US20060258866A1 - Carboxylic derivates - Google Patents

Carboxylic derivates Download PDF

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Publication number
US20060258866A1
US20060258866A1 US11/477,168 US47716806A US2006258866A1 US 20060258866 A1 US20060258866 A1 US 20060258866A1 US 47716806 A US47716806 A US 47716806A US 2006258866 A1 US2006258866 A1 US 2006258866A1
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Prior art keywords
amino
oxoethoxy
phenyl
acid
optionally substituted
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US11/477,168
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Lanna Li
Eva-Lotte Alstermark
Christina Olsson
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AstraZeneca AB
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AstraZeneca AB
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Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to US11/477,168 priority Critical patent/US20060258866A1/en
Publication of US20060258866A1 publication Critical patent/US20060258866A1/en
Priority to US11/772,474 priority patent/US20070244198A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms 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
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms 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 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms 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 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
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    • C07C323/39—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Definitions

  • the present invention relates to certain novel 3-(amino-oxo(alkyl, alkyloxy and alkylthio)phenyl) propanoic and propenoic acid derivatives, to processes for preparing such compounds, to their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.
  • lipid disorders dislipidemias
  • the metabolic syndrome including type 2 diabetes mellitus refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possibly type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins), small dense LDL particles and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
  • hyperinsulinaemia possibly type 2 diabetes mellitus
  • arterial hypertension possibly type 2 diabetes mellitus
  • central (visceral) obesity dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins), small dense LDL particles and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
  • VLDL very low density lipoproteins
  • HDL high density lipoprotein
  • the present invention provides a compound of formula I as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof wherein A is situated in the ortho, meta or para position and represents R is hydrogen;
  • the invention provides for a compound of formula I as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof wherein A is situated in the ortho, meta or para position and represents R is hydrogen;
  • R 5 and R 6 are independently selected substituents, comprising C, H, N, O, S or halogen atoms, which give compounds of the General Formula I a molecular weight ⁇ 650.
  • R 5 and R 6 are independently selected substituents, comprising C, N, O, S, Se, P or halogen atoms. 10.
  • the other is not an alkyl.
  • R 5 and R 6 independently represent hydrogen, C 1-3 alkyl, C 2-10 -alkenyl or C 2-10 alkynyl each of which is optionally substituted by one or more of the following which may be the same or different: C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl, heterocyclyl, heteroaryl, C 1-8 alkoxy (optionally substituted by one or more fluoro), C 3-8 cycloalkoxy, C 3-8 cycloalkenyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, C 3-8 cycloalkyl C 1-8 alkoxy, aryl C 1-8 alkoxy, heterocyclyl C 1-8 alkoxy or heteroaryl C 1-8 alkoxy, fluorine or hydroxy and wherein each of these substituents may optionally be substituted on carbon with one or more substituents which may be the same or different and selected from C 1-8 alkyl, C 3-8 cycloalkyl (option
  • R 5 and R 6 independently represent C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkenyl; aryl; heterocyclyl; or heteroaryl; wherein each of these groups is optionally substituted by one or more of the following: C 1-8 alkyl, C 1-8 alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally substituted by C 1-8 alkyl, C 1-8 alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano; or R 5 and R 6 together with the nitrogen atom to which they are attached form a single or a fused heterocyclic system.
  • A is CH 2 CH(OR t )COOR m wherein R t represents C 1-4 alkyl and wherein R m represents H or C 1-4 alkyl.
  • R 5 represents C 1-10 alkyl (optionally substituted by one or more C 1-4 alkoxy) and R 6 represents benzyl optionally substituted one or more of the following: halo; C 1-4 alkyl; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy; phenyl; benzyloxy or methanesulfonyloxy.
  • n 2, 3 or 4.
  • R 5 and R 6 independently represent benzyl optionally substituted one or more of the following: halo; C 1-4 alkyl; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy; phenyl; benzyloxy Pr methanesulfonyloxy.
  • R 3 and R 4 may be the same or different and each represents alkyl, aryl or alkylaryl. Alternatively R 3 and R 4 are hydrogen.
  • R 2 is hydrogen or fluorine.
  • Formula VI is useful as an intermediate in the process of manufacturing formula I.
  • alkyl denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl having from 3 to 6 carbon atoms.
  • lower alkyl denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms.
  • alkyl and lower alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkoxy denotes a group O-alkyl, wherein alkyl is as defined above.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • aryl denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such as naphthyl.
  • substituted denotes an alkyl or an aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl or cyano groups.
  • alkylaryl denotes a wherein n is an integer 1 to 6 and R r and R i are the same or different and each represents hydrogen or an alkyl or aryl group as defined above.
  • acyl denotes a group wherein R j is hydrogen, alkyl, alkoxy, aryl and alkylaryl as defined above.
  • alkenyl and alkynyl denote a straight or branched, substituted or unsubstituted unsaturated hydrocarbon group having one or more double or triple bonds and having a maximum of 6 carbon atoms, preferably 3 carbon atoms.
  • protective group denotes a protecting group as described in the standard text “Protecting groups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts.
  • the protective group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.
  • Cycloalkyl means a non-aromatic monocyclic or multicyclic ring system of from 3 carbon atoms up to 10 carbon atoms.
  • Aryl means an aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms.
  • Heterocycly means a non-aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms, containing at least one heteroatom.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms, containing at least one heteroatom.
  • prodrug as used in this specification includes derivatives of the carboxylic acid group which are converted in a mammal, particularly a human, into the carboxylic acid group or a salt or conjugate thereof. It should be understood that, whilst not being bound by theory, it is believed that most of the activity associated with the prodrugs arises from the activity of the compound of formula I into which the prodrugs are converted. Prodrugs can be prepared by routine methodology well within the capabilities of someone skilled in the art. Various prodrugs of carboxy are known in the art. For examples of such prodrug derivatives, see:
  • In vivo cleavable esters are just one type of prodrug of the parent molecule.
  • An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include C 1-6 alkoxymethyl esters, for example, methoxymethyl; C 1-6 alkanoyloxymethyl esters, for example, pivaloyloxymethyl; phthalidyl esters; C 3-8 cycloalkoxycarbonyloxyC 1-6 alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1-6 alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
  • the compounds of the invention may be prepared as outlined below. However, the invention is not limited to these methods. The compounds may also be prepared as described for structurally related compounds in the prior art. The reactions can be carried out according to standard procedures or as described in the experimental section.
  • Compounds of formula I may be prepared by reacting a compound of formula II wherein A is situated in the ortho, meta or para position and represents in which R 1 , R 2 , R 3 and R 4 are as previously defined and R represents —OR p , wherein R p is a protecting group for a carboxylic hydroxy group as described in the standard text “Protective Groups in Organic Synthesis”, 2 nd Edition (1991) by Greene and Wuts, with a de-protecting agent.
  • the protecting group may also be a resin, such as Wang resin or 2-chlorotrityl chloride-resin.
  • Protecting groups may be removed in accordance to techniques that are well known to those skilled in the art.
  • One such protecting group is where —OR p represents a C 1-6 alkoxy group or an arylalkoxy group eg benzyloxy, such that COR p represents an ester.
  • a de-protecting agent e.g. a hydrolysing agent, for example lithium hydroxide in a mixture of THF and water, at a temperature in the range of 0-100° C. to give compounds of formula I.
  • Compounds of formula II may be prepared by reacting a compound of formula III in which A, T and n are as previously defined with a compound of formula IV in which R 5 and R 6 are as previously defined in an inert solvent, for example dichloromethane, in the presence of a coupling agent, for example a carbodimide, eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or oxalyl chloride, optionally in the presence of a base particularly diisopropylethyl amine, and optionally in the presence of a catalyst, for example a basic catalyst, eg 4-dimethylaminopyridine, at a temperature in the range of ⁇ 25° C. to 150° C.
  • a coupling agent for example a carbodimide, eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or oxalyl chloride
  • Compounds of formula II may be prepared by reacting a compound of formula V in which A is as previously defined with a compound of formula VI in which R 5 and R 6 are as previously defined and X represents a leaving group, for example a halide, OSO 2 CH 3 , OTosyl, ONosyl, OSO 2 CF 3 , OC(O)OR, OP(O)(OR) 2 or OSO 2 OR, particularly chloro or bromo, in an inert solvent, for example acetonitrile, methyl isobutylketone, N-methylpyrrolidone, toluene, toluene/water, ethanol or isopropylacetate in the presence of a base, for example potassium carbonate, sodium hydroxide or triethylamine, at a temperature in the range of ⁇ 25° C.
  • a base for example potassium carbonate, sodium hydroxide or triethylamine
  • a catalyst may be used for example iodide or a quartenary ammonium salt, particularly sodium iodide or tetra-n-butylammonium-iodide, -bromide, -acetate or -hydrogensulphate.
  • Formulae VI can be:
  • inert solvent refers to a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.
  • the compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free acid, or a pharmaceutical acceptable organic or inorganic base addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.001-10 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5 mg to 500 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.
  • a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance.
  • This dyslipidaemia also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B.
  • VLDL very low density lipoprotein
  • HDL low high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.
  • Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties.
  • the cardiovascular disease conditions include macro-angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs are expected to be delayed.
  • the compounds may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity, cancer and states of inflammatory disease including neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis.
  • the compounds of the present invention are expected to be useful in controlling glucose levels in patients suffering from type 2 diabetes.
  • the present invention provides a method of treating or preventing dyslipidemias, the insulin resistance syndrome and/or metabolic disorders (as defined above) comprising the administration of a compound of formula I to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating or preventing type 2 diabetes comprising the administration of an effective amount of a compound of formula I to a mammal (particularly a human) in need thereof.
  • the present invention provides the use of a compound of formula I as a medicament.
  • the present invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment of insulin resistance and/or metabolic disorders.
  • the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and obesity.
  • the compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol.
  • the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
  • the compounds of the invention may be used alongside other therapies for the treatment of metabolic syndrome or type 2 diabetes and its associated complications, these include biguanide drugs, for example metformin, phenformin and buformin, insulin (synthetic insulin analogues, amylin) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors).
  • biguanide drugs for example metformin, phenformin and buformin
  • insulin synthetic insulin analogues, amylin
  • oral antihyperglycemics these are divided into prandial glucose regulators and alpha-glucosidase inhibitors.
  • An example of an alpha-glucosidase inhibitor is acarbose or voglibose or miglitol.
  • An example of a prandial glucose regulator is repaglinide or nateglinide.
  • the compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof may be administered in association with another PPAR modulating agent.
  • PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma and/or delta agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
  • a PPAR alpha and/or gamma agonist refers to BMS 298585, clofibrate, fenofibrate, bezafibrate, gemfibrozil and ciprofibrate; GW 9578, pioglitazone, rosiglitazone, rivoglitazone, balaglitazone, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433.
  • a PPAR alpha and/or gamma agonist refers to (S)-2-ethoxy-3-[4-(2- ⁇ 4-methanesulphonyloxy-phenyl ⁇ ethoxy)phenyl]propanoic acid and pharmaceutically acceptable salts thereof.
  • a sulfonylurea for example: glimepiride, gllibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide.
  • the sulfonylurea is glimepiride or glibenclamide (glyburide).
  • the present invention includes administration of a compound of the present invention in conjunction with one, two or more existing therapies described in this paragraph.
  • the doses of the other existing therapies for the treatment of type 2 diabetes and its associated complications will be those known in the art and approved for use by regulatory bodies for example the FDA and may be found in the Orange Book published by the FDA. Alternatively smaller doses may be used as a result of the benefits derived from the combination.
  • the present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent.
  • the cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase).
  • the HMG-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin, or a pharmaceutically acceptable salt, especially sodium or calcium, or a solvate thereof, or a solvate of such a salt.
  • a particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a more particular statin is atorvastatin calcium salt.
  • a particularly preferred statin is, however, a compound with the chemical name (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, [also known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
  • cholesterol-lowering agent also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • the present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
  • a bile acid sequestering agent for example colestipol or cholestyramine or cholestagel.
  • the present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor).
  • IBAT inhibitor an inhibitor of the ileal bile acid transport system
  • Suitable compounds possessing IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/
  • IBAT inhibitors suitable for use in the present invention are benzothiepines, and the compounds described in the claims, particularly claim 1 , of WO 00/01687, WO 96/08484 and WO 97/33882 are incorporated herein by reference.
  • Other suitable classes of IBAT inhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and 1,5-benzothiazepines.
  • a further suitable class of IBAT inhibitors is the 1,2,5-benzothiadiazepines.
  • IBAT inhibitory activity is (3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl ⁇ -D-glucopyranosiduronic acid (EP 864 582).
  • IBAT inhibitors include one of:
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from:
  • CETP cholesterol ester transfer protein
  • a cholesterol absorption antagonist for example azetidinones such as SCH 58235 and those described in U.S. Pat. No. 5,767,115 which are incorporated herein by reference;
  • MTP microsomal transfer protein
  • nicotinic acid derivative including slow release and combination products, for example, nicotinic acid (niacin), acipimox and niceritrol;
  • phytosterol compound for example stanols
  • an omega-3 fatty acid for example OmacorTM
  • an anti-obesity compound for example orlistat (EP 129,748) and sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);
  • an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker for example metoprolol, a mixed alpha/beta andrenergic blocker, an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator;
  • ACE angiotensin converting enzyme
  • an andrenergic blocker for example metoprolol, a mixed alpha/beta andrenergic blocker, an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator
  • CB1 antagonist or inverse agonist for example as described in WO01/70700 and EP 65635;
  • MCH Melanin concentrating hormone
  • modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;
  • a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof, including active metabolites, which can be used in combination with a compound of formula I include but are not limited to, the following compounds: alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosin
  • Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for uses in the present invention are ramipril and ramiprilat.
  • Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof for use in combination with a compound of formula I include, but are not limited to, compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  • Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
  • a method for for the treatment of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of one the other compounds described in this combination section, or a pharmaceutically acceptable-salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of one the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • kits comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a kit comprising:
  • a kit comprising:
  • a compound of the formula I or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of metabolic syndrome or type 2 diabetes and its associated complications in a warm-blooded animal, such as man.
  • a compound of the formula I or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • 1 H NMR and 13 C NMR measurements were performed on a Varian Mercury 300 or Varian UNITY plus 400, 500 or 600 spectrometers, operating at 1 H frequencies of 300, 400, 500 and 600 MHz, respectively, and at 13 C frequencies of 75, 100, 125 and 150 MHz, respectively. Measurements were made on the delta scale ( ⁇ ).
  • N-(2,4-Difluorobenzyl)octanamide (0.64 g, 2.4 mmol) was dissolved in freshly distilled THF (20 mL) and cooled on an ice bath under an argon atmosphere. Borane (3.0 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed for twenty hours and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (1.2 mL) and the mixture was stirred overnight and then concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a white precipitate, which was filtered off and dried in vacuo to give 0.40 g (58%) of a white salt.
  • N-(2,4-Difluorobenzyl)nonanamide (0.75 g, 2.6 mmol) was dried once by azeotropic distillation with toluene, dissolved in freshly distilled THF (23 mL), and cooled on an ice bath under an argon atmosphere.
  • Borane (3.3 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes.
  • the reaction mixture was refluxed for five hours and was then allowed to cool to room temperature.
  • the reaction was quenched by careful addition of 10% HCl (1.3 mL) and the mixture was stirred for three hours and then concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a white precipitate, which was filtered off and dried in vacuo to give 0.69 g (85%) of a white salt.
  • N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol) was dissolved in freshly distilled THF (220 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched at 0° C. by careful addition of 10% HCl (11 mL) and the mixture was stirred at room temperature for three hours and then concentrated in vacuo.
  • N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (29 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo.
  • N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo.
  • aqueous phase was extracted with ethyl acetate (2 ⁇ 100 mL) and the combined organic phase was dried over Na 2 SO 4 and concentrated in vacuo.
  • N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine 0.574 g, 2.00 mmol
  • ⁇ 4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy ⁇ acetic acid 0.593 g, 2.00 mmol
  • methylene chloride 20 mL
  • N,N-diisopropylethylamine 0.80 mL, 4.6 mmol
  • O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 0.674 g, 2.10 mmol
  • aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 , and concentrated in vacuo to afford 0.070 g (63%) of a colourless oil.
  • aqueous phase was extracted with ethyl acetate (2 ⁇ 50 mL) and the combined organic phase was dried over Na 2 SO 4 , and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 4.31 g (75%) of white solids.
  • the mixture was filtered through a filter plate and washed once with 2.0 ml of MeOH.
  • the filtrates were collected in 24-well plates with 4 ml glass vials. Then the solvent was removed in vacuo, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • polymer supported aldehyde resin (Novabiochem 2.85 mmol/g loading; 80-100 mg), to remove the excess of amine and 2 ml of dry THF.
  • the resulting mixture was stirred at rt for 6-8 h, filtered through a filter plate, washed once with 1.0 ml of THF and the filtrate was collected in 24-well plates with 4 ml glass vials. Then the solvent was removed in vacuo, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • the solutions are filtered through SCX-plates (Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)) to remove the excess of secondary amine.
  • SCX-plates Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)
  • the SCX columns are washed with 1.0 ml of THF.
  • the combined filtrates were collected in 24-well plates with 4 ml glass vials.
  • polymer supported isocyanate (Novabiochem 1.5 mmol/g; ca 100 mg) was added and the mixture was stirred for additional 6 h at RT. This is to remove any excess of secondary amine. Then the mixtures were filtered through filter plates into 247-well plates with 4 ml glass vials, followed by a wash of 1.0 ml THF. The filtrates were collected in 24-well plates with 4 ml glass vials. The solvent was removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • the dry residues (esters) are dissolved in 1.2 ml of THF. 400 ⁇ l of the solution is transferred to a preweighed blue well plate. The daughter plate is analysed by LC-MS (purified by preparative HPLC if needed) and the solvent is removed in vacuum, using the Hr-4 vacuum centrifuge (30° C., 5 h, vacramp). The dry compounds (daughter plate) are then quantified by automatic weighing and submitted to screen.
  • the mother plate (containing esters dissolved in 0.8 ml THF) is treated with 0.8 ml 0.175M LiOH (per-vial) overnight.
  • a compound contains a tertiary amine
  • the solution is poured onto an SCX column (Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)) to catch the product.
  • SCX columns are washed with 3 ⁇ 1.0 ml of THF/MeOH. Afterwards the product is eluted with 4.0 ml of MeOH, saturated with ammonia.
  • a compound does not contain a tertiary amine
  • the solvent is removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 12 h, vacramp).
  • the dry compounds are dissolved with 11.0 ml 0.2M HCl, followed by addition of 2.0 ml of DCM.
  • the mixtures are vigorously shaken for 30 min.
  • Phase separators (6 ml, Whatman) are used to separate the DCM layer, which contains the product, from the water phase.
  • the compounds are collected in 24-well plates with 4 ml glass vials.
  • the solvent is removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • the dry compounds are dissolved with 0.5 ml THF (or appropriate solvent) and transferred to a preweighed blue-well plate. This is repeated with 0.3 ml MeOH. The solvent is afterwards removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp). The plate is analysed by LC-MS (purified by preparative HPLC if needed) and the dry compounds are then quantified by automatic weighing and submitted to screen.
  • test compound solution was added.
  • Transiently transfected cells were exposed to compounds for about 24 hours before the luciferase detection assay was performed.
  • 100 ⁇ l of assay reagent was added manually to each well and plates were left for approximately 20 minutes in order to allow lysis of the cells. After lysis, luciferase activity was measured in a 1420 Multiwell counter, Victor, from Wallach.
  • the TZD pioglitazone was used as reference substance for activation of both human and murine PPAR ⁇ .
  • 5,8,11,14-Eicosatetrayonic acid (ETYA) was used as reference substance for human PPAR ⁇ .
  • EC 50 values For calculation of EC 50 values, a concentration-effect curve was established. Values used were derived from the average of two or three independent measurements (after subtraction of the background average value) and were expressed as the percentage of the maximal activation obtained by the reference compound. Values were plotted against the logarithm of the test compound concentration. EC 50 values were estimated by linear intercalation between the data points and calculating the concentration required to achieve 50% of the maximal activation obtained by the reference compound.
  • the compounds of formula I have an EC 50 of less than 0.1 ⁇ mol/l for PPAR ⁇ and particular compounds have an EC 50 of less than 0.0 ⁇ mol/l. Additionally in particular compounds the ratio of the EC 50 (PPAR ⁇ ): EC 50 (PPAR ⁇ ) is greater than 150:1. It is believed that this ratio is important with respect to the pharmacological activity of the compounds and to their therapeutic profile.
  • the compounds of the present invention exhibit improved DMPK (Drug Metabolism and Pharmacokinetic) properties for example they exhibit improved metabolic stability in-vitro. The compounds also have a promising toxicological profile.

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Abstract

The present invention provides a compound of formula I processes for preparing such compounds, their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance, methods for their therapeutic use and pharmaceutical compositions containing them.

Description

    FIELD OF THE INVENTION
  • The present invention relates to certain novel 3-(amino-oxo(alkyl, alkyloxy and alkylthio)phenyl) propanoic and propenoic acid derivatives, to processes for preparing such compounds, to their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.
    • BACKGROUND OF THE INVENTION
  • The metabolic syndrome including type 2 diabetes mellitus, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possibly type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins), small dense LDL particles and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
  • Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In type 2 diabetes mellitus atherosclerosis related conditions cause up to 80% of all deaths.
  • In clinical medicine there is awareness of the need to increase the insulin sensitivity in patients with the metabolic syndrome and thus to correct the dyslipidaemia which is considered to cause the accelerated progress of atherosclerosis. However, currently this is not a universally accepted diagnosis with well-defined pharmacotherapeutic indications.
  • The S-enantiomer of the compound of formula C below
    Figure US20060258866A1-20061116-C00001
  • 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, is disclosed in PCT Publication Number WO99/62872. This compound is reported to be a modulator of peroxisome proliferator-activated receptors (PPAR, for a review of the PPARs see T. M. Willson et al, J Med Chem 2000, Vol 43, 527) and has combined PPARα/PPARγ agonist activity (Structure, 2001, Vol 9, 699, P; Cronet et al). This compound is effective in treating conditions associated with insulin resistance.
  • Surprisingly a series of compounds has now been found which are selective PPARα modulators.
    • DESCRIPTION OF THE INVENTION
  • The present invention provides a compound of formula I
    Figure US20060258866A1-20061116-C00002
    as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof
    wherein
    A is situated in the ortho, meta or para position and represents
    Figure US20060258866A1-20061116-C00003
    R is hydrogen;
      • —ORa, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl;
      • —NRaRb, wherein Ra and Rb are the same or different and Ra is as defined above and Rb represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH, -Oalkyl, -Oaryl, -Oalkylaryl, —CORc or —SO2Rd, wherein Rc represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl;
        R1 is alkyl, aryl, alkenyl, alkynyl, or when A is
        Figure US20060258866A1-20061116-C00004
        R1 can also be cyano;
      • —ORe, wherein Re is alkyl, acyl, aryl or alkylaryl;
      • —O—[CH2]m—ORf, wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8;
      • —OCONRaRc, wherein Ra and Rc are as defined above;
      • —SRd, wherein Rd is as defined above;
      • —SO2NRaRf, wherein Rf and Ra are as defined above;
      • —SO2ORa, wherein Ra is as defined above;
      • —COORd, wherein Rd is as defined above;
        R2 is hydrogen, halogen, alkyl, aryl, or alkylaryl,
        R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl;
        T represents O, S or a single bond;
        n represents 1, 2, 3 or 4;
        R5 and R6 are independently selected substituents, comprising C, H, N, O, S, Se, P or halogen atoms, which give compounds of the General Formula I a molecular weight <650;
        with a first proviso that
        when A is CH2CH(OC2H5)COOC2H5 or CH2CH(OC2H5)COOH; T is O; n is 1 and R5 represents a C2-4alkyl group then R6 does not represent a group of formula
        Figure US20060258866A1-20061116-C00005
        wherein Rx represents chloro, trifluoromethyl or trifluoromethoxy, Ry represents H or fluoro;
        and a second proviso that when A is CH2CH(OC2H5)COOC2H5 or CH2CH(OC2H5)COOH; T is O; n is 1 and R5 represents hexyl or heptyl then R6 does not represent a group of formula
        Figure US20060258866A1-20061116-C00006
        wherein Rz represents phenyl, 2,4-difluorophenyl or cyclohexyl, and n is 1 or 2;
        provided that the compound of formula I is not:
    • (2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazinyl]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • α-methoxy-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-α-methyl-benzenepropanoic acid;
    • 4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-, benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-, benzenepropanoic acid;
    • (2S)-4-[2-[ethyl [(3-methylphenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methylhexyl)amino]-2oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[([1,1′-biphenyl]4-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • 3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-, ethyl ester-benzenepropanoic acid;
    • (2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(2-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • 4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-ethoxy-benzenepropanoic acid;
    • (2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • D-Phenylalanine, N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-, α-methyl ester;
    • (2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • α-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[ethyl [(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[2-(4-methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-(4-fluorophenoxy)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic acid;
    • (2S)-4-[2-(hexylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethoxy]-benzenepropanoic acid; or
    • (2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid.
  • According to another aspect the invention provides for a compound of formula I
    Figure US20060258866A1-20061116-C00007
    as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof wherein
    A is situated in the ortho, meta or para position and represents
    Figure US20060258866A1-20061116-C00008
    R is hydrogen;
      • —ORa, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl;
      • —NRaRb, wherein Ra and Rb are the same or different and Ra is as defined above and Rb represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH, -Oalkyl, -Oaryl, -Oalkylaryl, —CORc or —SO2Rd, wherein Rc represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl;
        R1 is alkyl, aryl, alkenyl, alkynyl, or when A is
        Figure US20060258866A1-20061116-C00009
        R1 can also be cyano;
      • —ORe, wherein Re is alkyl, acyl, aryl or alkylaryl;
      • —O—[CH2]m—ORf, wherein Re represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8;
      • —OCONRaRc, wherein Ra and Rc are as defined above;
      • —SRd, wherein Rd is as defined above;
      • —SO2NRaRf, wherein Rf and Ra are as defined above;
      • —SO2ORa, wherein Ra is as defined above;
      • —COORd, wherein Rd is as defined above;
        R2 is hydrogen, halogen, alkyl, aryl, or alkylaryl,
        R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl;
        T represents O, S or a single bond;
        n represents 1, 2, 3 or 4;
        R5 and R6 are independently selected substituents, comprising C, H, N, O, S, Se, P or halogen atoms, which give compounds of the General Formula I a molecular weight <650;
        with a first proviso that
        when A is CH2CH(OC2H5)COOC2H5 or CH2CH(OC2H5)COOH; T is O; n is 1 and R5 represents a C2-4alkyl group then R6 does not represent a group of formula
        Figure US20060258866A1-20061116-C00010
        wherein Rx represents chloro, trifluoromethyl or trifluoromethoxy, Ry represents H or fluoro;
        and a second proviso that when A is CH2CH(OC2H5)COOC2H5 or CH2CH(OC2H5)COOH; T is O; n is 1 and R5 represents hexyl or heptyl then R6 does not represent a group of formula
        Figure US20060258866A1-20061116-C00011
        wherein Rz represents phenyl, 2,4-difluorophenyl or cyclohexyl, and n is 1 or 2;
        provided that the compound of formula I is not:
    • (2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazinyl]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]3-α-methoxy-benzenepropanoic acid;
    • α-methoxy-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-α-methyl-α-benzenepropanoic acid;
    • 4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-, benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-, benzenepropanoic acid;
    • (2S)-4-[2-[ethyl [(3-methylphenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methylhexyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[([1,1′-biphenyl]-4-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • 3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(heptylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-, ethyl ester-benzenepropanoic acid;
    • (2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[2-(2pyridinyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • 4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-α-ethoxy-benzenepropanoic acid;
    • (2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • D-Phenylalanine, N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-, α-methyl ester;
    • (2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • α-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[ethyl [(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-[[2-(4methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-(4-fluorophenoxy)-α-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-α-phenoxy-benzenepropanoic acid;
    • (2S)-4-[2-(hexylamino)-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • (2S)-α-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethoxy]-benzenepropanoic acid;
    • (2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-α-methoxy-benzenepropanoic acid;
    • [[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]amino]ethyl]phenyl]methyl]-, diethyl ester-propanedioic acid;
    • 4-[2-(heptylamino)-2-oxoethyl]-α,α-dimethyl-, ethyl ester-benzenepropanoic acid;
    • 2-[[4-(2-amino-2-oxoethoxy)phenyl]methylene]-3-oxo-, methyl ester-butanoic acid;
    • 4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-α-phenyl-, ethyl ester-benzenepropanoic acid;
    • 4-[2-(heptylamino)-2-oxoethyl]-(α,α-dimethyl-, ethyl ester-benzenepropanoic acid;
    • 4-[2-[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-4-hydroxyphenyl]amino]-2-oxoethoxy]-α-(methylthio)-, ethyl ester-benzenepropanoic acid;
    • [[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]aminoethyl]phenyl]methyl]-propanedioic acid;
    • N-[3-[4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenylpropyl]-, methyl ester-glycine;
    • 4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-α-phenyl-benzenepropanoic acid;
    • N-[3-[4-[2-[methyl (2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenylpropyl]-glycine; or
      4-[3-[methyl(2-phenylethyl)amino]-3-oxopropyl]-α-phenyl-benzenpropanoic acid.
  • Particularly R5 and R6 are independently selected substituents, comprising C, H, N, O, S or halogen atoms, which give compounds of the General Formula I a molecular weight <650. Alternatively, R5 and R6 are independently selected substituents, comprising C, N, O, S, Se, P or halogen atoms. 10. According to one aspect of the invention, when either of R5 and R6 is hydrogen, the other is not an alkyl.
  • Particularly R5 and R6 independently represent hydrogen, C1-3alkyl, C2-10-alkenyl or C2-10alkynyl each of which is optionally substituted by one or more of the following which may be the same or different: C3-8cycloalkyl, C3-8cycloalkenyl, aryl, heterocyclyl, heteroaryl, C1-8alkoxy (optionally substituted by one or more fluoro), C3-8cycloalkoxy, C3-8cycloalkenyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, C3-8cycloalkyl C1-8alkoxy, aryl C1-8alkoxy, heterocyclyl C1-8 alkoxy or heteroaryl C1-8 alkoxy, fluorine or hydroxy and wherein each of these substituents may optionally be substituted on carbon with one or more substituents which may be the same or different and selected from C1-8alkyl, C3-8cycloalkyl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), heterocyclyl (optionally substituted by C1-6alkyl on any nitrogen), heteroaryl (optionally substituted by C1-8alkyl, C1-8-alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), C1-8alkoxy (optionally substituted by one or more fluoro), C3-8cycloalkoxy, C3-8 cycloalkyl C1-8alkoxy, aryloxy (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl C1-8alkoxy (wherein the aryl part is optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy, methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy,
  • or R5 and R6 independently represent C3-C8 cycloalkyl; C3-C8 cycloalkenyl; aryl; heterocyclyl; or heteroaryl; wherein each of these groups is optionally substituted by one or more of the following: C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano; or R5 and R6 together with the nitrogen atom to which they are attached form a single or a fused heterocyclic system.
  • Particularly A is CH2CH(ORt)COORm wherein Rt represents C1-4alkyl and wherein Rm represents H or C1-4alkyl.
  • A preferred group of compounds is represented by formula Ia
    Figure US20060258866A1-20061116-C00012
      • as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof
        wherein,
        T represents O or a single bond;
        n=1 or 2;
        R5 and R6 are independently selected C1-10alkyl (optionally substituted by one or more C1-4alkoxy); C5-7cycloalkylC1-4alkyl (optionally substituted cyano); benzyl or phenethyl (each of which is optionally substituted by one or more of the following: halo; C1-4alkyl; C1-4alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy; phenyl; benzyloxy; methanesulfonyloxy); indolylmethyl; or thienylmethyl.
  • In preferred groups of compounds of formula I and formula Ia, R5 represents C1-10alkyl (optionally substituted by one or more C1-4alkoxy) and R6 represents benzyl optionally substituted one or more of the following: halo; C1-4alkyl; C1-4alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy; phenyl; benzyloxy or methanesulfonyloxy.
  • Alternatively n represents 2, 3 or 4.
  • In other preferred groups of compounds of formula I and Ia R5 and R6 independently represent benzyl optionally substituted one or more of the following: halo; C1-4alkyl; C1-4alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy; phenyl; benzyloxy Pr methanesulfonyloxy.
  • R3 and R4 may be the same or different and each represents alkyl, aryl or alkylaryl. Alternatively R3 and R4 are hydrogen.
  • In one aspect of the invention R2 is hydrogen or fluorine.
  • A compound of formula VI:
    Figure US20060258866A1-20061116-C00013
    wherein R5, R6 and n is as defined in any of the preceding claims and X is a leaving group, such as a halide, OSO2CH3, OTosyl, ONosyl, OSO2CF3, OC(O)OR, OP(O)(OR)2 or OSO2OR, particularly chloro or bromo. Formula VI is useful as an intermediate in the process of manufacturing formula I.
  • The following definitions shall apply throughout the specification and the appended claims with regard to the group A.
  • Unless otherwise stated or indicated, the term “alkyl” denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl having from 3 to 6 carbon atoms. The term “lower alkyl” denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms. Examples of said alkyl and lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Unless otherwise stated or indicated, the term “alkoxy” denotes a group O-alkyl, wherein alkyl is as defined above.
  • Unless otherwise stated or indicated, the term “halogen” shall mean fluorine, chlorine, bromine or iodine.
  • Unless otherwise stated or indicated, the term “aryl” denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such as naphthyl.
  • Unless otherwise stated or indicated, the term “substituted” denotes an alkyl or an aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl or cyano groups.
  • Unless otherwise stated or indicated, the term “alkylaryl” denotes a
    Figure US20060258866A1-20061116-C00014
    wherein n is an integer 1 to 6 and Rr and Ri are the same or different and each represents hydrogen or an alkyl or aryl group as defined above.
  • Unless otherwise stated or indicated, the term “acyl” denotes a group
    Figure US20060258866A1-20061116-C00015
    wherein Rj is hydrogen, alkyl, alkoxy, aryl and alkylaryl as defined above.
  • Unless otherwise stated or indicated, the terms “alkenyl” and “alkynyl” denote a straight or branched, substituted or unsubstituted unsaturated hydrocarbon group having one or more double or triple bonds and having a maximum of 6 carbon atoms, preferably 3 carbon atoms.
  • Unless otherwise stated or indicated the term “protective group” (Rp) denotes a protecting group as described in the standard text “Protecting groups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts. The protective group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.
  • For the groups other than A the following definitions apply.
  • “Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring system of from 3 carbon atoms up to 10 carbon atoms.
  • “Aryl” means an aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms.
  • “Heterocycly.” means a non-aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms, containing at least one heteroatom.
  • “Heteroaryl” means an aromatic monocyclic or multicyclic ring system of up to 14 carbon atoms, containing at least one heteroatom.
  • The term “prodrug” as used in this specification includes derivatives of the carboxylic acid group which are converted in a mammal, particularly a human, into the carboxylic acid group or a salt or conjugate thereof. It should be understood that, whilst not being bound by theory, it is believed that most of the activity associated with the prodrugs arises from the activity of the compound of formula I into which the prodrugs are converted. Prodrugs can be prepared by routine methodology well within the capabilities of someone skilled in the art. Various prodrugs of carboxy are known in the art. For examples of such prodrug derivatives, see:
    • a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology. 42: 309-396, edited by K. Widder, et al. (Academic Press, 1985);
    • b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
    • c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);
    • d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and
    • e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).
  • The above documents a to e are herein incorporated by reference.
  • In vivo cleavable esters are just one type of prodrug of the parent molecule. An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters, for example, methoxymethyl; C1-6alkanoyloxymethyl esters, for example, pivaloyloxymethyl; phthalidyl esters; C3-8cycloalkoxycarbonyloxyC1-6alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
  • Specific compounds of the invention are:
    • (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[Benzyl (methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-Ethoxy-3-[4-(2-{heptyl [(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-3-(4{-2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
    • (2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4{-2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{(4-Chlorobenzyl) [4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid and
    • (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{(1,3-benzodioxol-5-ylmethyl)[3-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl) [4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
      and pharmaceutically acceptable salts thereof.
  • In the present specification the expression “pharmaceutically acceptable salts” is intended to define but is not limited to salts with bases.
  • It will also be understood that certain compounds of the present invention may exist in solvated as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms. Certain compounds of the present invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.
  • Methods of Preparation
  • The compounds of the invention may be prepared as outlined below. However, the invention is not limited to these methods. The compounds may also be prepared as described for structurally related compounds in the prior art. The reactions can be carried out according to standard procedures or as described in the experimental section. Compounds of formula I may be prepared by reacting a compound of formula II
    Figure US20060258866A1-20061116-C00016
    wherein
    A is situated in the ortho, meta or para position and represents
    Figure US20060258866A1-20061116-C00017
    in which R1, R2, R3 and R4 are as previously defined and R represents —ORp, wherein Rp is a protecting group for a carboxylic hydroxy group as described in the standard text “Protective Groups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts, with a de-protecting agent. The protecting group may also be a resin, such as Wang resin or 2-chlorotrityl chloride-resin. Protecting groups may be removed in accordance to techniques that are well known to those skilled in the art. One such protecting group is where —ORp represents a C1-6alkoxy group or an arylalkoxy group eg benzyloxy, such that CORp represents an ester. Such esters can be reacted with a de-protecting agent e.g. a hydrolysing agent, for example lithium hydroxide in a mixture of THF and water, at a temperature in the range of 0-100° C. to give compounds of formula I.
  • Compounds of formula II may be prepared by reacting a compound of formula III
    Figure US20060258866A1-20061116-C00018
    in which A, T and n are as previously defined with a compound of formula IV
    Figure US20060258866A1-20061116-C00019
    in which R5 and R6 are as previously defined in an inert solvent, for example dichloromethane, in the presence of a coupling agent, for example a carbodimide, eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or oxalyl chloride, optionally in the presence of a base particularly diisopropylethyl amine, and optionally in the presence of a catalyst, for example a basic catalyst, eg 4-dimethylaminopyridine, at a temperature in the range of −25° C. to 150° C.
  • Compounds of formulae III and IV may be prepared by methods described in the Examples or by analogous methods known to those skilled in the art.
  • Compounds of formula II may be prepared by reacting a compound of formula V
    Figure US20060258866A1-20061116-C00020
    in which A is as previously defined with a compound of formula VI
    Figure US20060258866A1-20061116-C00021
    in which R5 and R6 are as previously defined and X represents a leaving group, for example a halide, OSO2CH3, OTosyl, ONosyl, OSO2CF3, OC(O)OR, OP(O)(OR)2 or OSO2OR, particularly chloro or bromo, in an inert solvent, for example acetonitrile, methyl isobutylketone, N-methylpyrrolidone, toluene, toluene/water, ethanol or isopropylacetate in the presence of a base, for example potassium carbonate, sodium hydroxide or triethylamine, at a temperature in the range of −25° C. to 150° C. Optionally a catalyst may be used for example iodide or a quartenary ammonium salt, particularly sodium iodide or tetra-n-butylammonium-iodide, -bromide, -acetate or -hydrogensulphate.
  • Compounds of formulae V and VI may be prepared by methods described in the Examples or by analogous methods known to those skilled in the art.
  • Formulae VI can be:
    • 2-chloro-N-(2,4-difluorobenzyl)-N-octylacetamide
    • 2-chloro-N-(2,4-difluorobenzyl)-N-nonylacetamide
    • 2-chloro-N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)acetamide
    • 2-chloro-N-(2,4-difluorobenzyl)-N-methylacetamide
    • 2-chloro-N-heptyl-N-[(1-methyl-1H-indol-2-yl)methyl]acetamide
    • 2-chloro-N-(2,3-dimethoxybenzyl)-N-heptyl acetamide
    • N-butyl-2-chloro-N-(2,3-dimethoxybenzyl)acetamide
    • 2-chloro-N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)acetamide
    • 2-chloro-N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)acetamide
    • 2-chloro-N-ethyl-N-(2-fluorobenzyl)acetamide
    • N-[4-(benzyloxy)benzyl]-N-butyl-2-chloroacetamide
    • 2-chloro-N-hexyl-N-(2-phenylethyl)acetamide
    • 2-chloro-N,N-bis(4-chlorobenzyl)acetamide
    • N-(4-tert-butylbenzyl)-2-chloro-N-(4-chlorobenzyl)acetamide
    • 2-chloro-N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]acetamide
    • 2-chloro-N,N-bis[4-(trifluoromethyl)benzyl]acetamide
    • N-benzyl-2-chloro-N-ethylacetamide
    • N-(4-tert-butylbenzyl)-2-chloro-N-ethylacetamide
    • 2-chloro-N-ethyl-N-[4-(trifluoromethyl)benzyl]acetamide
    • 2-chloro-N-(4-cyclohexylbutyl)-N-(2,4-difluorobenzyl)acetamide
    • N-(2-biphenyl-4-ylethyl)-2-chloro-N-(2,4-difluorobenzyl)acetamide
    • 2-chloro-N-(4-chlorobenzyl)-N-(2-methoxybenzyl)acetamide
    • 4-{[butyl(chloroacetyl)amino]methyl}phenyl methanesulfonate
  • Compounds of formulae II, III, IV, V and VI are useful intermediates in the preparation of compounds of formula I. Compounds of formula II, III, V and VI are herein claimed as a further aspect of the present invention. The S-enantiomers of compounds of formula II, III and V are preferred. The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
  • The expression “inert solvent” refers to a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.
  • Pharmaceutical Preparations
  • The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free acid, or a pharmaceutical acceptable organic or inorganic base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.001-10 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5 mg to 500 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.
  • According to a further aspect of the invention there is thus provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • Pharmacological Properties
  • The present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B.
  • The compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.
  • Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties. The cardiovascular disease conditions include macro-angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs are expected to be delayed. Furthermore the compounds may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity, cancer and states of inflammatory disease including neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis.
  • The compounds of the present invention are expected to be useful in controlling glucose levels in patients suffering from type 2 diabetes.
  • The present invention provides a method of treating or preventing dyslipidemias, the insulin resistance syndrome and/or metabolic disorders (as defined above) comprising the administration of a compound of formula I to a mammal (particularly a human) in need thereof.
  • The present invention provides a method of treating or preventing type 2 diabetes comprising the administration of an effective amount of a compound of formula I to a mammal (particularly a human) in need thereof.
  • In a further aspect the present invention provides the use of a compound of formula I as a medicament.
  • In a further aspect the present invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment of insulin resistance and/or metabolic disorders.
  • Combination Therapy
  • The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and obesity. The compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
  • The compounds of the invention may be used alongside other therapies for the treatment of metabolic syndrome or type 2 diabetes and its associated complications, these include biguanide drugs, for example metformin, phenformin and buformin, insulin (synthetic insulin analogues, amylin) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors). An example of an alpha-glucosidase inhibitor is acarbose or voglibose or miglitol. An example of a prandial glucose regulator is repaglinide or nateglinide.
  • In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, may be administered in association with another PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma and/or delta agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular the compounds described in the patent applications listed on page 634) and J Med Chem, 2000, 43, 527 which are all incorporated herein by reference. Particularly a PPAR alpha and/or gamma agonist refers to BMS 298585, clofibrate, fenofibrate, bezafibrate, gemfibrozil and ciprofibrate; GW 9578, pioglitazone, rosiglitazone, rivoglitazone, balaglitazone, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041 and GW 2433. Particularly a PPAR alpha and/or gamma agonist refers to (S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxy-phenyl}ethoxy)phenyl]propanoic acid and pharmaceutically acceptable salts thereof.
  • In addition the combination of the invention may be used in conjunction with a sulfonylurea for example: glimepiride, gllibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide. Preferably the sulfonylurea is glimepiride or glibenclamide (glyburide). More preferably the sulfonylurea is glimepiride. Therefore the present invention includes administration of a compound of the present invention in conjunction with one, two or more existing therapies described in this paragraph. The doses of the other existing therapies for the treatment of type 2 diabetes and its associated complications will be those known in the art and approved for use by regulatory bodies for example the FDA and may be found in the Orange Book published by the FDA. Alternatively smaller doses may be used as a result of the benefits derived from the combination. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin, or a pharmaceutically acceptable salt, especially sodium or calcium, or a solvate thereof, or a solvate of such a salt. A particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more particular statin is atorvastatin calcium salt. A particularly preferred statin is, however, a compound with the chemical name (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, [also known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt. The compound (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, and its calcium and sodium salts are disclosed in European Patent Application, Publication No. EP-A-0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437444. This latter statin is now known under its generic name rosuvastatin.
  • In the present application, the term “cholesterol-lowering agent” also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
  • The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor).
  • Suitable compounds possessing IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/50051, EP 864 582, EP489423, EP549967, EP573848, EP624593, EP624594, EP624595 and EP624596 and the contents of these patent applications are incorporated herein by reference.
  • Particular classes of IBAT inhibitors suitable for use in the present invention are benzothiepines, and the compounds described in the claims, particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 are incorporated herein by reference. Other suitable classes of IBAT inhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and 1,5-benzothiazepines. A further suitable class of IBAT inhibitors is the 1,2,5-benzothiadiazepines.
  • One particular suitable compound possessing IBAT inhibitory activity is (3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl β-D-glucopyranosiduronic acid (EP 864 582). Other suitable IBAT inhibitors include one of:
    • 1,1-di oxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl) carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(5-carboxypentyl) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl) carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{(R)-1-[N″-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(ethyl) phosphoryl]ethyl}carbarmoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(hydroxy) phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-1 (R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxybutyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N—((S)-1-carboxypropyl) carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
    • 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and
    • 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
      or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from:
  • a CETP (cholesteryl ester transfer protein) inhibitor, for example those referenced and described in WO 00/38725 page 7 line 22-page 10, line 17 which are incorporated herein by reference;
  • a cholesterol absorption antagonist for example azetidinones such as SCH 58235 and those described in U.S. Pat. No. 5,767,115 which are incorporated herein by reference;
  • a MTP (microsomal transfer protein) inhibitor for example those described in Science, 282, 751-54, 1998 which are incorporated herein by reference;
  • a nicotinic acid derivative, including slow release and combination products, for example, nicotinic acid (niacin), acipimox and niceritrol;
  • a phytosterol compound for example stanols;
  • probucol;
  • an omega-3 fatty acid for example Omacor™;
  • an anti-obesity compound for example orlistat (EP 129,748) and sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);
  • an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker for example metoprolol, a mixed alpha/beta andrenergic blocker, an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator;
  • a CB1 antagonist or inverse agonist for example as described in WO01/70700 and EP 65635;
  • a Melanin concentrating hormone (MCH) antagonist;
  • a PDK inhibitor; or
  • modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;
  • or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof, including active metabolites, which can be used in combination with a compound of formula I include but are not limited to, the following compounds: alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for uses in the present invention are ramipril and ramiprilat.
  • Preferred angiotensin II antagonists, pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof for use in combination with a compound of formula I include, but are not limited to, compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan. Particularly preferred angiotensin II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
  • Therefore in an additional feature of the invention, there is provided a method for for the treatment of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of one the other compounds described in this combination section, or a pharmaceutically acceptable-salt, solvate, solvate of such a salt or a prodrug thereof.
  • Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of one the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • According to a further aspect of the present invention there is provided a kit comprising:
  • a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a first unit dosage form;
  • b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and
  • c) container means for containing said first and second dosage forms.
  • According to a further aspect of the present invention there is provided a kit comprising:
  • a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form;
  • b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and
  • c) container means for containing said first and second dosage forms.
  • According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of metabolic syndrome or type 2 diabetes and its associated complications in a warm-blooded animal, such as man.
  • According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
  • According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
    • EXAMPLES
  • 1H NMR and 13C NMR measurements were performed on a Varian Mercury 300 or Varian UNITY plus 400, 500 or 600 spectrometers, operating at 1H frequencies of 300, 400, 500 and 600 MHz, respectively, and at 13C frequencies of 75, 100, 125 and 150 MHz, respectively. Measurements were made on the delta scale (δ).
  • Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
  • Abbreviations
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • Pd/C palladium on charcoal
  • DMAP dimethylaminopyridine
  • t triplet
  • s singlet
  • d doublet
  • q quartet
  • m multiplet
  • bs broad singlet
  • dm doublet of multiplet
  • bt broad triplet
  • dd doublet of doublet
    • Example 1 (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(2,4-Difluorobenzyl)octanamide
  • To a solution of 2,4-difluorobenzylamine (0.43 g, 3.0 mmol) in methylene chloride (30 mL) were added octanoic acid (0.43 g, 3.0 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.1 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4—Concentration in vacuo afforded 0.78 g (96%) of an oil, which solidified upon standing.
  • 1H NMR (500 MHz, CDCl3): δ 0.81-0.90 (m, 3H), 1.18-1.33 (m, 8H), 1.54-1.66 (m, 2H), 2.12-2.21 (m, 2H), 4.42 (d, 2H), 5.82 (bs, 1H), 6.73-6.87 (m, 2H), 7.32 (m, 1H).
    • (ii) N-(2,4-Difluorobenzyl)-N-octylamine hydrochloride
  • N-(2,4-Difluorobenzyl)octanamide (0.64 g, 2.4 mmol) was dissolved in freshly distilled THF (20 mL) and cooled on an ice bath under an argon atmosphere. Borane (3.0 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed for twenty hours and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (1.2 mL) and the mixture was stirred overnight and then concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a white precipitate, which was filtered off and dried in vacuo to give 0.40 g (58%) of a white salt.
  • 1H NMR (400 MHz, CD3OD): δ 0.85-0.93 (m, 3H), 1.20-1.45 (m, 10H), 1.65-1.89 (m, 2H), 3.01-3.09 (m, 2H), 4.25 (s, 2H), 7.04-7.16 (m, 2H), 7.63 (m, 1H).
    • (iii) Ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added N-(2,4-difluorobenzyl)-N-octylamine hydrochloride (0.165 g, 0.57 mmol), DMAP (0.054 g, 0.45 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.082 g (38%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.80-0.90 (m, 3H), 1.14 (t, 3H), 1.17-1.30 (m, 13H), 1.42-1.64 (m, 2H), 2.86-3.00 (m, 2H), 3.20-3.40 (m, 3H), 3.59 (m, 1H), 3.95 (m, 1H), 4.15 (q, 2H), 4.59 (s, 2H), 4.69 and 4.70 (2s, 2H, rotamers), 6.71-6.88 (m, 4H), 7.07-7.18 and 7.20-7.31 (2m, 3H, rotamers).
    • (iv) (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.038 g, 0.071 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phase was washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 0.035 g (98%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ0.83-4.93 (m, 3H), 1.17 (t, 3H), 1.20-1.35 (m, 10H), 1.42-1.68 (m, 2H), 2.88-3.10 (m, 2H), 3.24-3.35 (m, 2H), 3.41 (m, 1H), 3.62 (m, 1H), 4.03 (m, 1H), 4.62 (s, 2H), 4.72 and 4.73 (2s, 2H, rotamers), 6.70-6.90 (m, 4H), 7.09-7.21 and 7.24-7.34 (2m, 3H, rotamers).
    • Example 2 (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(2,4-Difluorobenzyl)nonanamide
  • To a solution of 2,4-difluorobenzylamine (0.47 g, 3.3 mmol) in methylene chloride (30 mL) were added nonanoic acid (0.52 g, 3.3 mmol) and DMAP (0.40 g, 3.3 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4. Concentration in vacuo afforded 0.87 g (93%) of an oil, which solidified upon standing.
  • 1H NMR (600 MHz, CDCl3): δ 0.80-0.86 (m, 3H), 1.16-1.28 (m, 10H), 1.53-1.62 (m, 2H), 2.11-2.17 (m, 2H), 4.37 (d, 2H), 6.12 (bs, 1H), 6.70-6.81 (m, 2H), 7.27 (m, 1H).
    • (ii) (N-(2,4-Difluorobenzyl)-N-nonylamine hydrochloride
  • N-(2,4-Difluorobenzyl)nonanamide (0.75 g, 2.6 mmol) was dried once by azeotropic distillation with toluene, dissolved in freshly distilled THF (23 mL), and cooled on an ice bath under an argon atmosphere. Borane (3.3 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed for five hours and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (1.3 mL) and the mixture was stirred for three hours and then concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a white precipitate, which was filtered off and dried in vacuo to give 0.69 g (85%) of a white salt.
  • 1H NMR (400 MHz, CD3OD): δ 0.85-0.94 (m, 3H), 1.20-1.45 (m, 12H), 1.65-1.80 (m, 2H), 3.00-3.10 (m, 2H), 4.26 (s, 2H), 7.04-7.16 (m, 2H), 7.64 (m, 1H).
    • (iii) Ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added (N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57 mmol), DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.117 g (53%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.82-0.90 (m, 3H), 1.14 (t, 3H), 1.17-1.30 (m, 15H), 1.42-1.62 (m, 2H), 2.88-3.00 (m, 2H), 3.23-3.38 (m, 3H), 3.58 (m, 1H), 3.95 (m, 1H), 4.14 (q, 2H), 4.59 (s, 2H), 4.68 and 4.69 (2s, 2H, rotamers), 6.70-6.90 (m, 4H), 7.06-7.18 and 7.20-7.31 (2m, 3H, rotamers).
    • (iv) (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.038 g, 0.070 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phase was washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 0.034 g (94%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.83-0.93 (m, 3H), 1.17 (t, 3H), 1.20-1.35 (m, 12H), 1.144-1.66 (m, 2H), 2.90-3.10 (m, 2H), 3.25-3.34 (m, 2H), 3.42 (m, 1H), 3.62 (m, 1H), 4.04 (m, 1H), 4.62 (s, 2H), 4.72 and 4.73 (2s, 2H, rotamers), 6.73-6.90 (m, 4H), 7.09-7.21 and 7.24-7.34 (2m, 3H, rotamers).
    • Example 3 (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(2,4-Difluorobenzyl)-4-ethylbenzamide
  • To a solution of 2,4-difluorobenzylamine (3.58 g, 25.0 mmol) in methylene chloride (250 mL) were added 4-ethylbenzoic acid (3.94 g, 26.3 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over Na2SO4. Concentration in vacuo afforded 6.49 g (94%) of white solid.
  • 1H NMR (400 MHz, CDCl3): δ 1.24 (t, 3H), 2.69 (q, 2H), 4.64 (d, 2H), 6.45 (bs, 1H), 6.77-6.90 (m, 2H), 7.25 (d, 2H), 7.41 (m, 1H), 7.69 (d, 2H).
    • (ii) N-(2,4-Difluorobenzyl)-N-(4-ethylbenzyl)amine
  • N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol) was dissolved in freshly distilled THF (220 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched at 0° C. by careful addition of 10% HCl (11 mL) and the mixture was stirred at room temperature for three hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and aqueous 2 M K2CO3 (200 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.56 g (94%) of a yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.24 (t, 3H), 2.65 (q, 2H), 3.77 (s, 2H), 3.82 (s, 2H), 6.75-6.90 (m, 2H), 7.17 (d, 2H), 7.25 (d, 2H), 7.34 (m, 1H).
    • (iii) Ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) and N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)amine (1.57 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (240 g) with methanol (0-4% gradient) in methylene-chloride as the eluent and collection of pure fractions afforded 1.18 g (44%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H), 1.19-1.27 (m, 6H), 2.57-2.70 (m, 2H), 2.90-3.00 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.52, 4.54, 4.56 and 4.59 (4s, 4H, rotamers), 4.74 and 4.80 (2s, 2H, rotamers), 6.69-6.88 (m, 4H), 7.02-7.22 and 7.25-7.36 (2m, 7H, rotamers).
    • (iv) (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.13 g, 2.1 mmol) in acetonitrile (100 mL) was added aqueous 0.10 M LiOH (52 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 1.01 g (94%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H), 1.19-1.28 (m, 3H), 2.56-2.71 (m, 2H), 2.95 (m, 1H), 3.05 (m, 1H), 3.41 (m, 1H), 3.61 (m, 1H), 4.02 (m, 1H), 4.52, 4.54, 4.55 and 4.59 (4s, 4H, rotamers), 4.75 and 4.81 (2s, 2H, rotamers), 6.70-6.88 (m, 4H), 7.04-7.22 and 7.25-7.35 (2m, 7H, rotamers), 8.04 (bs, 1H).
    • Example 4 (2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) Ethyl (2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl}phenoxy]acetic acid (0.320 g, 1.08 mmol) in methylene chloride (10 mL) were added N-methylbenzylamine (0.145 g, 1.20 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was stirred at room temperature for three days. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×50 mL), aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 10 g Si/70 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.186 g (43%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.10-1.24 (m, 6H), 2.88-2.99 (m, 2H), 2.91 and 2.95 (2s, 3H, rotamers), 3.33 (m, 1H), 3.58 (m, 1H), 3.95 (m, 1H), 4.08-4.20 (m, 2H), 4.57 and 4.59 (2s, 2H, rotamers), 4.69 and 4.70 (2s, 2H, rotamers), 6.77 and 6.87 (2d, 2H, rotamers), 7.07-7.38 (m, 7H).
    • (ii) (2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.155 g, 0.39 mmol) in THF (20 mL) was added aqeuous 0.10 M LiOH (10 mL) and the reaction mixture was stirred overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 0.139 g (97%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.10-1.20 (m, 3H), 2.86-3.10 (m, 2H), 2.94 and 2.97 (2s, 3H, rotamers), 3.38 (m, 1H), 3.61 (m, 1H), 4.01 (m, 1H), 4.59 and 4.61 (2s, 2H, rotamers), 4.72 and 4.73 (2s, 2H, rotamers), 6.78 and 6.87 (2d, 2H, rotamers), 7.10-7.40 (m, 7H), 8.97 (bs, 1H).
    • Example 5 (2S)-2-Ethoxy-3-[4-(2-{heptyl [(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid (i) N-heptyl-N-[(1-methylindol-2-yl)methyl]amine
  • To a solution of 1-methylindole-2-carbaldehyde (1.59 g, 10.0 mmol) and heptylamine (1.49 mL, 10.0 mmol) in ethanol (50 mL) were added acetic acid (2.3 mL, 40 mmol) and sodium cyanoborohydride (0.75 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (5 mL) was added and the mixture was concentrated in vacuo The residue was taken up in ethyl acetate (75 mL) and aqueous 1 M KOH (75 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2×75 mL) and the combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a column of silica gel (130 g) with ethyl acetate (17-33% gradient) in heptane as the eluent yielded 1.57 g (61%) of a yellow oil, which solidified upon standing.
  • 1H NMR (400 MHz, CDCl3): δ 0.87-0.95 (m, 3H), 1.20-1.40 (m, 8H), 1.46-1.60 (m, 2H), 2.70 (t, 3H), 3.78 (s, 3H), 3.94 (s, 2H), 6.39 (s, 1H), 7.09 (m, 1H), 7.20 (m, 1H), 7.31 (d, 1H), 7.58 (d, 1H).
    • (ii) Ethyl (2S)-2-ethoxy-3-[4-(2-{heptyl [(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) and N-heptyl-N-[(1-methylindol-2-yl)methyl]amine (0.814 g, 3.15 mmol) in methylene chloride (30 mL) were added DMAP (0.403 g, 3.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.633 g, 3.30 mmol) and the reaction mixture was stirred at room temperature for three days. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a column of silica gel (100 g) with methanol (0-5% gradient) in methylene chloride as the eluent yielded 0.71 g (43%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.82-0.93 (m, 3H), 1.18 (t, 3H), 1.14-1.36 (m, 11H), 1.47-1.62 (m, 2H), 2.91-3.03 (m, 2H), 3.20-3.29 and 3.30-3.47 (2m, 3H, rotamers), 3.58 (s, 3H), 3.61 (m, 1H), 3.98 (m, 1H), 4.18 (q, 2H), 4.73 (s, 2H), 4.86 (s, 2H), 6.44 (s, 1H), 6.87 (d, 2H), 7.06-7.34 (m, 5H), 7.57 (d, 1H).
    • (iii) (2S)-2-Ethoxy-3-[4-(2-{heptyl [(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoic acid
  • To a solution of ethyl (2S)-2-ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethoxy)phenyl]propanoate (0.655 g, 1.22 mmol) in THF (60 mL) was added aqueous 0.10 M LiOH (30 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 2 M HCl, the mixture was extracted with ethyl acetate (3×75 mL) and the combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.61 g (95%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.80-0.93 (m, 3H), 1.13-1.34 (m, 11H), 1.46-1.62 (m, 2H), 2.97 and 3.10 (AB part of ABX system, 2H), 3.19-3.29 and 3.38-3.55 (2m, 3H, rotamers), 3.58 (s, 3H), 3.59 (m, 1H), 4.07 (m, 1H), 4.73 (s, 2H), 4.86 (s, 2H), 6.43 (s, 1H), 6.88 (d, 2H), 7.05-7.33 (m, 5H), 7.56 (d, 1H).
    • Example 6 (2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-Heptyl-2,3-dimethoxybenzamide
  • To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) in methylene chloride (250 mL) were added heptylamine (2.78 g, 27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over MgSO4. Concentration in vacuo afforded 6.81 g (98%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.82-0.91 (m, 3H), 1.20-1.43 (m, 8H), 1.53-1.66 (m, 2H), 3.40-3.48 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 7.02 (dd, 1H), 7.13 (t, 1H), 7.67 (dd, 1H), 7.93 (bs, 1H).
    • (ii) N-(2,3-Dimethoxybenzyl)-N-heptylamine
  • N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (29 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded 3.40 g (55%) of a light yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.83-0.91 (m, 3H), 1.20-1.35 (m, 8H), 1.42-1.54 (m, 2H), 2.54-2.61 (m, 2H), 3.79 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.83 (d, 1H), 6.88 (d, 1H), 7.01 (t, 1H).
    • (iii) Ethyl (2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (100 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.57 g (58%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.82-0.90 (m, 3H), 1.11-1.30 (m, 14H), 1.46-1.64 (m, 2H), 2.89-2.98 (m, 2H), 3.20-3.28 and 3.28-3.40 (2m, 3H, rotamers), 3.59 (m, 1H), 3.81, 3.82, 3.85 and 3.87 (4s, 6H, rotamers), 3.95 (m, 1H), 4.11-4.20 (m, 2H), 4.59, 4.69, 4.70 and 4.72 (4s, 4H, rotamers), 6.69-6.91 (m, 4H), 6.95 and 7.02 (2t, 1H, rotamers), 7.11 and 7.16 (2d, 2H, rotamers).
    • (iv) (2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.40 g, 2.55 mmol) in acetonitrile (100 mL) was added aqueous 0.10 M LiOH (50 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 1.29 g (98%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.81-4.91 (m, 3H), 1.13-1.32 (m, 1H), 1.46-1.64 (m, 2H), 2.94 (m, 1H), 3.07 (m, 1H), 3.25 and 3.34 (2m, 2H, rotamers), 3.44 (m, 1H), 3.59 (m, 1H), 3.82 (s, 3H), 3.86 and 3.88 (2s, 3H, rotamers), 4.03 (m, 1H), 4.60, 4.70, 4.72 and 4.74 (4s, 4H, rotamers), 6.70-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers), 7.12 and 7.17 (2d, 2H, rotamers).
    • Example 7 (2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-Butyl-2,3-dimethoxybenzamide
  • To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) in metylene chloride (250 mL) were added butylamine (2.01 g, 27.5 mmol) and DMAP (3.36 g, 21.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over MgSO4. Concentration in vacuo afforded 5.59 g (94%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.94 (t, 3H), 1.35-1.47 (m, 2H), 1.53-1.63 (m, 2H), 3.40-3.48 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 7.00 (dd, 1H), 7.11 (t, 1H), 7.66 (dd, 1H), 7.92 (bs, 1H).
    • (ii) N-Butyl-N-(2,3-dimethoxybenzyl)amine
  • N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded-2.74 g (54%) of a light yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H), 1.26-1.40 (m, 2H), 1.42-1.53 (m, 2H), 2.56-2.63 (m, 214), 3.79 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.83 (dd, 1H), 6.89 (dd, 1H), 7.01 (t, 1H).
    • (iii) Ethyl (2S)-3-(4-{2-[butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N}N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by 0-(benzotriazol-1-yl)-N,N,N′,′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (120 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.07 g (43%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.84-0.94 (m, 3H), 1.12-1.19 (m, 3H), 1.19-1.35 (m, 5H), 1.46-1.64 (m, 2H), 2.88-3.00 (m, 2H), 3.21-3.29 and 3.29-3.40 (2m, 3H, rotamers), 3.59 (m, 1H), 3.82, 3.82, 3.86 and 3.88 (4s, 6H, rotamers), 3.96 (m, 1H), 4.11-4.21 (m, 2H), 4.60, 4.70, 4.71 and 4.73 (4s, 4H, rotamers), 6.69-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers), 7.12 and 7.16 (2d, 2H, rotamers).
    • (iv) (2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.02 g, 2.0 mmol) in acetonitrile (80 mL) was added aqueous 0.10 M LiOH (40 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.96 g (98%) of a light yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.84-0.94 (m, 3H), 1.12-1.20 (m, 3H), 1.20-1.36 (m, 2H), 1.45-1.64 (m, 2H), 2.94 (m, 1H), 3.06 (m, 1H), 3.26 and 3.35 (2m, 2H, rotamers), 3.43 (m, 1H), 3.59 (m, 1H), 3.82 and 3.82 (2s, 3H, rotamers), 3.86 and 3.88 (2s, 3H, rotamers), 4.03 (m, 1H), 4.60, 4.70, 4.72 and 4.74 (4s, 4H, rotamers), 6.70-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers), 7.12 and 7.17 (2d, 2H, rotamers).
    • Example 8 (2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(4-Chlorobenzyl)-N-(4-isopropylbenzyl)amine
  • To a solution of 4-chlorobenzyl amine (2.83 g, 20.0 mmol) and 4-isopropylbenzaldehyde (2.96 g, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and aqueous 1 M KOH (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.80 g of crude product as a white semicrystalline oil. The product was used in the subsequent reaction step without further purification.
  • 1H NMR (400 MHz, CDCl3): δ 1.22 (d, 6H), 2.88 (sep, 1H), 3.84 (s, 4H), 5.72 (bs, 1H), 7.22 (d, 2H), 7.28 (d, 2H), 7.31 (bs, 4H).
    • (ii) Ethyl (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washes with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL, some emulsions), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on silica gel with methanol (0-5% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.28 g (46%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H), 1.19-1.28 (m, 9H), 2.82-3.02 (m, 3H), 3.35 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.49, 4.50, 4.52 and 4.54 (4s, 4H, rotamers), 4.74 and 4.77 (2s, 2H, rotamers), 6.75-6.86 (m, 2H), 7.04-7.36 (m, 10H).
    • (iii) (2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.15 g, 2.1 mmol) in acetonitrile (100 mL) was added aqueous 0.10 M LiOH (52 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 1.02 g (93%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.17 (t, 3H), 1.21-1.28 (m, 6H), 2.92 (m, 1H), 2.95 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.61 (m, 1H), 4.04 (m, 1H), 4.49, 4.50, 4.53 and 4.55 (4s, 4H, rotamers), 4.75 and 4.78 (2s, 2H, rotamers), 6.76.87 (m, 2H), 7.04-7.36 (m, 10H).
    • Example 9 (2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(Cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine
  • To a solution of 2,4-difluorobenzylamine (2.84 g, 20.0 mmol) and cyclohexanecarbaldehyde (2.60 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was diluted with aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g Si/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 2.40 g (50%) of white solids.
  • 1H NMR (400 MHz, CDCl3): δ 0.90-1.04 (m, 2H), 1.07-1.34 (m, 3H), 1.61-1.85 (m, 6H), 2.72 (d, 2H), 4.19 (s, 2H), 6.90 (m, 1H), 6.97 (m, 1H), 7.0 (bs, 1H), 7.63 (m, 1H).
    • (ii) Ethyl (2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine (0.574 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 20 g/70 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 0.59 g (57%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.83-1.02 (m, 2H), 1.08-1.30 (m, 9H), 1.51-1.82 (m, 6H), 2.88-3.00 (m, 2H), 3.10-3.22 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.63 (s, 2H), 4.70 and 4.71 (2s, 2H, rotamers), 6.72-6.90 (m, 4H), 7.05-7.18 and 7.18-7.29 (2m, 3H, rotamers).
    • (iii) (2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.297 g, 0.57 mmol) in acetonitrile (28 mL) was added aqueous 0.10 M LiOH (14 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.258 g (89%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): 0.80-1.00 (m, 2H), 1.03-1.30 (m, 6H), 1.48-1.80 (m, 6H), 2.92 (m, 1H), 3.01 (m, 1H), 3.10-3.20 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.99 (m, 1H), 4.62 (s, 2H), 4.72 (s, 2H), 6.70-6.88 (m, 4H), 7.05-7.19 and 7.19-7.29 (2m, 3H, rotamers).
    • Example 10 (2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid (i) Ethyl (2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl) propanoate
  • To a solution of N-ethyl-N-(2-fluorobenzyl)amine (0.843 g, 5.50 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.482 g, 5.00 mmol) in methylene chloride (50 mL) were added N,N-diisopropylethylamine (2.00 mL, 11.5 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.90 g (88%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.04-1.26 (m, 9H), 2.89-2.98 (m, 2H), 3.27-3.44 (m, 3H), 3.59 (m, 1H), 3.95 (m, 1H), 4.10-4.20 (m, 2H), 4.64, 4.67, 4.70, and 4.72 (4s, 4H, rotamers), 6.76 and 6.87 (2d, 2H, rotamers), 6.97-7.32 (m, 6H).
  • 13C NMR (100 MHz, CDCl3): δ 12.4, 13.9, 14.3, 15.1, 38.5, 41.0, 41.3 (d), 41.7, 44.3 (d), 60.9, 66.3, 67.6, 67.9, 80.4, 114.5, 114.6, 115.3 (d), 115.7 (d), 123.8 (d), 124.2 (d), 124.5 (m), 128.7, 128.7 129.1 (d), 129.5 (d), 130.3-130.6 (m), 130.5, 130.6, 156.8, 156.9, 160.9 (d), 161.1 (d), 168.0, 168.1, 172.6. (The number of peaks is larger than the number of carbon atoms due to rotamers.)
    • (ii) (2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
  • To a solution of ethyl (2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoate (0.980 g, 2.27 mmol) in acetonitrile (120 mL) was added aqueous 0.10 M LiOH (57 mL) and the reaction mixture was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.868 g (95%) of a pale yellow oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.05-1.28 (m, 6H), 2.87-2.99 (m, 1H), 2.99-3.10 (m, 1H), 3.33-3.45 (m, 3H), 3.61 (m, 1H), 4.01 (m, 1H), 4.65, 4.68, 4.72, and 4.73 (4s, 4H, rotamers), 6.77 and 6.87 (2d, 2H, rotamers), 6.96-7.33 (m, 6H), 9.04 (bs, 1H).
  • 13C NMR (100 MHz, CDCl3): δ 12.4, 13.9, 15.1, 38.0, 41.2, 41.4 (d), 41.7, 44.4 (d), 66.7, 67.4, 67.7, 79.8, 114.6, 114.7, 115.3 (d), 115.7 (d), 123.6 (d), 124.0 (d), 124.5 (m), 128.7, 129.2 (d), 129.6 (d), 130.0-130.8 (m), 130.6, 130.7, 156.8, 156.9, 160.9 (d), 161.1 (d), 168.4, 168.5, 175.6. (The number of peaks is larger than the number of carbon atoms due to rotamers.
    • Example 11 (2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) Ethyl (2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59 g, 12.0 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (2.96 g, 10.0 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (4.00 mL, 23.0 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.85 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150m L) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.80 g (33%) of a whitish oil.
  • 1H NMR (400 MHz, CDCl3): δ 0.80-0.95 (m, 3H), 1.12-1.20 (m, 3H), 1.20-1.35 (m, 5H), 1.44-1.61 (m, 2H), 2.88-3.02 (m, 2H), 3.19-3.28 and 3.29-3.41 (2m, 3H, rotamers), 3.60 (m, 1H), 3.97 (m, 1H), 4.16 (q, 2H), 4.54 and 4.55 (2s, 2H, rotamers), 4.66 and 4.72 (2s, 2H, rotamers), 5.50 and 5.06 (2s, 2H, rotamers), 6.76-7.00 (m, 4H), 7.07-7.21 (m, 4H), 7.28-7.47 (m, 5H).
    • (ii) (2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.116 g, 0.21 mmol) in acetonitrile (10 mL) was added aqueous 0.10 M LiOH (5 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 1 M KOH and washed with diethyl ether (2×50 mL). The aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.070 g (63%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ0.83-0.95 (m, 3H), 1.10-1.20 (m, 3H), 1.20-1.36 (m, 2H), 1.42-1.62 (m, 2H), 2.95 (m, 1H), 3.05 (m, 1H), 3.19-3.29 and 3.30-3.46 (2m, 3H, rotamers), 3.61 (m, 1H), 4.02 (m, 1H), 4.54 and 4.56 (2s, 2H, rotamers), 4.68 and 4.74 (2s, 2H, rotamers), 5.04 and 5.06 (2s, 2H, rotamers), 6.76-7.00 (m, 4H), 7.09-7.22 (m, 4H), 7.28-7.47 (m, 5H).
    • Example 12 (2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) Ethyl (2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g, 3.60-mmol) in methylene chloride (30 mL) were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.02 g (62%) of an oil, which solidified upon standing to give white solids.
  • 1H NMR (400 MHz, CDCl3): δ 1.17 (t, 3H), 1.23 (t, 3H), 2.90-3.00 (m, 2H), 3.36 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.50 (s, 2H), 4.76 (s, 4H), 6.80 (d, 2H), 7.03-7.11 (m, 4H), 7.15 (d, 2H), 7.21-7.35 (m, 4H).
  • 13C NMR (100 MHz, CDCl3): δ 14.4, 15.2, 38.5, 47.6, 49.2, 61.0, 66.3, 68.1, 80.3, 114.5, 128.5, 129.0, 129.3, 129.9, 130.7, 133.7, 133.9, 134.5, 135.0, 156.6, 168.7, 172.5.
    • (ii) (2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.597 g, 1.10 mmol) in acetonitrile (54 mL) was added aqueous 0.10 M LiOH (27 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 1 M KOH (to a total volume of 400 mL, pH˜9) and washed with diethyl ether (2×100 mL). (The extraction process was complicated by the formation of emulsions.) The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate (4×75 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.475 g (84%) of a whitish oil. 1H NMR (400 MHz, CDCl3): δ 1.19 (t, 3H), 2.97 and 3.08 (AB part of ABX system, 2H), 3.47 (m, 1H), 3.61 (m, 1H), 4.06 (m, 1H), 4.50 (s, 4H), 4.76 (s, 2H), 6.80 (d, 2H), 7.04-7.12 (m, 4H), 7.15 (d, 2H), 7.25 (d, 2H), 7.32 (d, 2H).
  • 13C NMR (100 MHz, CDCl3): δ 15.2, 37.7, 47.7, 49.3, 67.0, 68.0, 79.8, 114.7, 128.5, 129.0, 129.3, 129.9, 130.0, 130.9, 133.7, 133.9, 134.4, 135.0, 156.8, 168.8, 174.1.
    • Example 13 (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) N-(4-tert-Butylbenzyl)-N-(4-chlorobenzyl)amine
  • To a solution of 4-tert-butylbenzaldehyde (3.24 g, 20.0 mmol) and 4-chlorobenzylamine (2.43 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (50 mL) and aqueous 1 M KOH (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 4.31 g (75%) of white solids.
  • 1H NMR (400 MHz, CDCl3): δ 1.28 (s, 9H), 3.90 (s, 2H), 3.92 (s, 2H), 6.15 (bs, 1H), 7.28-7.33 (m, 6H), 7.40 (d, 2H).
  • 13C NMR (100 MHz, CDCl3): δ 31.3, 34.8, 50.1, 50.8, 126.3, 129.0, 129.4, 129.5, 130.9, 131.2, 135.3, 152.6.
    • (ii) Ethyl (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) in methylene chloride (30 mL) were added N-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol), N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on prepacked columns of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.459 g (27%) of a whitish oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H), 1.23 (t, 3H), 1.31 and 1.33 (2s, 9H, rotamers), 2.88-3.02 (m, 2H), 3.35 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.49 and 4.50 (2s, 2H, rotamers), 4.53 and 4.55 (2s, 2H, rotamers), 4.74 and 4.77 (2s, 2H, rotamers), 6.76-6.86 (m, 2H), 7.09 (d, 4H), 7.14 (d, 2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).
  • 3C NMR (100 MHz, CDCl3): δ 14.3, 15.2, 31.4, 34.7, 38.6, 47.8, 48.0, 49.1, 49.4, 60.9, 66.3, 67.7, 68.1, 80.4, 114.6, 114.6, 125.7, 126.0, 126.7, 128.3, 128.4, 128.8, 129.1, 129.9, 130.6, 130.6, 132.8, 133.4, 133.7, 134.8, 135.5, 150.8, 151.2, 156.7, 168.5, 168.6, 172.6. (The number of peaks is larger than the number of carbon atoms due to rotamers.)
    • (iii) (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.400 g, 0.71 mmol) in acetonitrile (36 mL) was added aqueous 0.10 M LiOH (18 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 2 M HCl, the solvent volume was reduced in vacuo and the mixture was extracted with ethyl acetate (3×75 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.375 g (99%) of a whitish oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 1.31 and 1.33 (2s, 9H, rotamers), 2.96 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.61 (m, 1H), 4.04 (m, 1H), 4.49 and 4.50 (2s, 2H, rotamers), 4.53 and 4.55 (2S, 2H, rotamers), 4.75 and 4.78 (2s, 2H, rotamers), 6.76-6.87 (m, 2H), 7.09 (d, 4H), 7.15 (d, 2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).
  • 13C NMR (100 MHz, CDCl3): δ 15.2, 31.5, 34.7, 37.9, 47.8, 48.0, 49.1, 49.5, 67.0, 67.6, 68.0, 79.8, 114.7, 114.8, 125.7, 126.1, 126.8, 128.3, 128.4, 128.9, 129.2, 129.9, 130.0, 130.8, 132.7, 133.4, 133.5, 133.7, 134.8, 135.4, 150.8, 151.2, 156.9, 168.6, 168.8, 174.7. (The number of peaks is larger than the number of carbon atoms due to rotamers.)
    • Example 14 (2S)-3-[4-(2-{(4-Chlorobenzyl) [4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid (i) Ethyl (2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy) phenyl]-2-ethoxypropanoate
  • To a suspension of N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]amine (0.989 g, 3.30 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) in methylene chloride (60 mL) were added N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.1 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (190 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on prepacked columns of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.02 g (59%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H), 1.22 (t, 3H), 2.90-3.00 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.52 (s, 2H), 4.59 (s, 2H), 4.76 and 4.78 (2s, 2H, rotamers), 6.77 and 6.81 (2d, 2H, rotamers), 7.03-7.11 (m, 2H), 7.11-7.19 (m, 2H), 7.20-7.36 (m, 4H), 7.53 and 7.60 (2d, 2H rotamers).
  • 13C NMR (100 MHz, CDCl3): δ 14.4, 15.2, 38.5, 47.8, 47.9, 49.5, 61.0, 66.3, 68.1, 68.2, 80.3, 114.5, 114.5, 125.7 (m), 126.0 (m), 127.4, 128.5, 128.6, 129.0, 129.3, 129.6-131.2 (m), 129.9, 130.8, 130.8, 133.8, 134.0, 134.3, 134.9, 140.2, 140.6, 156.5, 168.8, 172.5. (The number of peaks is larger than the number of carbon atoms due to rotamers. Trifluorinated carbon not reported)
  • (ii) (2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy) phenyl]-2-ethoxypropanoic acid To a solution of ethyl (2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoat (0.482 g, 0.83 mmol) in acetonitrile (42 mL) was added aqueous 0.10 M LiOH (21 mL) and the solution was stirred at room temperature overnight. After acidification with 2 M HCl, the solvent volume was reduced in vacuo and the mixture was extracted with ethyl acetate (3×75 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.407 g (89%) of a colourless oil.
  • 1H N (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.97 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.62 (m, 1H), 4.04 (m, 1H), 4.53 (s, 2H), 4.60 (s, 2H), 4.77 and 4.79 (2s, 2H, rotamers), 6.77 and 6.81 (2d, 2H, rotamers), 7.04-7.12 (m, 2H), 7.12-7.20 (m, 2H), 7.21-7.37 (m, 4H), 7.53 and 7.60 (2d, 2H, rotamers).
  • 13C NMR (100 MHz, CDCl3): δ 15.2, 37.9, 47.9, 48.0, 49.6, 66.9, 68.0, 68.1, 79.7, 114.6, 114.6, 125.7 (m), 126.0 (m), 127.3, 128.5, 128.6, 129.0, 129.3, 129.9, 130.2, 130.9, 133.8, 134.0, 134.2, 134.8, 140.1, 140.5, 156.6, 169.0, 175.2. (The number of peaks is larger than the number of carbon atoms due to rotamers. Trifluorinated carbon and quarternary carbon α to the trifluoromethyl group not reported.)
    • Example 15 (2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid (i) Ethyl (2S)-3-[4-(2-1{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxy-propanoate
  • To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine (0.733 g, 2.20 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting solution was diluted with methylene chloride (130 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.91 g (74%) of a whitish oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.15 (t, 3H), 1.22 (t, 3H), 2.90-3.00 (m, 1H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.61 (s, 2H), 4.63 (s, 2H), 4.79 (s, 2H), 6.78 (d, 2H), 7.15 (d, 2H), 7.26 (m, 2H), 7.53 (d, 2H), 7.60 (d, 2H).
  • 13C NMR (100 MHz, CDCl3): δ 14.3, 15.2, 38.5, 48.2, 49.8, 60.9, 66.3, 68.2, 80.3, 114.5, 125.8 (m), 126.1 (m), 127.4, 128.6, 130.1 (q), 130.8, 130.9, 140.1, 140.5, 156.5, 169.0, 172.5. (Trifluorinated carbon not reported.)
    • (ii) (2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxy-propanoic acid
  • To a solution of ethyl (2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy) phenyl]-2-ethoxypropanoate (0.662 g, 1.1 mmol) in acetonitrile (54 mL) was added aqueous 0.10 M LiOH (27 mL) and the solution was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 0.10 M LiOH (to a total volume of 300 mL, pH˜12) and washed with diethyl ether (2×100 mL). (The extraction process was complicated by the formation of emulsions.) The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.292 g (46%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.97 and 3.07 (AB part of ABX system, 2H), 3.46 (m, 1H), 3.62 (m, 1H), 4.05 (dd, 1H), 4.62 (s, 2H), 4.64 (s, 2H), 4.80 (s, 2H), 6.79 (d, 2H), 7.16 (d, 2H), 7.22-7.31 (m, 4H), 7.53 (d, 2H), 7.60 (d, 2H).
  • 3C NMR (100 MHz, CDCl3): δ 15.2, 37.8, 48.3, 49.9, 66.9, 68.1, 79.7, 114.6, 125.8 (m), 126.1 (m), 127.4, 128.6, 130.5 (q), 130.2, 130.9, 140.0, 140.4, 156.6, 169.1, 174.9. (Trifluorinated carbon not reported.)
    • Example 16 (2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) Ethyl (2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was stirred at room temperature for three days. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.129 g (31%) of a whitish oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.06-1.32 (m, 9H), 2.87-3.02 (m, 2H), 3.26-3.48 (m, 3H), 3.60 (m, 1H), 3.96 (m, 1H), 4.10-4.21 (m, 2H), 4.61 and 4.62 (2s, 2H, rotamers), 4.66 and 4.74 (2s, 2H, rotamers), 6.78 and 6.89 (2d, 2H, rotamers), 7.08-7.40 (m, 7H).
    • (ii) (2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.112 g, 0.27 mmol) in acetonitrile (14 mL) was added aqueous 0.10 M LiOH (7 mL) and the reaction mixture was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.096 g (92%) of a colourless oil.
  • 1H NMR (400 MHz, CDCl3): δ 1.05-1.21 (m, 6H), 2.85-3.10 (m, 2H), 3.28-3.48 (m, 3H), 3.61 (m, 1H), 4.01 (m, 1H), 4.61 and 4.62 (2s, 2H, rotamers), 4.67 and 4.75 (2s, 2H, rotamers), 6.76 and 6.88 (2d, 2H, rotamers), 7.08-7.38 (m, 7H), 8.78 (bs, 1H).
    • Example 17 (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid (i) Ethyl (2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
  • To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.706 g, 2.20 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.54 g (58%) of a colourless oil. 1H NMR (500 MHz, CDCl3): δ 1.07-1.25 (m, 9H), 1.30 and 1.32 (2s, 9H, rotamers), 2.88-3.00 (m, 2H), 3.28-3.40 and 3.40-3.48 (2m, 3H, rotamers), 3.60 (m, 1H), 3.96 (m, 1H), 4.12-4.20 (m, 2H), 4.57 and 4.59 (2s, 2H, rotamers), 4.66 and 4.73 (2s, 2H, rotamers), 6.78 and 6.89 (2d, 2H, rotamers), 7.09-7.20 (m, 4H), 7.31 and 7.36 (2d, 2H, rotamers).
    • (ii) (2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • To a solution of ethyl (2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.520 g, 1.11 mmol) in THF (50 mL) was added aqueous 0.10 M LiOH (25 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afforded 0.42 g (86%) of a colourless oil.
  • 1H NMR (500 MHz, CDCl3): δ 1.08-1.22 (m, 6H), 1.30 and 1.32 (2s, 9H, rotamers), 2.94 (m, 1H), 3.07 (m, 1H), 3.30-3.50 (m, 3H), 3.59 (m, 1H), 4.04 (m, 1H), 4.57 and 4.59 (2s, 2H, rotamers), 4.67 and 4.74 (2s, 2H, rotamers), 6.79 and 6.89 (2d, 2H, rotamers), 7.09-7.21 (m, 4H), 7.31 and 7.36 (2d, 2H, rotamers).
  • The following examples were prepared in a similar manner.
    • Example 18 (2S)-3-(4-{2-[(4-Cyclohexylbutyl) (2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid Example 19 (2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-biphenylylethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid Example 20 (2S)-3-(4-{3-[(2,4-Difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)-2-ethoxypropanoic acid Example 21 (2S)-3-(4-{3-[(Cyclohexylmethyl)(hexyl)amino]-3-oxopropyl}phenyl)-2-ethoxypropanoic acid Example 22 (2S)-3-[4-(2-{(4-Chlorobenzyl)[2-methoxybenzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid Example 23 (2S)-3-(4-{2-[(butyl)(4-methanesulfonyloxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
  • were performed by plate chemistry.
  • The following compounds were prepared by one of the following methods.
  • Method A
  • Reductive Amination
  • 1.0 ml of amine solutions was added to 0.8 ml of aldehyde solutions and the resulting mixtures were stirred for 12 h in sealed 4 ml glass vial.
  • Then ca. 300 mg of borohydride resin (Aldrich 2.5 mmol/g loading) was manually added to the individual vials, and the mixture was stirred for 8-12 h (no seal, H2-evolution; after 5 h add additional 1.0 ml of MeOH).
  • The mixture was filtered through a filter plate and washed once with 2.0 ml of MeOH. The filtrates were collected in 24-well plates with 4 ml glass vials. Then the solvent was removed in vacuo, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • To the residue was added polymer supported aldehyde resin (Novabiochem 2.85 mmol/g loading; 80-100 mg), to remove the excess of amine and 2 ml of dry THF. The resulting mixture was stirred at rt for 6-8 h, filtered through a filter plate, washed once with 1.0 ml of THF and the filtrate was collected in 24-well plates with 4 ml glass vials. Then the solvent was removed in vacuo, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • Method B
  • Amide Formation {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid To the residues were added the acid chloride solution (2.0 ml) and PS-DIEA (Argonaut 3.83 mmol/g loading; 70-80 mg) and the resulting mixture is stirred for 5-12 h.
  • The solutions were filtered through NH2-plates (Isolute; 500 mg) to remove any excess of acid chloride and washed with 1.0 ml THF. The filtrates were collected in 24-well plates with 4 ml glass vials.
  • If the formed amide does not contain a tertiary amino group, the solutions are filtered through SCX-plates (Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)) to remove the excess of secondary amine. The SCX columns are washed with 1.0 ml of THF. The combined filtrates were collected in 24-well plates with 4 ml glass vials.
  • If the formed amide does contain a tertiary amine group, polymer supported isocyanate (Novabiochem 1.5 mmol/g; ca 100 mg) was added and the mixture was stirred for additional 6 h at RT. This is to remove any excess of secondary amine. Then the mixtures were filtered through filter plates into 247-well plates with 4 ml glass vials, followed by a wash of 1.0 ml THF. The filtrates were collected in 24-well plates with 4 ml glass vials. The solvent was removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • Hydrolysis
  • The dry residues (esters) are dissolved in 1.2 ml of THF. 400 μl of the solution is transferred to a preweighed blue well plate. The daughter plate is analysed by LC-MS (purified by preparative HPLC if needed) and the solvent is removed in vacuum, using the Hr-4 vacuum centrifuge (30° C., 5 h, vacramp). The dry compounds (daughter plate) are then quantified by automatic weighing and submitted to screen.
  • The mother plate (containing esters dissolved in 0.8 ml THF) is treated with 0.8 ml 0.175M LiOH (per-vial) overnight.
  • If a compound contains a tertiary amine, the solution is poured onto an SCX column (Isolute; 1 g (SCX-2, PRS & SCX-3 can be used as well)) to catch the product. The SCX columns are washed with 3×1.0 ml of THF/MeOH. Afterwards the product is eluted with 4.0 ml of MeOH, saturated with ammonia.
  • If a compound does not contain a tertiary amine, the solvent is removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 12 h, vacramp). The dry compounds are dissolved with 11.0 ml 0.2M HCl, followed by addition of 2.0 ml of DCM. The mixtures are vigorously shaken for 30 min. Phase separators (6 ml, Whatman) are used to separate the DCM layer, which contains the product, from the water phase. The compounds are collected in 24-well plates with 4 ml glass vials. The solvent is removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp).
  • The dry compounds are dissolved with 0.5 ml THF (or appropriate solvent) and transferred to a preweighed blue-well plate. This is repeated with 0.3 ml MeOH. The solvent is afterwards removed in vacuum, using the HT-4 vacuum centrifuge (30° C., 5 h, vacramp). The plate is analysed by LC-MS (purified by preparative HPLC if needed) and the dry compounds are then quantified by automatic weighing and submitted to screen.
  • The following compounds were prepared by these methods:
    • (2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{(1,3-benzodioxol-5-ylmethyl) [3-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-[4-(2-{(4-chlorobenzyl) [4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl) [4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)propanoic acid
    • (2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
    • (2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid and
    • (2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid.
      Biological Activity
  • The compounds of the invention were tested in the assays described in WO 03/051821.
  • Assay Procedure
  • Stock solutions of compounds in DMSO were diluted in appropriate concentration ranges in master plates. From master plates, compounds were diluted in culture media to obtain test compound solutions for final doses.
  • After adjustment of the amount of cell medium to 75 μl in each well, 50 μl test compound solution was added. Transiently transfected cells were exposed to compounds for about 24 hours before the luciferase detection assay was performed. For luciferase assays, 100 μl of assay reagent was added manually to each well and plates were left for approximately 20 minutes in order to allow lysis of the cells. After lysis, luciferase activity was measured in a 1420 Multiwell counter, Victor, from Wallach.
  • Reference Compounds
  • The TZD pioglitazone was used as reference substance for activation of both human and murine PPARγ. 5,8,11,14-Eicosatetrayonic acid (ETYA) was used as reference substance for human PPARα.
  • Calculations and Analysis
  • For calculation of EC50 values, a concentration-effect curve was established. Values used were derived from the average of two or three independent measurements (after subtraction of the background average value) and were expressed as the percentage of the maximal activation obtained by the reference compound. Values were plotted against the logarithm of the test compound concentration. EC50 values were estimated by linear intercalation between the data points and calculating the concentration required to achieve 50% of the maximal activation obtained by the reference compound.
  • The compounds of formula I have an EC50 of less than 0.1 μmol/l for PPARα and particular compounds have an EC50 of less than 0.0 μmol/l. Additionally in particular compounds the ratio of the EC50 (PPARγ): EC50 (PPARα) is greater than 150:1. It is believed that this ratio is important with respect to the pharmacological activity of the compounds and to their therapeutic profile.
    Example no EC50 PPARα (μM) ratio EC50 (PPARγ):EC50 (PPARa)
    12 0.003 >1000
    13 0.008 >400
    15 0.003 >900

    In addition the compounds of the present invention exhibit improved DMPK (Drug Metabolism and Pharmacokinetic) properties for example they exhibit improved metabolic stability in-vitro. The compounds also have a promising toxicological profile.

Claims (7)

1-18. (canceled)
19. A compound of formula I
Figure US20060258866A1-20061116-C00022
as well as optical isomers and racemates therof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof,
wherein
A is situated in the para position and represents
Figure US20060258866A1-20061116-C00023
R is —ORa, wherein Ra represents hydrogen;
R1 is —ORe, wherein Re is alkyl
R2 is hydrogen;
R3 and R4 are hydrogen,;
T represents O;
n represents 1;
R5 is hydrogen;
R6 independently represent hydrogen, C1-13alkyl, C2-10alkenyl or C2-10alkynyl each of which is optionally substituted by one or more of the following which may be the same or different: C3-8cycloalkyl, C3-8cycloalkenyl, aryl, heterocyclyl, heteroaryl, C1-8alkoxy (optionally substituted by one or more fluoro), C3-8cycloalkoxy, C3-8cycloalkenyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, C3-8cycloalkyl C1-8alkoxy, aryl C1-8alkoxy, heterocyclyl C1-8 alkoxy or heteroaryl C1-8 alkoxy, fluorine or hydroxy and wherein each of these substituents may optionally be substituted on carbon with one or more substituents which may be the same or different and selected from C1-8alkyl, C3-8cycloalkyl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), heterocyclyl (optionally substituted by C1-6alkyl on any nitrogen), heteroaryl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), C1-8alkoxy (optionally substituted by one or more fluoro), C3-8cycloalkoxy, C3-8 cycloalkyl C1-8alkoxy, aryloxy (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl C1-8alkoxy (wherein the aryl part is optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy, methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy,
or R5 and R6 independently represent C3-C8 cycloalkyl; C3-C8 cycloalkenyl; aryl; heterocyclyl; or heteroaryl; wherein each of these groups is optionally substituted by one or more of the following: C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally substituted by C1-8alkyl, C1-8alkoxy (optionally substituted by one or more fluoro), halogen, hydroxy, nitro or cyano;
or R5 and R6 together with the nitrogen atom to which they are attached form a single or a fused heterocyclic system.
20. A compound according to claim 19;
wherein, R6 represents; C1-3alkyl, which is optionally substituted by aryl, and wherein the aryl is optionally substituted on carbon with C1-8alkoxy.
21. A compound according to claim 20,
wherein, R6 represents C1-13 alkyl, substituted by aryl, which in its turn is substituted on carbon with C1-8 alkoxy.
22. A compound according to claim 19, wherein R5 is H.
23. A compound according to claim 19, wherein R5 is H; and
R6 represents; C1-13alkyl, which is optionally substituted by aryl, and wherein the aryl is optionally substituted on carbon with C1-8alkoxy.
24. A compound according to claim 19, wherein R5 is H; and
R6 represents C1-13 alkyl, substituted by aryl, which in its turn is substituted on carbon with C1-8 alkoxy.
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