WO2003004458A1 - Composes nouveaux - Google Patents

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Publication number
WO2003004458A1
WO2003004458A1 PCT/SE2002/001323 SE0201323W WO03004458A1 WO 2003004458 A1 WO2003004458 A1 WO 2003004458A1 SE 0201323 W SE0201323 W SE 0201323W WO 03004458 A1 WO03004458 A1 WO 03004458A1
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WO
WIPO (PCT)
Prior art keywords
amino
dichlorobenzoyl
benzoate
ethoxy
biphenyl
Prior art date
Application number
PCT/SE2002/001323
Other languages
English (en)
Inventor
Anna-Lena Gustavsson
Lena Jendeberg
Patrick Roussel
Martin Slater
Markus Thor
Original Assignee
Biovitrum Ab
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 claimed from SE0102384A external-priority patent/SE0102384D0/xx
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2003004458A1 publication Critical patent/WO2003004458A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/17—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 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07D213/63—One oxygen atom
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • 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
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    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • 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
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Definitions

  • the present invention relates to novel compounds which are 2- (benzoylamino)benzoic acids and which modulate the activity of peroxisome proliferator- activated receptors (PPAR) ⁇ and/or ⁇ .
  • PPAR peroxisome proliferator- activated receptors
  • the said compounds are predicted to be useful in the treatment of metabolic diseases, e.g. type II diabetes.
  • PPARs peroxisome proliferator-activated receptors
  • PPARs were first cloned as the nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. It soon became clear that eicosanoids and fatty acids can also regulate gene transcription through PPARs.
  • PPARs act in a similar manner to other nuclear hormone receptors. First, they bind a specific element in the promoter region of target genes. PPAR and some other nuclear hormone receptors bind the promoter only as a heterodimer with the receptor for 9- cis retinoic acid, RXR (retinoid X receptor). Second, they activate transcription in response to binding ofthe hormone (ligand).
  • PPAR:RXR heterodimer binding ofthe ligand of either receptor can activate the complex, but binding of both ligands simultaneously is more potent.
  • Three PPAR isotypes have been identified: ⁇ , ⁇ (also called ⁇ and NUC1) and ⁇ .
  • PPAR ⁇ (GenBank Accession No. NM_005036) is expressed most in brown adipose tissue and liver, then kidney, heart and skeletal muscle.
  • PPAR ⁇ GenBank Accession No. NM_005037
  • PPAR ⁇ is mainly expressed in adipose tissue, and to a lesser extent in colon, the immune system and the retina.
  • PPAR ⁇ is found in many tissues but the highest expression is in the gut, kidney and heart.
  • PPARs are ligand-dependent transcription factors: activation of target gene transcription depends on the binding ofthe ligand to the receptor. Some ligands are shared by the three isotypes, such as polyunsaturated fatty acids and probably oxidized fatty acids.
  • Type I insulin-dependent diabetes mellitus
  • IDDM insulin-dependent diabetes mellitus
  • Type II non-insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • NTDDM is linked to heredity and obesity.
  • NIDDM is almost invariably accompanied by dyslipidemia, characterized by elevated triglycerides (TGs), VLDL-C and increased small dense LDL-C in combination with decreased levels of HDL-C and prolonged postprandial hyperlipidemia.
  • This form of dyslipidemia is highly atherogenic and thus represents a major risk factor for the development of premature atherosclerosis and coronary artery disease (CAD), which is the major cause of mortality in diabetic patients.
  • CAD coronary artery disease
  • a direct correlation between low HDL levels and incidence of CAD has been identified.
  • this pathological lipid profile or "lipotoxicity" is suggested to contribute to ⁇ - cell failure and as a consequence impaired glucose stimulated insulin release.
  • PPAR ⁇ and PPAR ⁇ are key sensors and transcriptional modulators of lipid and glucose homeostasis, respectively. Accordingly, a selective "dual action drug" that selectively binds and activates PPAR ⁇ and ⁇ is hypothesized to mechanistically target the two major metabolic abnormalities observed in type II diabetic patients and thus therapeutically intervene with insulin resistance, CAD and possibly also impaired insulin secretion or ⁇ -cell failure.
  • Murakami et al. discloses a thiazolidinedione derivative which activated both PPAR ⁇ and PPAR ⁇ , and restored reduced lipid oxidation, when administered to obese rats. It was suggested that PPAR ⁇ agonism has a protective effect against abnormal lipid metabolism in liver of obese rats. Agents modulating both PPAR ⁇ and PPAR ⁇ are also disclosed in Shibata, T. et al. (1999) Eur. J. Pharmacol. 364: 211-219; and in WO 99/19313.
  • Figure 1 shows the structure ofthe ligand-binding domain of human PPAR ⁇ , in complex with the compound according to Example 1 ofthe invention.
  • PPAR modulator is intended to mean a PPAR ligand that is capable of acting as an activator (agonist), or alternatively as an inhibitor (antagonist), in PPAR mediated transcriptional responses. Consequently, in a first aspect this invention provides a compound ofthe formula I
  • Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
  • X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and
  • R is a CrC ⁇ -alkyl or an optionally substituted aryl or heteroaryl group
  • R is an optionally substituted aryl or heteroaryl group; and when X is a heteroalkyl chain comprising from 1 to 4 carbon atoms and from
  • R is a C ⁇ -C 6 -alkyl or an optionally substituted aryl or heteroaryl group, with the proviso that when X is a bond, then R is not a C ⁇ -C 6 -alkyl; or said compound is not a dibenzoyl-bisanthranilic acid, or
  • Preferred compounds ofthe formula I include those wherein:
  • Ar is phenyl or naphthyl, optionally substituted in one or more positions independently by halogen, nitro, cyano, methoxy, or trifluoromethyl.
  • X is a bond
  • O-(CH 2 ) n wherein n is an integer 0 to 3, e.g. O, O-CH 2 , or O-(CH 2 )2; O-(CH 2 ) n -Y, wherein n is an integer 0 to 3, and Y is an atom selected from O, N and S, e.g. O-(CH 2 ) 2 -O, or O-(CH 2 ) 2 -S;
  • R is methyl or selected from the group consisting of, optionally substituted, phenyl, naphthyl, thienyl, pyridinyl, quinoxalinyl, benzoylphenyl, thiazolyl, furyl, imidazolyl, oxazolyl, pyrazinyl, quinolinyl, indolyl, benzofuran, benzothiophenyl (benzothienyl), pyrimidinyl, benzodioxolyl, with the proviso that when X is a bond then R is not methyl
  • R is an aryl or heteroaryl, it is independently substituted in one or more positions with
  • R can be independently substituted in one or more positions with methyl, ethyl, isopropyl, methoxy, thiomethoxy ethoxy, methylsulfonyl, formyl, acetyl, nitro, cyano, methylhydroxy, methylamino, carboxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, iodo, benzyloxy, amino, dimethylamino, acetylamino, phenyl, phenoxy, or benzoyl.
  • the following compounds are especially preferred:
  • C ⁇ g alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • Examples of said C _ alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C j .g alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said C g alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • aryl denotes aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms. Examples of said aryl include phenyl, indenyl and naphthyl.
  • heteroaryl denotes a mono- or bicyclic ring system (only one ring need to be aromatic, and substitution may be in any ring) having from 5 to 10 ring atoms (which are carbon atoms), in which one or more ofthe carbon ring atoms are other than carbon, such as nitrogen, oxygen, selenium, and sulfur.
  • heteroaryl examples include pyrrole, thiazole, imidazole, thiophene, furan, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, quinazolineindole, indole, isoindole, isoindoline, indoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2, 1 ,3 -benzothiadiazole, 2,1 ,3-benzoselenadiazole, benzimidazole, ind
  • heteroalkyl chain denotes a straight or branched, saturated or unsaturated, chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of O, N, and S.
  • the heteroatom(s) may be placed at any position ofthe heteroalkyl group.
  • the end products ofthe Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope ofthe invention group (e.g., lithium, sodium, potassium salts, hydrochloride, hydrobromide, and the like). All diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope ofthe invention.
  • Therapeutic or prophylactic treatment of mammals for conditions where modulation of either PPAR ⁇ or PPAR ⁇ activity, or the combination of both PPAR ⁇ and PPAR ⁇ activities, is of therapeutic benefit.
  • Such conditions could be e.g. diabetes, diabetes mellitus type 2, insulin resistance, impaired glucose tolerance and / or in combinations with dyslipidemias, obesity, atherosclerosis, coronary artery disease, PCOS, gestational diabetes, inflammation.
  • the compounds according to the invention are particularly useful for the treatment of type II diabetes, in combination(s) with dyslipidemias, obesity, atherosclerosis and coronary artery disease.
  • the compounds according to the invention can be used alone or in combinations) with sulfonylureas, metformin, alpha-glycosidase inhibitors, insulin or other anti-diabetic treatments/agents.
  • Reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • the compounds ofthe invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • the typical daily dose ofthe active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient and the route of administration.
  • the compounds according to the invention may also be administered as prodrugs that may be converted to the active ingredient in question after metabolic transformation in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
  • This invention also relates to a method of treatment or prevention of diabetes.
  • the method includes administering to a subject (e.g., a human, a mammal, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds ofthe formula I :
  • Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
  • X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
  • R is C ⁇ -C 6 -alkyl or an optionally substituted aryl or heteroaryl group.
  • the methods delineated herein can also include the step of identifying that the subj ect is in need of treatment of diabetes.
  • Also within the scope of this invention is a method for modulating (e.g., stimulating or inhibiting) peroxisome proliferator-activated receptors activities.
  • the method includes contacting the receptors with an effective stimulatory or inhibitory amount of a compound ofthe formula I.
  • “An effective amount” refers to an amount of a compound which confers a therapeutic effect on the treated subject.
  • the therapeutic effect maybe objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the dose level and frequency of dosage ofthe specific compound will vary depending on a variety of factors including the potency ofthe specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity ofthe condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the invention provides a process for the preparation of a compound as defined above.
  • the compounds according to the invention can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, the following methods.
  • the chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis ofthe compounds of Formula (I).
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2 n Ed., John Wiley and Sons (1991); L. Fieser and M.
  • the structures ofthe prepared compounds were confirmed by standard spectroscopical methods.
  • the NMR data was obtained on a Jeol JNM-EX 270 or a Bruker DRX 500 spectrometer.
  • Electrospray MS data was obtained on a Micromass platform LCMS spectrometer. Melting points, when given, were obtained on a Electrothermal IA9000 melting point apparatus, and are uncorrected.
  • TMAD 183 mg, 1.06 mmol
  • TMAD 183 mg, 1.06 mmol
  • a suspension of methyl 2-[(2,4- dichlorobenzoyl)amino]-5-hydroxybenzoate 240 mg, 0.71 mmol; prepared in Example XX
  • polymer bound triphenylphosphine 480 mg, 1.4 mmol
  • thiophene-2 -methanol 73 ⁇ l, 0.78 mmol
  • the suspension was shaken at room temperature over night and filtered through a plug of Celite.
  • Step 4 Lithium 2-f(2,4-dichlorobenzoyl)aminoJ-5-(2-thienylmethoxy)benzoate General procedure B
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate
  • 2-(3-thienyl)ethanol afforded the title compound (370 mg, 93%) as an oil by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate afforded the title compound (260 mg, 95%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)aminoJ-5-[(4-ethoxybenzyl)oxyJbenzoate
  • 4-ethoxybenzyl alcohol afforded the title compound (206 mg, 37%) as an yellow solid by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [3- (dimethylamino)benzyl]oxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [3- (dimethylaminojbenzyljoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methylphenyl)ethoxy]benzoate afforded the title compound (119 mg, 94%) as a solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl] oxy ⁇ ethoxy) benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl] oxy ⁇ ethoxy)benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl]oxy ⁇ ethoxy)benzoate afforded the title compound (98 mg, 100%) as a beige solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate
  • 2-(3-pyridinyloxy)ethanol (disclosed in WO 00/76984) afforded, the title compound (50 mg, 22%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- pyridinyloxy)ethoxy]benzoate afforded the title compound (35 mg, 96%) as a white solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate
  • 2-[2-(methylsulfanyl)phenoxy]ethanol afforded the title compound (6 mg, 2%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-
  • Step 1 Methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)ammo]benzoate
  • 2-(2-aminophenoxy)ethanol (disclosed in EP 0881488 and EP 0881225) afforded the title compound (25 mg, 11%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (22 mg, 99%) as a beige solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Step 2 Lithium 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (30 mg, 80%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6- trifluorophenoxyjethoxyjbenzoate
  • Step 2 Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2, 3, 6- trifluorophenoxyjethoxyjbenzoate
  • Step 1 Methyl 5-[2-([l ,l'-biphenyl] -3-yloxy)ethoxy] -2-[(2,4- dichlor Tavernzoyl) amino] benzoate
  • Step 2 Lithium 5-[2-([l, 1 '-biphenyl] -3-yloxy)ethoxy]-2-[(2, 4- dichlorobenzoy I) amino] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (phenylsulfanyl)ethoxy]benzoate afforded the title compound (25 mg, 88%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[(4-methyl-l,3-thiazol-5-yl)oxy] ethoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[(4-methyl-l,3-thiazol-5- yljoxyj ' ethoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate afforded the title compound (31 mg, 86%) as a yellow solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH- imidazol-l-yl)ethoxy]benzoate afforded the title compound (50 mg, 96%) as a brown-red solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(3-thienylmethoxy)benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate afforded the title compound (28 mg, 95%) as a white solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- pyridinylsulfany I) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- y I) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5 ⁇ [2-(5-methyl-2-phenyl-l,3-thiazol-4- yl) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate
  • 2-(5-ethyl-2-pyridinyl)ethanol afforded the title compound (90 mg, 38%) by the application ofthe general procedure A described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate Use of 2-(2-methoxyphenoxy)ethanol (previously described in J. Chem. Soc.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy) ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy)ethoxy]benzoate afforded the title compound (163 mg, 98%) as a solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate
  • Step 2 Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methoxyphenyl)ethoxy]benzoate afforded the title compound (quantitative yield) as a pink solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(6-nitro-2-pyridinyl)oxy]benzoate
  • Use of methyl 2-[(2,4-dicMorobenzoyl)amino]-5-[(6-nitro-2- pyridinyl)oxy]benzoate afforded the title compound (88 mg, 94%) as a yellow solid by the application ofthe general procedure B described in Example 1.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifluoromethyl)-2- pyridinyl] oxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifiuoromethyl)-2- pyridinyl] oxy ⁇ benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifluoromethyl)-2- pyridinyl]oxy ⁇ benzoate afforded the title compound (41 mg, 95%) as a yellow solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Step 2 Lithium 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Use of methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (84 mg, 83%) as a white solid by the application ofthe general procedure B described above.
  • 1H NMR (DMSO) £ 15.19 (s, IH), 8.68-8.44 (m, 3H), 7.80-7.51 (m, 4H), 7.23 (dd, J 8.70, 2.91 Hz IH); MS m/z 436 (M-l).
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(2-pyrimidinyloxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [(2E)-3-phenyl-2- propenyl] oxy ⁇ benzoate
  • D Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [(2E)-3-phenyl-2- propenyl] oxy ⁇ benzoate
  • Cinnamyl bromide 131 ⁇ l, 0.88 mmol was added to a stirred mixture of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate (300 mg, 0.88 mmol) and potassium carbonate (185 mg, 1.3 mmol) in DMF (10 ml). After heating at 65°C for 4 hours the mixture was allowed to cool and then chloroform was added. Filtration and concentration ofthe filtrate in vacuo gave a residue which subsequently was purified by chromatography on silica gel eluting with CHCI 3 to give the title compound (196 mg, 50%) as a white solid.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(3- methoxybenzyl)oxy]benzoate afforded the title compound (110 mg, 76%) as a white solid by the application ofthe general procedure B described above.
  • the crude isatoic anhydride (9.5 g, 27 mmol) was dissolved in dry methanol (670 ml) to which was added powdered anhydrous potassium carbonate (4.4 g, 31 mmol). The solution was allowed to stir at ambient overnight before being evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml) and the aqueous layer adjusted to pH 7.0 with concentrated hydrochloric acid before separating.
  • Step 3 Methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate
  • General procedure F To a stirred mixture of methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-iodobenzoate
  • Step 4 Lithium 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate General procedure G
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichloropheny i) benzoate
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl)amino] -5-(2, 4-dichlorophenyl) benzoate
  • Step 1 2-(2,4-dichlorophenyl)-6-(4-ethylphenyl)-l,3-benzoxazin-4-one
  • Step 2 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid
  • Step 1 Methyl 5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoate
  • (2,4-dimethoxy)pyrimidine-5-boronic acid 41 mg, 0.22 mmol
  • the crude product was used in the next step without further purification.
  • Step 2 2-[(2,4-Dichlofobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (17 mg, 21%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M+1) 448.
  • Step 1 Methyl 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3- carboxylate
  • 3-(acetamido)phenylboronic acid 40 mg, 0.22 mmol
  • Step 2 3'-(Acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl] -3-carboxylic acid
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [1,1 '-biphenyl] -3- carboxylate
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -3'-(trifluoromethoxy) [1 ,l'-biphenyl] -3- carboxylic acid
  • Step 1 Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-3 '-ethoxy [1, 1 '-biphenyl] -3-carboxylate
  • 3-(ethoxy)phenylboronic acid afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -3'-ethoxy[l ,1 '-biphenyl] -3-carboxylic acid
  • MS m/z (M-l) 428 Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (35 mg, 45%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 428.
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino) '-3 '-(hydroxymethyl) [1,1 '-biphenyl) -3- carboxylate
  • 3-(hydroxymethyl)phenylboronic acid 34 mg, 0.22 mmol
  • Step 2 4- [(2, 4-Dichlorobenzoyl)amino]-3 '-(hydroxymethyl) [1, 1 '-biphenyl] -3-carboxylic acid
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -3' -formyl[l,V -biphenyl] -3-carboxylate
  • Step 1 2-(2, 4-Dichlorophenyl)-6-(naphth-2-yl)-l, 3-benzoxazin-4-one
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid
  • Step 1 Methyl 4-[(2,4-Dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l,l'-bipheny ⁇ ]- 3-carboxylate
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino) '-3'-isopropyl-6'-methoxy[l ,V -biphenyl) '-3- carboxylic acid
  • Step 1 Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-4 '-fiuorofl, 1 '-biphenyl] -3-carboxylate
  • 4-fluorophenylboronic acid 31 mg, 0.22 mmol
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -4'-fluoro[l ,l'-biphenyl] -3-carboxylic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (27 mg, 37%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 402. EXAMPLE 55
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate
  • Step 2 Lithium 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino) 'benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate
  • Step 2 Lithium 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate afforded the title compound (13 mg, 100%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 432.
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid trifluoroacetate
  • Step 1 Methyl 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • 3-(carboxy)phenylboronic acid 47 mg, 0.28 mmol
  • the crude product was used in the next step without further purification.
  • Step 1 Methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,l'-biphenyl]-3- carboxylate
  • Step 2 2 '-(benzyloxy)-4-[(2, 4-dichlorobenzoyl) amino] [1, 1 ' -biphenyl] -3-benzoic acid
  • Use of methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl]-3- carboxylate afforded the title compound (10 mg, 30%) as a colorless solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 490 2 '-(benzyloxy)-4-[(2, 4-dichlorobenzoyl) amino] [1, 1 ' -biphenyl] -3-benzoic acid
  • Step 1 Methyl 4- [(2, 4-dichlorobenzoyl)amino] [1, 1 '-biphenyl] -3 -carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino] [1 ,1' -biphenyl] ' -3-carboxylate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl] -3-carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l -biphenyl) '-3-carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l, -biphenyl]-3- carboxylate afforded the title compound (38 mg, 99%) as a colorless solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 460 Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l -biphenyl) '-3-carboxylate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino) -3 '-(trifluoromethyl) [1,1 '-biphenyl] -3- carboxylate
  • Step 2 Lithium methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethyl) [1,1 '- biphenyl] -3-carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3 , -(trifluoromethyl)[l,r-biphenyl]-
  • Step 1 Methyl 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • 5-(chloro)thiophene-2-boronic acid 36 mg, 0.28 mmol
  • afforded the title compound 75 mg, 96%) as an yellow solid by the application ofthe general procedure F described above.
  • Step 2 Lithium 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -4'-phenoxy[l ,1 '-biphenyl] -3-carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,l '-biphenyl] -3-carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,r-biphenyl]-3- carboxylate afforded the title compound (40 mg, 98%) as an yellow solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 476 MS m/z (M-l) 476.
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,l '-biphenyl]-3- carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino] -2', 5'-dimethoxy[l , 1 '-biphenyl] -3- carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[ 1 , 1 '-biphenyl] -3- carboxylate afforded the title compound (38 mg, 99%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 444.
  • EXAMPLE 68 Lithium 4-[(2,4-dichlorobenzoyl)amino] -2', 5'-dimethoxy[l , 1 '-biphenyl] -3- carboxylate
  • Step 1 6-(3-Aminomethylphenyl)-2-(2, 4-dichlorophenyl)-l , 3-benzoxazin-4-one
  • Step 2 3'-(Aminomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,l '-biphenyl] -3-carboxylic acid
  • 6-(3 -aminomethylphenyl)-2-(2,4-dichlorophenyl)- 1 ,3 -benzoxazin-4-one afforded the title compound (4 mg, 18%) as a solid by the application ofthe general procedure G described above.
  • Step 1 Methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate
  • General procedure I To a sti ⁇ ed solution of methyl 2-amino-5-iodobenzoate (500 mg, 1.8 mmol) in dry THF (10 ml) in a STEMBLOCK chiller at 0°C under an atmosphere of nitrogen, diisopropylethylamine (0.53 ml, 3.0 mmol) was added.
  • Step 2 Methyl 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
  • General B2 To a sti ⁇ ed mixture of methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate (100 mg,
  • Step 3 Lithium 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
  • Step 1 Methyl 3'-(acetylamino)-4-(2-naphthoylamino)[l,l'-biphenyl] -3-carboxylate
  • 3-acetamidophenylboronic acid 51 mg, 0.29 mmol
  • afforded the title compound 47 mg, 46%>) as a beige solid by the application ofthe general procedure J described above.
  • Step 2 Lithium 3 '-(acetylamino)-4-(2-naphthoylamino) [1 , 1 '-biphenyl] -3-carboxylate
  • Use of methyl 3 '-(acetylamino)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 - carboxylate afforded the title compound (39 mg, 100%) as a yellow solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 423 MS m/z (M-l) 423.
  • Step 1 Methyl 3 '-(ltydroxymethyl)-4-(2-naphthoylamino)[l, 1 '-biphenyl] -3-carboxylate
  • 3-(hydroxymethyl)phenylboronic acid 44 mg, 0.29 mmol
  • afforded the title compound 39 mg, 41%) as a beige solid by the application ofthe general procedure
  • Step 1 6-(3-Acetamideophenyl)-2-[4-(trifl oromethyl)phenyl] -1 , 3-benzoxazine-4-one
  • Step 2 Lithium 3'-(acetylamino)-4-[[4-(trifluoromethyl)benzoyl]amino ⁇ [l,l '-biphenyl]-3- carboxylate
  • Step 1 6-[3-Hydroxymethyl)phenyl] -2-[4-(trifluoromethyl)phenyl] -1 , 3-benzoxazin-4-one
  • Use of methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino]benzoate (100 mg, 0.22 mmol) and 3-(hydroxymethyl)phenylboronic acid (42 mg, 0.28 mmol) afforded the title compound (86 mg, 98%) as a white solid by the application ofthe general procedure Jdescribed above.
  • Step 2 Lithium 3'-(hydroxymeihyl)-4- ⁇ [4-(trifluoromethyl)benzoyl]amino ⁇ [l,l'- biphenyl] -3 -carboxylate
  • Step 3 Lithium 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(8-quinolinyl)benzoate
  • Step 1 Methyl 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate
  • MS m/z (M-l) 494 MS m/z (M-l) 494.
  • Step 2 Lithium 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate Use of methyl 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate afforded the title compound (7 mg, 100%) as a white solid by the application ofthe general procedure G described above. MS m/z (M-l) 480.
  • Step 3 Lithium 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate
  • Step 2 Methyl 4-[(3, 5-dichlorobenzoyl) amino] [l,l'-biphenyl] -3-carboxylate
  • phenylboronic acid 38 mg, 0.31 mmol
  • afforded the title compound as a colorless solid 28 mg, 28%) by the application ofthe general procedure F described above.
  • Step 3 Lithium 4- [(3, 5-dichlorobenzoyl) amino] [1,1 '-biphenyl) '-3-carboxylate
  • Step 5 Lithium 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Methyl 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate
  • Step 1 Methyl 2-amino-5-(2-thienylmethoxy)benzoate hydrochloride A solution of tert-butylazodicarboxylate (TMAD) (4.21g, 18.3 mmol) in dry THF
  • Step 3 Lithium 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate trifluoroacetate
  • Step 4 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [l-methyl-lH-imidazol-4- yl)sulfonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Y Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [l-methyl-lH-imidazol-4- yl)sulfonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(2-pyridinylamino)ethoxy] ethoxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(2- pyridinylamino) ethoxy] ethoxy ⁇ benzoate
  • Step 1 Methyl 5-[2-(2- ⁇ [(3-chloro-4-methylphenyl)sulfonyl]amino ⁇ ethoxy)ethoxy]-2-
  • Step 2 Lithium 5-[2-(2- ⁇ [(3-chloro-4-methylphenyl)sulfonyl) ' amino ⁇ ethoxy) ethoxy) '-2- [(2, 4-dichlorobenzoyl) amino] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ 2-[(3- pyridinylsulfonyl)amino]ethoxy ⁇ ethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ 2-[(3-pyridinylsulfonyl)amino] ethoxy ⁇ ethoxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(2,4- difluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(2,4- difluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4- fluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 2 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4 ⁇ fluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino] -5-[2-(2- ⁇ [(4- isopropylanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • 4-isopropylphenyl isocyanate 34 mg, 0.21 mmol afforded the title compound (24 mg, 20%) by the application ofthe general procedure X described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4- isopropylanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl) amino] -5 -[2-(methylsulfanyl)ethoxy] benzoate
  • 2-(methylsulfanyl)ethanol afforded the title compound (8 mg, 4%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (methylsulfanyl)ethoxy]benzoate afforded the title compound (4.4 mg, 100%) as a white solid by the application ofthe general procedure B described above.
  • the compounds of formula I exhibit EC50 values on PPAR ⁇ and PPAR ⁇ in the range of 1-35 ⁇ M and 0.3-50 ⁇ M, respectively.
  • Crude extracts were prepared from E. coli (BL21(DE3)pLysS, Novagen) producing GST-PPAR ⁇ LBD or GST-PPAR ⁇ LBD fusion proteins by freeze thawing in buffer containing 50 mM Tris-HCl pH 7.9, 250 mM KC1, 10% glycerol, 1% Triton X-100, 10 mM DTT, lmM PMSF, 10 ⁇ g/mL DNase and 10 mM MgCl.
  • Competitive ligand binding assays were performed on immobilized GST-PPAR ⁇ LBD or GST-PPAR ⁇ LBD fusion proteins from crude extracts incubated with glutathione-Sepharose 4B (Amersham Pharmacia Biotech).
  • the slu ⁇ y was washed three times in binding buffer containing 50 mM Tris-HCL, pH7.9, 50 mM KC1, 0.1% Triton-XlOO, 10 mM DTT, 2 mM EDTA, dispensed in 96-well filter plates (MHVB N45, Millipore) and incubated with a fixed amount tritiated ligand and different concentrations of cold competing ligands. Equilibrium binding was reached after incubation for 2 hours at room temperature on a plate shaker.
  • the compounds of formula I exhibit K j values on PPAR ⁇ and PPAR ⁇ in the range of 1-70 ⁇ M and 0.3-35 ⁇ M, respectively.
  • Selected compounds of formula I were tested in animal models of relevance for measuring PPAR ⁇ efficacy.
  • the animal model used was ob/ob mouse and as a reference compound the known PPAR ⁇ ligand, rosiglitazone.
  • the animals were orally treated during 7 days and parameters as food intake, body weight, plasma glucose, insulin, cholesterol, triglycerides and free fatty acids were monitored.
  • Compounds of formula I were shown to give dose related pharmacological effects.
  • PPAR ⁇ ligand binding domain (LBD) has previously been described in literature (Nolte, R. T. et al. (1998) Nature 395: 137-143; Uppenberg, J. et al. (1998) J. Biol. Chem. 273: 31108-31112).
  • the present inventors have determined the structure of human PPAR ⁇ LBD in complex with one ofthe compounds (Example 1) according to the invention. As indicated in Fig. 1, the compound according to Example 1 was shown to be located in the ligand binding pocket of human PPAR ⁇ .
  • the compound was found in an elongated conformation and occupied a region in proximity with, and approximately parallel to, helix 3 (the numbering of helices and strands follow the convention of Uppenberg et al. supra) and in proximity to beta-strand 3 and helices 5 and 2b.
  • the interactions between the compound (ligand) according to the invention and human PPAR ⁇ can be separated into four categories: (1) Interaction between the dibromo-phenyl moiety ofthe ligand and the predominantly hydrophobic pocket of human PPAR ⁇ , in particular the side chains of Ile326, Met329, Leu330, Leu333, Ala292 and Arg288.
  • the compounds according to the invention bind in a novel binding mode. These compounds modulate the activity of PPARs in a range of agonistic effects determined in a cell based reporter assay.

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Abstract

La présente invention a trait à des dérivés de l'acide 2-(benzoylamino)benzoïque de formule (1), dans laquelle les variants Ar, X et R sont tels que définis dans la description. Lesdits composés modulent l'activité des récepteurs activés de la prolifération des (PPAR) peroxysomes α et/ou η, et sont utiles dans le traitement de maladies métaboliques, par exemple, le diabète de type II.
PCT/SE2002/001323 2001-07-03 2002-07-03 Composes nouveaux WO2003004458A1 (fr)

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SE0102384-5 2001-07-03
SE0102384A SE0102384D0 (sv) 2001-07-03 2001-07-03 New compounds
US30470601P 2001-07-11 2001-07-11
US60/304,706 2001-07-11

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WO2004018414A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Agents antibacteriens
WO2004076402A1 (fr) * 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh Derives d'arylcycloalkyle a chaines laterales ramifiees en tant que modulateurs de recepteur ppar, procede de preparation associe et utilisation de ces derives comme medicaments
US6890947B2 (en) 2002-09-12 2005-05-10 Hoffmann-La Roche Inc. Indolyl derivatives
US7098228B2 (en) 2002-11-25 2006-08-29 Hoffmann-La Roche Inc. Indolyl derivatives
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
WO2006034402A3 (fr) * 2004-09-21 2007-08-09 Synta Pharmaceutical Corp Composes pour l'inflammation et applications associees aux troubles immuns
WO2008019477A1 (fr) * 2006-08-17 2008-02-21 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
US7335671B2 (en) 2003-02-27 2008-02-26 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
WO2009076747A1 (fr) * 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
JP2009525287A (ja) * 2006-02-03 2009-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウイルスポリメラーゼインヒビター
US7645881B2 (en) 2004-07-22 2010-01-12 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2010087430A1 (fr) * 2009-01-30 2010-08-05 富山化学工業株式会社 Dérivé de l'acide n-acyle anthranilique ou son sel
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8242140B2 (en) 2007-08-03 2012-08-14 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2013082106A1 (fr) 2011-12-02 2013-06-06 The General Hospital Corporation Différenciation en adipocytes bruns
JP2013525448A (ja) * 2010-04-27 2013-06-20 カルシメディカ，インク． 細胞内カルシウムを調節する化合物
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
US20140364421A1 (en) * 2013-06-06 2014-12-11 Astellas Pharma Inc. Benzothiophene compound
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JP2015511224A (ja) * 2012-01-26 2015-04-16 ピーティーシー セラピューティクス， インコーポレイテッド 脊髄性筋萎縮症を治療するための化合物
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres

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US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
JP2009525287A (ja) * 2006-02-03 2009-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウイルスポリメラーゼインヒビター
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