorders, conditions or syndromes includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; and/or (c) slowing the progression of a disease, disorder, condition or syndrome or at least one of its clinical or subclinical symptoms thereof.
  • modulate refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule; by way of illustration and not limitation, agonists, partial agonists, inverse agonists, and antagonists of a G protein-coupled receptor are modulators of the receptor.
  • the compounds of invention are useful as modulators of the GPR119 receptor.
  • subject includes mammals preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs and non- domestic animals.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder, condition or syndrome, is sufficient to cause the effect in the subject which is the purpose of the administration.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of the invention may form salts.
  • Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • the invention extends to these stereoisomeric forms and to mixtures thereof.
  • the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • Screening of compounds of invention for GPR119 receptor modulation activity may be achieved by using various in-vitro and in-vivo protocols mentioned herein below or methods known in the art.
  • the invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein.
  • pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient such as a carrier or diluent.
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate GPR119 receptor mediated diseases described herein when administered to a subject.
  • the compounds of the invention may be associated with a pharmaceutically acceptable excipient such as a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient includes pharmaceutical agents that do not induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, stabilizers, surfactants, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the active compound of Formula (I) can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention, to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions formulation.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation; the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
  • oral administration may require a higher total daily dose, than an intravenous (direct into blood).
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, according to the potency of the active component or mode of administration.
  • Suitable doses of the compounds, for use in treating the diseases and disorders described herein, can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
  • the daily dosage of the GPR119 modulator can range from about 0.1 to about 30.0 mg/kg.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
  • the compound of Formula (I) and / or the pharmaceutical compositions of Formula (I) may be used either alone or in combination with one or more additional therapeutic agents for treating, preventing, managing diseases, disorders, syndromes or conditions associated with the modulation of the GPR119 receptor.
  • the compounds and compositions of the invention and the additional therapeutic agent as described herein may be administered simultaneously, sequentially or separately.
  • the combination of the compound of Formula (I) with any one or more additional therapeutic agent may be given to the subject in the same or separate dosage formulation.
  • the compound of Formula (I) and one or more additional therapeutic agents can be administered at essentially the same time i.e., concurrently, or at separately staggered times i.e., sequentially.
  • Combination therapy is understood to include all these regimens. Selection of additional therapeutic agents will, in large part, depend on the desired target therapy. Turner N, et al, Prog. Drug Res.
  • the additional therapeutic agent which can be used in combination with the compounds of invention include, but not limited to, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti- nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti- hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti- pancreatic agents, anti-metabolic syndrome agents, lipid lowering agents, anti-lipodystrophy agents, appetite suppressants, treatments for heart failure, treatments for peripheral arterial disease and anti-inflammatory agents.
  • a combination therapy may be used in modulating including preventing the onset of the symptoms or complications associated with diabetes or treating, preventing or reducing the risk of developing diabetes and its related symptoms, complications, and disorders, wherein the compounds of the invention can be effectively used in combination with, one or more additional therapeutic agents.
  • One or more additional therapeutic agents for diabetes includes but not limited to insulin and insulin analogs; insulin secretagogues such as sulfonylureas and analogs; meglitinides; insulin sensitizers such as biguanides; thiazolidinediones (PPAR); PPAR alpha/gamma dual agonists; alpha-glucosidase inhibitors; dipeptidyl peptidase-IV (DPP4) inhibitors; glucagon-like peptide- 1 (GLP-1) receptor agonists including glucagon-like peptides and its analogues, amylin agonists; glucagon antagonists; alpha2-antagonists and imidazolines; SGLT2 inhibitors; insulin signaling agonists, insulin mimetics, aldose reductase inhibitors; 11-beta-hydroxysteroid dehydrogenase Type I inhibitors; RXR agonists; fatty acid oxidation inhibitors; beta- agonists; phosphodie
  • Insulin and its analogs include insulin from animal source and recombinant insulin and its derivatives, for eg. short acting derivatives Lispro, aspart, glulisine and their protamine solutions and mixtures thereof, or the long acting derivatives, for e.g., glargine, detemir, and their modified formulations, for e.g., inhaled formulations comprising insulin, insulin via buccal route and the like.
  • Sulfonylureas and analogs includes, but not limited to, chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride and the like.
  • Meglitinides such as repaglinide, mitiglinide and the like. Biguanides includes, but not limited to, metformin, phenformin, buformin and the like.
  • Thiazolidinediones for e.g., ciglitazone, pioglitazone, troglitazone, rosiglitazone and the like.
  • PPAR-alpha agonists for e.g., fenofibrate, gemfibrozil and the like.
  • PPAR alpha/gamma dual agonists for e.g., muraglitazar, peliglitazar, and the like.
  • Dipeptidyl peptidase-IV (DPP4) inhibitors includes saxagliptin, sitagliptin, vildagliptin, denagliptin and the like.
  • Glucagon- like peptide-1 (GLP-1) receptor agonists for e.g., Exenatide, Liraglutide, AVE0010, R1583, SUN E7001, GSK-716155 and Exendin-4 (PC-DACTM) and the like.
  • Alpha2-antagonists and imidazolines includes, but not limited to, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan and the like.
  • SGLT2 inhibitors includes, but not limited to, dapaglifiozin, sergliflozin, canagliflozin, LX4211, BI-10773, BI-44847, ASP-1941, TS-071 and the like.
  • Alpha-glucosidase inhibitors includes, but not limited to, acarbose, miglitol, voglibose and the like.
  • Amylin analogs such as pramlintide and its derivatives.
  • insulin secretagogues for e.g., linogliride, insulinotropin, exendin-4, N,N-dimethyl-N'-[2-(4- morpholinyl)phenyl]guanidine (E)-2-butenedioate salt (BTS-675820), (-)-N-(trans-4- isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166)) and the like.
  • E -2-butenedioate salt
  • A-4166 isopropylcyclohexanecarbonyl
  • the compound of Formula (I) may be used in combination therapy for treating obesity or obesity- related disorders, wherein the compound of Formula (I) can be effectively used in combination with one or more therapeutic agents having synergistic effects such as anti -obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects.
  • Anti-obesity agents include but not limited to ⁇ -3 adrenoceptor agonist agents; gastrointestinal lipase inhibitors, leptins, cannabinoid-1 ("CB-1") receptor antagonists (such as rimonabant); PPAR delta agonists or partial agonists; dual PPAR alpha, PPAR delta agonists or partial agonists; dual PPAR delta, PPAR gamma agonists or partial agonists; pan PPAR agonists or partial agonists; neuropeptide Y; enterostatin; cholecytokinin; bombesin; amylin; histamine H3 receptors; serotonin 2C receptor agonists (5HT2c), dopamine D2 receptors; melanocyte stimulating hormone; corticotrophin releasing factor; galanin; gamma amino butyric acid (GABA), apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP
  • Some of the compounds that can be used in combination with the compounds of the invention include, but are not limited to, phenylpropanolamine, phentermine; orlistat, rimonabant, dexamphetamine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, sibutramine, QNEXA (combination of phentermine and topiramate), Lorcaserin, CONTRA VE (combination of naltrexone and bupropion) and the like.
  • the compound of Formula (I) may be used in combination therapy for treating, preventing, and/or managing lipodystrophy including HIV protease associated lipodystrophy. Accordingly, the compound of Formula (I) may be used in combination with HIV protease inhibitors, including but not limited to, REYATAZ and KALETRA and the like.
  • the compound of Formula (I) may be used in combination therapy for modulating metabolic syndrome for e.g., treating metabolic syndrome and its related symptoms, complications and disorders, wherein the compound of Formula (I) may be effectively used in combination with, for example, the active agents discussed above for modulating or treating diabetes, obesity, hyperlipidemia, atherosclerosis, and/or their respective related symptoms, complications and disorders.
  • Metabolic Syndrome or "Syndrome X" is described in Ford et al, J. Am. Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med. Chem.-rmm., Endoc. & Metab. Agents, 1 :1-24 (2001).
  • the compound of Formula (I) may be used in combination therapy in modulating hyperlipidemia.
  • suitable lipid lowering agents and anti- atherosclerotic agents for use in combination with the compounds of Formula (I) include one or more MTP/ApoB secretion inhibitors (e.g., dirlopatide, N-(2,2,2-trifluoroethyl)-9-[4- [4- [[ [4'-(trifluoromethyl) [1,1 -biphenyl] -2-yl]carbonyl-] amino] - 1 -piperidinyl]butyl] -9H- fiuorene-9-carboxamide methane sulfonate, CP-741952, SLx-4090; HMG Co A reductase inhibitors (e.g., atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin); squalene synthe
  • Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, and rosuvastatin.
  • Suitable anti-hypertensive agents for use in combination with the compounds of the invention include beta adrenergic blockers, calcium channel blockers (L- type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors (e.g., captopril, z
  • the compound of Formula (I) may be used in combination therapy with therapeutic agents showing therapeutic benefits of GPR 119 activity modulators derived from increasing levels of GIP and PPY.
  • the compound of Formula (I) may be used either alone or in combination with one or more therapeutically active drug for treating, preventing and/or managing a disease or disorder caused by low bone mass such as osteoporosis, and for increasing bone mass in an individual.
  • WO 2007/120689A2 discloses that administration of a GPR119 agonist to an individual, such as by oral administration, can act at the GPR119 receptor to increase the GIP level in the individual.
  • One or more therapeutically active drugs can be selected from the group consisting of calcium, vitamin D, estrogen, tibolone, selective estrogen receptor modulator (SERM; e.g., raloxifene, tamoxifen), biphosphonate (e.g., etidronate, alendronate, risedronate), calcitonin, la-hydroxylated metabolite of vitamin D, fluoride, thiazide, anabolic steroids, ipriflavone, vitamin K, parathyroid hormone (PTH), strontium, statin, osteoprotererin, EP4 receptor selective agonists, cannabinoid receptor type 2 (CB2) selective agonists, and p38 MAP kinase inhibitors.
  • SERM selective estrogen receptor modulator
  • biphosphonate e.g., etidronate, alendronate, risedronate
  • calcitonin la-hydroxylated metabolite of vitamin D, fluoride, thiazide,
  • the compound of Formula (I) may be used either alone or in combination with one or more therapeutically active drug for treating, preventing and/or managing a disease or disorder associated with inflammation.
  • suitable antiinflammatory agents for use in combination with the compounds of the invention include, but are not limited to, NSAIDS, prednisone, acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, sufentanyl, sunlindac, prednisolone, methylprednisolone, dexamethazone, flucatisone, betamethasone, hydrocortisone, and beclomethasone.
  • the above other therapeutic agents when employed in combination with the compounds of the invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, , or as otherwise determined by one of ordinary skill in the art.
  • the compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic active agents (pharmaceutical combinations) as described above.
  • dosages of the co-administered compounds will of course vary, depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • compounds of the invention will be administered in therapeutically effective amounts via one or more acceptable modes known in the art, either alone or in combination with one or more therapeutic agents.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the invention provides a compound of Formula (I) and pharmaceutical compositions thereof that are useful in treating diseases, disorders or conditions associated with the modulation of GPR119 receptors which includes, but are not limited to, treating, preventing, managing and/or slowing the progression of diabetes and related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, obesity, cardiovascular diseases, and metabolic syndrome and its component conditions.
  • the invention further provides methods of treating diseases, disorders or conditions modulated by the GPR119 receptor in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof.
  • the diseases, disorders or conditions associated with the modulation of the GPR119 receptors include Type 2 diabetes, Type 1 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, wound healing, retinopathy, neuropathy, nephropathy, obesity, Metabolic Syndrome, lipodystrophy including HIV protease associated lipodystrophy, lipid disorders, hypertension, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, vascular restenosis, peripheral arterial disease, and its sequela for example acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication, myocardial ischemia, stroke and heart failure.
  • the diseases, disorders or conditions associated with the modulation of GPR119 receptor includes inflammatory diseases such as psoriasis, rheumatoid arthritis and osteoarthritis, inflammatory bowel diseases, atherosclerosis and bone diseases including osteoporosis.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Schemes 1 to 3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art are also within the scope of the present invention. All the isomers of the compounds described are these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the compounds of Formula (I) may be obtained by treating substituted dichloropyrimidines (2) with substituted compound (3), in the presence of a base, to give compound (4).
  • the compound (4) is further treated with substituted indole compound (5), in the presence of a palladium catalyst, to give a compound of Formula (I).
  • compounds of Formula (I) may also be synthesized by reaction of compound (2) with a substituted indole (5) in the presence of palladium catalyst, to result in compound (6), which on further reaction with substituted compound (3), in the presence of a base, results in a compound of Formula (I) as outlined in scheme 2.
  • the compound of Formula (I) may be obtained by following the reactions described in the scheme 3.
  • the compound (8) is treated with substituted compound (5), in the presence of a palladium catalyst to give compound (9).
  • Deprotection of intermediate (9) may be carried out with appropriate reagents well-known to those who are skilled in the art of organic synthesis.
  • the deprotected product (10) then treated with Z-L where L is a leaving group such as a halide, mesylate, inflate, etc., by many methods known in the art under various conditions that are routine for those skilled in the art of organic synthesis, to give compounds of Formula (I).
  • Nomenclature of the compounds of the invention is according to ChemBioDraw version 12. Structures of the intermediates as well as the final compounds were confirmed by spectral data.
  • Step-A r/-butyl 4-((6-(5-(methylsulfonyl)-7H-indol- 1 -yl)pyrimidin-4-yl)oxy)piperidine- 1 - carboxylate
  • Step-B 5-(Methylsulfonyl)- 1 -(6-(piperidin-4-yloxy)pyrimidin-4-yl)- 1 H-indole hydrochloride:
  • Example- 1 tert-Butyl 4-((6-(5-(methylsulfonyl)-7H-indol-l-yl)pyrimidin- 4-yl)oxy)piperidine-l-carboxylate (Example- 1) (0.1 g, 0.211 mmol) in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added at 0°C and stirred at room temperature for 2-3 h. The solvent was removed in vacuo.
  • Step A 4-((6-(5-(Methylsulfonyl)-lH-indol-l-yl) pyrimidin-4-yl) oxy) piperidine-1- carbonitrile
  • reaction mixture was diluted with aqueous sodium carbonate and extracted with dichloromethane, the combined organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The resultant residue was purified by flash column chromatography to yield the title compound (0.049 g, 17%).
  • reaction mixture was diluted with saturated NaHC0 3 , the organic layer was separated dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo, the resultant residue was purified by flash column chromatography to give the title product as a white solid (0.05g, 43%).
  • Step-B tert-Butyl 4-((6-(5-pivalamido- 1 H-indol- 1 -yl)pyrimidin-4-yl)oxy)piperidine- 1 - carboxylate
  • Step-C N-(l -(6-(( 1 -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)- 1 H-indol-5- yl)pivalamide:
  • reaction mixture was concentrated in vacuo and the resultant amine was dissolved in 2-propanol (3 mL) diisopropylethylamine (0.15 mL, 0.891 mmol), 2-chloro-5-ethylpyrimidine (0.054 mL, 0.387 mmol) were added and stirred at 160°C for 8 h.
  • the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed with water, and the organic layer was dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • Step-A tert-Butyl 4-((6-(5-nitro- 1 H-indol- 1 -yl)pyrimidin-4-yl)oxy)piperidine- 1 -carboxylate
  • rt-Butyl 4-((6-(5-nitro-lH-indol-l-yl)pyrimidin-4-yl)oxy)piperidine-l -carboxylate was prepared by following a procedure similar to that described in Step-B of Example- 1 by using Intermediate- 1 and 5-nitro-lH-indole.
  • Step-B tert-Butyl 4-((6-(5-(methylsulfonamido)- 1 H-indol- 1 -yl)pyrimidin-4- yl)oxy)piperidine- 1 -carboxylate
  • Step-C N-(l -(6-(( 1 -(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)- 1 H-indol-5- yl)methanesulfonamide
  • Step- A 5-( 1 H-Tetrazol- 1 -yl)- 1 H-indole:
  • Step-B 1-tert-Butyl 2-ethyl 4-hydroxypyrrolidine-l,2-dicarboxylate
  • ethyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride 3.5 g, 17.9 mmol
  • dichloromethane 25 mL
  • triethylamine 6.22 mL, 44.72 mmol
  • di-tert- butyl dicarbonate 4.9 mL, 21.5 mmol
  • Step-C 1-tert-Butyl 2-ethyl 4-((6-chloropyrimidin-4-yl)oxy pyrrolidine- 1,2-dicarboxylate:
  • Step-D 1-tert-Butyl 2-ethyl 4-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyrimidin-4- yl)oxy)pyrrolidine- 1 ,2-dicarboxylate:
  • Step-A tert-Butyl-3-hydroxy-4,4-dimethoxypiperidine-l -carboxylate: To a stirred solution of /ert-butyl-4-oxo-l-piperidinecarboxylate (1.0 g, 5 mmol) in methanol (10 mL), KOH (0.65 g, 12 mmol) was added at 0°C. To this mixture, iodine (1.65 g, 6.52 mmol) in methanol (10 mL) was added drop wise at 0°C. The reaction mixture was stirred at room temperature for 2 h.
  • Step-B tert-Butyl 3-(benzyloxy)-4,4-dimethoxypiperidine-l-carboxylate:
  • Step-C tert-Butyl 3-(benzyloxy)-4-oxopiperidine-l-carboxylate:
  • Step-D ter/-Butyl 3-(benzyloxy)-4-hydroxypiperidine-l -carboxylate:
  • Step-E 1 -(6-((3-(Benzyloxy)- 1 -(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)-5- (methylsulfonyl)- 1 H-indole
  • Step-F 1 -(5-Ethylpyrimidin-2-yl)-4-((6-(5-(methylsulfonyl)- 1 H-indol- 1 -yl)pyrimidin -4- yl)oxy)piperidin-3 -ol : To a stirred solution of l-(6-((3-(Benzyloxy)-l-(5-ethylpyrimidin-2-yl)piperidin-4- yl)oxy)pyrimidin-4-yl)-5-(methylsulfonyl)-lH-indole (0.09 g, 0.17 mmol) in methanol (3 mL) a catalytic amount of Pd/C and ammonium formate (0.10 g, 1.7 mmol) were added and resultant reaction mixture was refluxed for 3 h.
  • Step-A 7-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one:
  • Step-B 7-Benzyl-3 -oxa-7-azabicyclo[3.3.1 ]nonan-9-ol :
  • Step-C tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate:
  • Step-E /ert-butyl 9-syn-((6-(5-(methylsulfonyl)-lH-indol-l-yl)pyrimidin-4-yl)oxy)-3-oxa-7- azabicyclo [3.3.1 ]nonane-7-carboxylate
  • Step-A 8-Benzyl-8-azabicyclo[3.2.1]octan-3-one:
  • 2,5-Dimethoxy tetrahydro furan (3.0 g, 22.7 mmol) was dissolved in IN HCI (50 mL) and stirred at 70°C for 1 h.
  • the reaction mixture was cooled to 0°C, acetone di-carboxylic acid (3.65 g, 25 mmol), HCI (2 mL), sodium acetate (2.23 g, 27.2 mmol) and benzyl amine (2.72 mL, 25 mmol) were added and stirred at room temperature for 10 h.
  • the reaction mixture was filtered through a pad of celite, the filtrate was diluted with aqueous NaOH solution and extracted with ethyl acetate.
  • Step-B 8-Benzyl-8-azabicyclo[3.2.1]octan-3-ol
  • Step-C /ert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate ⁇ exo isomer and endo isomer
  • Step-D tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (endo isomer)
  • Step-E -Butyl 3 -e «i o-((6-chloropyrimidin-4-yl)oxy)-8-azabicyclo[3.2.1 ]octane-8- carboxylate
  • Step-F tert-Butyl 3-e o-((6-(5-(methylsulfonyl)- 1 H-indol- 1 -yl)pyrimidin-4-yl)oxy)-8- azabicyclo [3.2.1 ] octane-8-carboxylate :
  • Step-A ter/-Butyl 4-(((6-chloropyrimidin-4-yl)oxy)methyl)piperidine- 1 -carboxylate:
  • Step-B te -Butyl 4-(((6-(5 -(methylsulfonyl)- 1 H-indol- 1 -yl)pyrimidin-4- yl)oxy)methyl)piperidine- 1 -carboxylate:
  • CHO-K1 Chinese Hamster Ovary (CHO-K1) cells were stably transfected with human GPR119 and were maintained in Ham's F-12 complete medium containing 10% heat inactivated FBS (Sigma, UK). The cells were maintained under a selection pressure with 500 g/ml G418 (GENETICIN). Stable clones were analyzed for functional cAMP response to OEA (oleoylethanolamide).
  • OEA oleoylethanolamide
  • cells were serum starvation for 18-24 h, trypsinized and seeded in 96 well plates at a density of 7500 cells/well. The cells were then treated with test compounds diluted in serum free Ham's F12 for 1 h at 37 °C. The cAMP levels were measured by using the cAMP femto kit (CisBio) by following the manufacturer's instructions. Following treatment with a test compound, the cells were lysed and cAMP levels were estimated by adding D2-labelled cAMP and europium-cryptate conjugated anti-cAMP antibody.
  • the FRET response is calculated as the ratio of fluorescence at 665 to fluorescence at 620 nm.
  • the unlabelled cAMP produced as a result of GPR119 activation/agonism competes with the D2-cAMP leading to a decrease in the FRET signal.
  • the FRET signal is inversely proportional to the amount of cAMP produced by the treated cells.
  • known concentrations of cAMP were added in order to get a standard linear curve for extrapolation of the cAMP values in the unknown/test samples. Fluorescence was measured on BMG Labtech PHERAstar machine.
  • the concentration of compound required to stimulate a half-maximal response was determined using the GraphPad Prism software.
  • the compounds prepared were tested using the above assay procedure and the results obtained are given below.
  • the EC 50 (nM) values of the compounds are set forth in Table- 1 wherein "A” refers to an EC50 value of less than 50 nM, "B” refers to an ECso value in range of 50.01 to 250 nM and "C” refers to an EC S0 value in range of 250.01 to 1000 nM.
  • Activity data has been given in Table- 1 for few representative compounds.
  • the compound of the present invention has been shown to decrease plasma glucose levels in vivo, indicating potential for use of the compounds of the present invention in the treatment of diabetes.

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Abstract

La présente invention concerne des composés de formule (I) utiles pour traiter, prévenir et/ou gérer les maladies, les troubles, les syndromes ou les états modulés par l'activité du récepteur GPR119. L'invention concerne également le procédé de préparation desdits composés et des compositions pharmaceutiques les contenant. L'invention concerne aussi des procédés de traitement, de prévention et/ou de gestion de maladies, de troubles, de syndromes ou d'états associés à la modulation du récepteur GPR119 au moyen de composés de formule (I), utilisés seuls ou en association.
PCT/IB2011/001916 2010-08-23 2011-08-19 Composés indolylpyrimidines en tant que modulateurs de gpr119 WO2012025811A1 (fr)

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WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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