WO2007132475A1 - Selective tr-beta 1 agonist - Google Patents

Selective tr-beta 1 agonist Download PDF

Info

Publication number
WO2007132475A1
WO2007132475A1 PCT/IN2007/000159 IN2007000159W WO2007132475A1 WO 2007132475 A1 WO2007132475 A1 WO 2007132475A1 IN 2007000159 W IN2007000159 W IN 2007000159W WO 2007132475 A1 WO2007132475 A1 WO 2007132475A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenoxy
dichloro
phenyl
dione
hydroxy
Prior art date
Application number
PCT/IN2007/000159
Other languages
French (fr)
Inventor
Saurin Raval
Preeti Raval
Braj Bhushan Lohray
Vidya Bhushan Lohray
Pankaj Ramanbhai Patel
Original Assignee
Cadila Healthcare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2007132475A1 publication Critical patent/WO2007132475A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds of general formula (I) which are thyroid receptor ligands and are preferably selective for the thyroid ho ⁇ none 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.
  • 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
  • THR- ⁇ and THR- ⁇ 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 body weight, 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 l animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the TEDR. ⁇ 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 ligands and are preferably selective for the thyroid hormone receptor beta I 9 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.
  • 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.
  • novel compounds of the present invention as antidiabetic agents, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
  • R OR 15 NHR 1 wherein Ri may be selected from H, optionally substituted groups selected from (Ci- C6)alkyl, (C 3 -C 7 )cycloalkyl, acyl, aryl, aralkyl groups; in a preferred embodiment the alkyl groups is selected from (Ci-C 3 )alkyl and the aryl group represents optionally substituted phenyl group;
  • R 2 represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (Ci-C 6 )alkyl, acyl, oxo, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives such as (Ci-C 3 )alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing -CONRsR 6 , -SO 2 NRSR O , wherein
  • R 5 and R 6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-C6)alkyl, (C3-C 7 )cycloalkyl, bicycloalkyl, aryl or the groups R 5 and R 6 together with the nitrogen atom to which they are attached, form a six 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 (Ci-C 6 )alkyl, phenyl, heteroaryl groups;
  • the various groups representing R 2 may be selected from - optionally substituted (Ci-C ⁇ )alkyl, acyl, oxo, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives such as (Ci-C 3 )alkyl esters and amides, or the groups representing -CONR 5 R 6 , -SO 2 NR 5 R 6 , wherein
  • R 5 and R 6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-Ce)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 six to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
  • R 3 , R 4 may be same or different and independently selected from H, halogen, optionally substituted (Q-C ⁇ alkyl groups;
  • X is selected from O, -CH 2 -, CO;
  • Y is selected from O, S, -NH or the group representing -CR 7 Rs, wherein R 7 , R 8 may be same or different and independently selected from hydrogen, halogen optionally substituted groups selected from (Q-C ⁇ alkyl groups; Z may be selected from H, groups;
  • the substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxy 1, halo, cyano, optionally substituted groups selected from (Ci-C 6 )alkyl, 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:
  • alkyl used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, /7-propyl, ⁇ o-propyl, «-butyl, sec-butyl, tert-butyl, amyl, t-am ⁇ l, «-pentyl, n- hexyl, w ⁇ -hexyl and the like;
  • 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;
  • 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, /so-propoxy, R-butoxy, t-butoxy, ⁇ -butoxy, pentyloxy, hexyloxy, and the like;
  • haloalkyl is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(Ci-C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • perhaloalkyl more preferably, perfluoro(Ci-C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • 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;
  • 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
  • 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, wo-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
  • carboxylic acid used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides;
  • 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
  • alkylthio 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;
  • thioalkyl 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;
  • 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: l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; 1 - [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -[ 1 ,2,4]triazolidine-3 , 5 - dione;
  • This amine 2 was converted to it's corresponding hydrazine compound 3 by reacting the amine 2_with NaNO 2 and then reducing with SnCl 2 .2H 2 O.
  • Compound 3 may be reacted with Ethyl ailophanate to give a compound of formula (1).
  • Further compound of formula (V) may be prepared by suitably deprotecting the protecting group R.
  • Step 1 Preparation of 4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine To a solution of Stannous chloride dihydrate (3.46 g, O.Ol ⁇ mol) in concentrated
  • Step 2 Preparation of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
  • Step 3 Preparation of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
  • a solution of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione (180 mg, 0.42 mmol) in CH 2 Cl 2 (5 mL) was cooled to -60 0 C under nitrogen atmosphere. To that IM BBr 3 solution (0.85 mL) was added dropwise.
  • reaction mixture was allowed to warm up to 20-25 0 C over 3 h. Then diluted with more ethyl acetate (25 mL) and quenched with H 2 O(20 mL). After stirring at 20-25 0 C for 30-45 min organic phase was separated, washed with H 2 O & brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 100 mg of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione.
  • Step 1 Preparation of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
  • Stannous chloride dihydrate 10.97 g, 0.048 mol
  • concentrated HCl 3 mL
  • 3,5-dichloro-4-(4'-methoxy-3'-sec-butyl- phenoxy)nitrobenzene 4.5 g, 0.012 mol
  • EtOH 25 mL
  • the reaction mixture was refluxed for 2 h.
  • the resulting mixture was brought at 20-30 0 C and diluted with ethyl acetate (100 mL).
  • the mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite.
  • Step 2 Preparation of [4-(3-sec-Buty l-4-methoxy-phenoxy)-3, 5 -dichloro-phenyl] - hydrazine To a mixture of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
  • Step 4 Preparation of 1 -[4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3, 5 -dichloro-phenyl] - [l,2,4]triazolidine-3,5-dione
  • 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 (1) 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 (1) according to this invention.
  • the quantity of active component that is, the compounds of formula (1) 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)
  • 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. 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 ligands and are preferably selective for the thyroid hoπnone 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
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 body weight, 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 l animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the TEDR. 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 WO 0039077, WO 04/067482, WO 04/093799, US 6,344,481, which are incorporated herein as reference. US 6960604 describes compounds of the following general formula as TR beta agonists
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 ligands and are preferably selective for the thyroid hormone receptor beta I9 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
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
It is one of the important objects of the present invention 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 diabetes.
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 embodiment is provided the use of the novel compounds of the present invention as antidiabetic agents, 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)5
Figure imgf000005_0001
wherein
R = OR15 NHR1 wherein Ri may be selected from H, optionally substituted groups selected from (Ci- C6)alkyl, (C3-C7)cycloalkyl, acyl, aryl, aralkyl groups; in a preferred embodiment the alkyl groups is selected from (Ci-C3)alkyl and the aryl group represents optionally substituted phenyl group;
R2 represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (Ci-C6)alkyl, acyl, oxo, (C3-C7)cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives such as (Ci-C3)alkyl esters and amides, sulfenyl derivatives, sulfonyl derivatives or the groups representing -CONRsR6 , -SO2NRSRO, wherein
R5 and R6 may be same or different and are independently selected from H, optionally substituted groups selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, bicycloalkyl, aryl or the groups R5 and R6 together with the nitrogen atom to which they are attached, form a six 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 (Ci-C6)alkyl, phenyl, heteroaryl groups;
In a preferred embodiment, the various groups representing R2 may be selected from - optionally substituted (Ci-Cδ)alkyl, acyl, oxo, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives such as (Ci-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 H, optionally substituted groups selected from (Ci-Ce)alkyl, (C3-C7)cycloalkyl, bicycloalkyl, phenyl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a six to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O;
R3, R4 may be same or different and independently selected from H, halogen, optionally substituted (Q-C^alkyl groups;
X is selected from O, -CH2-, CO;
Y is selected from O, S, -NH or the group representing -CR7Rs, wherein R7, R8 may be same or different and independently selected from hydrogen, halogen optionally substituted groups selected from (Q-C^alkyl groups; Z may be selected from H,
Figure imgf000006_0001
groups;
The substituents on alkyl, aryl, heteroaryl or cycloalkyl groups may be selected from hydroxy 1, halo, cyano, optionally substituted groups selected from (Ci-C6)alkyl, 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, /7-propyl, ώo-propyl, «-butyl, sec-butyl, tert-butyl, amyl, t-amγl, «-pentyl, n- hexyl, wø-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, /so-propoxy, R-butoxy, t-butoxy, ώø-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(Ci-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, wo-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: l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; 1 - [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 ,5 -dichloro-phenyl] -[ 1 ,2,4]triazolidine-3 , 5 - dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dibromo-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-
2-hydroxy-benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N-dimethyl- benzenesulfonamide; l-[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4-[4-hydroxy-3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } - imidazolidine-2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-N,N-diethyl-2-hydroxy- benzenesulfonamide; l-[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-imidazolidine-2,4-dione;
N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy- benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N-methyl- benzenesulfonamide; l-[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dibromo-phenyl]-imidazolidine-2,4-dione;
N,N-Dicyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzenesulfonamide; l-[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-imidazolidine-2,4-dione; N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzamide;
N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy- benzenesulfonamide; 1 - {4- [3 -(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy] -3 , 5 -dichloro-phenyl } - imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4- [3 -(4-chloro-benzoy l)-4-hydroxy-phenoxy] -phenyl } -imidazolidine-
2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N-dimethyl- benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N-diisopropyl- benzenesulfonamide;
1 - { 3 , 5 -Dichloro-4- [3 -(4-fluoro-benzoy l)-4-hydroxy-phenoxy] -phenyl} -imidazolidine-
2,4-dione; 1 -[3 , 5 -Dichloro-4-(4-hydroxy-3 -isopropyl-phenoxy)-phenyl] - [ 1 ,2,4] triazolidine-3 , 5 - dione;
N-Adamantan-l-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydr oxy-benzamide ;
1 - { 3 , 5 -Dichloro-4- [3 -(5 -chloro-thiophene-2-carbonyl)-4-hydroxy-phenoxy] -phenyl} - imidazolidine-2,4-dione; l-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-sulfonyl)-phenoxy]-phenyl}- imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4-dione; l-[4-(4-Hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4-dione; l-[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-imidazolidine-2,4-dione; l-{3,5-Dichloro-4-[3-(3-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-imidazolidine-
2,4-dione; l-(4-{3-[(4-tert-Butyl-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-3,5-dichloro- phenyl)-imidazolidine-2,4-dione; l-(3,5-Dichloro-4-{3-[(4-chloro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-imidazolidine-2,4-dione; l-(3,5-Dichloro-4-{3-[(5-chloro-thiophen-2-yl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-imidazolidine-2,4-dione; 1 -(3 ,5 -Dichloro-4- { 3 - [(3 -chloro-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy } - phenyl)-imidazolidine-2,4-dione;
1 -(3 , 5 -Dichloro-4- { 3 - [(4-fluoro-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy } - phenyl)-imidazolidine-2,4-dione; l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4- methoxy -phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione;
1 - [4-(3 -sec-Butyl-4- methoxy -phenoxy)-3 , 5 -dichloro-phenyl] -[ 1 ,2,4]triazolidine-3 , 5 - dione;
N-Bicyclop^.lJhept^-yl-S-p^-dibromo^^^-dioxo-imidazolidin-l-yO-phenoxy]- 2- methoxy -benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N,N-dimethyl- benzenesulfonamide; l-[4-(3-Benzyl-4- methoxy -phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione;
1 - { 3 ,5 -Dichloro-4-[4- methoxy -3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } - imidazolidine-2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin- 1 -yl)-phenoxy]-N,N-diethyl-2- methoxy - benzenesulfonamide; l-[3,5-Dichloro-4-(4- methoxy -3-isopropyl-phenoxy)-phenyl]-imidazolidine-2,4- dione; N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l -yl)-phenoxy]-2- methoxy - benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin- 1 -yl)-phenoxy]-2- methoxy -N-methyl- benzenesulfonamide; l-[4-(3-Benzyl-4- methoxy -phenoxy)-3,5-dibromo-phenyl]-imidazolidine-2,4-dione; N,N-Dicyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzenesulfonamide;
1 -[3,5-Dichloro-4-(3-ethyl-4- methoxy -phenoxy)-phenyl]-imidazolidine-2,4-dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzamide; N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy - benzenesulfonamide;
1 - {4-[3-(4-tert-Butyl-benzoyl)-4- methoxy -phenoxy]-3,5-dichloro-phenyl} - imidazolidine-2,4-dione; 1 - { 3 , 5 -Dichloro-4-[3 -(4-chloro-benzoyl)-4- methoxy -phenoxy] -phenyl} - imidazolidine-2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N,N-dimethyl- benzamide; 5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N,N- diisopropyl-benzenesulfonamide; l-{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4- methoxy -phenoxy]-phenyl}-imidazolidine-
2,4-dione; l-[3,5-Dichloro-4-(4- methoxy -3-isopropyl-phenoxy)-phenyl]-[l,2,4]triazolidine-3,5- dione;
N-Adamantan-l-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzamide;
1 - { 3 , 5 -Dichloro-4- [3 -(5 -chloro-thiophene-2-carbonyl)-4- methoxy -phenoxy] -phenyl} - imidazolidine-2,4-dione; l-{3,5-Dichloro-4-[4- methoxy -3-(piperidine-l-sulfonyl)-phenoxy]-phenyl}- imidazolidine-2,4-dione;
1 -[4-(3-sec-Butyl-4- methoxy -phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4- dione; l-[4-(4- methoxy -3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4- dione; l-[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4- [3 -(3 -chloro-benzoy l)-4-methoxy-phenoxy] -phenyl } -imidazolidine- 2,4-dione; The novel 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. Scheme; 1 (Y=CH2, Z=H) / HCI
Figure imgf000013_0001
Figure imgf000013_0002
c|/γNγOCH2CH3
O O Dimethyl Aniline
16 h / 120 0C
Deprotection
Figure imgf000013_0003
Figure imgf000013_0004
°
The biaryl ether of formula 1 wherein R 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) or H, and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 2. Reduction may be carried out using reducing agents like Raney Ni, Pd/C, SnCl2.2H2O and the like. This amine 2 may be reacted with (2-Chloro-acetyl)-carbamic acid ethyl ester to give a compound of formula (T). Further compound of formula (D may be prepared by suitably deprotecting the protecting group R. Scheme: 2 (Y=NH, Zf=H)
/ HCI
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
The protected biaryl ether of formula (1) wherein 'R' 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) or H, and all other symbols are as defined elsewhere in the specification, was reduced to give amino compound of formula 2. Reduction may be carried out using reducing agents like Raney Ni, Pd/C, SnCl2.2H2O and the like. This amine 2 was converted to it's corresponding hydrazine compound 3 by reacting the amine 2_with NaNO2 and then reducing with SnCl2.2H2O. Compound 3 may be reacted with Ethyl ailophanate to give a compound of formula (1). Further compound of formula (V) may be prepared by suitably deprotecting the protecting group R.
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.
IH NMR spectral data given in the examples (vide infra) are recorded using a 300 MHz spectrometer (Bruker AVANCE-300) and reported in δ scale. Until and otherwise mentioned the solvent used for' NMR is CDCI3 using tetramethyl silane as the internal standard.
EXAMPLE l
Preparation of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
Step 1 : Preparation of 4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine To a solution of Stannous chloride dihydrate (3.46 g, O.Olόmol) in concentrated
HCl (2.0 mL) was added to 3,5-dichloro-4-(4'-methoxy-3'-isopropyl- phenoxy)nitrobenzene (1.5 g, 0.004 mol) in EtOH (10 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-tert-Butyl-4-methoxy-phenoxy)-
3,5-dichloro-phenylamine (1.35 g; % Yield: 97 % ). Step 2: Preparation of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione
4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (1.35 g, 3.97 mmol), ClCH2CONHCOOEt (0.657 g, 3.97 mmol) and PHNMe2 (0.48 g, 3.97 mmol) was heated at 120-130 0C for about 14-16 h. Resulting mixture was cooled to 20-30 0C, suitably diluted with ethyl acetate, washed with H2O & brine. Organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 1.3 g of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione. 1H NMR : (DMSO-D6, 300MHz) : 1.34(9H, s), 3.79(3H, s), 4.37(2H, s), 6.42-6.46(1H, dd, Jj=3Hz, J2=9Hz), 6.7O(1H, s), 6.94-6.95(1H, d, J=3Hz), 7.63(2H, s)
% Yield: 77 %
Step 3 : Preparation of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione A solution of l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione (180 mg, 0.42 mmol) in CH2Cl2 (5 mL) was cooled to -60 0C under nitrogen atmosphere. To that IM BBr3 solution (0.85 mL) was added dropwise.
The reaction mixture was allowed to warm up to 20-25 0C over 3 h. Then diluted with more ethyl acetate (25 mL) and quenched with H2O(20 mL). After stirring at 20-25 0C for 30-45 min organic phase was separated, washed with H2O & brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 100 mg of l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]- imidazolidine-2,4-dione.
1H NMR : (DMSO-D6, 300MHz) : 1.29(9H, s), 4.46(2H, s), 6.28-6.32(1H, dd, Ji=3.1Hz, J2=8.7Hz), 6.64(1H, d, J=3.0Hz), 6.72(1H, d, J=3.0Hz), 7.83(2H, s) % Yield: 57 % EXAMPLE 2
Preparation of l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichIoro-phenyl]- imidazolidine72,4-dione
Step 1 : Preparation of 2-sec-Butyl-4-(2,6-dichloro-4-nitro-phenoxy)-phenol
To a solution of 3,5-dichloro-4-(4'-methoxy-3'-sec-butyl-phenoxy)nitrobenzene (1.0 g, 2.7 mmol) in CH2Cl2 (15 mL) was cooled to -60 0C under nitrogen atmosphere. To that IM BBr3 solution (5.4 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 3 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. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 0.489 g of 2-sec-Butyl-4-(2,6-dichloro-4- nitro-phenoxy)-phenol. % Yield: 49 % Step 2: Preparation of 4-(4-Amino-2,6-dichloro-phenoxy)-2-sec-butyl-phenol. To a solution of Stannous chloride dihydrate (1.24 g, 5.51 mmol) in concentrated HCl (0.6 mL) was added to 2-sec-Butyl-4-(2,6-dichloro-4-nitro-phenoxy)- phenol (0.489 g, 1.37 mmol) in EtOH (6.19 mL).The reaction mixture was refluxed for 2 h. The resulting mixture was brought at 20-30 0C and diluted with ethyl acetate (25 mL).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-(4-Amino-2,6-dichloro-phenoxy)-2-sec- butyl-phenol (0.444 g). % Yield: 99 % Step 3 : l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4- dione
4-(4-Amino-2,6-dichloro-phenoxy)-2~sec-butyl-phenol (0.444 g, 1.36 mmol),
ClCH2CONHCOOEt (0.225 g, 1.36 mmol) and PHNMe2 (0.164 g, 1.36 mmol) was heated at 120-130 0C for 16 h. Resulting mixture was cooled to 20-30 0C, diluted with ethyl acetate (25 mL), washed with H2O, brine. Organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography
(Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to 90:10) to give 52 mg of 1-
[4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 , 5 -dichloro-phenyl] -imidazolidine-2,4-dione 1H NMR : (DMSO-D6, 300MHz) : 0.75(3H, t, J=7.5Hz), 1.06(3H, d, J=6.9Hz), 1.42-
1.5(2H, m), 2.92-2.94(1H, m), 4.45(2H, s), 6.31-6.35(1H, dd, 1^3.3Hz, J2=8.7Hz),
6.57(1H, d, J=3Hz), 6.67 (IH, d, J=8.7Hz), 7.83(2H, s)
% Yield: 10 %
EXAMPLE 3 Preparation of l-[4-(3-sec-ButyI-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-
[l,2,4]triazoIidine-3,5-dione
Step 1: Preparation of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine To a solution of Stannous chloride dihydrate (10.97 g, 0.048 mol) in concentrated HCl (3.3 mL) was added 3,5-dichloro-4-(4'-methoxy-3'-sec-butyl- phenoxy)nitrobenzene (4.5 g, 0.012 mol) in EtOH (25 mL).The reaction mixture was refluxed for 2 h. The resulting mixture was brought at 20-30 0C and diluted with ethyl acetate (100 mL).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 (4.0 g).
% Yield: 96 %
Step 2: Preparation of [4-(3-sec-Buty l-4-methoxy-phenoxy)-3, 5 -dichloro-phenyl] - hydrazine To a mixture of 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine
(2.1 g, 0.006 mol) in acetic acid (10.5 mL) at 0-5 0C concentrated HCl (42 mL) was added. To that a solution Of NaNO2 (0.55 g, 0.008 mol) in H2O (1.6 mL) was added dropwise while maintaining temp at. 0-5 0C. The reaction was stirred at 0-5 0C for lh.To the reaction mixture Stannous chloride dihydrate (5.56 g, 0.024 mol) in concentrated HCl (5.5 mL) was added at 0-5 0C. The reaction mixture was again stirred at 0-5 0C for Ih. Resulting solid (2.1 g) was filtered and taken for next step without purification. Step 3 : Preparation of l-[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]- [l,2,4]triazolidine-3,5-dione
[4-(3 -sec-Butyl-4-methoxy-phenoxy)-3 , 5 -dichloro-phenyl] -hydrazine (2.1 g, 0.005 mol) (prepared as in step 2) was stirred with Ethyl allophanate (0.78 g, 0.005 mol) in xylene (15 mL) and NEt3 (0.82 mL) at 120 0C for 16 h. Xylene was evaporated under reduced pressure. The residue was taken in 10% NaOH solution (25 mL) and washed with diethyl ether. Aqueous phase was separated and acidified with 10% HCl at 10-20 0C to afford the product as solid. The solid product (0.88 g) was filtered. 1H NMR: (DMSO-D6, 300MHz) : 0.75(3H, t, J=7.32Hz), 1.07(3H, d, J=6.9Hz), 1.42- 1.52(2H, m), 2.95-3.02(1H, m), 3.71(3H, s), 6.42-6.46(1H, dd, 1^2.94Hz, J2=8.85Hz), 6.71(1H, d, J=3 Hz), 6.84(1H, d, J=8.94Hz), 7.74 (2H, s) % Yield: 35 %
Step 4: Preparation of 1 -[4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3, 5 -dichloro-phenyl] - [l,2,4]triazolidine-3,5-dione
To a solution of l-[4-(3-sec-Butyl-4-methoxy-phenoxy)-3, 5 -dichloro-phenyl] - [l,2,4]triazolidine-3,5-dione (0.88 g, 0.002 mol) in CH2Cl2 (15 mL) was cooled to -60
0C under nitrogen atmosphere. To that IM BBr3 solution (6.22 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 0C over 3 h. The mixture was diluted with more ethyl acetate (25 mL) and quenched with H2O (25 mL).
After stirring at 20-25 0C for 30 min organic phase separated, washed with H2O, brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (Silicgel, Hexane: ethyl acetate gradient elution from 95:5 to
90:10) to give 170 mg of l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-
[ 1 ,2,4]triazolidine-3 , 5 -dione
1H NMR : (DMSO-D6, 300MHz) : 0.75(3H, t, J=7.30Hz), 1.06(3H, d, J=6.87Hz), 1.4- 1.53(2H, m), 2.9O-2.96(1H, m), 6.31-6.35(1H, dd, J!=3.06Hz, J2=8.79Hz), 6.59(1H, d,
J=3Hz), 6.67(1H, d, J=8.7Hz), 7.72(2H, s)
% Yield: 18 %
Using appropriate starting materials and suitable modifications of the processes described above, 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 4
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dibromo-4-(2,4-dioxo-imidazolidin-l-yI)-phenoxy]- 2-hydroxy-benzamide
1H NMR : (DMSO-D6, 300MHz) : 1.11-1.18(3H, m), 1.3-1.52(4H, m), 1.5-1.75(1H, m),
2.06-2.25(2H, m), 3.6-3.75(1H, m), 4.47(2H, s), 6.64-6.68(1H, dd, Ji=3Hz, J2=9Hz),
6.84(1H, d, J=8.9 Hz), 7.55(1H, d, J=3Hz), 8.01(2H, s)
% Yield: 20 % - EXAMPLE 5
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N-dimethyl- benzenesulfonamide
1H NMR : (DMSO-D6, 300MHz) : 2.68(6H, s), 4.47(2H, s), 6.9O(1H, d, J=3.0Hz),
7.01(1H, d, J=8.91Hz), 7.08-7.12(1H, dd, J,=3.03Hz, J2=8.85Hz), 7.88(2H, s) % Yield: 48 %
EXAMPLE 6 l-[4-(3-BenzyI-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 3.81(2H, s), 4.46(2H, s), 6.36-6.40 (IH, dd, Ji=3Hz,
J2=9Hz), 6.58(1H, d, J=3.06Hz), 6.70 (IH, d, J=9.0Hz), 7.11-7.26(5H, m), 7.81(2H, s) % Yield: 72 %
EXAMPLE 7 l-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}- iniidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 1.43(4H, m), 1.54(2H, m), 3.2-3.4(4H, m), 4.47(2H, s), 6.41(1H, d, J=3Hz), 6.72-6.76(1H, dd, Ji=3.3Hz, J2=9.0Hz), 6.81(1H, d, J=8.7Hz),
7.84(2H, s)
% Yield: 16 %
EXAMPLE 8
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-N,N-diethyl-2-hydroxy- benzenesulfonamide
1H NMR : (DMSO-D6, 300MHz) : 0.97(6H, t, J=6.9Hz), 3.17-3.24(4H, m), 4.47(2H, s), . 6.92(1H, d, J=3Hz), 6.97(1H, d, J=8.7Hz), 7.05-7.09(1H, dd, Ji=3.15Hz, J2=8.91Hz),
7.82(2H, s) % Yield: 7 % EXAMPLE 9 l-[3,5-Dichloro-4-(4-hydroxy-3-isopropyI-phenoxy)-phenyl]-imidazolidine-2,4- dione 1U NMR : (DMSO-D6, 300MHz) : 1.09(6H, d, J=6.9Hz), 3.11-3.16(1H, m), 4.47(2H, s), 6.27-6.30(1H, dd, Ji=3.06Hz, J2=8.7Hz), 6.64-6.67(2H, m), 7.83(2H, s)
% Yield: 26 %
EXAMPLE 10
N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy- benzamide
1H NMR : (DMSO-D6, 300MHz) : 1.13-1.16(2H, m), 1.27-1.34(4H, m), 1.79(2H, m),
1.97(2H, m), 3.78(lH,m), 4.47(2H, s), 6.73-6.77(1H, dd, Ji=3.3Hz, J2=9Hz), 6.86(1H, d,
J=9Hz), 7.50(1H, d, J=3Hz), 7.87(2H, s)
% Yield: 22 % EXAMPLE 11
5-[2,6-Dichloro-4-(2,4-dioxo-imidazoIidin-l-yl)-phenoxy]-2-hydroxy-N-methyl- benzenesulfonamide
1H NMR : (DMSO-D6, 300MHz) : 2.37(3H, s), 4.48(2H, s), 6.9O(1H, d, J=3Hz),
6.99(1H, d, J=9Hz), 7.06-7.10(1H, dd,
Figure imgf000020_0001
J2=9Hz), 7.88(2H, s) % Yield: 12 %
EXAMPLE 12 l-[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dibromo-phenyl]-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 3.80(2H, s), 4.46(2H, s), 6.33-6.36(1H, dd, Ji=3Hz,
J2=6Hz), 6.55(1H, d, J=3Hz), 6.7O(1H, d, J=8.64Hz), 7.11-7.26(5H, m), 7.83(2H, s) % Yield: 19%
EXAMPLE 13
N,N-DicycIohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzenesulfonamide
1H NMR : (DMSO-D6, 300MHz) : 0.82-1.13(6H, m), 1.22-1.28(8H, m), 1.49-1.62(6H, m), 3.14-3.15(2H, m), 4.46(2H, s), 6.83(1H, d, J=3Hz), 6.97(1H, d, J=9Hz), 7.12(1H, m), 7.88(2H, s)
% Yield: 22 %
EXAMPLE 14 l-[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-imidazoIidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 1.06(3H, t, J=7.5Hz), 2.42-2.48(2H, m), 4.47(2H, s), 6.34-6.38(1H, dd, J1=SHz, J2=9Hz), 6.57(1H, d, J=3Hz), 6.67(1H, d, J=9Hz), 7.83(2H, s) % Yield: 9 % EXAMPLE 15
N-Bicyclo[2.2.1]hept-2-yI-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]- 2-hydroxy-benzamide
1H NMR : (DMSO-D6, 300MHz) : 1.13-1.18(4H, m), 1.46-1.64(4H, m), 2.22(2H, m),
3.71(1H, s), 4.48(2H, s), 6.7.-6.74(1H5 dd, Ji=3.06Hz, J2=8.97Hz), 6.85(1H, d,
J=I 1.3Hz), 7.54(1H, d, J=3.0Hz), 7.86(2H, s)
% Yield: 81 %
EXAMPLE 16 N-CycIohexyI-5-[2,6-dichIoro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy- benzenesulfonamide
1H NMR : (DMSO-D6, 300MHz) : 1.04-1.13(4H, m), 1.44-1.55(6H, m), 2.88(1H, m),
4.47(2H, s), 6.88(1H, d, J=3Hz), 6.97(1H, d, J=8.7Hz), 7.07-7.10(1H, m), 7.88(2H, s)
% Yield: 26 % EXAMPLE 17 l~{4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5-dichIoro-phenyl}- iinidazolidiiie-2,4~dione
1H NMR : (CDCl3, 400MHz) : 1.35(9H, s), 4.32(2H, s), 6.99(2H, s), 7.15(1H, d,
J=2.4Hz), 7.49(2H, d, J=8.4Hz), 7.62-7.65(4H, m) % Yield: 45 %
EXAMPLE 18 l-{3,5-Dichloro-4-[3-(4-chIoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}- imidazolidine-2,4-dione
1H NMR: (DMSO-D6, 400MHz) : 4.46(2H, s), 6.69(1H, d, J=3.2Hz), 6.92-6.99(2H5 m), 7.57(2H, d, J=8.4Hz), 7.69 (2H, d, J=8.4Hz ), 7.85(2H, s )
% Yield: 10 % EXAMPLE 19
5-[2,6-Dichloro-4-(2,4-dioxo-iraidazoIidin-l-yI)-phenoxy]-2-hydroxy-N,N-dimethyl- benzamide
1H NMR : (DMSO-D6, 300MHz) : 2.78-2.87(6H, m), 4.47(2H, s), 6.41(1H, d, J=3Hz), 6.74-6.84 (2H, m), 7.85(2H, s) % Yield; 10 % EXAMPLE 20
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N- diisopropyl-benzenesulfonamide 1HNMR : (CDCl3, 300MHz) : 1.21(12H, d, J=6.6Hz), 3.58-3.63(2H, m), 4.36(2H, s), 6.86(1H, d, J=3Hz), 6.96(1H, d, J=9Hz), 7.06-7.10(1H, dd, Ji=3Hz, J2=9Hz), 7.64(2H, s)
% Yield: 7 %
EXAMPLE 21 l-{3,5-DichIoro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyI}- imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.45(2H, s), 6.67(1H, m), 6.94(2H, m), 7.30-
7.36(2H, m) 7.73-7.78(2H, m), 7.85(2H, s)
% Yield: 17 % EXAMPLE 22 l-[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-[l,2,4]triazolidine-3,5- dione
1HNMR : (DMSO-D6, 300MHz) : 1.10(6H, d, J=6.87Hz), 3.09-3.18(1H, m), 6.27-
6.31(1H, dd, Ji=2.97Hz, J2=8.7Hz), 6.64-6.68(2H, m), 7.73(2H, s) % Yield: 67 %
EXAMPLE 23
N-Adamantan-l-yI-5-[2,6-dichloro-4-(2,4-dioxo-imidazoIidin-l-yl)-phenoxy]-2- hydroxy-benzamide
1H NMR : (DMSO-D6, 300MHz) : 1.63(6H, m), 2.09(9H, m), 4.48(2H, s), 6.85(2H, m), 7.29(1H, m), 7.87(2H, s)
% Yield: 50 %
EXAMPLE 24 l-{3,5-Dichloro-4-[3-(5-chloro-thiophene-2-carbonyl)-4-hydroxy-phenoxy]-phenyl}- imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.46(2H, s), 6.7O(1H, s), 6.94(2H, s), 7.25(1H, d, J=3.93Hz), 7.37(1H, d, J=3.93Hz) , 7.85(2H, s) % Yield: 21 % EXAMPLE 25 l-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-suIfonyl)-phenoxy]-phenyl}- imidazolidine-2,4-dione
1H NMR : (CDCl3, 300MHz) : 1.45-1.63(6H, m), 3.02(4H, t, J=5.4Hz), 4.38(2H, s), 6.84(1H, d, J=3.6Hz), 7.02(1H, d, J=9Hz), 7.07-7.11(1H, dd,
Figure imgf000023_0001
J2=9Hz), 7.66(2H, s)
% Yield: 11 %
EXAMPLE 26 l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyI-phenyl]-imidazoIidine-2,4- dione
1H NMR : (DMSO-D6, 300MHz) : 0.74(3H, t, J=7.3Hz), 1.04(3H, d, J=6.8Hz), 1.41-
1.44(2H, m), 2.03(6H, s), 2.9O-2.92(1H, m), 4.5(2H, s), 6.23-6.26(1H, m), 6.51(1H, d,
J=3Hz), 6.63 (IH, d, J=9Hz), 7.36(2H, s).
% Yield: 17 % EXAMPLE 27 l-[4-(4~Hydroxy-3-isopropyI-phenoxy)-3,5-dimethyl-phenyI]-imidazolidine-2,4- dione
1H NMR : (CDCl3, 300MHz) : 1.21(6H, d, J=8.1Hz), 2.14(6H, s); 3.13-3.18(1H, m),
4.37(2H, s), 6.27-6.31(1H, dd, J1=IJEz, J2=8.4Hz), 6.6O(1H, d, J=8.4Hz), 6.71(1H, d, J=3Hz), 7.26(2H, s)
% Yield: 30 %
EXAMPLE 28 l-[3,5-DichIoro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.46(2H, s), 6.64 (2H, d, J=7.2Hz), 6.87(1H, d, J=9.3Hz), 7.27-7.28(lH,d, J=6.9Hz), 7.37(2H, t, J=7.5Hz), 7.45(2H, d, J=6.9Hz),
7.85(2H, s)
% Yield: 14 %
EXAMPLE 29 l-{3,5-Dichloro-4-[3-(3-chIoro-benzoyl)~4-hydroxy-phenoxy]-phenyl}- imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.46(2H, s), 6.7O(1H, d, J=3.2Hz), 6.95(1H, d,
J=8.8Hz), 7.00-7.03(1H, m), 7.54(1H, d, J=8Hz), 7.61(2H, m), 7.68-7.70(1H, m), 7.85(2H, s)
% Yield: 97 % EXAMPLE 30 l-[3,5-Dichloro-4-(3-ethyI-4-methoxy-phenoxy)-phenyl]-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 1.07(3H, t, J=7.5Hz), 2.47-2.49(2H, m), 3.72(3H, s), 4.47(2H, s), 6.44-6.48(1H, dd,
Figure imgf000024_0001
J2=9Hz), 6.69-6.70(1H, d, J=3Hz), 6.85(1H, d,
J=8.94Hz), 7.85(2H, s)
% Yield: 63 %
EXAMPLE 31 l-[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-imidazolidine-2,4- dione
1H NMR : (CDCl3, 300MHz) : 1.18(6H, d, J=6.87Hz), 3.25-3.29(1H, m), 3.77(3H, s),
4.08(2H, s), 6.43-6.47(1H, dd, Ji=3Hz, J2=8.85 Hz), 6.62(2H, s), 6.67-6.70(1H, m),
6.84-6.85(1H, m),
% Yield: 34% EXAMPLE 32 l-[4-(3-tert-Butyl-4-methoxy-phenoxy)-3,5-dichIoro-phenyI]-imidazolidine-2,4- dione
1H NMR : (DMSO-D6, 300MHz) : 1.34(9H, s), 3.79(3H, s), 4.37(2H, s), 6.42-6.46(1H, dd, J!=3Hz, J2=9Hz), 6.72(1H, d, J=8.88Hz), 6.94(1H, d, J=3Hz), 7.63(2H, s) % Yield: 60 %
EXAMPLE 33 l-[4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 3.71(3H, s), 3.85(2H, s), 4.46(2H, s), 6.47-6.51(1H, dd, Ji=3Hz, J2=9Hz), 6.7O(1H, d, J=3Hz), 6.89(1H, d, J=9Hz), 7.12-7.17(3H, m), 7.22- 7.27(2H, m), 7.83(2H, s)
% Yield: 38 % EXAMPLE 34
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-
2-methoxy-benzamide
1H NMR : (CDCl3, 300MHz) : 1.16-1.3(8H, m), 2.29(2H, s), 3.86(1H, s), 3.93(3H, s), 4.35(2H, s), 6.92(1H, d, J=9Hz), 7.04-7.08(1H, dd, Ji=3Hz, J2=9Hz), 7.52(1H, d,
J=3.24Hz), 7.62(2H, s) ' % Yield: 40 %
EXAMPLE 35
N-Adamantan-l-yI-5-[2,6-dichloro-4-(2,4-dioxo-imidazoIidin-l-yl)-phenoxy]-2- methoxy-benzamide
1H NMR : (DMSO-D6, 300MHz) : 1.63(6H, m), 1.98(9H, m), 3.87(3H, s), 4.49(2H, s),
7.04-7.16(3H, m), 7.88(2H, s)
% Yield: 56 %
EXAMPLE 36 l-[3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-phenyl]-[l,2,4]triazolidine-3,5- dione
1H NMR : (DMSO-D6, 300MHz) : 1.11(6H, d, J=9Hz), 3.14-3.19(1H, m), 3.72(3H, s),
6.38-6.42(1H, dd, Ji=3Hz, J2=9Hz), 6.78-6.85(2H, m), 7.75(2H, s)
% Yield: 45 % EXAMPLE 37 l-[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-[l,2,4]triazolidine-3,5- dione
1H NMR : (DMSO-D6, 300MHz) : 0.75(3H, t, J=7.32Hz), 1.07(3H, d, J=6.9Hz), 1.42-
1.52(2H, m), 2.95-3.02(1H, m), 3.71(3H, s), 6.42-6.46(1H, dd, J!=2.94Hz, J2=8.85Hz), 6.71(1H, d, J=3 Hz), 6.84(1H, d, J=8.94Hz), 7.74 (2H, s)
% Yield: 35 %
EXAMPLE 38
Preparation of l-(4-{3-[(4-tert-Butyl-phenyl)-hydroxy-methyI]-4-hydroxy- phenoxy}-3,5-dichloro-phenyl)-imidazolidine-2,4-dione To a solution of l-{4-[3-(4-tert-Butyl-benzoyl)-4-hydroxy-phenoxy]-3,5- dichloro-phenyl}-imidazolidine-2,4-dione (300 mg, 0.58 mmol) (EXAMPLE 17) in
MeOH (1.5 mL) was added NaBH4 (66 mg, 1.7 mmol) at 0-5 0C. The reaction was stirred at 20-30 0C for 4 h. Reaction mixture was quenched with H2O. Product was extracted in ethyl acetate. Combined organic layer was washed with H2O, brine, dried over sodium sulphate and concentrated to afford crude product (290 mg). The crude product was purified by column chromatography (Silicgel, Hexane: ethyl acetate from
90:10) to give .203 mg of l-(4-{3-[(4-tert-Butyl-phenyl)-hydroxy-methyl]-4-hydroxy- phenoxy}-3,5-dichloro-phenyl)-imidazolidine-2,4-dione.
1H NMR : (CDCl3, 400MHz) : 1.31(9H, s), 4.34(2H, s), 5.92(1H, s), 6.49(1H, d,
J=2.8Hz), 6.58-6.61(1H, dd, Ji=3.2Hz, J2=9.2Hz), 6.81(1H, d, J=8.8Hz), 7.30(2H, d,
J=8.4Hz), 7.39(2H, d, J=8.4Hz), 7.60(2H, s)
% Yield: 67 % Using appropriate starting materials EXAMPLES 39-42 were prepared in analogous manner to that described in EXAMPLE 38.
EXAMPLES 39 l-(3,5-Dichloro-4-{3-[(4-chloro-phenyI)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)~imidazolidine-2,4-dione 1H NMR : (DMSO-D6 400MHz) : 4.47(2H, s), 5.82(1H, s), 6.50-6-53(1H, dd,
Ji=3.2Hz, J2=8.8 Hz), 6.68 (IH, d , J=8.8Hz), 6.87(1H, d , J=3.2Hz), 121-132 (4H, m),
7.84(2H, s)
% Yield: 97 %
EXAMPLES 40 l-(3,5-Dichloro-4-{3-[(5-chloro-thiophen-2-yI)-hydroxy-methyl]-4-hydroxy- phenoxy}-phenyl)-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.47(2H, s), 5.97(1H, d, J=4;35Hz), 6.17(1H, d,
J=4.68Hz), 6.59(1H, s), 6.74(1H, d, J=8.76Hz), 6.80 (IH, d, J=2.91Hz), 6.85(1H, d,
J=3.72Hz), 7.84(2H, s) % Yield: 50 %
EXAMPLES 41 l-(3,5-Dichloro-4-{3-[(3-chloro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}- phenyl)-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.47(2H, s), 5.84-5.88(1H, m), 6.52 -6.55(1H, dd, Ji=3.2Hz, J2=8.8Hz), 6.69(1H, d, J=8.8Hz), 6.87(1H, d, J=3.2Hz), 7.22-7.31(4H, m),
7.85(2H, s)
% Yield: 97 %
EXAMPLES 42 l-(3,5-DichIoro-4-{3-[(4-fluoro-phenyl)-hydroxy-methyI]-4-hydroxy-phenoxy}- phenyl)-imidazolidine-2,4-dione
1H NMR : (DMSO-D6, 300MHz) : 4.47(2H, s), 5.84(1H, s), 6.51(1H, d, J=5.31Hz),
6.67(1H, d, J=8.79Hz), 6.87(1H, s), 7.07(2H, m), 7.28(2H , m), 7.84(2H, s)
% Yield: 64 %
Activity data:
In vitro 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 imgf000027_0001
Table 2 :
Figure imgf000027_0002
Figure imgf000028_0001
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 (1) 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 (1) according to this invention.
The quantity of active component, that is, the compounds of formula (1) 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 imgf000029_0001
wherein
Figure imgf000029_0002
wherein Ri is selected from H, optionally substituted groups selected from (Q- C6)alkyl, (C3-C7)cycloalkyl, acyl, aryl, aralkyl groups;
R2 represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (Ci-Ce)alkyl, acyl, oxo, (C3-C7)cycloalkyl, aryl, heteroaryl, 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 are same or different and are independently selected from H, optionally substituted groups selected from (Ci-C6)alkyl, (C3- C7)cycloalkyl, bicycloalkyl, aryl or the groups R5 & R6 together with the nitrogen atom to which they are attached, form a six 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- C6)alkyl groups; X is selected from O, -CH2-, CO; Y is selected from O, S, -NH or the group representing -CR7R8, wherein R7, R8 are same or different and independently selected from hydrogen, halogen optionally substituted groups selected from (Q- Cό)alkyl groups; Z may be selected from H, (Q-C3)alkyl groups.
2. The compounds as claimed in claim 1, wherein the alkyl groups representing Ri is selected from (Q-C3)alkyl and the aryl group representing Ri represents optionally substituted phenyl group.
3. The compounds as claimed in claim 1, wherein R2 represents optionally substituted (Q-C6)alkyl, acyl, oxo, phenyl, heteroaryl, benzyl, carboxylic acid and its derivatives selected from (Ci-C3)alkyl esters and amides, or the groups representing -CONR5R6 ,
Figure imgf000030_0001
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 six to eight membered cyclic ring which may optionally contain one or more hetero atoms selected from N, S, O. '
4. The compound as claimed in claim 1 wherein substituents on R2 are selected from hydroxy, halo, optionally substituted groups selected from (Ci-C6)alkyl, phenyl, heteroaryl groups.
5. The compounds as claimed in claims 1-4 wherein the substituents on alkyl, aryl, heteroaryl or cycloalkyl groups are selected from hydroxyl, halo, cyano, optionally substituted groups selected from (CpC6)alkyl, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups.
6. The compounds as claimed in claim 5, wherein the substituents on these substitutes are selected from hydroxyl, halo, cyano, optionally substituted groups selected from (Ci-Ce)alkyl, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups.
7. The compounds as claimed in claim 1 selected from l-[4-(3-tert-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4- dione;
1 - [4-(3 -sec-Butyl-4-hydroxy-phenoxy)-3 , 5 -dichloro-phenyl] -imidazolidine-2,4- dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-[l,2,4]triazolidine-3,5- dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dibromo-4-(2,4-dioxo-imidazolidin-l-yl)- phenoxy]-2-hydroxy-benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N- dimethyl-benzenesulfonamide; l-[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4-dione; l-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-l-carbonyl)-phenoxy]-phenyl}- imidazolidine-2,4-dione; 5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-N,N-diethyl-2-hydroxy- benzenesulfonamide; l-[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-imidazolidine-2,4- dione; N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzamide ;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N-methyl- benzenesulfonamide; l-[4-(3-Benzyl-4-hydroxy-phenoxy)-3,5-dibromo-phenyl]-imidazolidine-2,4-dione; N,N-Dicyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzenesulfonamide; l-[3,5-Dichloro-4-(3-ethyl-4-hydroxy-phenoxy)-phenyl]-imidazolidine-2,4-dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)- phenoxy]-2-hydroxy-benzamide; N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzenesulfonamide;
1 - {4-[3 -(4-tert-Buty l-benzoyl)-4-hydroxy-phenoxy] -3,5 -dichloro-phenyl } - imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4- [3 -(4-chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } - imidazolidine-2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N- dimethyl-benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2-hydroxy-N,N- diisopropyl-benzenesulfonamide ; 1 - { 3 , 5 -Dichloro-4- [3 -(4-fluoro-benzoyl)-4-hydroxy-phenoxy] -phenyl } - imidazolidine-2,4-dione; l-[3,5-Dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-[l,2,4]triazolidine-
3,5-dione;
N-Adamantan-l-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- hydroxy-benzamide;
1 - { 3 , 5 -Dichloro-4- [3 -(5 -chloro-thiophene-2-carbonyl)-4-hydroxy-ρhenoxy] - phenyl}-imidazolidine-2,4-dione; 1 - { 3 , 5 -Dichloro-4- [4-hydroxy-3 -(piperidine- 1 -sulfonyl)-phenoxy] -phenyl} - imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4- dione; 1 - [4-(4-Hydroxy-3 -isopropyl-phenoxy)-3 , 5 -dimethyl-phenyl] -imidazolidine-2,4- dione; l-[3,5-Dichloro-4-(6-hydroxy-biphenyl-3-yloxy)-phenyl]-imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4- [3 -(3 -chloro-benzoyl)-4-hydroxy-phenoxy] -phenyl } - imidazolidine-2,4-dione; 1 -(4- { 3 -[(4-tert-Butyl-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy } -3,5 -dichloro- phenyl)-imidazolidine-2,4-dione;
1 -(3 , 5 -Dichloro-4- { 3 - [(4-chloro-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy} - phenyl)-imidazolidine-2,4-dione;
1 -(3 , 5 -Dichloro-4- { 3 - [(5 -chloro-thiophen-2-yl)-hydroxy-methyl] -4-hydroxy- phenoxy}-phenyl)-imidazolidine-2,4-dione;
1 -(3 , 5 -Dichloro-4- { 3 - [(3 -chloro-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy} - phenyl)-imidazolidine-2,4-dione;
1 -(3 , 5 -Dichloro-4- { 3 - [(4-fluoro-phenyl)-hydroxy-methyl] -4-hydroxy-phenoxy} - phenyl)-imidazolidine-2,4-dione; 1 - [4-(3 -tert-Butyl-4-methoxy-phenoxy)-3 , 5 -dichloro-pheny 1] -imidazolidine-2,4- dione;
1 - [4-(3 -sec-Butyl-4- methoxy -phenoxy)-3 , 5 -dichloro-pheny 1] -imidazolidine-2,4- dione;
1 - [4-(3 -sec-Butyl-4- methoxy -phenoxy)-3 , 5 -dichloro-pheny 1] -[1 ,2,4] triazolidine- 3,5-dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dibromo-4-(2,4-dioxo-imidazolidin-l-yl)- phenoxy]-2- methoxy -benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N,N- dimethyl-benzenesulfonamide; l-[4-(3-Benzyl-4- methoxy -phenoxy)-3,5-dichloro-phenyl]-imidazolidine-2,4- dione;
1 - { 3 , 5 -Dichloro-4-[4- methoxy -3 -(piperidine- 1 -carbonyl)-phenoxy] -phenyl } - imidazolidine-2,4-dione; 5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-N,N-diethyl-2- methoxy
-benzenesulfonamide;
1 -[3,5-Dichloro-4-(4- methoxy -3-isopropyl-phenoxy)-phenyl]-imidazolidine-2,4- dione; N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N-methyl- benzenesulfonamide; l-[4-(3-Benzyl-4- methoxy -phenoxy)-3,5-dibromo-phenyl]-imidazolidine-2,4- dione;
N,N-Dicyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzenesulfonamide; l-[3,5-Dichloro-4-(3-ethyl-4- methoxy -phenoxy)-phenyl]-imidazolidine-2,4-dione;
N-Bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)- phenoxy]-2- methoxy -benzamide;
N-Cyclohexyl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzenesulfonamide;
1 - {4- [3 -(4-tert-Butyl-benzoyl)-4- methoxy -phenoxy] -3,5 -dichloro-phenyl} - imidazolidine-2,4-dione; l-{3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4- methoxy -phenoxy]-phenyl}- imidazolidine-2,4-dione;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N5N- dimethyl-benzamide;
5-[2,6-Dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -N5N- diisopropyl-benzenesulfonamide;
1 - { 3 , 5 -Dichloro-4- [3 -(4-fluoro-benzoyl)-4- methoxy -phenoxy] -phenyl} - imidazolidine-2,4-dione; l-[3,5-Dichloro-4-(4- methoxy -3-isopropyl-phenoxy)-phenyl]-[l,2,4]triazolidine-
3,5-dione; N-Adamantan-l-yl-5-[2,6-dichloro-4-(2,4-dioxo-imidazolidin-l-yl)-phenoxy]-2- methoxy -benzamide;
1 -{355-Dichloro-4-[3-(5-chloro-thiophene-2-carbonyl)-4- methoxy -phenoxy]- phenyl } -imidazolidine-2,4-dione; l-IS^-Dichloro^-^- methoxy -S-Cpiperidine-l-sulfony^-phenoxyj-phenyl}- imidazolidine-2,4-dione; l-[4-(3-sec-Butyl-4- methoxy -phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4- dione; l-[4-(4- methoxy -3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-imidazolidine-2,4- dione; l-[3,5-Dichloro-4-(6-methoxy-biphenyl-3-yloxy)-phenyl]-imidazolidine-2,4-dione;
1 - { 3 , 5 -Dichloro-4- [3 -(3 -chloro-benzoy l)-4-methoxy-phenoxy] -phenyl } - imidazolidine-2,4-dione.
8. A pharmaceutical composition which comprises compounds of formula (I), as claimed in any preceding claims and a pharmaceutically acceptable carrier, diluent . or excipients.
9. 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.
10. A medicine for treating/reducing dyslipidemia or obesity which comprises administering a compound of foπnula (I), as defined in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients to a patient in need thereof.
11. 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.
12. A process for preparing compounds of formula (I) comprising the steps of: i) reacting a compound of formula (2) with (2-Chloro-acetyl)-carbamic acid ethyl ester & a suitable base to obtain a compound of formula (1)..
Figure imgf000034_0001
H) suitably deprotecting the protecting group 'R' to obtain further compound of formula (V).
13. A process for preparing compounds of formula (I) comprising the steps of: i) reacting compound 3 with Ethyl allophanate in suitable solvents to obtain compounds of formula (1);
Figure imgf000035_0001
ii) suitably deprotecting the protecting group 'R' to obtain further compound of formula (V).
PCT/IN2007/000159 2006-05-15 2007-04-23 Selective tr-beta 1 agonist WO2007132475A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN749/MUM/2006 2006-05-15
IN749MU2006 2006-05-15

Publications (1)

Publication Number Publication Date
WO2007132475A1 true WO2007132475A1 (en) 2007-11-22

Family

ID=38582078

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000159 WO2007132475A1 (en) 2006-05-15 2007-04-23 Selective tr-beta 1 agonist

Country Status (1)

Country Link
WO (1) WO2007132475A1 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086878A2 (en) 2009-01-09 2010-08-05 Cadila Healthcare Limited Thyroid receptor modulators
WO2010122980A1 (en) 2009-04-20 2010-10-28 田辺三菱製薬株式会社 Novel thyroid hormone β receptor agonist
WO2012000896A2 (en) 2010-06-28 2012-01-05 Bayer Cropscience Ag Heterocyclic compounds as agents for pest control
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2019054514A1 (en) 2017-09-14 2019-03-21 国立研究開発法人理化学研究所 Method for producing retinal tissues
WO2020184720A1 (en) 2019-03-13 2020-09-17 大日本住友製薬株式会社 Method for evaluating quality of transplant neural retina, and transplant neural retina sheet
WO2022054924A1 (en) 2020-09-11 2022-03-17 大日本住友製薬株式会社 Medium for tissue for transplantation
WO2022054925A1 (en) 2020-09-11 2022-03-17 国立研究開発法人理化学研究所 Complex containing neural retina-containing cell aggregates and matrix, and method for manufacturing same
WO2023090427A1 (en) 2021-11-19 2023-05-25 国立研究開発法人理化学研究所 Production method for sheet-like retinal tissue

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039077A2 (en) * 1998-12-24 2000-07-06 Karo Bio Ab Thyroid receptor ligands
EP1088819A2 (en) * 1999-09-30 2001-04-04 Pfizer Products Inc. 6-azauracil derivatives as thyroid receptor ligands
EP1148054A1 (en) * 2000-04-21 2001-10-24 Pfizer Products Inc. Thyroid receptor ligands
US6344481B1 (en) * 1999-03-01 2002-02-05 Pfizer Inc. Thyromimetic antiobesity agents
WO2004067482A2 (en) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor
WO2004093799A2 (en) * 2003-04-18 2004-11-04 Bristol-Myers Squibb Company Thyroid receptor ligands

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039077A2 (en) * 1998-12-24 2000-07-06 Karo Bio Ab Thyroid receptor ligands
US6344481B1 (en) * 1999-03-01 2002-02-05 Pfizer Inc. Thyromimetic antiobesity agents
EP1088819A2 (en) * 1999-09-30 2001-04-04 Pfizer Products Inc. 6-azauracil derivatives as thyroid receptor ligands
EP1148054A1 (en) * 2000-04-21 2001-10-24 Pfizer Products Inc. Thyroid receptor ligands
WO2004067482A2 (en) * 2003-01-24 2004-08-12 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor
WO2004093799A2 (en) * 2003-04-18 2004-11-04 Bristol-Myers Squibb Company Thyroid receptor ligands

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086878A2 (en) 2009-01-09 2010-08-05 Cadila Healthcare Limited Thyroid receptor modulators
WO2010122980A1 (en) 2009-04-20 2010-10-28 田辺三菱製薬株式会社 Novel thyroid hormone β receptor agonist
US8791266B2 (en) 2009-04-20 2014-07-29 Mitsubishi Tanabe Pharma Corporation Thyroid hormone β receptor agonist
US8686004B2 (en) 2010-06-28 2014-04-01 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2012000896A2 (en) 2010-06-28 2012-01-05 Bayer Cropscience Ag Heterocyclic compounds as agents for pest control
US9044015B2 (en) 2010-06-28 2015-06-02 Bayer Cropscience Ag Heterocyclic compounds as pesticides
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2019054514A1 (en) 2017-09-14 2019-03-21 国立研究開発法人理化学研究所 Method for producing retinal tissues
WO2020184720A1 (en) 2019-03-13 2020-09-17 大日本住友製薬株式会社 Method for evaluating quality of transplant neural retina, and transplant neural retina sheet
WO2022054924A1 (en) 2020-09-11 2022-03-17 大日本住友製薬株式会社 Medium for tissue for transplantation
WO2022054925A1 (en) 2020-09-11 2022-03-17 国立研究開発法人理化学研究所 Complex containing neural retina-containing cell aggregates and matrix, and method for manufacturing same
WO2023090427A1 (en) 2021-11-19 2023-05-25 国立研究開発法人理化学研究所 Production method for sheet-like retinal tissue

Similar Documents

Publication Publication Date Title
WO2007132475A1 (en) Selective tr-beta 1 agonist
PT1720544E (en) Novel azabicyclic derivatives, preparation method thereof and pharmaceutical compositions containing same
US20080280923A1 (en) 1-Benzylindole-2-Carboxamide Derivatives
US20060089371A1 (en) Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist
JP2008534593A (en) Glucagon receptor antagonist compounds, compositions containing such compounds, and methods of use thereof
CA2693032A1 (en) Nmda receptor antagonists for neuroprotection
WO2009047240A1 (en) Indole derivatives useful as ppar activators
US8420851B2 (en) Selective TR-β 1 agonist
JP2005514452A (en) Phenyl (alkyl) carboxylic acid derivatives and dionic phenylalkyl heterocyclic derivatives and their use as pharmaceuticals having serum glucose and / or serum lipid lowering activity
JP5057982B2 (en) Histamine H3 receptor inhibitor, manufacture and therapeutic use
JP2003519110A (en) Compounds active at the glucocorticoid receptor
AU2009309229B2 (en) Thyroid receptor ligands
FR2983859A1 (en) 1,3,5-TRIAZINE-2-AMINE DERIVATIVES, THEIR PREPARATION AND THEIR DIAGNOSTIC AND THERAPEUTIC USE
US8410135B2 (en) 4,5 dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators
WO2010086878A2 (en) Thyroid receptor modulators
JP2010530367A (en) 4,5-Dihydro- (1H) -pyrazole derivatives as cannabinoid CB1 receptor modulators
WO2013102929A1 (en) Novel compounds for treatment of diabetes, obesity or related disorders
WO2008062424A2 (en) Substituted 4,5-dihydro-1h-pyrazole derivatives as cannabinoid modulators
FR2948120A1 (en) 5,6-BISARYL-2-PYRIMIDINE CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS ANTAGONISTS OF UROTENSIN II RECEPTORS
MX2007007910A (en) Compositions and methods of treating cell proliferation disorders

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07766923

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07766923

Country of ref document: EP

Kind code of ref document: A1