AP780A - Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist to PPAR-gamma. - Google Patents

Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist to PPAR-gamma. Download PDF

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Publication number
AP780A
AP780A APAP/P/1997/000935A AP9700935A AP780A AP 780 A AP780 A AP 780A AP 9700935 A AP9700935 A AP 9700935A AP 780 A AP780 A AP 780A
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ARIPO
Prior art keywords
phenyl
alkyl
optionally substituted
heterocyclic group
methyl
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APAP/P/1997/000935A
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AP9700935A0 (en
Inventor
Timothy Mark Willson
Robert Antony Mook Jr
Istvan Kaldor
Brad Richard Henke
David Norman Deaton
Jon Loren Collins
Jeffrey Edmond Cobb
Markus Brackeen
Matthew Jude Sharp
John Mark Ocallaghan
Greg Alan Erickson
Grady Evan Boswell
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Glaxo Group Ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

A compound having formula (I), wherein A is selected from the group consisting of: (i) phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms, C1-6alkyl, C1-3alkoxy, C1-3fluoroalkoxy, nitrile, or -NR7R8 where R7 and R8 are independently hydrogen or C1-3alkyl; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ring (a), wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) C1-6alkylene; (v) -MC1-6alkyiene or C1-6alkyleneMC1-6alkylene, wherein M is O, S, or-NR2 wherein R2 represents hydrogen or C1-3 alkyi; (vi) a 5-or 6-membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C1-3 alkyl; and (vii) Het-C1-6alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above; Alk represents C1-3alkylene; R1 represents hydroqen or C1-Salkyl; Z is selected from the group consisting of: (viii) -(C1-3alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR3R4, wherein R3 represents hydrogen or C1-Salkyl, and R4 represents -Y-(C=O)-T-R5, or -Y-(CH(OH))-T-R5.

Description

Chemical Compounds
The present invention relates to certain novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit activation, including agonist activity, to peroxisome proliferator-activated receptor gamma (PPAR-gamma) thereby enabling them to modulate the blood glucose levels in mammals.
The treatment of Type II or Non-Insulin Dependent Diabetes Mellitus (NIDDM) remains unsatisfactory despite the widespread use of insulin, sulfonylureas (e.g. chlorpropamide, tolbutamide, tolazamide), and biguanides (e.g, phenformin, metformin) as oral hypoglycaemic agents. Treatment of NIDDM usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin. Unfortunately the available hypoglycaemics suffer from a wide range of undesirable toxic effects which limits their usefulness in treatment of NIDDM. There is thus a clear need for the development of novel hypoglycaemic agents which may be less toxic or which suceed where others are ineffective.
In the last decade a class of compounds known as thiazolidinediones (e.g. U.S. Pat Nos. 5,089,514, 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in animal models of NIDDM and also reduce lipid and insulin levels in these animal models. Recently, the thiazolidinedione troglitazone was shown to have these same beneficial effects in human patients suffering from impaired glucose tolerance, a metabolic condition that precedes the development of NIDDM, as in patients suffering from NIDDM (J. J. Nolan et. al., N. Eng. J. Med. 1188-1193, 331 (1994)). While the mechanism of action is unclear, thiazolidinediones do not cause increases in insulin secretion or in the number or affinity of insulin receptor binding sites, suggesting that thiazolidinediones amplify post-receptor events in the insulin signaling cascade (J. R. Colca and D. R. Morton, "Antihyperglycemic thiazolidinediones: ciglitazone and its analogs," in New Antidiabetic Drugs, C. J. Bailey and P. R. Flatt, eds., Smith-Gordon, New York, 255-261 (1990)).
Thiazolidinediones also induce the in vitro adipocyte differentiation of preadipocyte cell lines (A. Hiragun, et. al. J. Cell. Physiol. 124-130, 134 (1988); R. F. Kleitzen, et. al., Mol. Pharmacol. 393-398, 41 (1992)). Treatment of pre-adipocyte cell lines with the thiazolidinedione pioglitazone results in increased expression of the adipocyte-spec'flc genes aP2 and adipsin as well as the glucose transporter proteins GLUT-1 and GJJT-4, which suggests that the hypoglycaemic effects of thiazolidinediones seen in vivo may be mediated through adipose tissue.
Recently, an orphan member of the steroid/thyroid/retinoid receptor superfamily of ligand-activated transcription factors termed Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) has been discovered. PPAR-gamma is one of a subfamily of closely related PPARs encoded by independent genes (C. Dreyer, et. al., Cell 879-887, 68 (1992); A. Schmidt, et. al., Mol. Endocrinol. 1634-1641, 6, (1992); Y. Zhu, et. al., J. Biol. Chem. 26817-26820, 268 (1993); S. A. Kliewer et. al., Proc. Nat. Acad. Sci. USA 7355-7359, 91, (1994)). Three mammalian PPARs have been isolated and termed PPAR-alpha, PPAR-gamma, and NUC-1. These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin. Met. 291-296, 4 (1993)). It has now been reported that thiazolidinediones are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones.
We have now discovered a novel group of compounds which bind to and activate the PPAR-gamma receptor. These compounds also show good blood-glucose lowering activity and are therefore of use in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia, and are of particular use in the treatment of Type II diabetes.
These compounds are also indicated to be of use for the treatment and/or prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis. In addition, these compounds are indicated to be useful for the regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa.
Accordingly, the present invention is directed to compounds having the formula (I):
wherein A is selected from the group consisting of: (i) phenyl, wherein said phenyl is optionally substituted by one or more of the following groups; halogen atoms, C^alkyl, C1.3 alkoxy, C,.3 fluoroalkoxy, nitrile, or -NR7R8 where R7 and R8 are independently hydrogen or C1.3alkyl; (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ring
; wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) alkylene;
(v) -MC^alkylene or Ci^alkyleneMC-,^alkylene, wherein M is O, S, or -NR2 wherein R2 represents hydrogen or Ci_3alkyl; (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C-,.3 alkyl; and (vii) Het-C^alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above;
Aik represents Ci.3alkylene; R1 represents hydrogen or alkyl; Z is selected from the group consisting of: (viii) -(C^alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR3R4, wherein R3 represents hydrogen or CV3 alkyl, and R4 represents -Y-(C=O)-T-R5 , or -Y-(CH(0H))-T-R5, wherein: (a) Y represents a bond, alkylene, C2^ alkenylene, C4.6 cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more alkyl groups and/or one or more halogen atoms; (b) T represents a bond, Cv3 alkyleneoxy, -0- or -N(R6)-, wherein R6 represents hydrogen or CV3 alkyl; (c) R5 represents C145 alkyl, C4_6 cycloalkyl or cycloalkenyl, phenyl (optionally substituted by one or more of the following groups; halogen atoms, Cv3 alkyl, C-|.3 alkoxy groups, Co.3alkyleneNR9R10 (where each R9 and R10 is independently hydrogen, CV3 alkyl, -SO2C1.3alkyl, or -CO2C1.3alkyl, -SO2NHC1.3alkyl), C0.3 alkyleneCO2H, C0.3 alkyleneCO2C1.3alkyl, or OCH2C(O)NH2), a 5- or 6- membered heterocyclic group as defined in point (ii) above, a bicylic fused ring wherein ring D represents a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfui md optionally substituted by (=0), which bicyclic ring is attached to T via a ring atom of ring D: or -C^alkyleneMR11 M is 0, S, or -NR2 wherein R12 and R11 are independently hydrogen or Ct.3 alkyl; or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof.
Those skilled in the art will recognize that stereocenters exist in compounds of Formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of Formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic,
methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, c'uminium, calcium, zinc, N,N1-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.
The terms C^alkyl or alkylene and C^alkyl or alkylene as used herein respectively contain 1 to 3 or 1 to 6 carbon atoms and appropriately include straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term C2^alkenyl or alkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenyl and alkenylene groups, in particular propenylene or the like.
The term C-,.3 alkyleneoxy as used herein denotes -O-C^ alkylene-, wherein CV3 alkylene is substantially as defined above, e.g. -0-CH2- etc.
The terms C4.6 cycloalkyl, C4^ cycloalkylene, C4.6 cycloalkenyl and C4.6 cycloalkenylene include cyclic groups containing 4 to 6 carbon atoms, such as cyclopentane, cyclopentylene, cyclohexane, cyclohexylene, cyclohexene and cyclohexenylene.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered unsubstituted heterocycloalkyl groups and substituted or unsubstituted heteroaryl groups, e.g. substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyI, triazolyl or tetrazolyl.
By substituted heterocyclic group is meant a 5 or 6 membered heteroaryl group substituted by one or more of the following; halogen atoms, alkyl, Cv3 alkoxy groups, Cq_3 alkylene N R9R10 (where each R9 and R10 is idependently hydrogen, Cv 3 alkyl, -SO2C^.3 alkyl or CO2Ci_3 alkyl, -SO2NHCi_3 alkyl), Cq_3 alkylene CO2H, 0θ.3 alkylene CO2C,.3 alkyl, -OCH2C(O)NH2, -Cv3 fluoroalkyl, -CN or alkyl.
In formula (I) above, in the case where Y represents a bond, the nitrogen atom of -NR3R4 is directly linked to -(C=O) or (CH(OH)) of R4, ie. Z represents -N(R3)-(C=O)-T-R5 or -N(R3)(CH(OH))-T-R5. Similarly, in the case where T represents a bond, (C=O) or (CH(OH)) of R4 is directly linked to R5, ie. Z represents -N(R3)-Y-(C=O)-R5 or -N(R3)-Y-(CH(OH))-R5. It may be the case that both Y and T represent a bond, whereby Z represents -N(R3)-(C=O)-R5 or -N(R3)-(CH(OH))-R5.
Aptly A represents any of phenyl, heteroaryl (e.g. pyridyl) or
wherein fused ring C represents a 5-membered heteroaryl group containing at least one nitrogen heteroatom and optionally a further heteroatom selected from nitrogen and oxygen (e.g. oxazolyl, imidazolyl). Particularly A represents any of phenyl, pyridyl, piperazinyl, or benzoxazolyl, any of which can optionally be substituted by one or more CV3 alkyl, especially phenyl, piperazinyl, or pyridyl. B suitably represents ar.y of C-i.3alkylene (e.g. methylene), -N(CH3)Ci_3alkylene (e.g. -N(CH3)(CH2)2-) or Het-C^ alkylene, wherein Het represents a 5- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen and sulfur (e.g. pyrrolidinyl, oxazolyl and thiazolyl) and aptly substituted by Cv3alkyl. Particularly B represents -N(CH3)(CH2)2, oxazolyl -C^ alkylene, which oxazolyl is optionally substituted by Ci.3 alkyl, or thiazolyl which is optionally substituted by C-i_3 alkyl.
Appropriately Aik represents methylene.
Appropriately R1 represents hydrogen, methyl or ethyl, especially hydrogen.
Suitably Z may represent -(C^alkylene) phenyl substituted by one or more halogen atoms, such as optionally substituted benzyl. Preferably Z represents -NR3R4 substantially as hereinbefore described. Generally R3 represents hydrogen. As hereinbefore described, R4 represents -Y-(C=O)-T-R5, or -Y-(CH(OH))-T-R5 especially -Y(C=O)-T-R5, and particular groupings represented by R4 include: Y represents phenyl (optionally substituted by one or more halogen atoms, r one or more Ci_3alkyl e.g. methyl groups), T represents a bond or an oxygen atom, and R5 represents C1.3 alkyl or phenyl (optionally substituted by one or more halogen atoms or one or more Cv3 alkyl groups); Y represents a heterocyclic group substantially as hereinbefore described (e.g. thienyl), T represents a bond and R5 represents phenyl (optionally substituted by one or more halogen atoms or one or more CV3 alkyl groups); Y represents C^alkenylene- (e.g. propenylene), T represents a bond and R5 represents phenyl (optionally substituted by one or more halogen atoms); Y represents C4.6cycloalkenylene- (e.g. cyclohexenylene), T represents a bond and R5 represents phenyl; Y represents phenyl, T represents a bond and R5 represents a heterocyclic group substantially as hereinbefore described (e.g. piperidyl); Y represents a bond, T represents a bond and R5 represents a bicyclic ring substantially as hereinbefore described (e.g. D represents a 6-membered heterocyclic ring, in particular pyranyl substituted by (C=0)); Y represents phenyl, T represents a bond and R5 represents C^cycloalkyl (e.g. cyclohexyl); Y represents phenyl, T represents alkyleneoxy (e.g. -O-CH2-) or N(R6)- (e.g. -NH-) and R5 represents phenyl.
Preferably when Z represents NR3R4 R3 represents H and R4 represents Y-(C=O)-T-R5 the said NH and said (C=0) are positioned ortho to each other on Y (which is phenyl), T is a bond or -0-, R5 is alkyl, or phenyl (optionally substituted by one or more: halogen atoms, Cv3 alkyl, C-,.3 alkoxy groups, Co_3alkyleneNR9R10 where each R9 and R10 is independently hydrogen, CV3 alkyl, -SO2C1.3alkyl, or -0020ν 3alkyl, - SO2NHC1.3alkyl, C0.3 alkyleneCO2H, alkyleneCO2C1.3alkyl, or -OCH2C(O)NH2).
Particularly suitably Y represents phenyl, T represents a bond or -0- and R5 represents CV3 alkyl or phenyl e.g. R4 represents
wherein R13 represents phenyl or OCH3.
An appropriate subgroup of compounds according to the present invention can be represented by formula (la)
wherein A and B are substantially as hereinbefore described, and Ar represents phenyl or a 5- or 6- membered heteroaryl group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and salts and solvates thereof.
Suitably in formula (la), A is selected from phenyl, pyridyl and benzoxazoyl. In particular, A in Formula (la) represents phenyl or pyridyl. Furthermore, B in Formula
(la) is suitably selected from -NR^^alkylene substantially as hereinbefore described and Het-C^alkylene optionally substituted by Ci_3alkyl substantially as hereinbefore described. In particular, B in Formula (la) represents -N(CH3)(CH2)2- or oxazolyl-C^alkylene, which oxazolyl is optionally substituted by Ci_3alkyl, e.g. methyl. A particular subgroup of the compounds of formula 1 are compounds of formula (I): wherein; A is selected from the group consisting of: (i) phenyl optionally substituted by one or more halogen atoms; (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ring
wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) alkylene; (v) -NR^^alkylene, wherein R2 represents hydrogen or Ομ3 alkyl; (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by Cv3 alkyl; and (vii) Het-C^alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above;
Aik represents C^alkylene; R1 represents hydrogen or Cv3 alkyl; Z is selected from the group consisting of: (viii) -(C^alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR3R4, wherein R3 represents hydrogen or Ο·,.3 alkyl, and R4 represents -Y-(C=O)-T-R5 , or -Y-(CH(OH))-T-R5, wherein: (a) Y represents a bond, alkylene, C2^ alkenylene, C4.6 cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more Cv3 alkyl groups and/or one or more halogen atoms; (b) T represents a bond, Cv3 alkyleneoxy, -0- or -N(R6)-, wherein R6 represents hydrogen or CV3 alkyl; (c) R5 represents alkyl, C4.6 cycloalkyl or cycloalkenyl, phenyl optionally substituted by one or more halogen atoms or one or more Cv3 alkyl groups, a 5- or 6- membered heterocyclic group as defined in point (ii) above, or a bicylic fused ring
wherein ring D represents a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=0), which bicyclic ring is attached to T via a ring atom of ring D; or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof.
Particular compounds according to the present invention include:
3-(4-Benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt 3-(4-Benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid methyl ester 2(S)-(2-Benzoyl-cyclohex-1-enylamino)-3-(4-benzyloxy-phenyl)-propionic acid dicyclohexylamine salt 2- (2-benzoylphenylamino)-3-(4-benzyloxyphenyl) propanoic acid 3- (4-Benzyloxy-phenyl)-2-(2-benzyloxy-phenylamino)-propionic acid methyl ester 3-(4-Benzyloxy-phenyl)-2-(phenylcarbamoyl-phenylamino)-propionic acid methyl ester 3-(4-Benzyloxy-phenyl)-2-[2-(piperidine-1-carbonyl)-phenylamino]-propionic acid methyl ester 2-(3-Benzoyl-thiophen-2-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid 2- (2-Benzoyl-thiophen-3-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid 3- (4-Benzyloxy-phenyl)-2(S)-[(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid methyl ester. 2-(2-Benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid ethyl ester 2- (1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid dicyclohexylamine salt 3- {4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid 3-{4-[2-(Benzoxazol-2yl-methyl-amino)-ethoxy]-phenyl}-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-[3-(3-iodo-phenyl)-1-methyl-3-oxo-propenylamino]-propionic acid dicyclohexylamine salt 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-4-methyl-phenylamino)-propionic acid 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-4-chloro-phenylamino)-propionic acid 3-[4-(1-Benzoxazol-2-yl-pyrrolidin-3-yloxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid 3-[4-(1-benzoxazol-2-yl)-pyrrolidin-2R-yl-methoxy)-phenyl]-2-(2-benzoyl-pheny(amino)-propionic acid 3-[4-(1-benzoxazol-2-yl)-pyrrolidin-2S-yl-methoxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyI}-2-(2-cyclohexanecarbonyl-phenyiamino)-propionic acid 3-{4-[2-Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-thiophen-3-ylamino)-propionic acid. 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-benzyl-propionic acid trifluoroacetate. 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-bromo-benzyl)-propionic acid trifluoroacetate. 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-[(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid. 2(S)-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid 2- (2-Benzoyl-phenylamino)-3-{4-[2-(4-chlorophenyl)-thiazol-4ylmethoxy]-phenyl}-propionic acid 3- [4-(2-Benzoimidazol-1-yl-ethoxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-methoxy)-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-fluoro)-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(5-methyl-thien-2-yl)-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-1-phenyl-1H-pyrazol-3-yl)-ethoxy]-phenylj-propionic acid

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