WO2008062469A2 - Selective tr-beta 1 agonist - Google Patents

Selective tr-beta 1 agonist Download PDF

Info

Publication number
WO2008062469A2
WO2008062469A2 PCT/IN2007/000493 IN2007000493W WO2008062469A2 WO 2008062469 A2 WO2008062469 A2 WO 2008062469A2 IN 2007000493 W IN2007000493 W IN 2007000493W WO 2008062469 A2 WO2008062469 A2 WO 2008062469A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
phenoxy
amino
acetic acid
dichloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2007/000493
Other languages
French (fr)
Other versions
WO2008062469A3 (en
Inventor
Saurin Raval
Preeti Raval
Braj Bhushan Lohray
Vidya Bhushan Lohray
Pankaj R. Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA2666427A priority Critical patent/CA2666427C/en
Priority to EP07866730A priority patent/EP2079678B1/en
Priority to NZ576324A priority patent/NZ576324A/en
Priority to BRPI0716345-2A priority patent/BRPI0716345A2/en
Priority to AU2007322977A priority patent/AU2007322977B2/en
Priority to JP2009534055A priority patent/JP5021752B2/en
Priority to HK09110341.6A priority patent/HK1131603B/en
Priority to EA200970426A priority patent/EA017306B1/en
Priority to US12/446,820 priority patent/US8420851B2/en
Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Priority to MX2009004619A priority patent/MX2009004619A/en
Priority to KR1020097008754A priority patent/KR101165215B1/en
Priority to ES07866730T priority patent/ES2400973T3/en
Publication of WO2008062469A2 publication Critical patent/WO2008062469A2/en
Publication of WO2008062469A3 publication Critical patent/WO2008062469A3/en
Priority to IL198047A priority patent/IL198047A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention relates to novel compounds of general formula (I) which are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.
  • TR thyroid receptor
  • Thyroid hormone Triiodothyronine (Triiodothyronine; T3) is an important endocrine signaling hormone and it is essential for normal development, differentiation and maintenance of metabolic balance in mammals. Natural thyroid hormone, T3 exhibit its physiological effect by acting on a Thyroid Hormone Receptor (THR), which belongs to the nuclear hormone receptor super family. There are two different isoforms of Thyroid Hormone Receptors, THR- ⁇ and THR- ⁇ . Further these two isoforms are sub-classified as ⁇ l; ⁇ 2 and ⁇ l; ⁇ 2 subtypes. THR ⁇ l is prevalent in liver (85%), while THR ⁇ l is mainly present in cardiac tissue (Yen P. M., Physiol. Rev; 81 (2001) 1097-1142).
  • T3 maintains bodyweight, metabolic rate, body temperature, mood and regulate serum cholesterol.
  • Hypothyroidism is associated with weight gain, high levels of low-density lipoproteins (LDL) cholesterol and depression.
  • LDL low-density lipoproteins
  • Hyperthyroidism leads to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, bone loss and anxiety.
  • T3 The natural thyroid hormone T3 does not show any selectivity in binding to both of the THR isoforms (THR ⁇ l and THR ⁇ l). Thus, administration of T3 lowers plasma cholesterol, low-density lipoprotein (LDL) and triglyceride levels in animal models and humans.
  • LDL low-density lipoprotein
  • T3 cannot be used therapeutically to treat hypercholesterolemia and obesity due to its cardiac side effects.
  • knockout animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the THR ⁇ l isoform.
  • some effects of T3 may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation (Cheng S., Steroids; 70 (2005); 450-454).
  • THR ⁇ l agonist could lead to specific therapies for disorders such as obesity and hyperlipidemia, while avoiding the cardiovascular and other toxicities of native thyroid hormones.
  • compounds mimicking only the beneficial effects of the thyroid hormone and lacking their cardiac side effects potentially could be used to treat a number of conditions such as obesity and dyslipidemia.
  • THR agonists that interact selectively with the ⁇ l isoform of the THR offer an especially attractive method for avoiding cardio-toxicity (J. D. Baxter; Trends Endocrinol. Metab., 15 (2004); 154-157).
  • the present invention describes novel compounds that are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta I 5 which are useful for the treatment of a number of conditions such as obesity and dyslipidemia.
  • TR thyroid receptor
  • the novel compounds are defined by the general formula (I) as given below.
  • the compounds of the present invention are useful in the treatment of the human or animal body, by regulation of selective thyroid hormone receptor gene expression.
  • the compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of obesity and dyslipidemia.
  • PREFERRED EMBODIMENTS The main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of obesity and dyslipidemia.
  • compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture are provided.
  • R OR 1 , NHR 1 wherein R 1 may be selected from H, optionally substituted groups selected from ar(C ! -C 6 )alkyl groups; in a preferred embodiment the alkyl groups is selected from (Q-C ⁇ alkyl and the aryl group represents optionally substituted phenyl group;
  • R 2 represents hydrogen, hydroxyl, halo, acyl, oxo, optionally substituted groups selected from (CrC 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives selected from (C 1 -C 3 )alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing - CONR 5 R 6 , -SO 2 NR 5 R 6 , wherein
  • R 5 & R 6 may be same or different and are independently selected from H, optionally substituted groups selected from (d-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, bicycloalkyl, aryl or the groups R 5 & R 6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
  • R 2 may be selected from hydroxy, halo, optionally substituted groups selected from (Q-C ⁇ alkyl, phenyl,, heteroaryl groups; In a preferred embodiment, the various groups representing R 2 may be selected from
  • R 5 and R 6 may be same or different and are independently selected from H 5 optionally substituted groups selected from (C 1 - C 6 )alkyl, (C 3 -C 7 )cycloalkyl, bicycloalkyl, phenyl or the groups R 5 & R 6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, O; R 3 , R 4 may be same or different and are independently selected from H, halogen, optionally substituted (Q-C ⁇ alkyl groups; X is selected from O, -CH 2
  • the substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxyl, halo, cyano, optionally substituted groups selected from (C 1 -C 6 )SUCyI, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups. When any of these groups are further substituted, the substituents on these substitutes may be selected from those described above.
  • radicals described above may be selected from: the "alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, wo-propyl, «-butyl, sec-butyl, tert-butyl, amyl, /-amyl, ra-pentyl, n- hexyl, wo-hexyl and the like; the "cycloalkyl” or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; , - the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl
  • heteroaryl or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from
  • the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphth
  • the "acyl” group used either alone or in combination with other radicals is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, zso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
  • ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as
  • the "alkylthio" group used either alone or in combination with other radicals denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted;
  • the "thioalkyl” group used either alone or in combination with other radicals denotes an alkyl group, as defined above, attached to a group of formula -SR', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, pheny
  • sulfenyl group or “sulfenyl derivatives” used alone or in combination with other radicals, represents a bivalent group, -SO- or R x SO, where R x is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above;
  • the "sulfonyl” group or “sulfones derivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -SO 2 -, or R x SO 2 -, where R x is as defined above.
  • the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • Preferred compounds according to the present invention include but not limited to:
  • the compounds of this invention may be prepared using the reactions and techniques described in the following section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be appreciated that some routine alterations/modifications including requirement of one or more additional steps which may be required for obtaining the compounds of the present invention in preferred yields but are considered to be within the scope of a person skilled in the art, are to be considered to be within the scope of the present invention. Scheme: 1
  • 'Ak 1 represents suitable alkyl group
  • 'PG' ' represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3.
  • Reduction may be carried out using suitable reducing agents such as Raney Ni, Pd/C, SnCl 2 .2H 2 O and the like.
  • This amine 3 may be reacted with suitable alkyl haloacetate in suitable base(s) such as diisopropyl ehtylamine (1Pr 2 -NEt), pyridine, N 5 N dimethyl aniline or like in solvents selected from DMF 5 THF and the like or their mixtures to give a compound of formula 4. Further compound of formula 4 was refluxed in suitable alkyl haloformate to give compound of formula 5. Suitable deprotection and hydrolysis of compound of formula 5 gives compound of formula (I)
  • 'Ak' represents suitable alkyl group
  • PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G.
  • 'PG' represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3.
  • Reduction may be carried out using suitable reducing agents such as Raney Ni, Pd/C, SnCl 2 .2H 2 ⁇ and the like.
  • This amine 3 may be reacted with suitable alkyl haloacetates in suitable base(s) such as iPr2-NEt, pyridine, N 5 N dimethyl aniline and the like in suitable solvents such as DMF 5 THF or their suitable mixtures to give a compound of formula 4
  • suitable base(s) such as iPr2-NEt, pyridine, N 5 N dimethyl aniline and the like in suitable solvents such as DMF 5 THF or their suitable mixtures
  • ClCOOAr in suitable base such as pyridine, NEt 3 and the like in suitable solvents such as dichloromethane, chloroform and the like or their suitable mixtures to give compound of formula 5.
  • PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3.
  • Reduction may be carried out using suitable reducing agents such as Raney Ni, PdVC, SnCl 2 ⁇ H 2 O and the like.
  • This amine 3 may be reacted with suitable alkyl halo acetates in suitable base such as iPr2-NEt, pyridine, N 5 N dimethyl aniline and the like in suitable solvents such as DMF 5 THF and the like to give a compound of formula 4
  • suitable alkyl halo acetates in suitable base such as iPr2-NEt, pyridine, N 5 N dimethyl aniline and the like in suitable solvent(s) such as DMF 5 THF and the like or their suitable mixtures to give a compound of formula 5.
  • Step 1 Preparation of ⁇ [4-(3-sec-ButyI-4-hydroxy-phenoxy)-3,5-dichIoro-phenyI]- ethoxycarbonyl-amino ⁇ -acetic acid
  • Step 1 Preparation of 4-(3- sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
  • Stannous chloride dihydrate (194.6 g, 0.86 mol) in concentrated HCl (80.0 mL) was added to 3, 5-dichloro-4-(4'-methoxy-3 -sec-butyl - phenoxy)nitrobenzene (80 g, 0.21 mol) in EtOH (400 mL).
  • the reaction mixture was refluxed for about 2 h.
  • Step 2 [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester
  • Step 3 ⁇ [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino ⁇ -acetic acid ethyl ester
  • Step 4 ⁇ [4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino ⁇ -acetic acid.
  • Step 1 Preparation of [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4- methoxy-phenoxycarbonyO-aminoj-acetic acid ethyl ester
  • Step 1 Preparation of ⁇ [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonylmethyl-amino ⁇ -acetic acid ethyl ester
  • Step 2 Preparation of ⁇ [4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- carboxymethyl-amino ⁇ -acetic acid
  • ⁇ [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonylmethyl-amino ⁇ -acetic acid ethyl ester (12.5 g, 0.02 mol) in CH 2 Cl 2 (250 mL) was cooled to -60 0 C under nitrogen atmosphere.
  • IM BBr 3 solution 122 mL was added dropwise.
  • reaction mixture was allowed to warm up to 20-25 0 C over 5 h. then diluted with more CH 2 Cl 2 (250 mL) and quenched with H 2 O. After stirring at 20-25 0 C for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product.
  • Step 3 ⁇ [3 ⁇ 5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino ⁇ -acetic acid ethyl ester
  • Step 4 ( ⁇ 3,5-Dichloro-4-[3 -(4-chloro-benzoyl)-4-methoxy-phenoxy] -phenyl ⁇ - ethoxycarbonyl-amino)-acetic acid ethyl ester A mixture of ⁇ [3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino ⁇ -acetic acid ethyl ester (7.25 g, 0.0
  • Step 5 Preparation of ( ⁇ 3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]- phenyl ⁇ -ethoxycarbonyl-amino)-acetic acid
  • T3 and selected compounds disclosed in the present invention were determined according to the general protocol described in PNAS, August 19, 2003,vol. 100 (17) 10067-10072. Many of the compounds were found to be reducing cholesterol and having very little effect on the heart rate. Therefore, these compounds have the potential to be further developed as selective TR- beta agonists for the treatment of human and other animals in need of such treatment.
  • novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of formula (I) or pharmaceutical compositions containing them are useful as Thyroid hormone receptor ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc.
  • the pharmaceutical composition is provided by employing conventional techniques.
  • the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
  • the quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel compounds of general formula (I) which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor beta(TR-Beta). Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.

Description

SELECTIVE TR-BETA 1 AGONIST
FIELD OF INVENTION
The present invention relates to novel compounds of general formula (I) which are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.
Figure imgf000002_0001
(1)
BACKGROUND TO THE INVENTION Thyroid hormone (Triiodothyronine; T3) is an important endocrine signaling hormone and it is essential for normal development, differentiation and maintenance of metabolic balance in mammals. Natural thyroid hormone, T3 exhibit its physiological effect by acting on a Thyroid Hormone Receptor (THR), which belongs to the nuclear hormone receptor super family. There are two different isoforms of Thyroid Hormone Receptors, THR-α and THR-β. Further these two isoforms are sub-classified as αl; α2 and βl; β2 subtypes. THRβl is prevalent in liver (85%), while THR αl is mainly present in cardiac tissue (Yen P. M., Physiol. Rev; 81 (2001) 1097-1142).
At normal levels, T3 maintains bodyweight, metabolic rate, body temperature, mood and regulate serum cholesterol. Hypothyroidism is associated with weight gain, high levels of low-density lipoproteins (LDL) cholesterol and depression.
Hyperthyroidism leads to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, bone loss and anxiety.
The natural thyroid hormone T3 does not show any selectivity in binding to both of the THR isoforms (THRαl and THR βl). Thus, administration of T3 lowers plasma cholesterol, low-density lipoprotein (LDL) and triglyceride levels in animal models and humans. However, T3 cannot be used therapeutically to treat hypercholesterolemia and obesity due to its cardiac side effects. However, knockout animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the THR αl isoform. Thus some effects of T3 may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation (Cheng S., Steroids; 70 (2005); 450-454).
Development of specific and selective thyroid hormone receptor ligands, particularly THR βl agonist could lead to specific therapies for disorders such as obesity and hyperlipidemia, while avoiding the cardiovascular and other toxicities of native thyroid hormones. Thus, compounds mimicking only the beneficial effects of the thyroid hormone and lacking their cardiac side effects (tachycardia and arrhythmia) potentially could be used to treat a number of conditions such as obesity and dyslipidemia. In this regard, THR agonists that interact selectively with the βl isoform of the THR offer an especially attractive method for avoiding cardio-toxicity (J. D. Baxter; Trends Endocrinol. Metab., 15 (2004); 154-157).
Various compounds have been disclosed as possible agonists of THR β . Some of the more relevant ones for the present invention includes WO2007039125, WO 0039077, US20040157844 which are incorporated herein as reference.
US20020035153 describes compounds of the following general formula as Thyromimetics.
Figure imgf000003_0001
However, none of these compounds have been commercially developed and looking at the beneficial potential and medical need for such compounds, there remains a need for developing further compounds with better therapeutic and/or safety profile. Herein, we disclose novel compounds which shows activity as THR β agonists. SUMMARY OF THE INVENTION
The present invention describes novel compounds that are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta I5 which are useful for the treatment of a number of conditions such as obesity and dyslipidemia. The novel compounds are defined by the general formula (I) as given below.
Figure imgf000004_0001
(D The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of selective thyroid hormone receptor gene expression. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of obesity and dyslipidemia. PREFERRED EMBODIMENTS The main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of obesity and dyslipidemia. In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
In another embodiment is provided pharmaceutical compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of obesity and dyslipidemia, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals. DETAILED DESCRIPTION:
Accordingly, the present invention relates to compounds of the general formula (I),
Figure imgf000005_0001
(1) wherein R = OR1, NHR1 wherein R1 may be selected from H, optionally substituted groups selected from
Figure imgf000005_0002
ar(C!-C6)alkyl groups; in a preferred embodiment the alkyl groups is selected from (Q-C^alkyl and the aryl group represents optionally substituted phenyl group;
R2 represents hydrogen, hydroxyl, halo, acyl, oxo, optionally substituted groups selected from (CrC6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives selected from (C1 -C3)alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing - CONR5R6 , -SO2NR5R6, wherein
R5 & R6 may be same or different and are independently selected from H, optionally substituted groups selected from (d-C6)alkyl, (C3-C7)cycloalkyl, bicycloalkyl, aryl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
The substituents on R2 may be selected from hydroxy, halo, optionally substituted groups selected from (Q-C^alkyl, phenyl,, heteroaryl groups; In a preferred embodiment, the various groups representing R2 may be selected from
- optionally substituted (Q-C^alkyl, acyl, oxo, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives such as (d-C3)alkyl esters and amides, or the groups representing -CONR5R6 , -SO2NR5R6, wherein R5 and R6 may be same or different and are independently selected from H5 optionally substituted groups selected from (C1- C6)alkyl, (C3-C7)cycloalkyl, bicycloalkyl, phenyl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, O; R3, R4 may be same or different and are independently selected from H, halogen, optionally substituted (Q-C^alkyl groups; X is selected from O, -CH2-, CO; 'n' represents O or 1 ;
R7 represents H, optionally substituted groups selected from (Ci-C6)alkyl, aryl groups; with the provision that when n =0, R7 does not represent 'H'. The substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxyl, halo, cyano, optionally substituted groups selected from (C1-C6)SUCyI, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups. When any of these groups are further substituted, the substituents on these substitutes may be selected from those described above. In a further preferred embodiment the groups, radicals described above may be selected from: the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, wo-propyl, «-butyl, sec-butyl, tert-butyl, amyl, /-amyl, ra-pentyl, n- hexyl, wo-hexyl and the like; the "cycloalkyl" or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; , - the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n~ propoxy, /sø-propoxy, «-butoxy, f-butoxy, wø-butoxy, pentyloxy, hexyloxy, and the like; - the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(d -C6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - the "aryl" or "aromatic" group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
- the "heteroaryl" or "heteroaromatic" group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from
O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
- the "acyl" group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, zso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; the "oxo" or "carbonyl" group used either alone (-C=O-) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=O-) substituted with an alkyl radical described above such as acyl or alkanoyl;
- the "carboxylic acid" group, used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides; - the "ester" group used alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; the "amide" group used alone or in combination with other radicals, represents an aminocarbonyl radical (H2N-C=O-), wherein the amino group is mono- or di- substituted or unsubstituted, more preferably the groups are selected from methylamide, dimethylamide, ethylamide, diethylamide, and the like;
- the "alkylthio" group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted; the "thioalkyl" group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted;
- the "sulfenyl" group or "sulfenyl derivatives" used alone or in combination with other radicals, represents a bivalent group, -SO- or RxSO, where Rx is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above;
- the "sulfonyl" group or "sulfones derivatives" used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -SO2-, or RxSO2-, where Rx is as defined above. More preferably, the groups may be selected from "alkylsulfonyl" wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl" wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
Preferred compounds according to the present invention include but not limited to:
{ [3 ,5-Dichloro-4-(4-hydroxy-3 -isopropyl-phenoxy)-phenyl]-ethoxycarbonyl-amino } - acetic acid; {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid;
{ [4-(3 -Benzyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenylj-ethoxycarbonyl-amino } -acetic acid; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid;
( { 3 ,5 -Dichloro-4-[4-hydroxy-3 -(piperidine- 1 -carbonyl)-phenoxy]-phenyl } - ethoxycarbonyl-amino)-acetic acid;
{[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid;
{[3,5-Dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid;
( { 3 ,5 -Dichloro-4- [4-hy droxy-3 -(4-methyl-piperazine- 1 -carbonyl)-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid; { [3,5-Dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid;
{[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-hydroxy-phenoxy)-ρhenyl]- ethoxycarbonyl-amino} -acetic acid;
{ [3 ,5-Dichloro-4-(4-hy droxy-3 -propyl-phenoxy)-phenyl] -ethoxycarbonyl-amino } - acetic acid;
{[3,5-Dichloro-4-(4-hydroxy-3-isopropylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid;
{[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid; {[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid;
({3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid;
{[3,5-Dichloro-4-(3-diethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid;
({3,5-Dichloro-4-[3-(5-chloro-thiophene-2-carbonyl)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid; {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-ethoxycarbonyl-amino}- acetic acid;
{[3,5-Dichloro-4-(4-hydroxy-3-phenylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyI- amino} -acetic acid; ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid;
{[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyI]-carboxymethyl-amino}- acetic acid;
({3,5 -Dichloro-4- [3 -(2,4-dichloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid;
[[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
({4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid; ( { 3 ,5-Dichloro-4- [3 -(3 -chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } -ethoxycarbonyl- amino)-acetic acid;
{[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-carboxymethyl-atnino}- acetic acid;
({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- carboxymethyl-amino)-acetic acid;
(Carboxymethyl-{3,5-dichIoro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- amino)-acetic acid;
(Carboxymethyl-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]- phenyl}-amino)-acetic acid; ({4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- carboxymethyl-amino)-acetic acid;
{Carboxymethyl-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-amino}- acetic acid;
[[355-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-atnino]-acetic acid;
(Carboxymethyl-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-l-sulfonyl)-phenoxy]- phenyl}-amino)-acetic acid; { [4-(3 -tert-Butyl-4-hydroxy-phenoxy)-3 ,5-dichloro-phenyl]-carboxymethyl -amino } - acetic acid;
[[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4'hydroxy- phenoxycarbonyl)-amino] -acetic acid; {Carboxyraethyl-[3,5-dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- amino} -acetic acid;
{Carboxymethyl-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-amino}- acetic acid;
[[3,5-Dichloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[{355-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; [ { 3 ,5 -Dichloro-4- [4-hy droxy-3 -(piperidine- 1 -sulfonyl)-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[4-(4-Hydroxy-3-ϊsopropyl-phenoxy)-3,5-dimethyl-pb.enyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[{4-[3-(4-tert-JButyI-benzoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4-hydroxy- phenoxycarhonyl)-amino]-acetic acid;
[{3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[3,5-Dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; {Carboxymethyl-[3 ,5-dichloro-4-(3 -ethyl-4-hydroxy-phenoxy)-phenyl]-amino } -acetic acid;
[{3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
[[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy-phenoxycarbonyl)- amino] -acetic acid;
[[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; [[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; [{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-
(4-hydroxy-phenoxycarbonyl)-amino]-acetic acid;
[{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dibromo-phenyl}-
(4-hydroxy~phenoxycarbonyl)-aminoJ-acetic acid;
[ { 3 ,5 -Dichloro-4- [4-hydroxy-3 -(4-hydroxy-benzoyl)-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[{3,5-Dichloro~4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyI}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[(3,5-Dichloro-4-{3-[(4-chloro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-(4-hydroxy-phenoxycarbonyl)-amino]-acetic acid; [{4-[3-(Azepane-l-sulfonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
({3,5-Dichloro-4-[3-(l-etliyl-propoxy)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid;
[[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyI-phenyI]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[ \ 3 ,5 -Dichloro-4-(3 -cyclohexylsuIfanioyl-4-hydroxy-phenoxy)-phenyl] -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycai'bonyl)-amino] -acetic acid; ({3,5 -Dicliloro-4-[4-hydroxy-3 -(3 -methyl-benzoyl)-phenoxy] -phenyl } -ethoxycarbonyl- amino)-acetic acid;
[ { 3 ,5 -Dichloro-4- [4-hydroxy-3 -(pyrrolidine- 1 -sulfonyl)-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
{ [3 ,5 -Dichloro-4-(4-hydroxy-3 -isobutoxy-phenoxy)-phenyl] -ethoxycarbonyl-amino } - acetic acid;
{[3,5-Dichloro-4-(3-cyclohexylmethoxy-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid; [ { 3 ,5 -Dichloro-4- [4-hydroxy-3 -(3 -methyl-benzoyl)-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
[{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; ({335-Dibromo-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-elhoxycarbonyl- amino)-acetic acid;
({355-Dichloro-4-[4-hydroxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyO-aminoj-acetic acid;
{[3,5-Dichloro-4-(3-isopropyl-4-methoxy-ρhenoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
{ [4-(4-Benzyloxy-3 -isopropy l-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbonyl-araino } - acetic acid ethyl ester; { [4-(3 -sec-Butyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbonyl-amino } - acetic acid ethyl ester;
{[4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyI}- ethoxycarbonyl-aminoj-acetic acid ethyl ester;
( { 3 ,5-Dichloro-4- [4-methoxy-3 -(piperidine- 1 -carbonyl)-phenoxy]-phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyI]-ethoxycarbonyl-amino}-acetic acid ethyl ester; {[3,5-Dichloro-4-(3-cyclohexylcarbamoyl-4-methoxy-phenoxy)-phenyI]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
({3,5-Dichloro-4-[4-methoxy-3-(4-methyl-piperazine-l-carbonyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino}-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester; { [3 ,5-Dichloro-4-(4-methoxy-3 -propyl-phenoxy)-phenyl] -ethoxycarbonyl-amino } - acetic- acid ethyl ester;
{[3,5-Dichloro-4-(3-isopropylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester; {[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
{[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
( { 3 ,5 -Dichloro-4- [3 -(4-fluoro-benzoy ϊ)-4-methoxy-phenoxy] -phenyl } -ethoxycarbonyl- amino)-acetic acid ethyl ester;
{[335-Dichloro-4-(3-diethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester;
( { 3 ,5 -Dichloro-4- [3 -(5 -chloro-thiophene-2-carbonyl)-4-methoxy-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester; { [4-(3-sec-Butyl-4-methoxy-phenoxy)-3 ,5 -dimethyl-phenyl] -ethoxycarbonyl-amino } - acetic acid ethyl ester;
{[3,5-Dichloro-4-(4-methoxy-3-phenylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid ethyl ester;
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-355-dimethyl-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(2,4-dichloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester; [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
( {4- [3 -(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy]-3 ,5-dichloro-phenyl} - ethoxycarbonyl-amino)-acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid ethyl ester;
{ [4-(3-sec-Butyl-4-methoxy-phenoxy)-3 ,5-dichloro-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbόnylmethyl-amino)-acetic acid ethyl ester; ({3,5 -Dichloro-4- [4-methoxy-3 -(piperidine- 1 -carbony l)-phenoxy] -phenyl } - ethoxycarbonylmethyl-aminoj-acetic acid ethyl ester;
({4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonylmethyl-amino)-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester;
[[3,5 -Dichloro-4-(3 -isopropyl-4-methoxy-phenoxy)-phenyl] -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
( { 3 ,5-Dichloro-4-[4-methoxy-3 -(piperidine- 1 -sulfonyl)-phenoxy]-phenyl } - ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; {[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester;
[[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; {P-S-Dichlona^^S-dimethylcarbamoyl^-methoxy-phenoxy^-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester;
{Ethoxycarbonylmethyl-[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]- amino} -acetic acid ethyl ester;
[ [3 ,5 -Dichloro-4-(3 -dimethylsulfamoyl-4-methoxy-phenoxy)-phenyl] -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[ { 3 ,5-Dichloro-4- [4-methoxy-3 -(piperidine- 1 -carbony l)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[{3,5-Dichloro-4-[4-methoxy-3-(piperidine-l-sulfonyl)-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[[4-(3-Isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [{4-[3-(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[ { 3 ,5 -Dichloro-4- [3 -(4-chloro-benzoyl)-4-methoxy-phenoxy] -phenyl } -(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; [[3,5-Dichloro-4-(3-isopropylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester;
[{3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[[3,5 -Dichloro-4-(3 -ethyl-4-methoxy-phenoxy)-phenyl] -(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; [ [4-(3 -Benzyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl] -(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[ {4-[3 -(Bicy.ck>[2.2.1 ]hcpt-2-ylsulfamoyl)-4-methoxy-phenoxy]-3 ,5-dichloro-phenyl } - (4-methoxy-phenoxycarborryl)-amino] -acetic acid ethyl ester;
[ {4-[3 -(Bicyclo [2.2.1 ]hept-2-ylsulfamoyl)-4-methoxy-phenoxy]-3 ,5-dibromo-phenyl } -
(4-methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[{3,5 -Dichloro-4- [4-methoxy-3 -(4-methoxy-benzoyl)-phenoxy] -phenyl } -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[{4-[3-(Azepane-l-sulfonyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
({4-[4-Benzyloxy-3-(l-ethyl-propoxy)-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
[[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [[3,5-Dichloro-4-(3-cyclohexylsulfanioyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[ { 3 ,5-Dichloro-4-[4-methoxy-3 -(morpholine-4-sulfonyl)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester; ( { 3 ,5-Dichloro-4-[4-methoxy-3 -(3-methyl-benzoyl)-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester;
[ { 3 ,5 -Dichloro-4- [4-methoxy-3 -(pyrrolidine- 1 -sulfonyl)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)~amino]-acetic acid ethyl ester;
{ [4-(4-Benzyloxy-3 -isobutoxy-phenoxy)-3 ,5 -dichloro-phenylj-ethoxycarbonyl-amino } - acetic acid ethyl ester;
{[4-(4-Benzyloxy-3-cyclohexylmethoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonyl-amino}-acetic acid ethyl ester;
[{3,5 -Dichloro-4-[4-methoxy-3 -(3 -methyl-benzoyl)-phenoxy] -phenyl} -(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; [{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
({3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid ethyl ester;
({3,5-Dichloro-4-[4-methoxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-aminoj-acetic acid ethyl ester;
[ {3 ,5-DichloiO-4-[4-methoxy-3 -(4-methyl-benzoyl)-phenoxy] -phenyl} -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
The compounds of this invention may be prepared using the reactions and techniques described in the following section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be appreciated that some routine alterations/modifications including requirement of one or more additional steps which may be required for obtaining the compounds of the present invention in preferred yields but are considered to be within the scope of a person skilled in the art, are to be considered to be within the scope of the present invention. Scheme: 1
R7 = Alkyl (Ak), n=0
Figure imgf000018_0001
'Ak1 represents suitable alkyl group
The biaryl ether of formula 2 wherein 'PG'' represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3. Reduction may be carried out using suitable reducing agents such as Raney Ni, Pd/C, SnCl2.2H2O and the like. This amine 3 may be reacted with suitable alkyl haloacetate in suitable base(s) such as diisopropyl ehtylamine (1Pr2-NEt), pyridine, N5N dimethyl aniline or like in solvents selected from DMF5THF and the like or their mixtures to give a compound of formula 4. Further compound of formula 4 was refluxed in suitable alkyl haloformate to give compound of formula 5. Suitable deprotection and hydrolysis of compound of formula 5 gives compound of formula (I)
Scheme: 2 R7 = alkyl, R2 = COAr, n =0
Figure imgf000019_0001
'Ak' represents suitable alkyl group
The biaryl ether of formula 2 wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G.
M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd ft
Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3. Reduction may be carried out using reducing agents such as Raney Ni, Pd/C, SnCl2.2H2O and the like. This amine 3 may be reacted with suitable alkyl haloacetate in suitable base such as iPr2-NEt, pyridine, N5N dimethyl aniline or like in suitable solvent(s) such as DMF5THF and the like or their mixtures to give a compound of formula 4. Further compound of formula 4 was refluxed in suitable alkyl haloformates to give compound of formula 5. Compound of Formula 5 was reacted with suitable aromatic acids or suitable aromatic acid chloride and appropriate acylating agents to obtain compound of Formula 6. Deprotection and hydrolysis of compound of formula 6, using suitable reagents & techniques as is known in the art, gives compound of formula (1}
Scheme: 3
R7 = Aryl, n=0
Figure imgf000020_0001
The biaryl ether of formula 2 wherein 'PG' represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3. Reduction may be carried out using suitable reducing agents such as Raney Ni, Pd/C, SnCl2.2H2θ and the like. This amine 3 may be reacted with suitable alkyl haloacetates in suitable base(s) such as iPr2-NEt, pyridine, N5N dimethyl aniline and the like in suitable solvents such as DMF5THF or their suitable mixtures to give a compound of formula 4 Further compound of formula 4 was reacted with ClCOOAr in suitable base such as pyridine, NEt3 and the like in suitable solvents such as dichloromethane, chloroform and the like or their suitable mixtures to give compound of formula 5. Deprotection and hydrolysis of compound of formula 5 by techniques and reagents known in the art gives compound of formula (I) Scheme: 4 R7=H, (when 'n' =1)
k
Figure imgf000021_0001
The biaryl ether of formula 2 wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3 rd Ed., 201-245 along with references therein), and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 3. Reduction may be carried out using suitable reducing agents such as Raney Ni, PdVC, SnCl2^H2O and the like. This amine 3 may be reacted with suitable alkyl halo acetates in suitable base such as iPr2-NEt, pyridine, N5N dimethyl aniline and the like in suitable solvents such as DMF5THF and the like to give a compound of formula 4 Again compound of formula 4 was reacted with suitable alkyl halo acetates in suitable base such as iPr2-NEt, pyridine, N5N dimethyl aniline and the like in suitable solvent(s) such as DMF5THF and the like or their suitable mixtures to give a compound of formula 5. Deprotection and hydrolysis of compound of formula 5 by techniques and reagents known in the art gives compound of formula QQ The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. As will be clear from the specification, few different subclasses of compounds within the single general formula (I) have been described. These different subclasses can be prepared by suitable modifications/alterations of one or two of the general processes described in the schemes. Example 2, Example 23, Example 26 and Example 20 each describe in detail processes of preparing compounds of each of the general sub classes. After describing actual processes for preparing compounds of each sub class, characterization data of all the compounds prepared have been provided in random order. However, all the compounds can be prepared by following one of the three processes described earlier with suitable changes as may be specific to the compounds.
IH NMR spectral data given in the examples (vide infra) are recorded using either a 300 MHz spectrometer (Bruker AVANCE-300) or a 400 MHz spectrometer (Bruker Avance2) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCIs using tetramethyl silane as the internal standard. EXAMPLE 2
Preparation of {[4-(3-sec-ButyI-4-hydroxy-phenoxy)-3,5-dichIoro-phenyI]- ethoxycarbonyl-amino}-acetic acid Step 1 : Preparation of 4-(3- sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine To a solution of Stannous chloride dihydrate (194.6 g, 0.86 mol) in concentrated HCl (80.0 mL) was added to 3, 5-dichloro-4-(4'-methoxy-3 -sec-butyl - phenoxy)nitrobenzene (80 g, 0.21 mol) in EtOH (400 mL).The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30 0C and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 4-(3-sec-Butyl-4-methoxy- phenoxy)-3,5-dichloro-phenylamine (71.8 g; 98 % yield).
Step 2: [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester
To 4-(3- sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (71.8 g, 0.21 mol) was added ethyl bromoacetate (35.26 g, 0.21 mol) and diisopropylethyl amine (27.92 g, 0.21 mol) in DMF (718 mL ) were stirred at 120 0C for 18 h. The reaction mixture was poured in to ice-water . The product was taken up in ethyl acetate, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography over flash silica gel (Hexane : Ethylacetate 90:10) to afford the pure product [4-(3-sec-Butyl-4- methoxy-phenoxy)-3, 5 -dichloro-phenylamino] -acetic acid ethyl ester.( 48.0 g, 54 % yield )
Step 3 : {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester
[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (0.9 g, 2.1 mmol) was stirred with ethyl chloroformate ( 8 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with H2O, brine and dried over sodium sulphate, filtered and concentrated to give {[4-(3-sec-butyl-
4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester.( 0.8 g, 76 % yield)
Step 4 : {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino} -acetic acid.
A solution of {[4-(3-sec-butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester (0.8 g, 1.6 mmol) in CH2Cl2 (16 mL) was cooled to -60 °C under nitrogen atmosphere. To that IM BBr3 solution (4.8 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 5 h. then diluted with more CH2Cl2 (25 mL) and quenched with H2O. After stirring at 20-25
0C for 30 min, organic phase was separated, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (Hexane : Ethylacetate 90:10) to afford the pure product {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonyl-arnino} -acetic acid ethyl ester. (0.77 g, 99 % Yield)
The ester (0.77 g, 1.5 mmol) was dissolved in MeOH (18 mL) and to it a solution of NaOH ( 0.19g, 4.75 mmol) in H2O (5.6 mL) was added and it was stirred at 60 0C for 1 hr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. Aqueous layer was acidified to pH 4 using 10 % HCl solution and extracted with ethyl acetate The organic layer was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 0.75 g of crude product The crude product was purified by column chromatography (Silica gel, Chloroform : Methanol) gradient elution from 95:5 to 90:10 to give pure {[4~(3-sec-Butyl-4~hydroxy- phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid.(0.125 g, 18 % yield)
EXAMPLE 23
Preparation of [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5~dichIoro-phenyl]-(4- hydroxy-phenoxycarbonyl)-amino] -acetic acid t.
Step 1 : Preparation of [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4- methoxy-phenoxycarbonyO-aminoj-acetic acid ethyl ester
A solution of [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]- acetic acid ethyl ester (Example 2, step2) (5.0 g, 0.01 mol) in CH2Cl2 (30 mL) was cooled to 0-5 0C under nitrogen atmosphere. To the solution 4-methoxy phenyl chloroformate (8.75 g, 0.046 mol) in CH2Cl2 (20 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 3 h., diluted further with more CH2Cl2 (25 mL) and quenched with water. After stirring at 20-25 0C for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography over flash silica gel (hexane: ethyl acetate 90:10) to afford the pure product [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester (6.4 g, 95 % yield) Step 2: Preparation of [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid
To a solution of [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4- methoxy-phenoxycarbonyO-aminoj-acetic acid ethyl ester (6.4 g, 0.01 mol) in CH2Cl2
(128 mL) was cooled to -60 0C under nitrogen atmosphere. To that IM BBr3 (boron tribromide) solution (44.44 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 5 h. then diluted with more CH2Cl2 (30 mL) and quenched with H2O. After stirring at 20-25 0C for 30 min, organic phase was separated, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel
(chloroform : methanol) gradient elution from 95:5 to 90:10 to give pure [[4-(3-sec- Butyl-4-hydroxy-phenoxy)-3,5-dichloro-ρhenyl]-(4-hydroxy-phenoxycarbonyl)-aminoj- acetic acid (3.3 g, 58 % yield)
EXAMPLE 26
Preparation of {[4-(3-sec-ButyI-4-hydroxy-phenoxy)-3,5-dichIoro-phenyl]- carboxymethyl-amino} -acetic acid
Step 1 : Preparation of {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester
To [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester (Example 2, step2) (48.0 g, 0.11 mol), ethyl bromoacetate (188 g, 1.12 mol) and diisopropylethylamine (145.57 g, 1.12 mol) in DMF (480 mL) were stirred at 120
0C for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10 ) to give pure {[4-(3-sec-Butyl-4- methoxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbonylmethy 1-amino } -acetic acid ethyl ester ( 27.1 g, 47 % yield ).
Step 2: Preparation of {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- carboxymethyl-amino} -acetic acid To a solution of {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester (12.5 g, 0.02 mol) in CH2Cl2 (250 mL) was cooled to -60 0C under nitrogen atmosphere. To that IM BBr3 solution (122 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 5 h. then diluted with more CH2Cl2 (250 mL) and quenched with H2O. After stirring at 20-25 0C for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (chloroform : methanol) gradient elution from 95:5 to 90:10 to give pure {[4-(3-sec-Butyl-4- hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -carboxymethyl-amino } -acetic acid (6.8 g, 63 % yield) EXAMPLE 20
Preparation of ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]- phenyl}-ethoxycarbonyl-amino)-acetic acid Step 1 : 3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine
To a solution of stannous chloride dihydrate (32.38 g, 0.14 mol) in concentrated HCl (11 mL) was added 3,5-dichloro-4-(4-methoxy-phenoxy)nitrobenzene (11.3 g, 0.03 mol) in EtOH (56.5 mL).The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30 0C and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give 3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g; % Yield: 99 % ). Step 2: [3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester
3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g, 0.03 mol), ethyl bromoacetate (5.39 g, 0.03 mol) and diisopropylethylamine (5.1 g, 0.03 mol) in 50 mL of DMF were stirred at 120 0C for 18 h. The reaction mixture was poured in to ice- water . The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel, (hexane : ethyl acetate 90:10) to afford pure [3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester. (10.0 g, 76 % yield)
Step 3 : {[3}5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester
[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester (10.0 g, 0.02 mol) was stirred with ethyl chloroformate (95 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give {[3,5-Dichloro-4-(4-methoxy- phenoxy)-phenyl]-ethoxycarbonyl-amino} -acetic acid ethyl ester ( 7.25 g, 61 % Yield) Step 4 : ({3,5 -Dichloro-4-[3 -(4-chloro-benzoyl)-4-methoxy-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester A mixture of {[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino}-acetic acid ethyl ester (7.25 g, 0.016mol) and 4-chlorobenzoic acid (5.13 g, 0.03 mol) in Eaton's reagent (25 mL) was heated at 60 0C for 16 h. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethylacetate 90:10) to afford pure ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]- phenyl}-ethoxycarbonyl-amino)-acetic acid ethyl ester. (3.36 g, 36 % yield) Step 5 : Preparation of ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]- phenyl } -ethoxycarbonyl-amino)-acetic acid
A solution of {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester (3.36 g, 5.7 mmol) in CH2Cl2 (67 rnL) was cooled to -60 0C under nitrogen atmosphere. To that IM BBr3 solution (11.57 mL) was added dropwise. The reaction mixture was stirred at -40 to -60 0C over 0.5 to
1 h. then diluted with more CH2Cl2 (50 mL) and quenched with H2O. After stirring at
20-25 0C for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography silica gel (hexane : ethyl acetate 90:10) to afford the pure product ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid ethyl ester. ( 2.27 g, 70 % Yield)
The ester (2.27 g, 4.0 mmol) was dissolved in MeOH (14 mL) and to that solution of NaOH (0.48g, 12 mmol) in H2O (7 mL) was added and it was stirred at 60 0C for lhr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. The aqueous layer was acidified to pH 4 using 10 % HCl solution and extracted with ethyl acetate The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give pure product ({3,5- Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid. (1.7 g, 79 % yield) Using appropriate starting materials and suitable modifications of one or more of the processes described above, either alone or in suitable combination of the steps disclosed therein, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art, the following compounds were prepared in an analogous manner. EXAMPLE 1
{[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid 1H NMR : (CDCl3, 300MHz) : 1.22-1.25(9H, m), 3.18(1H, m), 4.22-4.24(2H, m),
4.37(2H, s) 6.39(1H, m), 6.61-6.64(1H, d, J=8.7Hz), 6.85(1H, s), 7.39(2H, s)
% Yield: 18 %
EXAMPLE 2 { [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenylj-ethoxycarbonyl-amino } - acetic acid
1H NMR : (CDCl3, 300MHz) : 0.86(3H, t, J=7.35Hz), 1.21(3H5 d, J=6.9Hz)5 1.22-
1.26(2H, m), 1.55-1.57(3H, m), 2.89-2.94(1H, m)5 4.22-4.24(2H5 m), 4.38(2H, s), 6.40-
6.41(1H, m), 6.64(1H, d, J=9Hz), 6.78(1H5 d, J=2.88Hz), 7.38(2H, s) % Yield: 18 %
EXAMPLE 3 {[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid
1H NMR : (DMSO-D6, 300MHz) : 1.15(3H, t, J=7.05Hz), 3.82(2H, s), 4.11(4H, m), 6.61(1H, m), 6.7O(1H, m), 6.73(1H, m), 7.18-7.25(5H, m), 7.54(2H3 s)
% Yield : 25 %
EXAMPLE 4
({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid 1H NMR : (DMSO-D6, 300MHz) : 1.15-1.19(7H, m), 1.47-1.71(4H, m), 2.21-2.26(2H, m), 3.72(1H, bs), 4.09-4.16(2H, q5 J=6.96Hz & 7.02Hz), 4.34(2H, s), 6.68-6.72(1H, dd,
J=2.94Hz & 8.94 Hz)5 6.85(1H, d, J=8.94Hz)5 7.58(2H5 s), 7.66(1H, d, J=2.85Hz)
% Yield : 86 %
EXAMPLE 5 ({3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid
1H NMR : (DMSO-D6 300MHz) : 1.15(3H, t, J=7Hz), 1.43(4H5 m), 1.54(2H, m)5 3.14(4H5 m)5 4.06-4.14(2H5 m), 4.34(2H5 s), 6.46(1H5 d5 J=2.94Hz); 6.72-6.83(2H, m), 7.55(2H, s) % Yield : 80 % EXAMPLE 6
{[355-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl-aniino}-acetic acid 1H NMR: (DMSO-D6, 300MHz): 1.07(3H, t, J=7.47Hz), 1.15(3H, t, J=7.02Hz), 2.48-
2.52(2H5 m), 4.06-4.13(2H, q, J=6.87Hz & 7.02Hz), 4.31(2H, s), 6.32-6.36(1H, dd,
J=3.15Hz & 8.79Hz), 6.62(1H5 d, J=3Hz), 6.67(1H, d5 J=8.7Hz)5 7.54(2H, s)
% Yield : 38 % EXAMPLE 7
{[355-Dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid
1H NMR : (DMSO-D6 300MHz) : 1.16(3H, t, J=6.9Hz)5 1.2-1.3(6H, m), 1.5-1.6(4H, m), 3.78(1H, m), 4.07-4.14(2H, q, J=6.93Hz & 6.99Hz), 4.30(2H, s), 6.69-6.73(1H5 dd, J=3.03Hz & 9.06Hz), 6.85(1H, d, J=9Hz), 7.57(3H, s)
% Yield : 39 % EXAMPLE 8
({3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-piperazine-l-carbonyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid 1H NMR : (CD3OD5 300MHz) : 1.23(3H, t, J=7.67Hz), 2.92(3H5 s), 3.29(4H5 m),
3.71(4H5 m)5 4.16-4.23(2H5 q5 J-6.78Hz & 7.02Hz)5 4.35(2H5 s), 6.71(1H, m), 6.85(2H5 m), 7.52(2H5 s)
% Yield: 59 % EXAMPLE 9 { [3 ,5-Dichloro-4-(3 -dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl] -ethoxycarbonyl- amino} -acetic acid
1U NMR : (CD3OD5 300MHz) : 1.25(3H5 m), 2.97(6H5 s)5 4.18-4.20(2H5 m), 4.35(2H5 s),
6.6(1H5 m)5 6.8(2H5 m)5 7.51(2H5 s) % Yield : 77 % EXAMPLE 10
{[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid
1H NMR : (DMSO-D6, 300MHz) : 1.16(3H, t5 J=7Hz), 1.67-1.69(2H, m), 2.03- 2.09(2H, m)5 2.20(2H, m), 3.14(1H5 m), 4.07-4.14(2H5 q5 J=6.7Hz & 6.7Hz)5 4.33(2H5 s), 6.72-6.75(1H5 m)5 6.85(1H5 d, J=9Hz), 7.57(3H5 m) % Yield : 72 % EXAMPLE 11
{[3,5-Dichloro-4-(4-hydroxy-3-propyl-phenoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid
1H NMR : (DMSO-D6, 300MHz) : 0.85(3H, t, J=7.33Hz), 1.15(3H, t, J=7.02Hz), 1.47- 1.49(2H5 m), 2.48-2.49(2H, m), 4.07-4.09(2H, m), 4.17(2H, s), 6.37-6.40(1H, m),
6.56(1H, d, J=3Hz), 6.68(1H, d, J=8.79Hz), 7.55(2H, s)
% Yield : 10 % EXAMPLE 12
{[3,5-Dichloro-4-(4-hydroxy-3-isopropylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid
1H NMR : (DMSO-D6, 300 MHz) : 1.14-1.22(9H, m), 2.52(1H, m)5 4.07-4.14(2H5 m),
4.34(2H, s), 6.69-6.73(1H5 dd, J=3Hz & 8.94Hz), 6.84(1H5 d, J=9Hz), 7.57(2H5 s),
7.60(1H5 d, J=3.06Hz)
% Yield : 74 % EXAMPLE 13
{[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid
1H NMR: (DMSO-D6, 300MHz): 1.15(3H, t, J=6.90Hz), 1.29(9H5 s), 4.06-4.13(2H5 q,
J=6.87Hz & 6;99Hz), 4.28(2H, s), 6.29(1H, d, J=5.99Hz)5 6.66(1H5 d, J=8.71Hz), 6.73(1H5 m), 7.54(2H5 s)
% Yield : 25 % EXAMPLE 14
{[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid 1H NMR : (DMSO-D6, 300MHz) : 1.14(3H, t, J=7Hz), 4.05-4.12(2H5 q, J=6.93Hz &
7.14Hz)5 4.22(2H5 s)5 6.6O-6.64(1H, dd, J=3.3Hz & 8.7Hz), 6.7O(1H, d, J=2.8Hz),
6.89(1H, d, J=8.7Hz), 7.28-7.30(1H, m), 7.34-7.39(2H5 m), 7.46-7.48(2H5 m), 7.56(2H5 s)
% Yield : 20 % EXAMPLE 15
({3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid 1H NMR : (DMSO-D6, 300MHz) : 1.11(3H, t, J=6.04Hz), 4.05-4.12(2H, q, J=7.11Hz & 7.11Hz), 4.23(2H, s), 6.72(1H, m>, 6.94(2H, m), 7.30-7.35(2H, m), 7.56(2H, s), 7.73-7.78(2H, m) % Yield : 81 % EXAMPLE 16
{[3,5-Dichloro-4-(3-diethylcarbanioyl-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid
1H NMR : (CDCl3, 300MHz) : 1.15(6H, t, J=6.99Hz), 1.26(3H, m), 3.40-3.49(4H, m), 4.21-4.24(2H, q, J=7.14Hz & 7.14Hz), 4.37(2H, s), 6.60(1 H, m), 6.95-6.98(2H, m), 7.40(2H, s) % Yield: 87 % EXAMPLE 17
( { 3 ,5 -Dichloro-4- [3 -(5 -chloro-thiophene-2-carbony l)-4-hydroxy-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid 1H NMR : (DMSO-D6, 300MHz) : 1.13(3H, t, J=6.7Hz), 4.03-4.10(2H, q, J=6.96Hz & 7.23Hz), 4.13(2H, s), 6.76(1H5 d, J=2.4Hz), 6.89-6.97(2H, m), 7.25(1H, d, J=3.9Hz), 7.38(1H, d, J=4.2Hz), 7.57(2H, s) % Yield: 81 % EXAMPLE* ft,- {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-ethoxycarbonyl-amino}- acetic acid
1H NMR: (DMSO-D6, 300MHz) : 0.74(3H, t, J=7.2Hz), 1.06(3H, d, J=6.8Hz), 1.13- 1.18(3H, m), 1.41-1.49(2H5 m), 2.00(6H, s), 2.71-2.95(1H, m), 4.00-4.05(2H5 m), 4.18(2H5 s), 6.22(1H5 d, J=6.3Hz)5 6.54(1H, m), 6.64(1H5 d, J=8.7Hz)5 7.04(2H5 s) % Yield : 90 % EXAMPLE 19
{[3,5-Dichloro-4-(4-hydroxy-3-phenylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid
1H NMR : (CDCl3, 300MHz) : 1.28(3H5 1, J=7.17Hz), 4.21-4.25(2H5 m). 4.39(2H, s), 6.91-6.98(1H, m), 7.13(1H5 m). 7.21-7.26(2H5 m), 7.37-7.42(4H5 m), 7.55-7.57(2H5 d, J=7.8Hz) % Yield : 91 % EXAMPLE 20 ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid
1H NMR : (CDCl3, 300MHz) : 1.25-1.33(3H, m), 4.21-4.24(2H, m), 4.36(2H, s), 7.01- 7.08(3H, m), 7.38(2H5 m), 7.46(2H5 d, J=8.43Hz), 7.63(2H5 d, J=8.43Hz) % Yield : 79 % EXAMPLE 21
{ [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dimethyl-phenyl] -carboxymethy 1-aniino } - acetic acid
1H NMR : (DMSO-D6, 300MHz) : 0.75(3H5 1, J=7.2Hz), 1.06(3H, d, J=6.6Hz)5 1.13- 1.44(2H5 m), 1.96(6H, d, J=8.7Hz)5 2.84-2.91(1H5 m), 4.01(4H5 s), 6.15-6.21(3H, m), 6.45-6.62(2H5 m) % Yield : 75 % EXAMPLE 22
({355-Dichloro-4-[3-(2,4-dichloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid
1H NMR : (CDCl3, 300MHz) : 1.25-1.28(3H, m), 4.22-4.25(2H5 m), 4.36(2H, s), 6.78(1H5 m), 7.00(2H, m)5 7.32-7.36(3H5 m), 7.49(2H5 s) % Yield : 15 % EXAMPLE 23 [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (DMSO-D6, 300MHz) : 0.75(3H5 1, J=7.2Hz)5 1.07(3H, d, J=6.9Hz), 1.40- 1.53(2H5 m), 2.89-2.96(1H, m), 4.44(2H5 s), 6.29-6.32(1H5 dd5 J=3.3Hz & 8.7Hz ), 6.57(2H5 d5 J=8.7Hz)5 6.65(2H5 d5 J=3.3Hz)5 6.92(2H5 d5 J=9Hz), 7.82(2H5 s) % Yield : 58 % EXAMPLE 24
({4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-355-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid
1H NMR : (CDCl3, 300MHz) : 1.25(3H5 m)5 1.36(9H5 s), 4.21-4.24(2H5 m)5 4.35(2H5 S)5 6.97-7.02(3H5 m), 7.37(2H5 s), 7.51(2H, d, J=8.3 IHz)5 7.66(2H5 d, J=8.28Hz) % Yield : 64 % EXAMPLE 25 ({3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid
1H NMR: (DMSO-D6, 300MHz): 1.14(3H, t, J=7.02Hz), 4.06-4.13(2H, q, J=6.87Hz & 6.99Hz), 4.32(2H5 s), 6.75(1H, m), 6.94-7.02(2H, m), 7.53(3H, m), 7.61 (2H, d, 1=1.17Hz), 7.69(1 H, d, J=7.59Hz) % Yield: 43 % EXAMPLE 26
{[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-carboxymethyl-amino}- acetic acid 1H NMR : (DMSO-D6, 300MHz) : 0.76(3H, t, J=7.23Hz)5 1.07(3H, d, J=6.9Hz), 1.45- 1.52(2H, m), 2.90-2.92(1H5 m), 3.98(4H5 bs), 6.22(1H, m), 6.45(2H, s), 6.62-6.65(2H, m)
% Yield : 63 % EXAMPLE 27 ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-ρhenyl}- carboxyniethyl-amino)-acetic acid
1H NMR : (DMSO-D6, 300MHz) : 1.10-1.21(4H5 m), 1.46(4H, d, J=7.5Hz), 2.21(2H5 d), 3.7O(1H, m), 4.11(4H5 s), 6.62(2H, d, J=4Hz)5 6.81(1H5 d, J=9Hz), 7.60(1H5 d, J=2.7Hz), 8.43(1H5 d5 J=8.8Hz) % Yield : 43 % EXAMPLE 28
(Carboxymethyl-{355-dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- amino)-acetic acid
1H NMR : (DMSO-D6, 300MHz) : 4.12(4H, s), 6.66-6.70(3H5 m), 6.90(2H5 s), 7.57(2H5 d5 J=8.55Hz)5 7.68(2H5 d, J=8.58Hz) % Yield : 81 % EXAMPLE 29
(Carboxymethyl-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]- phenyl}-amino)-acetic acid 1H NMR : (DMSO-D6, 300MHz) : 1.43(4H5 bs), 1.54(2H5 bs), 3.15(4H5 m), 3.97(4H, s), 6.40(1H5 m), 6.47(2H5 s), 6.67(1H5 m), 6.78(1H5 d, J=8.82Hz) % Yield : 32 % EXAMPLE 30 ({4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- carboxyrnethyl-amino)-acetic acid
1H NMR : (DMSO-D6, 300MHz) : 1.22-1.28(6H, m), 1.42-1.45(2H5 m), 2.07(2H, m), 3.49(1H, s), 3.98(4H, s), 6.48(2H, m), 6.91(3H5 m) % Yield : 26 % EXAMPLE 31
{ Carboxymethyl- [355-dichloro-4-(4-hydroxy-3 -isopropyl-phenoxy)-phenyl] -amino } - acetic acid
1H NMR : (DMSOD6, 300MHz) : 1.10(6H, d5 J=8.8Hz), 3.08-3.17(1H5 m), 4.14(4H5 s), 6.19-6.23(1H5 dd, J=3Hz & 8.7Hz)5 6.62-6.67(4H5 m) % Yield : 41 % EXAMPLE 32
[[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid 1H NMR : (CDCl3, 300MHz) : 1.22-1.28(6H5 m)5 3.14-3.19(1H5 m), 4.46(2H5 s), 6.35- 6.38(1H5 m)5 6.59-6.62(1H5 m)5 6.76-6.79(2H, m), 6.87(1H5 m)5 6.98(2H5 d, J=8.7Hz)5 7.49(2H5 s) % Yield: 16 % EXAMPLE 33 (Carboxymethyl-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-l-sulfonyl)-phenoxy]- phenyl}-amino)-acetic acid
1H NMR : (CDCl3, 300MHz) : 1.25(2H5 m)5 1.62(4H5 m), 3.01(4H, m), 4.23(4H5 s), 6.60(2H5 s), 6.83(1H, m), 7.00(1H5 m), 7.05(1H5 m) % Yield: 10 % EXAMPLE 34
{ [4-(3 -tert-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -carboxymethyl-amino } - acetic acid
1H NMR : (DMSO-D6, 300MHz) : 1.29(9H, s)5 4.14 (4H5 s), 6.2O-6.24(1H, dd, JM2.87HZ & 8.65Hz)5 6.63 (IH, d, J=8.73Hz), 6.67(2H5 s), 6.73(1H, d5 J=2.87Hz) % Yield: 12 % EXAMPLE 35
[[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid 1H NMR: (CDCl3, 300MHz) : 1.38(9H, s), 4.45(2H5 s), 6.3O-6.32(1H, m), 6.49- 6.52(1H, m), 6.71-6.77(2H, m), 6.95-6.99(3H, m), 7.60(2H, s) % Yield : 98 % EXAMPLE 36 {Carboxymethyl-[3,5-dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenylj- amino} -acetic acid
1H NMR : (DMSO-D6, 300MHz) : 2.81(6H, s), 4.00(4H5 s), 6.42(1H5 d, J=3Hz)5 6.48(2H5 s)5 6.64-6.68(1H5 dd, J=3Hz & 8.7Hz)5 6.79(1H5 d, J=9Hz) % Yield: 82 % EXAMPLE 37
{ Carboxymethyl-[4-(4-hydroxy-3 -isopropyl-phenoxy)-3 ,5-dimethyl-phenyl] -amino } - acetic acid
1H NMR : (DMSO-D6, 400MHz) : 0.93(6H, d, J=6.8Hz)5 1.90(6H5 s), 3.09-3.14(1H5 m). 4.02(4H5 s), 6.12-6.15(1H5 dd5 J=2.8 & 8.4Hz)5 6.24(2H5 s), 6.58-6.63(2H, m) % Yield: 50 % EXAMPLE 38
[[3,5-Dichloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (QE)Cl35 400MHz) : 2.71(6H, s), 4.45(2H5 s), 6.76(2H5 d5 J=8Hz), 6.94(3H5 d, J=7.2Hz), 7.02(1H5 d5 J=8.8Hz), 7.08(1H5 d, J=8Hz)5 7.51(2H5 s) % Yield : 71 % EXAMPLE 39
[[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid 1H NMR: (DMSO-D6, 400MHz): 2.87(6H5 bs), 4.5(2H5 s), 6.49(1H5 d, J=2.4Hz),
6.73(3H5 d5 J=8.4Hz), 6.82(1H5 d, J=9.2Hz), 6.92(2H5 d5 J=8.8Hz)5 7.8(2H5 s) % Yield: 56 % EXAMPLE 40
[{355-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid
1H NMR : (DMSO-D6, 400 MHz) : 1.41-1.52(6H, m), 3.16-3.19(4H5 m), 4.45(2H5 s), 6.47(1H5 d, J=2.8Hz), 6.72-6.76(3H5 m), 6.81(1H5 d, J=8.8Hz)5 6.93(2H, d, J=8.8Hz), 7.84(2H5 s) % Yield : 23 % EXAMPLE 41
[{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-sulfonyl)-ρhenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid 1H NMR : (CDCl3, 400 MHz) : 1.44(2H, in), 1.59(4H3 m), 3.02(4H, m), 4.46(2H, s),
6.77(2H, m), 6.92-7.00(4H3 m), 7.05(1H5 m), 7.51(2H3 s)
% Yield: 77 %
EXAMPLE 42
[[4-(4-Hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (DMSO-D6, 400MHz) : 1.09(6H, d, J=6.8Hz)3 2.03(6H3 s), 3.09-3.16(1H, m), 4.26(2H3 bs), 6.15-6.18 (IH3 dd, J=2.8Hz & 8.8Hz), 6.62(1H3 d, J=8.8Hz)3
6.66(1H, d, J=3.2Hz), 6.71(2H3 d, J=8.4Hz)3 6.88(2H3 d, J=8.4Hz), 7.19(2H3 s)
% Yield: 14 % EXAMPLE 43
[{4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR: (CDCl3, 400MHz): 1.33(9H3 s), 4.39(2H, s), 6.69-6.72(2H, m), 6.92(2H3 d3
J=8.4Hz), 6,9£(2H3 d, J=8.8Hz), 7.26-7.32(1H3 m), 7.47-7.50(4H3 m), 7.65(2H3 d3 J=fi.4Hz)
% Yield : 66 % EXAMPLE 44
[ { 3 ,5 -Dichloro-4- [3 -(4-chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid 1H NMR: (CDCl3, 400MHz): 4.51(2H, s), 6.79(2H3 d, J=8.4Hz), 6.99-7.04(4H, m),
7.07(1H, d, J=2.8Hz), 7.43(2H3 d, J=7.6Hz)3 7.49 (2H, s), 7.61(2H, d, J=8Hz)
% Yield : 68 % EXAMPLE 45
[[3,5-Dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyI]-(4-hydroxy- phenoxycarbony^-aminoj-acetic acid
1H NMR : (DMSO-D6, 400MHz) : 0.93(6H3 d, J=6.8Hz), 3.20-3.25(1H3 m), 4.24(2H, d, J=6.4Hz), 6.53(2H5 m), 6.65(1H3 m), 6.75(2H3 d, J=8.8Hz), 6.84(2H3 m), 6.90-
6.98(2H, m) % Yield : 42 % EXAMPLE 46
{Carboxymethyl-[3,5-dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-amino}-acetic acid 1H NMR: (DMSO-D6, 400MHz): 1.06(3H5 1, J=7.4Hz), 2.43-2.48(2H, m), 4.10(4H, s), 6.28-6.31(1H5 dd, J=3.2Hz & 8.8Hz), 6.57(1H, d, J=3.2Hz), 6.63-6.66(3H, m) % Yield: 55% EXAMPLE 47
[ { 3 ,5 -Dichloro-4- [3 -(3 -chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (CDCl3, 400MHz) : 4.36(2H, bs), 6.71(2H, d, J-6.8Hz), 6.89(4H, m), 6.99- 7.04(1H, m), 7.15(1H, m), 7.47-7.51(4H5 m), 7.58(1H5 m) % Yield : 68% EXAMPLE 48 [[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy-phenoxycarbonyl)- amino] -acetic acid
1H NMR : (DMSO-D6, 400MHz) : 1.07(3H5 1, J=7.4Hz), 2.44-2.48(2H5 m), 4.44(2H5 s), 6.33-6.36(1H5 dd, J=2.8Hz & 8.4Hz)5 6.64-6.68(2H5 m)5 6.73(2H5 d5 J=8.8Hz)5 6.92(2H, d5 J=8.8Hz), 7.67(2H5 s) % Yield : 16% EXAMPLE 49
[[355-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR: (CD3OD5 400MHz): 4.24(2H5 s), 6.61-6.64(1H5 m), 6.71-6.82(4H5 m), 6.96(2H5 d, J=8Hz), 7.27(1H5 d, J=7.2Hz), 7.35(2H5 d5 J=7.2Hz), 7.48(2H5 d, J=7.2Hz)5 7.64(2H5 s) % Yield: 35% EXAMPLE 50
[[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (CD3OD5 400MHz) : 3.86(2H5 s)5 4.5(2H5 s), 6.46-6.49(2H5 dd, J=2.8Hz & 8.8Hz), 6.69(1H5 d, J=8.4Hz), 6.76(2H5 d, J=8.8Hz)5 6.95(2H5 d, J=7.6Hz), 7.15- 7.17(5H5 m)5 7.57 (2H5 s) % Yield : 18% EXAMPLE 51
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid 1H NMR : (CD3OD, 400MHz) : 1.47-1.59(2H3 m), 1.79-1.86(2H, m), 1.95-1.97(2H, m), 3.63-3.69(1H5 m), 4.45(2H, s), 6.77(2H, d, J=8.8Hz)5 6.92-6.96(3H, m), 7.01(1H, d, J=3.2Hz), 7.04(1H, d, J=3.2Hz), 7.68(2H, s) % Yield : 39% EXAMPLE 52 [{4-[3-(Bicyclo[2.2.1]hept-2-ylsuIfamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- (4-hydroxy-phenoxycarbonyl)-aminoJ -acetic acid
1H NMR : (CD3OD, 400MHz) : 0.95-0.99(2H, m), 1.06(1 H, m), 1.29-1.34(2H, m), 1.37-1.42(2H, m), 2.00(2H, m), 2.14(1H, m), 3.01-3.02(1H, m), 4.41(2H, s), 6.76(2H, d, J=8.8Hz), 6.94-6.98(3H, m), 7.07(2H, d, J=6.8Hz), 7.69(2H, s) % Yield : 16% EXAMPLE 53
[{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dibromo-phenyl}- (4-hydroxy-phenoxycarbonyl)-amino]-acetic acid
1H NMR : (DMSO-D6, 400MHz) : 0.85-0.93(3H5 m), 1.22-1.28(3H, m), 1.35-1.45(2H, m), 1.89(1H, m), 2.06(1H, m), 2.92-2.93(1H, m), 4.23(2H, s), 6.53(1H, s), 6.62(1H, d, J=5.6Hz), 6.75(2H, d, J=8.8Hz), 6.83-6.93(3H5 m), 6.99(2H, d, J=2.4Hz), % Yield : 14% EXAMPLE 54
[{3,5-Dichloro-4-[4-hydroxy-3-(4-hydroxy-benzoyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR : (CD3OD, 400MHz) : 4.34(2H, s), 6.76(2H, d, J=8.8Hz), 6.79-6.85(3H, m), 6.98(3H5 d, J=8.8Hz), 7.11-7.14(1H, dd, J=3.2Hz & 9.2Hz)5 7.56-7.58(2H, m), 7.65(2H5 s) % Yield : 34% EXAMPLE 55
[{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid 1H NMR: (DMSO-D6, 400MHz): 4.35(2H, s), 6.53(1H5 m), 6.71-6.76(3H, m), 6.89- 6.94(4H, m), 7.30-7.34(2H, m), 7.74-7.77(3H; m) % Yield: 48% EXAMPLE 56 [(3,5-Dichloro-4-{3-[(4-chloro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-(4-hy droxy-phenoxycarbonyl)-amino] -acetic acid
1H NMR : (CD3OD5 400MHz) : 4.4(2H, s), 6.01(1H, s), 6.55-6.58(1H, dd, J=2.8Hz & 8.8Hz), 6.68(1H, d, J=8.8Hz), 6.76(2H, d, J=8.8Hz), 6.85(1H, m) , 6.96(2H5 d, J=8Hz), 7.25-7.31(4H, m), 7.61(2H, s) % Yield : 90% EXAMPLE 57
[{4-[3-(Azepane-l-sulfonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4-hydroxy- phenoxy carbonyl)-amino] -acetic acid
1H NMR: (CDCl35 400MHz): 1.52(4H, bs), 1.64(4H5 bs), 3.27(4H5 bs), 4.46(2H5 s), 6.76(2H, d5 J=8.4Hz), 6.96-7.02(5H5 m), 7.51 (2H5 s) % Yield : 95% EXAMPLE 58
({3,5-Dichloro-4-[3-(l-ethyl-propoxy)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid 1H NMR : (DMSO-D6, 400MHz) : 0.82(6H5 t, J=7.4Hz), 1.15(3H5 t, J=7Hz), 1.55- 1.6(4H5 m), 4.06 (IH, t, J=5Hz), 4.08-4.12 (2H5 m), 4.29(2H5 s) , 6.04-6.07(1H5 dd, J=2Hz & 8.8Hz)5 6.47(1H5 m), 6.67(1H5 d, J=8.4Hz)5 7.55(2H5 s) % Yield : 89% EXAMPLE 59 [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-355-dimethyl-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid
1H NMR: (DMSO-D6, 400MHz): 0.7(3H5 t, J=7.2Hz), 1.23(3H5 d, J=7.2Hz), 1.38- 1.51(2H5 m), 2.07(6H5 s), 2.86-3.0(1H5 m), 4.27(2H5 s), 6.2O-6.22(1H, dd, J=2.4Hz & 8.4Hz), 6.57(1H, d, J=2.8Hz)5 6.63(1H5 d, J=8.8Hz), 6.71(2H5 d, J=7.6Hz), 6.88(2H5 d, J=8.8Hz), 7.17-7.20(2H, m) % Yield: 24% EXAMPLE 60 [[3,5-Dichloro-4-(3-cyclohexylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid
1H NMR: (DMSO-D6, 400MHz) : 0.94-1.16(6H5 m), 1.54(4H, d, J=8.8Hz), 2.89(1H, m), 4.48(2H5 s), 6.73(2H, d, J=8.8Hz), 6.92-6.98(4H, m), 7.19(1H, d, J=7.2Hz), 7.72(2H, s) % Yield: 99% EXAMPLE 61
[ {3 , 5-Dichloro-4- [4-hydroxy-3 -(moφholine-4-sulfonyl)-phenoxy] -phenyl } -(4- hy droxy-phenoxycarbonyl)-amino] -acetic acid 1H NMR: (DMSO-D6, 400MHz): 3.04(4H, bs), 3.55(4H, bs), 4.44(2H5 s), 6.73(2H5 d, J=8.4Hz), 6.92(2H, d, J=8.4Hz), 7.01-7.08(3H5 m), 7.72(2H5 s) % Yield: 10% EXAMPLE 62
({3,5-Dichloro-4-[4-hydroxy~3-(3-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid
1H NMR: (CDCl3, 400MHz): 1.36(3H, m), 2.40(3H5 s), 4.19(2H5 m), 4.29(2H5 s), 6.99- 7.09(3H, m), 7.28 -7.35(4H5 m), 7.44-7.51(2H, m) % Yield: 83% EXAMPLE 63. [{3,5-Dichloro-4-[4-hydroxy-3-(pyrrolidine-l-sulfonyl)-phenoxy]-ρhenyl}-(4- hydroxy-phenoxycarbonyl)-amino] -acetic acid
1H NMR: (DMSO-D6, 400MHz): 1.71(4H, t, J=6.4Hz), 3.22(4H, t, J=6.0Hz)5 4.46(2H, s)5 6.73(2H5 d, J=8.4Hz), 6.93(2H5 d5 J=8.4Hz), 6.99-7.07(3H5 m), 7.72(2H5 s) % Yield : 52% EXAMPLE 64
{ [3,5-Dichloro-4-(4-hydroxy-3 -isobutoxy-phenoxy)-phenyl] -ethoxycarbonyl -amino} - acetic acid
1H NMR: (CDCl3, 400MHz): 1.04(6H5 ds J=6.8Hz)5 1.25(3H, t, J=6.6Hz), 2.08- 2.17(1H5 m), 3.79(2H5 d5 J=6'.8Hz)5 4.19-4.25(2H5 q, J=6.8Hz & 6.8Hz)5 4.36(2H5 s), 6.09-6.12(1H5 dd, J=2.8Hz & 8.8Hz)5 6.61(1H5 d5 J=2.8Hz), 6.76(1H5 d, J=8.8Hz), 7.38(2H5 s) % Yield: 80% EXAMPLE 65 {[3,5-Dichloro-4-(3-cyclohexylmethoxy-4-hydroxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid
1H NMR: (CDCl3, 400MHz): 1.05(3H5 m), 1.26-1.32(6H, m), 1.6-1.86(5H, m), 3.81(2H5 d, J=6Hz), 4.21- 4.26(2H, q, J=6.8Hz & 7.2Hz), 4.38(2H5 s), 6.09-6.12(1H, dd, J=2.4Hz & 8.8Hz), 6.6(1H, d, J=2.4Hz), 6.76(1H, d, J=8.4Hz), 7.38(2H, s) % Yield: 53 % EXAMPLE 66
[{3,5-Dichloro-4-[4-hydroxy-3-(3-methyl-benzoyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid 1H NMR : (DMSO-D6, 400MHz) : 2.32(3H5 s), 4.21(2H, bs), 6.53(2H5 m ), 6.62(2H5 m), 6.75(2H5 d, J=8.8Hzj, 6.82(1H5 m), 6.89(2H5 d, J=8.8Hz), 7.36-7.46(4H5 m) % Yield: 32 % EXAMPLE 67
[{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR: (DMSO-D6, 400MHz): 4.43(2H5 s), 6.73(3H, d, J=8.8Hz), 6.90-6.95(4H5 m), 7.57(2H, d, J=8.4Hz), 7.68(2H5 d, J=8.4Hz)5 7.83(2H3 s) % Yield: 42 % EXAMPLE S ({3,5-Dibromo-4-[3-(4-chloro-bcnzoyl)-4-hydroxy-phenoxy]-phenyl) ethoxycarbonyl- amino)-acetic acid
1H NMR: (DMSO-D6, 400MHz): 1.14(3H5 t, J=6.8Hz), 4.05-4.11(2H5 q, J=6.8Hz & 6.8Hz)5 4.22(2H5 s), 6.71(1H5 d5 J=2.4Hz), 6.92-6.96(2H5 m), 7.57(2H5 d, J=8.4Hz), 7.68-7.71(4H5 m) % Yield: 98 % EXAMPLE 69
({3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid
1H NMR : (DMSO-D6, 400MHz) : 1.14(3H5 1, J=7Hz), 2.36(3H5 s), 4.06-4.12(2H5 q, J=6.8Hz & 6.8Hz)5 4.32(2H, s), 6.68(1H5 d, J=2.4Hz)5 6.92-6.98(2H5 m), 7.30(2H5 d, J=8Hz), 7.55-7.59(4H5 m) % Yield : 95 % EXAMPLE 70 [{3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid
1H NMR: (DMSO-D6, 400MHz): 2.34(3H, s), 4.22(2H, s), 6.53(1H, s), 6.60-6.65(2H, m), 6.71-6.76 (IH, m), 6.82-6.85(1H, m), 6.89-6.96(3H, m), 7.31(2H, d, J=4.8Hz)5 7.57(2H, d, J=8.0Hz)3 7.83(1H, s) % Yield : 55 % Example 71
{[3,5-Dichloro-4-(3-isopropyl-4-methoxy-ph.enoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester 1H NMR: (CDCl3, 300MHz): 1.19(6H3 d, J=6.4Hz), 1.29-1.35(6H, m), 3.24-3.31(1H, m), 3.76(3H5 s), 4.19-4.28(4H, m), 4.31(2H, s), 6.43-6.46(1H, dd, J=2.8Hz & 8.8Hz), 6.69(1H, d, J=8.8Hz), 6.87(1H, d, J=2.8Hz), 7.38(2H, s) Example 72
{[4-(4-Benzyloxy-3-isopropyl-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester
1H NMR : (CDCl3, 300 MHz): 1.24(6H5 d, J=6.9 Hz)5 1.31(6H, t, J=7.2Hz), 3.35- 3.40(1H5 m), 4.21-4.24(4H5 m), 4.31(2H5 s), 5.01(2H, s), 6.41-6.45(1H5 dd, J=2.9Hz & 8.7Hz)5 6.77(1H, d, J=8.9Hz)5 6.9O(1H, d, J=2.4Hz), 7.34-7.44(7H3 m) Example 73 { [4-(3 -sec-Butyl-4-methoxy-phenoxy)-3 , 5 -dichloro-phenyl] -ethoxycarbonyl -amino } - acetic acid ethyl ester
1H NMR : (CDCl35 300MHz) : 0.83(3H5 t, J=7.35Hz), 1.16(3H5 d5 J=6.93Hz)5 1.23- 1.26(2H5 m), 1.28-1.33(4H5 m), 1.33-1.53(2H5 m), 3.03-3.10(1H5 m), 3.77(3H5 s), 4.18- 4.27(4H5 m), 4.31(2H, s), 6.45-6.49(1H3 dd, J=3.0Hz & 8.79Hz)5 6.74(1H5 d, J=8.6Hz)5 6.8(1H3 d3 J=2.9 IHz)3 7.47(2H5 s) Example 74
{ [4-(3 -Benzyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl]-ethoxycarbonyl-amino } - acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.25-1.38(6H5 m), 3.7(3H5 s), 3.93(2H3 s), 4.12-4.30(6H5 m), 6.54-6.57(1H5 dd, J=3.09Hz & 8.7Hz), 6.69-6.75(2H, m), 7.17-7.36(5H, m), 7.45(2H5 s) Example 75
({4-[3-(Bicyclo[2.2.1]hept-2-yIcarbamoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.13-1.19(2H9 m), 1.26-1.31(7H, m), 1.50(2H5 m), 1.54(3H5 m)5 1.82-1.88(1H, m), 2.30(2H5 s), 3.93(3H5 s), 4.18-4.27(4H5 q, J=7.02Hz &
7.14Hz)5 4.30(2H5 s), 6.93(1H, d, J=8.88Hz), 7.02(1H, m), 7.37(2H5 s), 7.61 (IH, d5
J=2.6Hz)
Example 76
{[3,5-Dichloro-4-(3-ethyl-4-niethoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.17(3H5 1, J=7.5Hz)5 1.24-1.26(3H5 m), 1.28-1.33(3H5 m)
2.56-2.64(2H5 q5 J=7.44Hz & 7.47Hz)5 3.78(3H, s), 4.22-4.29(4H, m), 4.31(2H, s) 6.50-
6.54(1H5 dd, J=3.03Hz & 8.79Hz)5 6.71(1H5 d, J=8.8Hz), 6.77(1H5 d, J=3Hz)5
7.39(2H,s) Example 77
{[355-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-ρhenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.24-1.33(6H5 m), 2.84(3H5 s), 3.08(3H5 s), 3.79(3H5 s),
4.19-4.29(4H, m), 4.31(2H5 s), 6.70 (IH5 d, J=2.7Hz), 6.81-6.90(2H5 m), 7.38(2H, s) Example 78
{[3,5 -Dichloro-4-(3 -cyclobutylcarbamoyl-4-metlioxy-phenoxy)-phenyl] - ethoxycarbonyl-amino} -acetic acid ethyl ester
1H NMR: (CDCl35 300MHz): 1.23-1.34(6H5 m), 1.77-1.80(2H, m), 1.91-1.97(2H5 m),
2.41(2H5 bs), 3.95(3H5 s), 4.20-4.27(4H, q, J=6.93Hz & 7.08Hz)5 4.30(2H5 s), 4.47- 4.55(1H5 m), 6.94(1H5 d, J=8.9Hz), 7.03(1H5 m), 7.37(2H5 s), 7.60(1H5 s) Example 79
{[3,5-Dichloro-4-(4-methoxy-3-propyl-phenoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester
1H NMR : (DMSO-D6, 300MHz) : 0.85(3H5 t, J=7.32Hz), 1.13-1.22(6H5 m), 1.44- 1.52(2H, m), 2.44-2.48(2H5 m), 3.71(3H5 s), 4.07-4.19(4H5 m), 4.43(2H5 s), 6.48-
6.52(1H, dd, J=3.09Hz & 8.85Hz), 6.68(1H5 d, J=3Hz), 6.86(1H5 d, J=8.9Hz), 7.56(2H5 s) Example 80 {[3,5-Dichloro-4-(3-isopropylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester
1H NMR : (CDCl3, 300MHz) : 1.22 -1.34(12H, m), 3.95(3H, s), 4.20-4.27(5H, m), 4.31(2H, s), 6.92(1H, d, J=9Hz), 7.38(2H3 m), 7.62(1H5 m), 7.78(1H, d, J=6.9Hz) Example 81
{[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester
1H NMR: (CDCI3, 300MHz): 1.23-1.33(6H, m), 3.76(3H, s), 4.20-4.28(4H, m), 4.30(2H, s), 6.8O(1H, d, J=3Hz), 6.85(1H, d, J=2.7Hz), 6.91(1H, m), 7.26(1H, m), 7.29- 7.41 (4H, m), 7.50(2H, d, J=7Hz) Example 82
({3,5 -Dichloro-4- [3 -(4-fluoro-benzoyl)-4-methoxy-phenoxy] -phenyl } -ethoxycarbonyl- amino)-acetic acidethyl ester
1H NMR: (CDCl3, 300MHz) : 1.23-1.30(6H, m), 3.69(3H, s), 4.20-4.28(4H, m), 4.30(2H, s), 6.85(1H, d, J=3Hz), 6.90-7.0(2H, m), 7.07-7.13(2H5 m), 7.38(2H, s), 7.81- 7.86(2H5 m) Example 83
{[3,5-Dichloro-4-(3-diethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester 1H NMR : (DMSO-D6, 300MHz) : 0.91(3H5 1, J=6.9Hz), 1.07(3H, t, J=7.0Hz), 1.12- 1.22(6H, m), 3.01-3.03(4H5 m), 3.72(3H5 s), 4.02-4.18(4H5 m), 4.43(2H5 s), 6.51(1H5 d, J=3Hz), 6.84-6.88(1H, dd, J=3Hz & 9Hz)5 7.04(1H5 d, J=9Hz), 7.58(2H5 s) Example 84
({3,5-Dichloro-4-[3-(5-chloro-thiophene-2-carbonyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester
1H NMR : (CDCl3, 300MHz) : 1.23-1.321(6H5 m), 3.77(3H5 s), 4.22-4.28(4H5 m), 4.30(2H, s)5 6.84(2H5 s), 6.92-6.97(3H, m), 7.38(2H5 s) Example 85
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-355-dimethyl-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 0.83(6H5 1, J=6.2Hz), 1.03-1.32(6H, m), 1.49-1.60(2H5 m), 2.10(6H5 s), 3.11-3.18(1H5 m), 4.20-4.27(4H, m), 4.31(2H5 s), 4.99(2H5 s), 6.37(1H5 d, J=6 Hz), 6.74(2H5 d, J=8.7Hz), 7.02(2H5 s), 7.31-7.43(5H5 m) Example 86
{[3,5-Dichloro-4-(4-methoxy-3-phenylcarbamoyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.26-1.29(6H, m), 4.04(3H, s), 4.19-4.28(4H, m), 4.32(2H, s) 7.01(1H, d, J=9Hz), 7.09-7.14(2H, m), 7.32-7.39(4H5 m), 7.62-7.70(3H5 m) Example 87
({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-ethoxycarbonyl- amino)-acetic acid ethyl ester
1H NMR : (CDCl3, 300MHz) : 1.28-1.32(6H, m), 3.68(3H, s), 4.18-4.30(4H, m), 4.31(2H3 s), 6.82-6.86(1H, m), 6.92(1H, d, J=8.8Hz), 6.97-7.01(1H, m), 7.38-7.42(4H, m), 7.72-7.75(2H, m) Example 88
({3,5-Dichloro-4-[3-(2,4-dichloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester 1H NMR : (CDCl3, 300MHz) : 1.26-1.31(6H, m), 3.58(3H, s), 4.19-4.29(4H5 m), 4.32(2H, s), 6.86(1H, d5 J=9Hz), 7.05-7.15(2H5 m), 7.30-7.40(3H, m), 7.51(2H5 s) Example 89
[[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbβnyl)-amino] -acetic acid ethyl ester 1H NMR : (CDCl35 300MHz) : 0.83(3H, t, J=7.5Hz)5 1.16(3H, d, J=7.2Hz)5 1.23- 1.34(3H5 m), 1.48-1.62(2H5 m) , 3.02-3.09(1H5 m), 3.76(3H5 s), 3.79(3H5 s), 4.27- 4.29(2H5 m), 4.39(2H5 bs)5 6.44-6.48(1H, dd, J=3Hz & 8.7Hz)5 6.70(1H5 d, J=8.7Hz)5 6.82(1H5 d, J=3Hz), 6.88(2H5 d, J=8.7Hz), 7.05(2H5 d5 J=8.7Hz), 7.49(2H, s) Example 90 ({4-[3-(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.28-1.32(6H5 m), 1.35(9H5 s), 3.7(3H5 s), 4.15-4.28(4H, m), 4.29(2H5 s), 6.82(1H5 m), 6.91-6.94(2H5 m), 7.37(2H5 m)5 7.43-7.50(2H5 m), 7.75- 7.78(2H5 m) Example 91
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester 1H NMR : (CDCl3, 400MHz) : 0.83(3H, t, J=JAUz), 1.15(3H, d, J=6.8Hz), 1.24-
1.28(6H, m), 1.5-1.6(2H5 m), 3.04-3.05(1H, m), 3.76(3H, s), 4.10(4H, s), 4.22-4.28(4H, m), 6.44-6.47(1H, dd, J=2.8Hz & 8.8Hz)3 6.59(2H, s), 6.69(1H, d, J=9.2Hz), 6.78(1H5 d, J=3.2Hz) Example 92
( { 3 ,5 -Dichloro-4-[3 -(4-chloro-benzoyl)-4-methoxy-ρhenoxy] -phenyl } - ethoxycarbonylmethyl-amino)-acetic acid ethyl ester
1H NMR: (CDCl3 , 300MHz) : 1.24-1.29(6H5 m), 3.68(3H, s), 4.09(4H, s), 4.14-
4.31(4H, m), 6.57(2H5 m), 6.84-6.94(3H5 m), 7.40(2H3 d, J=8.43Hz)5 7.75(2H3 d5 J=8.43Hz) Example 93
[[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (CDCl3, 300MHz): 1.19(6H, d, J=6.84Hz), 1.28-1.34(3H5 m), 3.25-3.30(1H5 m), 3.77(3H5 s), 3.79(3H5 s), 4.26-4.29(2H3 m), 4.40(2H5 bs), 6.41-6.45(1H3 dd,
J=3.03Hz & 8.79Hz)5 6.69(1H3 d3 J=8.88Hz), 6.86-6.89(3H5 m)5 7.05(2H, d, J=8.79Hz),
7.50(2H, s) Example 94
[[4-(3-tert-Bntyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR : (CDCl3, 300MHz) : 1.26-1.29(3H, m), 1.35(9H5 s), 3.78(3H5 s), 3.79(3H3 s), 4.29(2H5 m), 4.39(2H, bs), 6.4O-6.44(1H, dd, J=3Hz & 8.79Hz), 6.7(1H3 d, J=8.85Hz), 6.88(2H5 d, J=8.67Hz)3 6.99-7.06(3H5 m), 7.50(2H5 s) Example 95 [[355-Dichloro-4-(3-dimethylsulfamoyl-4-niethoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR : (CDCl3, 400MHz) : 1.14(3H3 t, J=I 1.2Hz)5 2.83(6H5 s), 3.79(3H5 s), 3.89(3H, s), 4.29(2H5 m), 4.40(2H, bs), 6.59-6.86(2H, m), 6.95(2H, d, J=9.2Hz), 7.04(2H5 d, J=8.8Hz), 7.41(1H, s), 7.51(2H, s) Example 96
[[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester 1H NMR : (CDCl3, 300MHz) : 1.29-1.34(3H5 m), 2.84(3H, s), 3.08(3H, s), 3.8(6H, s), 4.20-4.29(2H5 m), 4.40 (2H, s), 6.71(1H, d, J=2.64Hz), 6.82-6.89(4H, m), 7.05(2H, d, J=8.8Hz)5 7.69(2H, s) Example 97 [ { 355-Dichloro-4-[4-methoxy-3 -(piperidine- 1 -sulfonyl)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.30-1.34(6H5 m), 1.50-1.52(3H, m), 3.17-3.2(4H, m), 3.79(3H, s), 3.88(3H, s), 4.28-4.29(2H, m), 4.40(2H, bs), 6.87(2H, d, J=8.4Hz), 6.93(1H, d, J=8.8Hz), 6.99-7.05(3H, m), 7.4O(1H, d, J=3.2Hz), 7.51(2H, s) Example 98
[[4-(3-Isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(4-methoxy- pheηoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.17(6H5 d, J=6.8Hz), 1.27-1.32(3H, m), 2.12(6H, s), 3.23-3.30(1H, m), 3.76(6H, s), 4.24-4.27(2H5 m), 4.38(2H, s), 6.32-6.35(1H5 dd, J=3Hz & 8.7Hz)5 6.65(1H5 d, J=8.8Hz), 6.80(1H5 d, J=2.8Hz), 6.84-6.86(2H, m), 7.03- 7.05(2H, m), 7.14(2H, s) Example 99
[ {4- [3 -(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy] -3 ,5-dichloro-phenyl } -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester 1H NMR : (CDCl3, 400MHz) : 1.24-1.33(12H, m), 3.70(3H5 s), 3.79(3H5 s), 4.27(2H5 s)5 4.37 (2H5 s), 6.83-6.94(5H5 m), 7.03(2H5 d5 J=8.4Hz)5 7.44(2H5 d, J=8.4Hz), . 7.49(2H5 s)5 7.76(2H5 d5 J-8.4Hz) Example 100
[{3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoχycarbonyl)-amino] -acetic acid ethyl ester
1U NMR: (CDCl3, 400MHz): 1.24(3H5 1, J=7.2Hz), 3.66(3H5 s), 3.85(3H5 s), 4.27(2H5 m), 4.38(2H5 s), 6.86-6.9(4H, m), 6.98-7.04(3H5 m), 7.38(2H, d5 J=2.4Hz)5 7.5(2H5 s)5 7.72(2H5d5 J=6.8Hz) Example 101 [[3,5-Dichloro-4-(3-isopropylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester 1H NMR: (CDCl3, 400MHz): 1.05(6H, d, J=6.8Hz), 1.32(3H, t, J=6.8Hz)5 3.4-3.45(1 H, m), 3.79(3H5 s), 3.95(3H, s), 4.28(2H, bs), 4.41 (2H, s), 6.87(2H5 d, J=8.8Hz), 6.96(1H5 d, J=8.8Hz), 7.04(3H5 d, J=8.8Hz), 7.41(1H5 d, J=2.8Hz)5 7.52(2H,s) Example 102 {[355-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester
1H NMR : (CDCl35 400MHz) : 1.16(3H, t, J=7.6 Hz)5 1.26-1.32(6H5 m)5 2.58-2.60(2H5 m), 3.77(3H5 s), 4.11(4H5 s), '4.23-4.28(4H5 q, J=6.8Hz & 7.2Hz)5 6.52-6.53(1H5 m), 6.60(2H5 s), 6.6(1H5 d5 J=8.8Hz)5 6.74(Ih, d, J=3.4Hz) Example 103
[{355-Dichloro-4-[3-(3-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz) : 1.24-1.32(3H5 m), 3.68(3H5 s), 3.79(3H, s), 4.27(2H5 bs)5 4.37-4.45(2H5 m), 6.86-6.88(3H5 m), 6.93(1H5 d5 J=8.4Hz), 6.99-7.04(3H5 m), 7.34- 7.38(1H, m), 7.50-7.53(3H, m), 7.64-7.66(1H5 m), 7.77(1H5 s) Example 104
[[355-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyl]-(4-raethoxy- phenoxycarbonyl)-arnino] -acetic acid ethyl ester
1H NMR : (CDCl3, 400MHz) : 1.17(3H5 t, J~7.4Hz), 1.3(2H5 t, J=7.2Hz), 2.57- 2.63(21I5 q5 J=7.6IIz & 7.6 Hz)5 3.78(611, s), 4.28(2H5 m), 4.39(2H5 s), 6.50-6.53(1H5 dd5 J=3.2Hz & 8.8Hz), 6.7(1H3 d, J=8.8Hz)5 6.77(1H5 s), 6.88(2H5 d5 J=8.8Hz), 7.05(2H5 d, J=8.8Hz)5 7.50(2H5 s) Example 105
[[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.24-1.32(3H, t, J=7.0Hz), 3.76(3H5 s), 3.79(3H, s), 4.27- 4.38(2H5 m), 4.45(2H5 bs)5 6.76-6.79(1H, dd, J=3.2Hz & 8.8Hz), 6.86-6.89(4H5 m), 7.04(2H5 d, J=8.4Hz), 7.25-7.33(1H5 m), 7.36-7.40(2H5 m), 7.49-7.51(4H, m) Example 106 [[4-(3-BenzyI-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR : (CDCl3, 400MHz) : 1.24-1.33(3H5 m), 3.75(3H, s), 3.79(3H5 s), 3.93(2H5 s), 4.28-4.39(2H5 m), 4.42(2H, s), 6.54-6.57(1H, dd, J=2.8Hz & 8.8Hz), 6.69-6.74(2H, m), 6.87(2H, d, J=8.8Hz), 7.04(2H, d, J=8.4Hz), 7.13-7.18(3H, m), 7.22-7.25(2H, m),
7.47(2H, s) Example 107
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.32(3H, t, J=7.2Hz), 1.51-1.56(2H, m), 1.69-1.75(2H, m), 1.98-2.03(2H, m), 3.74(1H, m), 3.79(3H, s), 3.96(3H, s)5 4.29(2H5 m)5 4.41(2H, s),
6.87(2H, d, J=8.4Hz), 6.96(1H, d, J=9.2Hz), 7.04(3H, d, J=8.8Hz), 7.37(1H, d,
J=2.8Hz), 7.52(2H, s) Example 108
[{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfanioyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-
(4-methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR : (CDCl3, 400MHz) : 0.98-1.01(2H, m), 1.10-1.19(2H, m), 1.26-1.27(2H3 m),
1.30-1.34(4H5 m), 1.37-1.40(3H, m), 3.09-3.11(1H, m), 3.79(3H, s), 3.94(3H5 s), 4.29(2H, m), 4.41(2H5 bs)5 6.87(2H, d, J=8.8Hz), 6.97(1H5 d, J=9.2Hz), 7.03-7.06(3H, m), 7.41(1H5 s), 7.52(2H5 s) Example 109
[{4-[3-(Bicyclo[2.2.1]hept-2-yIsuIfamoyl)-4-methoxy-phenoxy]-355-dibromo-phenyl}- (4-methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester 1H NMR: (CDCl3, 400MHz): 0.98-1.00(2H5 m), 1.10-1.19(2H5 m), 1.30-1.39(5H5 m), 2.03-2.04(2H5 m), 2.17-2.20(2H5 m), 3.09-3.14(1H, m)5 3.79(3H5 s), 3.94(3H5 s), 4.29(2H5 m), 4.48(2H5 s), 6.87(2H, d5 J=8.4Hz), 6.96-6.99(1H5 m), 7.05(3H5 d5 J=8.8Hz)5 7.39(1H5 d, J=2.8Hz)5 7.72(2H5 s) Example 110 [{3,5-Dichloro-4-[4-methoxy-3-(4-methoxy-benzoyl)-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR : (CDCl3, 400MHz) : 1.28-1.32(3H5 m), 3.70(3H5 s), 3.81(3H5 s), 3.86(3H, s), 4.26(2H5 s), 4.37-4.45(2H5 m), 6.83(1H, d5 J=3.2Hz), 6.85-6.94(6H5 m), 7.03(2H5 d, J=8.4Hz), 7.49(2H, s), 7.78-7.81(2H5 m) Example 111
[{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester 1H NMR: (CDCl3, 400MHz): 1.31(3H, t, J=7.2Hz), 3.68(3H5 s), 3.79(3H, s), 4.27(2H5 bs), 4.45(2H5 bs), 6.86-6.92(2H5 m), 7.02-7.11(3H, m), 7.49(2H, s), 7.81-7.84(2H5 m) Example 112
[{4-[3-(Azepane-l-sulfonyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-(4-methoxy- phenoxycarbony^-aminoj-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.32(3H, t, J=7.0Hz), 1.60-1.61(4H5 m), 1.71(4H5 bs), 3.31-3.34(4H, m), 3.79(3H5 s), 3.88(3H, s), 4.29(2H5 m), 4.47(2H5 s), 6.86-6.92(3H5 m), 6.97-6.99(1H5 m), 7.04(2H, d5 J=8.8Hz), 7.44(1H, d, J=3.2Hz), 7.51(2H5 s) Example 113 ( { 4-[4-Benzyloxy-3 -(I -ethyl-propoxy)-phenoxy] -3,5 -dichloro-phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 0.95(6H, t, J=7.2Hz), 1.3 (6H5 t, J=7.2Hz), 1.64-1.74 (4H5 m), 4.09-4.13(1H5 m), 4.19-4.28(4H5 m), 4.3(2H, s), 5.04(2H5 s), 6.15-6.18(1H5 dd, J=2.4Hz & 8.8Hz)5 6.57(1H, d, J=2Hz)5 6.78(2H5 d5 J=8.8Hz)5 7.30-7.43(7H5 m) Example 114
[[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz) : 0.82(3H5 1, J=7.2Hz)5 1.14(3H5 d, J=6.8Hz)5 1.30(3H5 1, J=6.8Hz), ϊ.4»-1.60(2H, m), 2.12(6H5 s), 3.01-3.06(1H5 m), 3.74(3H5 s), 3.78(3H5 s), 4.24-4.27(2H5 m), 4.38-4.48(2H5 m), 6.35-6.38(1H, dd,.J=2.8Hz & 8.8Hz)5 6.66(1H, d, J=8.8Hz)5 6.72(1H5 d5 J=2.8Hz), 6.85(2H, d, J=8.4Hz), 7.04(2H5 d, J=8.8Hz), 7.14(2H5 s) Example 115
[[3,5-Dichloro-4-(3-cyclohexylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.11-1.27(8H, m), 1.29-1.34(3H5 m), 1.68-1.72(2H, m),
3.11-3.13(1H, m), 3.79(3H5 s), 3.94(3H, s), 4.25-4.28(2H5 m), 4.41(2H9 bs), 4.83(1H, d,
J=7.6Hz), 6.87(2H5 d, J=8.0Hz)5 6.94-6.97(1H5 m), 7.05(3H5 d5 J=8.4Hz), 7.40-
7.41(1H5 m), 7.52(2H5 s) Example 116
[ { 3 ,5 -Dichloro-4- [4-methoxy-3 -(morpholine-4-sulfonyl)-phenoxy] -phenyl} -(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester 1H NMR: (CDCl3, 400MHz): 1.32(3H, t, J=7.2Hz), 3.23(4H5 " t, J=4.8Hz), 3.71 (4H, t,
J=4.8Hz), 3.79(3H5 s), 3.89(3H, s), 4.41(2H, m), 4.46(2H, s), 6.87(2H, d, J=8.8Hz),
6.92(1H, d, J=4.8Hz), 6.95 -7.03(3H, m), 7.4(1H, d, J=2.8Hz), 7.52(2H, s) Example 117 [ { 3 ,5 -Dichloro-4- [4-methoxy-3 -(pyrrolidine- 1 -sulfony l)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR : (DMSO-D6, 400MHz) : 1.32(3H, t, J=7.2Hz), 1.81-1.84(4H, m), 3.36-
3.39(4H5 m), 3.79(3H, s), 3.90(3H, s), 4.29(2H5 m), 4.40-4.47(2H, bs), 6.87(2H, d,
J=8.8Hz)5 6.94(1H, d, J=8.8Hz), 7.04(3H, d, J=8.8Hz), 7.44(1H, d, J=2.8Hz), 7.51(2H, s)
Example 118
{ [4-(4-Benzyloxy-3 -isobutoxy-phenoxy)-3 ,5 -dichloro-phenylj-ethoxycarbonyl-amino } - acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz): 1.05(6H, d, J=6.8Hz), 1.26-1.32(6H5 m), 2.12-2.19(1H, m), 3.77(2H, d, J=6.4Hz)5 4.19-4.28(4H5 m), 4.31(2H, s), 5.05(2H, s), 6.08-6.11(1H, dd, J=2.4Hz & 8.4Hz), 6.64(1H5 d, J=2.8Hz), 6.77(1H, d, J=8.8Hz), 7.29-7.30(1H, m),
7.33-7.38(4H, m), 7.42-7.44(2H, m) Example 119
[ { 3 ,5-Dichk>rό-4- [4-methoxy-3 -(3 -methyl-benzoyl)-phenoxy] -phenyl } -(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester
1H NMR: (CDCl3, 400MHz) : 1.30(3H, t, J=7.2Hz), 2.37(3H, s), 3.68(3H, s), 3.78(3H, s), 4.27(2H, s), 4.37-4.45(2H5 bs), 6.84-6.87(3H5 m), 6.92(1H, d5 J=9.2Hz), 7.02(3H5 d, J=8Hz), 7.30(1H5 d, 1=7.6Hz), 7.35(1H5 d5 J=7.2Hz), 7.49(2H5 s), 7.56(1H, d5 J=7.6Hz)5 7.64(1 H, s) Example 120
[{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester
1H NMR: (DMSO-D6, 400MHz): 4.43(2H, s), 6.73(3H5 d, J=8.8Hz)5 6.90-6.95(4H5 m), 7.57(2H5 d, J=8.4Hz), 7.68(2H5 d, J=8.4Hz), 7.83(2H5 s) Example 121
[{355-Dichloro-4-[4-methoxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester 1H NMR: (CDCl3, 400MHz) : 1.3(3H, t, J=7.2Hz), 2.36(3H, s), 3.68(3 H, s), 4.27(2H, s), 4.37-4.45(2H, bs), 6.83-6.99(5H, m), 7.03(2H, d, J=8.0Hz), 7.22(2H, d, J=8.0Hz), 7.49(2H, s), 7.71(2H, d5 J=8.0Hz)
Activity data:
Invitro TR-α & TR-β activities were determined as per in-house protocols and the results of representative compounds are provided in tables 1 & 2 below as a proof of the efficacies of the novel class of compounds disclosed above.
Table 1 :
Figure imgf000052_0001
Table 2:
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000054_0001
* Fold Induction w.r.t T3(100 nni)
The data above clearly indicates that several of the novel compounds of the present invention are selective to TR-beta receptor and therefore have potential therapeutically beneficial properties.
In-vivo studies:
Dose-response effects of T3 and selected compounds disclosed in the present invention on, cholesterol lowering and change in heart rate in cholesterol-fed rats (treated for 7 days) was determined according to the general protocol described in PNAS, August 19, 2003,vol. 100 (17) 10067-10072. Many of the compounds were found to be reducing cholesterol and having very little effect on the heart rate. Therefore, these compounds have the potential to be further developed as selective TR- beta agonists for the treatment of human and other animals in need of such treatment.
The novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as Thyroid hormone receptor ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc. The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention. The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

Claims

We claim
1. A compound of formula (I) including its tautomers and pharmaceutically acceptable salts
Figure imgf000056_0001
Formula (1) wherein, R = ORi, NHRi, wherein further R1 is selected from H, optionally substituted groups selected from (Q-C^alkyl, Br(C1 -C6)alkyl groups; R2 represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (Q-C^alkyl, acyl, oxo, (C3- C7)cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives selected from (Ci-C3)alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing -CONR5R6, -SO2NR5R6, wherein R5 & R6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-C^alkyl, (C3-C7)cycloalkyl, bicycloalkyl, aryl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O; R3, R4 are same or different and independently selected from H, halogen, optionally substituted (Q-C^alkyl groups; X is selected from O, - CH2-, CO; V represents the integers O or 1; R7 represents H, optionally substituted groups selected from (Q-C^alkyl, aryl groups; with the provision that when n =0, R7 does not represent 'H'.
2. A compound of formula (I) as claimed in claim 1, wherein R1 is selected from H, optionally substituted groups selected from (C1-C3)alkyl, phenyl(C i-C3)aIkyl groups; R2 is selected from acyl, oxo groups or optionally substituted groups selected from (C1-C6)alkyl, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives selected from (CrC3)alkyl esters and amides, or the groups representing
-CONR5R6 , -SO2NR5R<5, wherein R5 & R6 may be same or different and are independently selected from H, optionally substituted groups selected from (C1-
C6)alkyl, (C3-C7)cycloalkyl, bicycloalkyl, phenyl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, O; R-3, R4 are same or different and independently selected from H, halogen, optionally substituted (d-C6)alkyl groups; X is selected from O, -CH2-, CO; 'n' represents 0 or 1; R7 represents H, optionally substituted groups selected from (C]- C6)alkyl, aryl groups; with the provision that when n =0, R7 does not represent 'H'.
3. The compound as claimed in claim 1 or 2 wherein the substituents on R2 are selected from hydroxy, halo, or optionally substituted groups selected from (C1- Ce)alkyl, phenyl, heteroaryl groups.
4. The compound as claimed in claim 1 or 2 wherein the substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxyl, halo, cyano, optionally substituted groups selected from (C1-C6)alkyl, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups.
5. The compound as claimed in any one of claims 1 to 4 selected from {[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid;
{ [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbony 1- amino} -acetic acid;
{ [4-(3 -Benzyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbony 1-amino } - acetic acid; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro- phenyl } -ethoxycarbonyl-amino)-acetic ac jd;
({ 3 ,5 -Dichloro-4- [4-hydroxy-3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid;
{ [3 ,5 -Dichloro-4-(3 -ethyl-4-hydroxy-phenoxy)-phenyl] -ethoxycarbonyl-amino } - acetic acid;
{[3,5-Dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- ethoxycarbony 1-amino} -acetic acid;
({3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-piperazine-l-carbonyl)-phenoxy]- phenyl } -ethoxycarbonyl-amino)-acetic acid; {[3,5 -Dichloro-4-(3 -dimethylcarbamoyl-4-hydroxy-phenoxy)-ρhenyl]- ethoxycarbony 1-amino} -acetic acid;
{[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-hydroxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid; { [3 ,5-Dichlor'o-4-(4-hydroxy-3 -propyl-phenoxy)-phenylj -ethoxycarbonyl-amino } - acetic acid;
{[3,5-Dichloro-4-(4-hydroxy-3~isopropylcarbamoyl-phenoxy)-phenyl]- ethoxycarbonyl-amino } -acetic acid; {[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino} -acetic acid;
{[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid;
({3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid;
{ [3 ,5 -Dichloro-4-(3 -diethylcarbamoyl-4-hydroxy-phenoxy)-phenyl] - ethoxycarbonyl-amino} -acetic acid;
( { 3 ,5 -Dichloro-4-[3 -(5 -chloro-thiophene-2-carbonyl)-4-hydroxy-phenoxy] - phenyl}-ethoxycarbonyl-amino)-acetic acid; { [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dimethyl-phenyl] -ethoxycarbonyl- amino} -acetic acid;
{[3,5-Dichloro-4-(4-hydroxy-3-phenylcarbamoyl-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid;
( { 3, 5-Dichloro-4-[3 -(4-chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } - ethoxycarbonyl-aminoj-acetic acid;.
{[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-carboxymethyl- amino} -acetic acid;
({3,5-Dichloro-4-[3-(2,4-dichloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid; [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
({4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid;
({3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-hydrbxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid;
{[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-carboxymethyl- amino} -acetic acid; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro- phenyl}-carboxymethyl-amino)-acetic acid;
(Carboxymethyl-{3,5-dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]- phenyl}-amino)-acetic acid; (Carboxymethyl- { 3 ,5 -dichloro-4- [4-hydroxy-3 -(piperidine- 1 -carbonyl)-phenoxy] - phenyl} -amino)-acetic acid;
({4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dichloro- phenyl } -carboxymethyl-amino)-acetic acid;
{Carboxymethyl-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]- amino} -acetic acid;
[[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
(Carboxymethyl-{3,5-dichloro-4-[4-hydroxy-3-(piperidme-l-sulfonyl)-phenoxy]- phenyl}-amino)-acetic acid; { [4-(3 -tert-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -carboxymethyl- amino} -acetic acid;
[[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
(Carboxyni-ethyl-[3,5-dichloro-4-(3-dimethylcarbanioyl-4-hydroxy-phenoxy)- phenyl] -amino } -acetic acid;
{Carboxymethyl-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]- amino} -acetic acid;
[[3,5-Dichloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; [[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-sulfonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid; [[4-(4-Hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; [{4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid;
[{3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; [[3,5-Dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
{Carboxymethyl-[3,5-dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-amino}- acetic acid;
[{3,5 -Dichloro-4-[3 -(3 -chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid;
[[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; [ [4-(3 -Benzyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; r{4-[3-(Bicyclor2.2.11hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3.5-dichloro- phenyl} -(4-hydroxy-phenoxycarbonyl)-amino]-acetic acid;
[{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dibromo- phenyl}-(4-hydroxy-ρhenoxycarbonyl)-amino]-acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(4-hydroxy-benzoyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino] -acetic acid; [{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[(3,5-Dichloro-4-{3-[(4-chloro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-(4-hydroxy-phenoxycarbonyl)-amino]-acetic acid;
[{4-[3-(Azepane-l-sulfonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid;
({3,5-Dichloro-4-[3-(l-ethyl-propoxy)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid; [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[[3,5-Dichloro-4-(3-cyclohexylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid; [{3,5-Dichloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino] -acetic acid;
({3,5 -Dichloro-4- [4-hydroxy-3 -(3 -methyl-benzoyl)-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid;
[{3,5-Dichloro-4-[4-hydroxy-3-(pyrrolidine-l-sulfonyl)-phenoxy]-phenyl}-(4- hydroxy-phenoxycarbonyl)-amino]-acetic acid;
{[3,5-Dichloro-4-(4-hydroxy-3-isobutoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid;
{[3,5-Dichloro-4-(3-cyclohexylmethoxy-4-hydroxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid; [{3,5-Dichloro-4-[4-hydroxy-3-(3-methyl-benzoyl)-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
[{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-(4-hydroxy- phenoxycarbonyl)-amino] -acetic acid;
({3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid;
({3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid;
[ { 3 ,5-Dichloro-4- [4-hydroxy-3 -(4-methyl-benzoyl)-phenoxy] -phenyl } -(4-hydroxy- phenoxycarbonyl)-amino]-acetic acid; {[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester;
{[4-(4-Benzyloxy-3-isopropyl-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester;
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl- amino } -acetic acid ethyl ester;
{ [4-(3 -Benzyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbonyl-amino } - acetic acid ethyl ester; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-methoxy-phenoxy]-3,5-dichloro- phenyl}-ethoxycarbonyl-amino)-acetic acid ethyl ester; ( { 3 ,5-Dichloro-4- [4-methoxy-3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester; { [3 ,5-Dichloro-4-(3 -ethyl-4-methoxy-phenoxy)-phenyl] -ethoxycarbonyl-amino } - acetic acid ethyl ester;
{[3;5-Dichloro-4-(3-cyclohexylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
( { 3 ,5-Dichloro-4- [4-methoxy-3 -(4-methyl-piperazine- 1 -carbonyl)-phenoxy] - phenyl }-ethoxycarbonyl-amino)-acetic acid ethyl ester;
{[355-Dichloro-4-(3-dϊmethylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester; {[3,5-Dichloro-4-(4-methoxy-3-propyl-phenoxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-isopropylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
{ [4-(3 -tetstfButyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl] -ethoxycarbonyl- amino} -acetic acid ethyl ester;
{[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-ethoxycarbonyl-amino}- acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester; {[3,5-Dichloro-4-(3-diethylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(5-chloro-thiophene-2-carbonyl)-4-methoxy-phenoxy]- phenyl}-ethoxycarbonyl-amino)-acetic acid ethyl ester; {[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester;
{[3,5-Dichloro-4-(4-methoxy-3-phenylcarbamoyl-phenoxy)-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester; ( { 3 ,5-Dichloro-4- [3 -(4-chloro-benzoyl)-4-methoxy-phenoxy] -phenyl } - ethoxycarbonyl-amino)-acetic acid ethyl ester;
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dimethyl-ρhenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester; ({3,5-Dichloro-4-[3-(2,4-dichloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
[[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
({4-[3-(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
({3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
{[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichlorό-phenyl]- ' ethoxycarbonylmethyl-amino} -acetic acid ethyl ester; ({4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-methoxy-phenoxy]-3,5-dichloro- phenyl}-ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; ( { 3 ,5-Dichloro-4- [3 -(4-chloro-benzoyl)-4-methoxy-phenoxy] -phenyl } - ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; ({3,5-Dichloro-4-[4-methoxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}- ethoxycarbonylmethyl-amino)-acetic acid ethyl ester;
( {4- [3 -(Bicyclo [2.2.1 ]hept-2-ylsulfamoyl)-4-methoxy-phenoxy] -3 ,5 -dichloro- phenyl}-ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; {[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester; [[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; . ({3,5-Dichloro-4-[4-methoxy-3-(piperidine-l-sulfonyl)-phenoxy]-phenyl}- ethoxycarbonylmethyl-amino)-acetic acid ethyl ester; { [4-(3 -tert-Butyl-4-methoxy-phenoxy)-3 ,5 -dichloro-phenyl] - ethoxycarbonylmethyl-amino} -acetic acid ethyl ester;
[[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; {[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-phenoxy)-phenyl]- ethoxycarbonylmethyl-amino} -acetic acid ethyl ester; {Ethoxycarbonylmethyl-[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl- phenyl] -amino} -acetic acid ethyl ester; [[335-Dichloro-4-(3-dimethylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[ { 3 ,5 -Dichloro-4- [4-methόxy-3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[ { 3 ,5-Dichloro-4- [4-methoxy-3 -(piperidine- 1 -sulfonyl)-phenoxy] -phenyl } -(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester; [[4-(3-Isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; [{4-[3-(4-tert-Butyl-benzoyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[{3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[[3,5-Diclilfiro-4-(3-isopropylsulfarnoyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyty-aminoj-acetic acid ethyl ester;
{[3,5-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyl]-ethoxycarbonylmethyl- amino} -acetic acid ethyl ester;
[{3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [[3,5-Dichloro-4-(3-ethyl-4-methoxy-phenoxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester-; [[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester; [[4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester; [{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-methoxy-phenoxy]-3,5-dichloro- phenyl}-(4-methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[{4-[3_(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-methoxy-phenoxy]-3,5-dibromo- phenyl}-(4-methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester; [{3,5-Dichloro-4-[4-methoxy-3-(4-methoxy-benzoyl)-phenoxy]-phenyl}-(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
[{4-[3-(Azepane-l-sulfonyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl}-(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
({4-[4-Benzyloxy-3-(l-ethyl-propoxy)-phenoxy]-3,5-dichloro-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
[[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dimethyl-ρhenyl]-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester; [[3,5-Dichloro-4-(3-cyclohexylsulfamoyl-4-methoxy-phenoxy)-phenyl]-(4- methoxy-phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[ { 3 ,5-Dichloro-4-[4-methoxy-3-(moφholine-4-sulfonyl)-phenoxy]-phenyl } -(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
({3,5-Dichloro-4-[4-mcthoxy-3-(3-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
[ { 3 ,5 -Dichloro-4- [4-methoxy-3 -(pyrrolidine- 1 -sulfonyl)-phenoxy] -phenyl} -(4- methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester;
{ [4-(4-Benzyloxy-3 -isobutoxy-phenoxy)-3 ,5-dichloro-phenyl]-ethoxycarbonyl- amino} -acetic acid ethyl ester; *■ {[4-(4-Benzyloxy-3-cyclohexylmethoxy-phenoxy)-3,5-dichloro-phenyl]- ethoxycarbonyl-amino} -acetic acid ethyl ester;
[{3,5-pichloro-4-[4-methoxy-3-(3-methyl-benzoyl)-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester;
[{3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino]-acetic acid ethyl ester;
({3,5-Dibromo-4-[3-(4-chloro-benzoyl)-4-methoxy-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester; ({3,5-Dichloro-4-[4-methoxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}- ethoxycarbonyl-amino)-acetic acid ethyl ester;
[{3,5-Dichloro-4-[4-methoxy-3-(4-methyl-benzoyl)-phenoxy]-phenyl}-(4-methoxy- phenoxycarbonyl)-amino] -acetic acid ethyl ester.
6. A pharmaceutical composition which comprises compounds of formula (I), as claimed in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients. .
7. A method of preventing or treating diseases caused by dyslipidemia or obesity comprising administering an effective, non-toxic amount of compound of formula (I) or suitable pharmaceutical composition as defined in any preceding claims to a patient in need thereof.
8. A medicine for treating/reducing dyslipidemia or obesity which comprises administering a compound of formula (I), as defined in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients to a patient in need thereof.
9. Use of compounds of formula (I), their pharmaceutical compositions and medicines containing them as defined in any previous claims as a medicament suitable for the treatment of diseases mentioned in any of the aforesaid claims.
PCT/IN2007/000493 2006-10-31 2007-10-15 Selective tr-beta 1 agonist Ceased WO2008062469A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US12/446,820 US8420851B2 (en) 2006-10-31 2007-10-15 Selective TR-β 1 agonist
NZ576324A NZ576324A (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
BRPI0716345-2A BRPI0716345A2 (en) 2006-10-31 2007-10-15 COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD TO PREVENT OR TREAT DISEASE CAUSED BY DISLIPIDEMINE OR OBESITY, MEDICINE FOR TREATMENT AND / OR REDUCTION OF DISLIPIDEMIA OR OBESITY AND USE
AU2007322977A AU2007322977B2 (en) 2006-10-31 2007-10-15 Selective TR-BETA 1 agonist
JP2009534055A JP5021752B2 (en) 2006-10-31 2007-10-15 Selective TRbeta1 agonist
HK09110341.6A HK1131603B (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
EA200970426A EA017306B1 (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
CA2666427A CA2666427C (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
MX2009004619A MX2009004619A (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist.
EP07866730A EP2079678B1 (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
KR1020097008754A KR101165215B1 (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist
ES07866730T ES2400973T3 (en) 2006-10-31 2007-10-15 TR-beta 1 selective agonist
IL198047A IL198047A (en) 2006-10-31 2009-04-06 Selective tr-beta 1 agonist, pharmaceutical composition comprising the same and use thereof in the preparation of medicaments

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1813/MUM/2006 2006-10-31
IN1813MU2006 2006-10-31

Publications (2)

Publication Number Publication Date
WO2008062469A2 true WO2008062469A2 (en) 2008-05-29
WO2008062469A3 WO2008062469A3 (en) 2008-07-10

Family

ID=39277345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000493 Ceased WO2008062469A2 (en) 2006-10-31 2007-10-15 Selective tr-beta 1 agonist

Country Status (16)

Country Link
US (1) US8420851B2 (en)
EP (1) EP2079678B1 (en)
JP (1) JP5021752B2 (en)
KR (1) KR101165215B1 (en)
AU (1) AU2007322977B2 (en)
BR (1) BRPI0716345A2 (en)
CA (1) CA2666427C (en)
EA (1) EA017306B1 (en)
ES (1) ES2400973T3 (en)
IL (1) IL198047A (en)
MX (1) MX2009004619A (en)
NI (1) NI200900072A (en)
NZ (1) NZ576324A (en)
PT (1) PT2079678E (en)
WO (1) WO2008062469A2 (en)
ZA (1) ZA200902449B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010049946A3 (en) * 2008-10-27 2010-07-29 Cadila Healthcare Limited Thyroid receptor ligands
WO2010086878A2 (en) 2009-01-09 2010-08-05 Cadila Healthcare Limited Thyroid receptor modulators
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2602248A1 (en) * 2011-12-05 2013-06-12 University Of Leicester Novel pyrrole compounds

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6787652B1 (en) 1999-09-30 2004-09-07 Pfizer, Inc. 6-Azauracil derivatives as thyroid receptor ligands
EP1088819B1 (en) 1999-09-30 2005-06-15 Pfizer Products Inc. 6-azauracil derivatives as thyroid receptor ligands
ATE310733T1 (en) * 2000-04-21 2005-12-15 Pfizer Prod Inc THYROID RECEPTOR LIGANDS
DE10038007A1 (en) * 2000-08-04 2002-02-14 Bayer Ag New amino and amido diphenyl ethers for drugs
TW200504021A (en) 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
US7557143B2 (en) * 2003-04-18 2009-07-07 Bristol-Myers Squibb Company Thyroid receptor ligands
AU2007279092B2 (en) 2006-07-24 2012-12-13 Ucb Pharma S.A. Substituted aniline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010049946A3 (en) * 2008-10-27 2010-07-29 Cadila Healthcare Limited Thyroid receptor ligands
CN102197019A (en) * 2008-10-27 2011-09-21 卡迪拉保健有限公司 Thyroid receptor ligands
AU2009309229B2 (en) * 2008-10-27 2012-03-15 Cadila Healthcare Limited Thyroid receptor ligands
JP2012506854A (en) * 2008-10-27 2012-03-22 カディラ・ヘルスケア・リミテッド Thyroid receptor ligand
WO2010086878A2 (en) 2009-01-09 2010-08-05 Cadila Healthcare Limited Thyroid receptor modulators
WO2010086878A3 (en) * 2009-01-09 2010-10-21 Cadila Healthcare Limited Thyroid receptor modulators
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2602248A1 (en) * 2011-12-05 2013-06-12 University Of Leicester Novel pyrrole compounds
WO2013083975A3 (en) * 2011-12-05 2013-08-08 University Of Leicester Novel pyrrole derivatives
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives

Also Published As

Publication number Publication date
JP5021752B2 (en) 2012-09-12
CA2666427C (en) 2011-12-13
AU2007322977A1 (en) 2008-05-29
JP2010508263A (en) 2010-03-18
WO2008062469A3 (en) 2008-07-10
EP2079678A2 (en) 2009-07-22
US8420851B2 (en) 2013-04-16
PT2079678E (en) 2013-03-05
IL198047A0 (en) 2009-12-24
CA2666427A1 (en) 2008-05-29
NI200900072A (en) 2010-01-26
EA200970426A1 (en) 2009-10-30
EA017306B1 (en) 2012-11-30
MX2009004619A (en) 2009-05-15
HK1131603A1 (en) 2010-01-29
KR20090076948A (en) 2009-07-13
EP2079678B1 (en) 2012-12-19
US20100048550A1 (en) 2010-02-25
ES2400973T3 (en) 2013-04-15
BRPI0716345A2 (en) 2014-08-05
KR101165215B1 (en) 2012-07-11
IL198047A (en) 2013-08-29
AU2007322977B2 (en) 2010-08-12
ZA200902449B (en) 2010-04-28
NZ576324A (en) 2011-08-26

Similar Documents

Publication Publication Date Title
WO2007132475A1 (en) Selective tr-beta 1 agonist
US6316503B1 (en) LXR modulators
JP4113266B2 (en) Nitrogen compounds
JP2005162759A (en) Oxamic acid and its derivatives as thyroid receptor ligands
AU2007322977B2 (en) Selective TR-BETA 1 agonist
EP3573972B1 (en) Rorgamma modulators and uses thereof
EP2435400A2 (en) Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
CA2922716C (en) Aromatic compound and use thereof in the treatment of disorders associated with bone metabolism
WO2019105234A1 (en) Aromatic compound, pharmaceutical composition thereof and use thereof
HK1131603B (en) Selective tr-beta 1 agonist
AU2009309229B2 (en) Thyroid receptor ligands
CA2572153C (en) Phenylcarboxylic acid derivatives and use thereof for the treatment of diabetes
WO2010086878A2 (en) Thyroid receptor modulators
EP3266777A1 (en) Quinuclidine derivative
WO2007039482A1 (en) Thiophene derivatives for the treatment of diabetes
CN116655518A (en) A kind of isatin derivative and its preparation method and application
HK1160636A (en) Thyroid receptor ligands

Legal Events

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

Ref document number: 07866730

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 198047

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2007866730

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2666427

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 576324

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2007322977

Country of ref document: AU

Ref document number: 2009040567

Country of ref document: EG

ENP Entry into the national phase

Ref document number: 2009534055

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020097008754

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/004619

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 12009500843

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2007322977

Country of ref document: AU

Date of ref document: 20071015

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 200970426

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 12446820

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: PI0716345

Country of ref document: BR

Free format text: VIDE PARECER NO E-PARECER.

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: PI0716345

Country of ref document: BR

Free format text: EM ADITAMENTO A EXIGENCIA PUBLICADA NA RPI 2231 DE 08/10/2013, APRESENTE DOCUMENTOS COMPROBATORIOS (POR EXEMPLO: CONTRATO SOCIAL DE MARTINEZ & MOURA BARRETO S/S LTDA.) QUE COMPROVEM QUE O SIGNATARIO DAS PETICOES NO 018090022052 DE 30/04/2009, NO 018090033200 DE 26/06/2009, NO 018100038479 DE 14/10/2010 E NO 018130039367 DE 04/12/2013 TEM PODERES PARA ATUAR EM NOME DO DEPOSITANTE, UMA VEZ QUE BASEADO NO ARTIGO 216 DA LEI 9.279/1996 DE 14/05/1996 (LPI) "OS ATOS PREVISTOS NESTA LEI SERAO PRATICADOS PELAS PARTES OU POR SEUS PROCURADORES, DEVIDAMENTE QUALIFICADOS.".

ENP Entry into the national phase

Ref document number: PI0716345

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090430