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WO2013062837A1 - Dérivés de la pipéridine utilisés comme agonistes du récepteur gpr119 - Google Patents

Dérivés de la pipéridine utilisés comme agonistes du récepteur gpr119 Download PDF

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Publication number
WO2013062837A1
WO2013062837A1 PCT/US2012/060708 US2012060708W WO2013062837A1 WO 2013062837 A1 WO2013062837 A1 WO 2013062837A1 US 2012060708 W US2012060708 W US 2012060708W WO 2013062837 A1 WO2013062837 A1 WO 2013062837A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
mmol
cycloalkyl
int
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PCT/US2012/060708
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English (en)
Inventor
John J. Acton, Iii
Harold B. Wood
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Merck Sharp & Dohme Corp.
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Publication of WO2013062837A1 publication Critical patent/WO2013062837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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

Definitions

  • the present invention relates to G-protein coupled receptor agonists.
  • the present invention is directed to agonists of GPR 119 that are useful for the treatment of diabetes, especially type 2 diabetes, obesity, the metabolic syndrome and related diseases and conditions.
  • Diabetes is a disease derived from multiple causative factors. It is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • T2DM noninsulin-dependent diabetes mellitus
  • insulin is still produced in the body, and patients demonstrate resistance to the effects of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissue.
  • T2DM noninsulin-dependent diabetes mellitus
  • T2DM noninsulin-dependent diabetes mellitus
  • These patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as they compensate for the reduced effectiveness of insulin by secreting increased amounts of insulin.
  • GPCR G-protein coupled receptors
  • GPRl 19 agonists therefore have the potential to function as anti-hyperglycemic agents that produce weight loss.
  • l WO2005/007647 published on 27 January 2005, WO2005/121121 published on 22 December 2005, WO2006/067531 published on 29 June 2006, WO2006/067532 published 29 June 2006, WO2007003964 published on 11 January 2007, and WO2007003962 published on 11 January 2007 relate to GPR 119 agonist compounds.
  • the invention is directed to substituted piperidinyl compounds of formula I:
  • the invention further relates to methods of treating diabetes and related diseases and conditions.
  • the invention is directe I:
  • X is O or CH 2 ;
  • Y is O or NH
  • Z is CH 2 or C(O);
  • ring A is aryl, or heteroaryl, wherein the heteroaryl ring contains 1-3 N, O, or S;
  • R 1 is 5 or 6-membered heteroaryl, -C(0)OCi-6alkyl, or -C(0)OC 3- 6cycloalkyl, wherein heteroaryl contains 1-3 N, O atoms, wherein the heteroaryl group is unsubstituted or substituted by halo, Ci -6 alkyl, or haloC 1-6 alkyl, and wherein the cycloalkyl is unsubstituted or substituted by C ] -6 alkyl or haloC i -6alkyl ;
  • R 2 is hydrogen, haloC 1-6 alkyl or C 1-6 alkyl;
  • R 3 is hydrogen, or hydroxy;
  • R 4 is hydrogen, or C 1-6 alkyl, alternatively, R 3 and R 4 are taken together to form a cyclopropyl group;
  • R 5 is halo, -N(C 1-6 alkyl) 2 , -N(H)(C 1-6 alkyl), C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 2-6 alkenyl, hydroxy, nitro, C ⁇ alkoxy, or thioCi -6 alkoxy;
  • R 6 is -NS(0) 2 C 1-3 alkyl, CN, -NCOC 1-3 alkyl, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH- hydroxyCi -6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl; and n is 0, 1, 2, or 3.
  • the invention is directed to compounds of formula I or a
  • X is O or CH 2 .
  • X is O.
  • X is CH 2 .
  • the invention is directed to compounds of formula I or a
  • Z is CH 2 or C(O). In one class of this embodiment, Z is CH 2 . In another class of this embodiment, Z is C(O).
  • the invention is directed to compounds of formula I or a
  • Y is O or NH.
  • Y is O.
  • Y is NH.
  • the invention is directed to compounds of formula I or a
  • R 5 is halo, -N(C 1-6 alkyl) 2 , -NiH Ci-ealkyl), C ⁇ . 6 alkyl, haloC 1-6 alkyl, hydroxyC ⁇ alkyl, C 2 . 6 alkenyl, hydroxy, nitro, C 1-6 alkoxy, or thioC!.
  • R 5 is halo, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxy, nitro, C ⁇ alkoxy, or thioCi- alkoxy.
  • R 5 is halo. In a subclass of this class, R 5 is fluoro.
  • the invention is directed to compounds of formula I or a
  • R 6 is -NS(0) 2 C 1-3 alkyl, CN, -NCOCi -3 alkyl, C(0)C, -6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyCi -6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3- 6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R 5 is halo, d ⁇ alkyl, haloCt-ealkyl, hydroxyC 1-6 alkyl, hydroxy, nitro, C 1-6 alkoxy, or thioC 1-6 alkoxy. In a subclass of this class, R 5 is halo. In a subclass of this class, R 5 is fluoro.
  • R 6 is CN, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH- hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R 5 is halo, C 1-6 alkyl, haloCi -6 alkyl, hydroxyC 1-6 alkyl, hydroxy, nitro, Ci -6 alkoxy, or thioCi.6alkoxy.
  • R 5 is halo.
  • R 5 is fluoro.
  • R 5 is fluoro
  • the invention is directed to compounds of formula I or a
  • ring A is aryl, or heteroaryl, wherein the heteroaryl ring contains 1-3 N, O, or S.
  • ring A is aryl, or 6-membered heteroaryl, wherein the heteroaryl ring contains 1-2 N.
  • the invention is directed to compounds of formula I or a
  • ring A is aryl; and R 6 is -NS(0) 2 C 1-3 alkyl, CN, - NCOCi -3 alkyl, C(0)C 1-6 alkyl, C(0)NHCi -6 alkyl, C(0)NH-hydroxyC 1 . 6 alkyl, C(0)NHC 3- 6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • ring A is phenyl; and R 6 is -NS(0) 2 C 1-3 alkyl, CN, -NCOCr 3 alkyl, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3 - 6 cycloalkyl, COOH, or S(0) 2 Ci -3 alkyl.
  • R 5 is halo; and R 6 is CN, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or SCO ⁇ d. 3 alkyl.
  • R 5 is fluoro; and R 6 is CN, COOH, ° ° ,
  • the invention is directed to compounds of formula I or a
  • ring A is heteroaryl.
  • ring A is a 6-membered heteroaryl, wherein the heteroaryl ring contains 1-2 N.
  • the invention is directed to compounds of formula I or a
  • ring A is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl
  • R 5 is halo, -N(C 1-6 alkyl) 2 , -N(H)(C 1-6 alkyl), C 1-6 alkyl, haloC 1-6 alkyl, hydroxy C 1-6 alkyl, C 2- 6alkenyl, hydroxy, nitro, C ⁇ alkoxy, or thioCi- 6 alkoxy
  • R 6 is -NS(0) 2 C 1-3 alkyl, CN, - NCOCi -3 alkyl, C(0)Ci -6 alkyl, C(0)NHCi -6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3- 6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C ]-3 alkyl.
  • ring A is pyridinyl
  • R 6 is CN, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyC 1- ealkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R 5 is halo; and R 6 is CN, C(0)C 1-6 alkyl, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C ! . 3 alkyl.
  • the invention is directed to compounds of formula I or a
  • R 1 is aryl, 5 or 6-membered heteroaryl, -0(0)00!.
  • heteroaryl contains 1-3 N, O atoms, wherein the aryl, or heteroaryl groups are unsubstituted or substituted by halo, C 1-6 alkyl, or haloC 1- alkyl, and wherein the cycloalkyl is unsubstituted or substituted by Ci-ealkyl or haloC 1-6 alkyl.
  • R is
  • R is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R is In yet another subclass of this embodiment, R is In another subclass of this embodiment, R is
  • the invention is directed to compounds of formula I or a
  • R 1 is a 5 or 6-membered heteroaryl, wherein the heteroaryl ring contains 1-3 N or O atoms, and wherein the heteroaryl group is unsubstituted or substituted by halo, Ci-6alkyl, or haloC 1-6 alkyl.
  • R 1 is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or oxadiazolyl, unsubstituted or substituted by halo, C 1-6 alkyl, or haloCuealkyl.
  • R 1 is pyridinyl.
  • R 1 is pyrimidinyl.
  • R 1 is pyrazinyl.
  • R 1 is pyridazinyl.
  • the invention is directed to compounds of formula I or a
  • R is hydrogen, haloCi-ealkyl or C 1-6 alkyl.
  • R 2 is hydrogen or methyl. In one subclass of this class, R is hydrogen. In one subclass of this class, R is methyl.
  • the invention is directed to compounds of formula I or a
  • R 3 is hydrogen or hydroxy
  • R 4 is hydrogen, or C ⁇ . alkyl, alternatively, R 3 and R 4 are taken together to form a cyclopropyl group.
  • R 3 is hydrogen or hydroxy; and R 4 is hydrogen.
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 3 is hydroxy
  • R 4 is hydrogen
  • R 3 and R 4 are taken together form a cyclopropyl group. In one subclass of this class, R 3 and R 4 are taken together to for In one subclass of this class, R 3 and R 4 are taken together to . In one subclass of this class, R 3 and R 4 are taken together to form
  • the invention is directed to compounds of formula I or a
  • ring A is phenyl
  • R 6 is CN, C(0)C 1-6 alkyl, C(0)NHd ealkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or yl.
  • R 1 is ; . 5 or
  • ring A is pyridinyl
  • R 6 is CN, C(0)C 1-6 alkyI, C(0)NHC 1-6 alkyl, C(0)NH-hydroxyCi- 6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl,
  • the invention is directed to compounds of formula I or a
  • ring A is phenyl
  • R 6 is CN, C(0)C 1-6 alkyl, C(0)NHCj ealkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R 1 is
  • ring A is pyridinyl
  • R 6 is CN, C(0)C 1-6 alkyl, C(0)NHCi -6 alkyl, C(0)NH-hydroxyC 1 - 6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R 1 is
  • the invention is directed to compounds of formula I or a
  • ring A is phenyl
  • R 6 is CN, C(0)Ci -6 alkyl, C(0)NHCi 6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3-6 cycloalkyl, COOH, or S(0) 2 C 1-3 alkyl.
  • R In a subclass of this class, R In another class of this embodiment, ring A is pyridinyl, and R 6 is CN, C(0)C 1- alkyl, C(0)NHCi -6 alkyl, C(0)NH-hydroxyC 1-6 alkyl, C(0)NHC 3-6 cycloalkyl, C(0)C 3 . 6 cycloalkyl 5 COOH, or S(0) 2 Ci -3 alkyl.
  • R is
  • the invention is directed to compounds of formula la
  • R , R , R , R and n are previously defined.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the invention is directed to compounds of formula lb
  • harmaceutically acceptable salt wherein 1 , R 5 , R 6 and n are previously defined.
  • R 1 is .
  • the invention is directed to compounds of formula Ic
  • R 1 is .
  • the invention is directed to compounds of formula Id
  • the invention is directed to compounds of formula lb
  • R is
  • alkyl as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • cycloalkyl means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated if no number of atoms is specified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused.
  • Cycloalkyl also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • Alkoxy refers to an alkyl group linked to oxygen.
  • Haloalkoxy and “haloalkylO” are used interchangeably and refer to halo substituted alkyl groups linked through the oxygen atom.
  • Haloalkoxy include mono- substituted as well as multiple halo substituted alkoxy groups, up to perhalo substituted alkoxy. For example, trifiuoromethoxy is included.
  • Haloalkyl include mono- substituted as well as multiple halo substituted alkyl groups, up to perhalo substituted alkyl. For example, trifluoromethyl is included.
  • Heteroaryl (HAR) unless otherwise specified, means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic.
  • heteroaryl groups include: pyrrolyl or pyrrole, isoxazolyl or isoxazole, isothiazolyl or isothiazole, pyrazolyl or pyrazole, pyridyl, oxazolyl or oxazole, oxadiazolyl or oxadiazole, thiadiazolyl or thiadiazole, thiazolyl or thiazole, imidazolyl or imidazole, triazolyl or triazole, tetrazolyl or tetrazole, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl or benzisoxazole, benzoxazolyl or benzoazole, benzothiazolyl or benzothiazole, benzothiadiazolyl or benzothiadiazole, dihydrobenzofuranyl or dihydrobenzofurane, indolinyl or ind
  • dihydrobenzothienyl indolizinyl or indolizine, cinnolinyl or cinnoline, phthalazinyl or phthalazine, quinazolinyl or quinazoline, naphthyridinyl or naphthyridine, carbazolyl or carbazole, benzodioxolyl or benzodioxole, quinoxalinyl or quinoxaline, purinyl or purine, furazanyl or furazane, isobenzylfuranyl or isobenzylfurane, benzimidazolyl or benzimidazole, benzofuranyl or benzofurane, benzothienyl or benzothiene, quinolyl or quinoline, oxo- dihydroqunoline, indolyl or indole, oxindole, isoquinolyl or isoquinoline, dibenzofuranyl or dibenz
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Thioalkoxy means alkoxy group whereby the oxygen group is replaced by sulfur.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein.
  • different isotopic forms of hydrogen (H) include protium ( H) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within the formulas described herein can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound.
  • Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers.
  • any enantiomer of a compound of the formulas described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are also included in the present invention.
  • GPR 119 GPR 119 receptor
  • Said compounds may be used for the manufacture of a medicament for treating one or more of diseases or conditions, including, without limitation:
  • noninsulin dependent diabetes mellitus type 2 diabetes
  • neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition
  • hypertriglyceridemia (elevated levels of triglyceride-rich-lipoproteins);
  • the compounds are agonists of the GPR119 receptor, the compounds will be useful for lowering glucose, lipids, and insulin resistance in diabetic patients and in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition.
  • the compounds are useful to ameliorate hyperinsulinemia, which often occurs in diabetic or pre- diabetic patients, by modulating the swings in the level of serum glucose that often occurs in these patients.
  • the compounds are useful for treating or reducing insulin resistance.
  • the compounds are useful for treating or preventing gestational diabetes.
  • the compounds are useful to delay or for preventing vascular restenosis and diabetic retinopathy.
  • the compounds of this invention are useful in improving or restoring ⁇ -cell function, so that they may be useful in treating type 1 diabetes or in delaying or preventing a patient with type 2 diabetes from needing insulin therapy.
  • the compounds, compositions, and medicaments as described herein are further useful for reducing the risks of adverse sequelae associated with metabolic syndrome, or Syndrome X, and in reducing the risk of developing atherosclerosis, delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis.
  • Sequelae of atherosclerosis include angina, claudication, heart attack, stroke, and others.
  • the compounds may be useful for reducing appetite and body weight in obese subjects and may therefore be useful in reducing the risk of co-morbidities associated with obesity such as hypertension, atherosclerosis, diabetes, and dyslipidemia.
  • One embodiment of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor (e.g., simvastatin, atorvastatin, and the like).
  • the compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (e.g., stanol esters, sterol glycosides or azetidinones such as ezetimibe), AC AT inhibitors (e.g., avasimibe), CETP inhibitors (e.g. anacetrapib), niacin, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors.
  • cholesterol absorption inhibitors e.g., stanol esters, sterol glycosides or azetidinones such as ezetimibe
  • AC AT inhibitors e.g., avasimibe
  • CETP inhibitors e.g. anacetrapib
  • niacin niacin
  • bile acid sequestrants e.g. anacetrapib
  • microsomal triglyceride transport inhibitors e
  • Another embodiment of the invention provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof.
  • the compound may be used alone or
  • an anti-obesity agent such as a lipase inhibitor (e.g., orlistat,) or a monoamine neurotransmitter uptake inhibitor (e.g., sibutramine or phentermine).
  • a lipase inhibitor e.g., orlistat
  • a monoamine neurotransmitter uptake inhibitor e.g., sibutramine or phentermine
  • the compound may also be used advantageously in combination with CB-1 inverse agonists or antagonists (e.g., rimonabant or taranabant).
  • the present invention further relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises
  • Yet another embodiment of the invention that is of interest relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat atherosclerosis.
  • Yet another embodiment of the invention that is of interest relates to a method of delaying the onset of one of the aforementioned conditions and disorders where insulin resistance is a component in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to delay the onset of said condition.
  • Yet another embodiment of the invention that is of interest relates to a method of reducing the risk of developing one of the aforementioned conditions and disorders where insulin resistance is a component in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to reduce the risk of developing said condition.
  • Yet another embodiment of the invention that is of interest relates to a method of treating a condition or reducing the risk of developing a condition or delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) impaired glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, (21) hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat said condition,
  • insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides;
  • HMG-CoA reductase inhibitors (i) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPARa agonists, (v) PPAR a /ydual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
  • antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, (e.g., lisinopril, losartan); said compounds being administered to the patient in an amount that is effective to treat said condition.
  • angiotensin converting enzyme inhibitors e.g., angiotensin II receptor antagonists or renin inhibitors, (e.g., lisinopril, losartan); said compounds being administered to the patient in an amount that is effective to treat said condition.
  • any suitable route of administration may be employed for providing a mammal, especially a human, with an effective amount of a compound of the present invention.
  • Dosage forms may include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the formulas described herein or a pharmaceutically acceptable salt thereof are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams.
  • the total daily dose will generally be from about 1 milligram to about 350 milligrams.
  • the dosage for an adult human may be as low as 0.1 mg.
  • the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
  • Oral administration will usually be carried out using tablets or capsules. Examples of doses in tablets and capsules are 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 rag, 9.5 mg, 10 mg, 12 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, 700 mg, 750 mg, 800 mg and 1000 mg.
  • Other oral forms may also have the same or similar dosages.
  • compositions of the present invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt” refer to non-toxic salts of the compounds described herein which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds described herein include, but are not limited to, the following: acetate,
  • benzenesulfonate benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, hexylresorcinate, hydrobromide, hydrochloride,
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N- di
  • a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
  • compositions are typically suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the particular active ingredient selected. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art.
  • compounds of the formulas described herein, or the pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with the pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage form.
  • Solid pharmaceutical carriers are therefore typically employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • Such compositions and preparations typically comprise at least about 0.1 percent of active compound, the remainder of the composition being the carrier.
  • the percentage of active compound in these compositions may, of course, be varied and is conveniently between about 2 percent to about 60 percent of the weight of the dosage form. The amount of active compound in such
  • therapeutically useful compositions is such that an effective dosage will be delivered.
  • the active compound can be administered intranasally as, for example, in the form of liquid drops or a spray.
  • the tablets, capsules and the like also typically contain a binder.
  • suitable binders include gum tragacanth, acacia, gelatin and a synthetic or semisynthetic starch derivative, such as hydroxypropylmethylcellulose (HPMC); excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and in some instances, a sweetening agent such as sucrose, lactose or saccharin.
  • a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • Syrups and elixirs typically contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl or propylparabens as a preservative, a dye and a flavoring such as cherry or orange flavor.
  • the compound of the formulas described herein or a pharmaceutically acceptable salt thereof may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water, saline or another biocompatible vehicle, suitably mixed with a surfactant, buffer, and the like.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in an oil. Under ordinary conditions of storage and use, these preparations can also contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions and dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions and dispersions.
  • the preparation should be prepared under sterile conditions and be fluid to the extent that easy syringability exists. It should be sufficiently stable under the conditions of manufacture and storage and preserved against the growth of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and suitable oils.
  • compounds of the present invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases and conditions described herein.
  • Such other drugs may be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the formulas described herein or a pharmaceutically acceptable salt thereof.
  • a compound of the formulas described herein or a pharmaceutically acceptable salt thereof In the treatment of patients who have type 2 diabetes, insulin resistance, obesity, metabolic syndrome, neurological disorders, and co-morbidities that accompany these diseases, more than one drug is commonly administered.
  • the compounds of this invention may generally be administered to a patient who is already taking one or more other drugs for these conditions.
  • the combination therapy also includes therapies in which a compound of the formulas described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the formulas described herein.
  • Examples of other active ingredients that may be administered separately or in the same pharmaceutical composition in combination with a compound of the formulas described herein include, but are not limited to:
  • DPP-4 dipeptidyl peptidase-IV
  • PPARy agonists such as the glitazones (e.g. pioglitazone), and other PPAR ligands, including (1) PPARa/ ⁇ dual agonists (e.g., muraglitazar, ); (2) PPARa agonists, such as fenofibric acid derivatives (e.g., gemfibrozil), (3) selective PPARy modulators (SPPARyM's); and (4) PPARy partial agonists;
  • PPARa/ ⁇ dual agonists e.g., muraglitazar,
  • PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil)
  • SPPARyM's selective PPARy modulators
  • biguanides such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as GlumetzaTM, FortametTM, and GlucophageXRTM; and
  • amylin and amylin analogs such as pramlintide
  • a-glucosidase inhibitors e.g., acarbose
  • incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists;
  • LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (e.g., simvastatin), (ii) bile acid sequestering agents (e.g., cholestyramine), (iii) inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acyl CoArcholesterol acyltransferase inhibitors, (e.g., avasimibe);
  • HMG-CoA reductase inhibitors e.g., simvastatin
  • bile acid sequestering agents e.g., cholestyramine
  • inhibitors of cholesterol absorption e.g., ezetimibe
  • acyl CoArcholesterol acyltransferase inhibitors e.g.,
  • HDL-raising drugs e.g., niacin and nicotinic acid receptor agonists
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs or NS AIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;
  • antihypertensive agents such as ACE inhibitors (e.g.,lisinopril), A-II receptor blockers (e.g., losartan), renin inhibitors (e.g., aliskiren), beta blockers, and calcium channel blockers;
  • ACE inhibitors e.g.,lisinopril
  • A-II receptor blockers e.g., losartan
  • renin inhibitors e.g., aliskiren
  • beta blockers e.g., calcium channel blockers
  • GKAs glucokinase activators
  • inhibitors of 1 ⁇ -hydroxysteroid dehydrogenase type 1 e.g., those disclosed in U.S. Patent No. 6,730,690;
  • CETP inhibitors e.g., anacetrapib
  • AMPK AMP-activated Protein Kinase
  • MGAT-1 and MGAT-2 inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2
  • MGAT-2 acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2
  • agonists of the TGR5 receptor also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR
  • PTP-1B protein tyrosine phosphatase- IB
  • DPP-4 dipeptidyl peptidase-IV
  • DPP-4 inhibitors include, without limitation, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
  • DPP-4 dipeptidyl peptidase-IV
  • DPP-4 dipeptidyl peptidase-IV
  • Another embodiment of the invention that is of interest relates to the use of a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating a disease or condition described herein.
  • the compounds of the invention can be prepared using the synthetic schemes described herein as well as any of several alternate methods which will be apparent to a chemist skilled in the art.
  • AIBN is azobisisobutyronitrile; Cbz is carboxybenzyloxy; DCM is dichloromethane; DIPEA (DIE A) is N,N-Diisopropylethylamine, or Hunig's base; DMF is N,N- dimethylformamide; DMSO is dimethyl sulfoxide; Et is ethyl; EtOAc is ethyl acetate; EtOH is ethanol; MeOH is methanol; HC1 is hydrochloric acid; HEPES is 4-(2-hydroxyethyl)-l- piperizineethanesulfonic acid; Hex is hexyl; HPLC is high performance liquid chromatography; Hz is Hertz; iPrOAc is isopropyl acetate; LCMS (LC/MS) is liquid chromatography mass spectrometry; LiHMDS is lithium hexamethyldisiliazide; M is molar; MS is mass spectrometry; m
  • the cyclic acetal core described in these examples can be prepared by any of several methods. A particularly convenient method is outlined in schemes 1 and 2 below.
  • Knovenagel condensation product of a malonate diester with a Cbz-protected piperidinyl aldehyde can be optionally cyclopropanated, then hydrogenolyzed, the amine coupled with an appropriate substituent, and optionally C-alkylated to provide a piperidinyl propanedioate.
  • Reduction of the diester to the diol can be accomplished by several methods, with LAH reduction and NaB ⁇ /LiCl reduction in THF/ethanol being particularly convenient.
  • the diols are then treated with an appropriate aromatic or heteroaromatic aldehyde or ketone under acid catalysis conditions to provide the acetal (or ketal) core structure.
  • SCHEME 1. General Synthetic Scheme for the "Alkyl" Series.
  • aryl and heteroaryl aldehydes and ketones shown in the schemes are commercially available or may be prepared from readily accessible aryl, heterocyclic, or other congeners via a host of routes. Many intermediates are accessible through either modification of a pre-formed heteroaryl scaffold or through de novo ring synthesis.
  • Direct displacement of labile heteroaryl halides or similar leaving groups can often be used to introduce heteroaryl nitrogen substituents at R 1 directly.
  • Direct displacement on heteroaryl systems are all well known to the skilled artisan, and may include the use of organic or inorganic bases in a suitable solvent and the use of heat to facilitate the displacement.
  • the fully elaborated GPR119 agonist is then prepared via the diester reduction and cyclization steps described above.
  • the synthesis of 3-substituted 1,2,4-oxadiazoles can be accomplished by treating an unprotected piperidine with cyanogen bromide in the presence of base refluxed in a suitable chlorinated solvent to give the cyanopiperidine.
  • the cyano intermediate can then be converted to a 3 -substituted 1,2,4-oxadiazole via reaction with an N- hydroxyalkylimidamide or N-hydroxyarylimidamide .
  • carbamate analogs at R 1 are described as follows.
  • Commercially available alkyl or aryl chloroformates or preformed succinamides can be used in the acylation of the nitrogen of the deprotected piperidine intermediate via treatment with base, such as DIEA or TEA, to yield the carbamate GPRl 19 agonist analogs following completion of the remainder of the route.
  • Int-1 (1.947 g, 5 mmol) was dissolved in ethanol (33 mL). Evacuated and charged the solution with nitrogen, then added 10% Pd-C (0.399 g, 0.375 mmol). Evacuated and charged the solution with hydrogen three times, then allowed to stir. The reaction was monitored for completeness by TLC. Once the reaction was complete, it was filtered over celite and the filtrate was evaporated by rotary evaporation to give the title compound.
  • Int-2 (0.730 g, 2.84 mmol) was dissolved in methylene chloride (10 mL). Added sodium bicarbonate (0.715 g, 8.51 mmol) in 1.4 mL of water, followed by cyanogen bromide (0.361 g, 3.40 mmol) in 0.18 mL methylene chloride, and allowed to stir at room temperature. The reaction was monitored by TLC; once complete it was diluted with additional aqueous sodium bicarbonate and methylene chloride. The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. Silica gel chromatography was used to purify the product.
  • the reaction was then diluted with water and ethyl acetate. The layers were separated, then the aqueous layer was extracted a second time with ethyl acetate. The combined organics were washed with water and then brine. The organic layer was dried over sodium sulfate, filtered and evaporated.
  • the crude isolate was purified by silica gel chromatography eluting with 20- 35% ethyl acetate/hexanes to give both the target compound and some mixed fractions. The mixed products were subjected to a repeat chromatography to produce additional purified title compound.
  • Lithium chloride (8.54 mg, 0.201 mmol) and sodium borohydride (0.152 g, 4.03 mmol) were suspended in 0.5 mL each of THF and ethanol.
  • Int-6 (0.370 g, 1.007 mmol) was dissolved in 0.5 mL each of THF and ethanol and added to the reaction dropwise, then the vessel that held Int-6 was rinsed with an additional 0.5 mL of 1/1 THF/ethanol and the rinsate was also added to the reaction. The reaction was then stirred overnight, after which LC/MS showed complete conversion to the diol. The reaction was quenched with careful addition of 4 mL of IN HC1.
  • the aqueous was extracted a second time with ethyl acetate.
  • the combined organics were then washed once each with saturated NaHC03 and brine.
  • the organic layer was dried over sodium sulfate, filtered and evaporated.
  • the crude was purified by silica gel chromatography, eluting with a gradient of 70-100% EtOAc/hexanes, followed by a flush of ethyl acetate. TLC was used (CAM stain) to analyze f actions and the title compound was isolated.
  • Int-15 (0.764 g, 2.0 mmol) was dissolved in 10 mL THF.
  • Lithium aluminum hydride (LAH) (0.095 g, 2.500 mmol) was added in small portions over 5-10 minutes (note that reaction does exotherm).
  • TLC showed partial reaction so an additional 20 mg LAH was added, and after 20 minutes reaction was complete.
  • the reaction was quenched by carefully adding about 0.5-0.75 mL of 5N NaOH, then adding magnesium sulfate and stirring for about 10 minutes. Filtered the solid and washed with THF, then evaporated the filtrate and pumped on high vacuum.
  • the crude was purified by silica gel chromatography, eluting with 50-100% EtOAc/hexane to give the target compound as a white solid.
  • 2-Ethenyl-5-(methylsulfonyl)pyridine (Int-19): 2-Bromo-5-methylsulfonylpyridine (236 mg, 1.0 mmol), potassium vinyltrifluoroborate (161 mg, 1.200 mmol) and l,r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16.33 mg, 0.020 mmol) were dissolved/suspended in 10 mL of a 2/1 mixture of 2- propanol and water. Triethylamine (418 ⁇ , 3.00 mmol) was then added and the reaction was heated to 90°C.
  • Int-21 (350 mg, 1.074 mmol) was dissolved in ethanol (2.68 mL) and heated to 50 0 C. A warmed solution of silver nitrate (374 mg, 2.201 mmol) in water (0.5 mL, 27.8 mmol) was then added dropwise. The reaction was heated for 45 minutes, then cooled to room temperature, diluted with water and filtered. The filtered solid was washed three times with ethyl acetate, collecting the filtrate. The aqueous was extracted 2x with ethyl acetate, and it too contains product. The combined organics (extract and filtrate wash) were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by column chromatography on silica gel, eluting with 10-35% EtOAc/hexanes to give title compound as a white solid.
  • Int-25 was prepared in an analogous fashion to Int-20 starting with Int-23 directly above.
  • GPR119 EC 50 >10000 nM
  • Other acetal type final compounds were prepared by Method A using diols prepared as described above and aldehydes that were either sourced commercially or prepared as described above. In all cases the trans isomer elutes before the cis isomer on silica gel using hexane/ethyl acetate as mobile phase.
  • Example 17 and Example 18 were prepared by treating Int-25 and Int-4 using Method A.
  • Example 17 (106.7 mg, 0.228 mmol) was dissolved in tetrahydrofuran (1.25 mL), methanol (0.625 mL), and 0.456 mL of IN NaOH and stirred overnight. LC/MS at 20 hours shows reaction is complete. Neutralized with 0.456 mL of IN HC1, then diluted with water and extracted twice with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, evaporated and pumped on high vacuum to give title compound.
  • Example 19 (25 mg, 0.055 mmol) was dissolved/suspended in 0.55 mL of dichloromethane. Oxalyl chloride (30.3 ⁇ , 0.061 mmol), and catalytic DMF (0.5 ⁇ , 6.46 ⁇ mol) were then added and the reaction was stirred for approximately 2-3 minutes. 2-Amino-2-methyl-l-propanol (10.51 ⁇ , 0.110 mmol) was added to the reaction, at which time solid came out of solution. The reaction was partitioned between water and dichloromethane. The organic was dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by PTLC to give the title compound.
  • Method B Int-17 (31.2 mg, 0.154 mmol), Int-9 (40 mg, 0.154 mmol), and p-toluenesulfonic acid monohydrate (4.40 mg, 0.023 mmol) were suspended in toluene (1.5 mL). Heated to 90°C for about 90 minutes, then added activated powdered molecular sieves and stirred another 3 hours. Filtered and evaporated, then purified on silica gel, eluting with 5% EtOAc/CH 2 Cl 2 over 360 mL followed by 5-15% EtOAc/CH 2 Cl 2 over 360 mL. The trans isomer eluted first, followed by the cis isomer.
  • Examples 23 and 24 were prepared by combining Int-9 and Int-18 using method B.
  • Examples 25 and 26 were prepared by combining Int-9 and 4-methylsulfonylbenzaldehyde using method A.
  • Examples 27 and 28 were prepared by combining Int-17 and Int-11 using method A.
  • Method C Int-17 (24.98 mg, 0.124 mmol), Int-7 (35 mg, 0.124 mmol), and p-toluenesulfonic acid monohydrate (3.52 mg, 0.019 mmol) were suspended in toluene (1.2 mL) and heated to 90°C for about 90 minutes. Subsequent addition of activated molecular sieves failed to drive the reaction to completion, nor did extended reaction time or the addition of zinc chloride.
  • Examples 31 and 32 were prepared by combining Int-18 and Int-7 using method C.
  • Int-17 (12.73 mg, 0.063 mmol), Int-13 (19 mg, 0.063 mmol), and p-toluenesulfonie acid monohydrate (1.796 mg, 9.44 ⁇ ) were suspended in toluene (0.63 mL) and heated to 90°C for about 3 hours.
  • LC/MS shows target formed.
  • TLC shows a number of spots, one major. No triol present.
  • the reaction was purified directly by silica gel chromatography, eluting with 30-60% EtOAc/hexane to give the title compound.
  • Method D A suspension of Int-16 (59.6 mg, 0.2 mmol) and 4-methylsuIfonylbenzaldehyde (36.8 mg, 0.200 mmol) in dichloromethane (1.6 mL) was treated with by DL-10-camphorsulfonic acid (46.5 mg, 0.200 mmol), after which the reaction went into solution. At 1 hour the reaction was only partially complete, so powdered, oven dried molecular sieves were added and stirring continued overnight. Filtered the reaction over celite and evaporated filtrate.
  • the crude isolate was purified by silica gel chromatography, eluting isocratically with CH 2 Cl 2 , followed by a gradient of 0-10% (1/1 Hex/EtOAc) in CH 2 C1 2 and isocratic elution at 10% (1/1 Hex/EtOAc) in CH 2 C1 2 to give the higher rf isomer (major product). Continued eluting with a gradient of 10- 20% (1/1 Hex/EtOAc) in CH 2 C1 2 to give some mixed fractions and purified lower rf isomer (minor product). Mixed fractions were purified again by silica gel chromatography to give additional purified material.
  • Major product was identified as racemic cis (Example 34), and the minor product was identified as racemic trans (Example 35).
  • GPR119 EC 50 3.1 nM
  • Other cis and trans cyclopropylacetals were prepared as Examples 34 and 35 by combining Int- 16 with various aldehydes prepared above utilizing method D. Data is shown in the table below.
  • Example 40 101 mg, 0.210 mmol, 96 % yield
  • enantiomer B Example 41 (93.7 mg, 0.194 mmol, 89 % yield) as crystalline white solids.
  • Example 40 The analytical conditions for separating Example 40 are: OD column (4.6x250mm), 30% MeOH/C0 2 at 100 bar, 40 degrees C, 2.4 mL/min. Retention times: enantiomer A 8.67 minutes, enantiomer B 11.37 minutes. Ratio 1/1.
  • GPR119 EC 50 : 29.3 nM Methyl 4- ⁇ l-[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]-c «-5 -dioxaspiro[2.5]oct-6-yl ⁇ -2- fluorobenzoate (Int-39) and
  • Example 43 was prepared from Int-40 (24.8 mg, 0.054 mmol) using the hydrolysis method directly above.
  • Example 42 A solution of Example 42 (17 mg, 0.038 mmol) in CH 2 C1 2 (190 nl)was treated with HATU (19.6 mg, 0.052 mmol) and DIEA (9.0 ⁇ , 0.052 mmol), followed by cyclopropylamine (5.35 ⁇ , 0.076 mmol). The reaction was stirred for 72 hours. The reaction was purified directly by silica gel chromatography, eluting with 20-50% EtOAc/hexane to give title compound as a white solid. LCMS: t R 2.34 min (m/e 487.0 (M+l)) (4 minute run).
  • Example 43 was reacted with cyclopropylamine as in the preparation of Example 44 above to give the title Example 45.
  • Example 43 was reacted with 2-amino-2-methyl-l-propanol as in the preparation of Example 44 above to give the title Example 46.
  • Example 42 was reacted with ⁇ , ⁇ -dimethylhydroxylamine hydrochloride as in the preparation of Example 44 above to give the title Int-42.
  • Example 43 was reacted with N,0-dimethylhydroxylamine hydrochloride as in the preparation of Example 44 above to give the title Int-43.
  • Example 48 (4- ⁇ l-[l-(5-chIoropyrimidin-2-yl)piperidin-4-yl]-i'r i5-5,7-dioxaspiro[2.5]oct-6-yl ⁇ -2- fluorophenyl)(cyclopropyl)methanone (Example 48): Int-43 was treated as in the preparation of Example 47 to give title Example 48.
  • GPR119 EC 50 2.5 nM l-fl-(5-chloropyrimidin-2-yl)piperidin-4-yl1-6-[4-(methylsulfonyl)phenyl1-5- azaspiro [2.51 octane (2 isomers)
  • Benzyl 4-[2-cyano-2-(ethoxycarbonyI)cyclopropyl]piperidine-l-carboxylate (Int-27): NaH (1.794 g, 44.9 mmol) was added to a flame dried flask under nitrogen, then washed twice with hexanes and decanted. The flask was evacuated and charged with nitrogen, after which trimethylsulfoxonium iodide (9.87 g, 44.9 mmol) was added. Anhydrous DMSO (50 mL) was added to the reaction vessel with a dropping funnel over about 3-5 minutes. Gas evolved, and the suspension was stirred for 90 minutes.
  • Int-26 (13.65 g, 39.9 mmol) was dissolved in 110 ml of anhydrous DMSO, then added to the reaction vessel with a dropping funnel over about 10 minutes. After olefin is consumed, the reaction was poured onto ice water and extracted 3x with ethyl acetate. The ethyl acetate was washed 4x with water and once with brine, then dried over sodium sulfate, filtered and evaporated. The residue was pumped on high vacuum. The crude was purified by silica gel chromatography, eluting with a gradient from 15-40% EtOAc/hexane to give the title compound.
  • Int-27 (5.21 g, 14.62 mmol) was dissolved in EtOH (70 ml, 1199 mmol). The flask was evacuated and charged with nitrogen, then added palladium hydroxide (1.026 g, 1.462 mmol). The vessel was then evacuated and charged three times with hydrogen gas and monitored by TLC until complete. The reaction was filtered over celite and the filtrate was evaporated. Then added heptane and repeated the evaporation, after which the crude was pumped briefly on high vacuum. The crude isolate was dissolved in DMF (36.5 ml). To this solution was added 2,5- dichloropyrimidine (2.287 g, 15.35 mmol) and cesium carbonate (14.29 g, 43.9 mmol).
  • the reaction was stirred for 72 hours.
  • the reaction was diluted with water and extracted twice with ethyl acetate.
  • the combined ethyl acetate layers were washed three times with water and once with brine, dried over sodium sulfate, filtered and evaporated.
  • the residue was purified by silica gel chromatography, eluting with 15-40% EtOAc/hexanes to give title Int-28 as a white solid.
  • extract A The acidic aqueous was then basified with aqueous NaHC0 3 and extracted twice with ethyl acetate. This organic was dried, filtered and evaporated, designated extract B.
  • LC MS indicates that extract B is title compound of sufficient purity to carry forward.
  • the aqueous was basified with NaHC0 3 solution (caution! Gas Evolution!), then extracted 2x with ethyl acetate. TLC of each of the 3 extracts shows similarities, so they were combined to give about 50 mg of crude isolate.
  • the residue was purified by silica gel chromatography eluting with 15-100% EtOAc/hexane over 20 column volumes to give multiple products.
  • the major product was further purified by PTLC to give 2 compounds which appear to be the diastereomeric lactones by NMR and LCMS. These lactones are a known side product of the intramolecular Ritter reaction (see Org. Lett. 2000, 2(20), 3083-3086).
  • HEK Human embryonic kidney
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • HEPES buffer 4-(2-hydroxyethyl)-l-piperazineethane sulfonic acid
  • hygromycin fetal bovine serum
  • the transfected cells were harvested using a non- enzymatic cell dissociation solution (GIBCO 2672), pelleted and resuspended in stimulation buffer (DMEM, 25 mM HEPES, 0.1% bovine serum albumin (BSA), pH 7.4 in the presence of ⁇ phosphodiesterase inhibitors).
  • DMEM non- enzymatic cell dissociation solution
  • BSA bovine serum albumin
  • pH 7.4 pH 7.4 in the presence of ⁇ phosphodiesterase inhibitors
  • CHO cell lines stably transfected with the permissive guanine nucleotide binding protein alpha 15 (Gal 5) and murine GPR119 were maintained in DMEM media containing FBS, penicillin-streptomycin, puromycin, and G418 (geneticin).
  • human embryonic kidney (HEK)293 Flp-In cells (Invitrogen, Carlsbad, CA) were stably transfected with a human SNP variant (S309L) of GPR119 and maintained in DMEM media containing FBS, penicillin-streptomycin, and hygromycin.
  • Agonist activation of the GPR119 receptor was measured in receptor transfected cells described above, treated with compounds of this invention, using a commercial homogenous time resolved fluorescence (HTRF) kit for measurement of cAMP (CisBio, Bedford, MA).
  • the assay was performed in 96-well half- volume plates (murine) or 384-well plates (human) following the manufacturers instructions. Briefly, suspended cells were incubated with a dose titration of test compound at RT for 60 min, lysed, and incubated with HTRF reagents for an additional 60 min. The plate was read using an Envision multilabel reader (Perkin Elmer) adjusted to read time resolved fluorescence and the cAMP concentrations were extrapolated from a cAMP calibration curve.
  • Envision multilabel reader Perkin Elmer
  • GPR119 agonists exhibit a concentration-dependent increase in intracellular cAMP.
  • concentration of test compound required to stimulate a half-maximal response (EC50), and efficacy as compared to an internal agonist control, was determined from a sigmoidal 4-parameter curve fit of the resulting plot of normalized activity versus compound concentration. Evaluation of GDIS in static isolated mouse islets.
  • pancreatic islets of Langerhans were isolated from the pancreata of 10-12 wk-old
  • the KRB medium contained, in mM, 143.5 Na + , 5.8 K + , 2.5 Ca 2+ , 1.2 Mg 2+ , 124.1 CI-, 1.2 P0 4 3 -, 1.2 S0 4 2+ , 25 C0 3 2" , and 10 HEPES, pH 7.4, in addition to 2 mg/ml bovine serum albumin, and either 2 (G2) or 16 (G16) mM glucose (pH 7.4).
  • the static incubation was performed with round-bottomed 96-well plates (one islet/well with 200 ⁇ KRB medium). The compounds were added to KRB medium just before the initiation of the 60-min incubation. Insulin concentration in aliquots of the incubation buffer was measured by the ultra-sensitive rat insulin EIA kit from ALPCO Diagnostics (Windham, NH).
  • an oral composition of a compound of the present invention 50 mg of any of the examples is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule.
  • pharmacologic response may vary depending upon the particular active compound selected, formulation and mode of administration. All such variations are included within the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des composés pipéridine substitués, leurs sels pharmaceutiquement acceptables, ainsi que des compositions pharmaceutiques et des méthodes de traitement. Cette invention concerne des agonistes du récepteur couplé à la protéine G, et concerne en particulier des agonistes du récepteur GPR119 utilisés dans le traitement du diabète, notamment du diabète de type 2, de l'obésité, du syndrome métabolique et de maladies et d'affections associées.
PCT/US2012/060708 2011-10-24 2012-10-18 Dérivés de la pipéridine utilisés comme agonistes du récepteur gpr119 WO2013062837A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140296202A1 (en) * 2011-10-24 2014-10-02 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as gpr119 agonists
CN110590650A (zh) * 2019-09-24 2019-12-20 上海毕得医药科技有限公司 一种6-（甲基磺酰基）吡啶甲醛的合成方法

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Publication number Priority date Publication date Assignee Title
US20090203676A1 (en) * 2005-06-30 2009-08-13 Oscar Barba G-protein Coupled Receptor Agonists
US20090221639A1 (en) * 2006-04-06 2009-09-03 Lisa Sarah Bertram Heterocyclic GPCR Agonists
US20110028501A1 (en) * 2008-04-14 2011-02-03 Harold B Wood Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2011019538A1 (fr) * 2009-08-13 2011-02-17 Merck Sharp & Dohme Corp. Composés cyclopropyle substitués, compositions contenant de tels composés et procédés de traitement

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090203676A1 (en) * 2005-06-30 2009-08-13 Oscar Barba G-protein Coupled Receptor Agonists
US20090221639A1 (en) * 2006-04-06 2009-09-03 Lisa Sarah Bertram Heterocyclic GPCR Agonists
US20110028501A1 (en) * 2008-04-14 2011-02-03 Harold B Wood Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2011019538A1 (fr) * 2009-08-13 2011-02-17 Merck Sharp & Dohme Corp. Composés cyclopropyle substitués, compositions contenant de tels composés et procédés de traitement

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140296202A1 (en) * 2011-10-24 2014-10-02 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as gpr119 agonists
US9018200B2 (en) * 2011-10-24 2015-04-28 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as GPR119 agonists
CN110590650A (zh) * 2019-09-24 2019-12-20 上海毕得医药科技有限公司 一种6-（甲基磺酰基）吡啶甲醛的合成方法

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