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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  1. Original document published without claims.
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Families Citing this family (175)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3215048B2 (en) 1996-04-03 2001-10-02 日本たばこ産業株式会社 Propionic acid derivatives and uses thereof
CA2259487A1 (en) 1996-07-01 1998-01-08 Margaret Mary Faul Hypoglycemic and hypolipidemic compounds
CN1233241A (en) * 1996-08-19 1999-10-27 日本烟草产业株式会社 Propionic acid derivatives and uses thereof
EP1006794B1 (en) 1997-03-12 2007-11-28 Robert W. Esmond A method for treating or preventing alzheimer's disease
DE69815008T2 (en) * 1997-09-19 2004-04-01 Ssp Co., Ltd. Alpha-substituted phenylpropionic acid derivatives and medicaments containing them
AU738134B2 (en) * 1997-10-02 2001-09-06 Sankyo Company Limited Amidocarboxylic acid derivatives
US6444816B1 (en) * 1997-10-27 2002-09-03 Dr. Reddy's Research Foundation Fused 7-oxo-pyrimidinyl compounds, preparation, composition and use thereof
US6329372B1 (en) * 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6583157B2 (en) 1998-01-29 2003-06-24 Tularik Inc. Quinolinyl and benzothiazolyl modulators
EP1053227B1 (en) 1998-01-29 2008-11-05 Amgen Inc. Ppar-gamma modulators
DE69919334T2 (en) 1998-02-26 2005-08-04 Celltech Therapeutics Ltd., Slough PHENYLALANINE DERIVATIVES AS INHIBITORS OF ALPHA4 INTEGRINEN
GB9805655D0 (en) 1998-03-16 1998-05-13 Celltech Therapeutics Ltd Chemical compounds
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
PT1077957E (en) 1998-05-11 2004-10-29 Takeda Chemical Industries Ltd OXY-IMINOALCANOIC ACID DERIVATIVES
GB9811159D0 (en) 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9811969D0 (en) 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
RU2243214C2 (en) * 1998-06-04 2004-12-27 Астразенека Аб New derivatives and analogues of 3-arylpropionic acid
SE9801992D0 (en) 1998-06-04 1998-06-04 Astra Ab New 3-aryl-2-hydroxypropionic acid derivative I
MA26634A1 (en) 1998-06-04 2004-12-20 Astra Ab NOVEL 3-ARYL PROPIONIC ACID DERIVATIVES AND THE LIKE
SE9801990D0 (en) 1998-06-04 1998-06-04 Astra Ab New 3-aryl propionic acid derivatives and analogs
EP1087963B1 (en) * 1998-06-19 2004-08-25 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
GB9814414D0 (en) 1998-07-03 1998-09-02 Celltech Therapeutics Ltd Chemical compounds
GB9817118D0 (en) 1998-08-07 1998-10-07 Glaxo Group Ltd Pharmaceutical compounds
GB9821061D0 (en) 1998-09-28 1998-11-18 Celltech Therapeutics Ltd Chemical compounds
GB9821222D0 (en) 1998-09-30 1998-11-25 Celltech Therapeutics Ltd Chemical compounds
US6589969B1 (en) 1998-10-16 2003-07-08 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivatives and drugs containing the same as the active ingredient
GB9825652D0 (en) 1998-11-23 1999-01-13 Celltech Therapeutics Ltd Chemical compounds
GB9826174D0 (en) 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
JP2002532416A (en) * 1998-12-17 2002-10-02 マインドセット・バイオファーマシューティカルズ・（ユーエスエイ）・インコーポレイテッド Enhancing brain glucose utilization
US6127394A (en) * 1999-03-08 2000-10-03 The University Of Mississippi 1,2-Dithiolane derivatives
US6204288B1 (en) 1999-03-08 2001-03-20 The University Of Mississippi 1,2-dithiolane derivatives
RU2219172C2 (en) * 1999-04-06 2003-12-20 Санкио Компани, Лимитед α-SUBSTITUTED DERIVATIVES OF CARBOXYLIC ACIDS
CZ20013711A3 (en) * 1999-04-16 2002-07-17 Dr. Reddy's Research Foundation Novel polymorphous forms of antidiabetic agents, process of their preparation and pharmaceutical preparations in which they are comprised
WO2000063189A1 (en) * 1999-04-16 2000-10-26 Novo Nordisk A/S Crystalline r- guanidines, arginine or (l) -arginine (2s) -2- ethoxy -3-{4- [2-(10h -phenoxazin -10-yl)ethoxy]phenyl}propanoate
US6528507B1 (en) 1999-04-16 2003-03-04 Dr. Reddy's Laboratories Limited Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
DE60021368T2 (en) * 1999-04-19 2006-07-27 Lexicon Pharmaceuticals (New Jersey), Inc. PPAR (GAMMA) AGONISTS FOR THE TREATMENT OF TYPE II DIABETES
CA2367356A1 (en) * 1999-04-20 2000-10-26 Per Sauerberg New compounds, their preparation and use
US6972294B1 (en) 1999-04-20 2005-12-06 Novo Nordisk, A/S Compounds, their preparation and use
US6369055B1 (en) 1999-04-20 2002-04-09 Novo Nordisk A/S Compounds, their preparation and use
US6274608B1 (en) 1999-04-20 2001-08-14 Novo Nordisk A/S Compounds, their preparation and use
US7414128B2 (en) 1999-04-20 2008-08-19 Dr. Reddy's Laboratories, Limited Crystalline R-guanidines, Arginine or (L)-Arginine (2S)-2-Ethoxy-3-{4-[2-(10H -phenoxazin-10-yl)ethoxy]phenyl}propanoate
AU3957900A (en) * 1999-04-20 2000-11-02 Novo Nordisk A/S New compounds, their preparation and use
WO2000063209A1 (en) * 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
ES2261202T3 (en) * 1999-04-28 2006-11-16 Sanofi-Aventis Deutschland Gmbh TRIARIL ACID DERIVATIVES AS LINKS TO THE PPAR RECEIVER.
TR200103848T2 (en) * 1999-04-28 2002-04-22 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, their process for their preparation and their use for antiobesity and as hypocholesterolemic agents.
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
JP4618845B2 (en) * 1999-06-09 2011-01-26 杏林製薬株式会社 Substituted phenylpropionic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha agonists
GB9913782D0 (en) * 1999-06-14 1999-08-11 Smithkline Beecham Plc Novel compounds
GB9914977D0 (en) * 1999-06-25 1999-08-25 Glaxo Group Ltd Chemical compounds
US7041691B1 (en) 1999-06-30 2006-05-09 Amgen Inc. Compounds for the modulation of PPARγ activity
NZ530833A (en) * 1999-06-30 2005-08-26 Tularik Inc Compounds for the modulation of PPARgamma activity
DK1206457T3 (en) 1999-08-27 2004-02-16 Lilly Co Eli Biaryl-oxa (thia) zole derivatives and their use as modulators PPAPs
EP1219595B1 (en) 1999-09-17 2006-01-18 Kyorin Pharmaceutical Co., Ltd. O-anisamide derivatives
TWI260321B (en) * 1999-09-22 2006-08-21 Bristol Myers Squibb Co Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
EP1939188A1 (en) * 1999-09-22 2008-07-02 Bristol-Myers Squibb Company Oxa-and thiazole derivatives useful as antidiabetic and antiobesity agents
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
SE9904415D0 (en) * 1999-12-03 1999-12-03 Astra Ab New process
DE60008921T2 (en) * 1999-12-03 2005-01-20 Astrazeneca Ab CRYSTALLINE FORM OF (S) -2-ETHOXY-3-4- (2-4-METHANSULFONYLOXYPHENYL-ETHOXY) PHENYL] PROPANIC ACID
CZ20021911A3 (en) * 1999-12-03 2002-10-16 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic compounds and their salts as well as their employment in medicine
SE9904413D0 (en) * 1999-12-03 1999-12-03 Astra Ab Comminuted form
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
JP4316787B2 (en) * 2000-01-11 2009-08-19 壽製薬株式会社 An ether or amide derivative, a process for producing the same, and a therapeutic agent for diabetes containing the same,
JP2001261674A (en) * 2000-03-22 2001-09-26 Mitsui Chemicals Inc Benzothiophene derivative and intranuclear receptor agonist
WO2001079173A2 (en) 2000-04-17 2001-10-25 Celltech R & D Limited Enamine derivatives as cell adhesion molecules
US6653332B2 (en) 2000-05-03 2003-11-25 Tularik Inc. Combination therapeutic compositions and method of use
FR2808798A1 (en) * 2000-05-09 2001-11-16 Hoechst Marion Roussel Inc New N-heterocyclyl-aminoacid derivatives and analogs, are vitronectin analogs useful e.g. for treating osteoporosis, tumor growth or metastasis, inflammation or cardiovascular disease
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
US20030171399A1 (en) 2000-06-28 2003-09-11 Tularik Inc. Quinolinyl and benzothiazolyl modulators
JP2004502762A (en) 2000-07-07 2004-01-29 セルテック　アール　アンド　ディ　リミテッド Squaric acid derivatives as integrin antagonists containing bicyclic heteroaromatic rings
EP1305291A1 (en) 2000-08-02 2003-05-02 Celltech R&D Limited 3-substituted isoquinolin-1-yl derivatives
WO2002013864A1 (en) * 2000-08-16 2002-02-21 Sankyo Company, Limited Medicinal compositions for preventing and treating cancer
ES2288982T3 (en) * 2000-08-23 2008-02-01 Eli Lilly And Company DERIVATIVES OF OXAZOLIL-ARYLOXYACETIC ACID AND ITS USE AS PPAR AGONISTS.
BR0113409A (en) * 2000-08-23 2003-07-01 Lilly Co Eli Peroxisome Proliferator Activated Receptor Agonists
ES2295200T3 (en) 2000-08-23 2008-04-16 Eli Lilly And Company OXAZOLIL-ARILPROPIONIC ACID DERIVATIVES AND ITS USE AS PPAR AGONISTS.
GB0030845D0 (en) * 2000-12-18 2001-01-31 Smithkline Beecham Plc Novel treatment
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
CZ20031772A3 (en) * 2000-12-25 2003-11-12 Ono Pharmaceutical Co., Ltd. Dihydronaphthalene derivative and agent containing such derivative as an active components
EP1695716A2 (en) 2000-12-26 2006-08-30 Sankyo Company, Limited Medicinal compositions containing diuretics and insulin sensitizers
MY138301A (en) 2001-01-26 2009-05-29 Schering Corp The use of substituted azetidinone compounds for the treatment of sitosterolemia
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
EP1413331B1 (en) 2001-01-26 2007-10-03 Schering Corporation Combinations of the peroxisome proliferator-activated receptor (PPAR) activator fenofibrate with sterol absorption inhibitor ezetimibe for vascular indications
EP1911462A3 (en) 2001-01-26 2011-11-30 Schering Corporation Compositions comprising a sterol absorption inhibitor
CA2440680C (en) 2001-03-12 2010-06-01 Roberto Pellicciari Steroids as agonists for fxr
ATE480236T1 (en) * 2001-04-25 2010-09-15 Takeda Pharmaceutical USE OF THE ABC EXPRESSION PROMOTER PIOGLITAZONE FOR THE TREATMENT OF ARTERIOSCLEROSIS OBLITERANS
MXPA03010435A (en) * 2001-05-15 2004-03-09 Hoffmann La Roche Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes.
PL367676A1 (en) 2001-05-29 2005-03-07 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic derivatives and medicinal use thereof
PL367639A1 (en) 2001-05-29 2005-03-07 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic compound and medicinal use thereof
DE10127126A1 (en) * 2001-06-05 2002-12-19 Forschungszentrum Juelich Gmbh Protected tyrosine derivatives, process for their preparation and their use in the preparation of O- (2- [· 18 · F] -fluoroethyl) -L-tyrosine
SK14922003A3 (en) 2001-06-07 2005-04-01 Eli Lilly And Company Modulators of peroxisome proliferator-activated receptors (PPAR)
CA2449256A1 (en) * 2001-06-07 2002-12-19 Eli Lilly And Company Modulators of peroxisome proliferator activated receptors
EP1414785A1 (en) * 2001-07-30 2004-05-06 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
US7067530B2 (en) 2001-07-30 2006-06-27 Novo Nordisk A/S Compounds, their preparation and use
EP1414806A1 (en) * 2001-07-30 2004-05-06 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
US20030171377A1 (en) * 2001-08-29 2003-09-11 Bigge Christopher Franklin Antidiabetic agents
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
AU2002336609B2 (en) 2001-09-21 2006-08-24 Merck Sharp & Dohme Corp. Treatment of xanthoma with azetidinone derivatives as sterol absorption inhibitors
TW200300681A (en) * 2001-11-12 2003-06-16 Ono Pharmaceutical Co Carboxylic acid derivative compound and medicament containing same as active ingredient
NZ532909A (en) 2001-11-30 2006-08-31 Lilly Co Eli Peroxisome proliferator activated receptor agonists
WO2003053440A1 (en) * 2001-12-11 2003-07-03 Sankyo Company, Limited Medicinal composition
AU2002367154A1 (en) * 2001-12-21 2003-07-15 Smithkline Beecham Corporation Dosing regimen for ppar-gamma activators
WO2003059895A1 (en) 2002-01-17 2003-07-24 Toaeiyo Ltd. Halogenobenzyl aminopropionic acid derivatives
CA2474353A1 (en) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Method for screening a drug ameliorating insulin resistance
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
JP2004277397A (en) * 2002-05-24 2004-10-07 Takeda Chem Ind Ltd 1, 2-azole derivative
EP1513817A1 (en) * 2002-05-24 2005-03-16 Takeda Pharmaceutical Company Limited 1, 2-azole derivatives with hypoglycemic and hypolipidemic activity
GB0214149D0 (en) * 2002-06-19 2002-07-31 Glaxo Group Ltd Chemical compounds
RU2325381C2 (en) 2002-07-09 2008-05-27 Бристол-Маерс Сквибб Компани Displaced heterocyclic derivatives and their application
WO2004004665A2 (en) 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
TWI343915B (en) * 2002-10-07 2011-06-21 Hoffmann La Roche Chirale ppar agonists
WO2004037248A2 (en) * 2002-10-24 2004-05-06 Carex Sa Modulation of peroxisome proliferator activated receptors activity
JP2006508188A (en) 2002-11-06 2006-03-09 シェーリング　コーポレイション Cholesterol absorption inhibitors for the treatment of demyelination
PL210871B1 (en) * 2002-11-08 2012-03-30 Hoffmann La Roche Substituted 4-alkoxyoxazol derivatives as ppar agonists
CA2505322A1 (en) * 2002-11-08 2004-05-21 Takeda Pharmaceutical Company Limited Receptor function regulator
US7268157B2 (en) * 2002-11-26 2007-09-11 Shenzhen Chipscreen Biosciences, Ltd. Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity
US6653334B1 (en) 2002-12-27 2003-11-25 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
JP2006520755A (en) 2003-02-14 2006-09-14 イーライ リリー アンド カンパニー Sulfonamide derivatives as PPAR modulators
GB0303600D0 (en) * 2003-02-17 2003-03-19 Glaxo Group Ltd Novel therapeutic method and compositions
US20060142356A1 (en) * 2003-02-17 2006-06-29 Davis Adrian F Novel therapeutic method and compositions for topical administration
WO2004081003A1 (en) 2003-03-07 2004-09-23 Schering Corporation Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholeterolemia
MXPA05009502A (en) 2003-03-07 2005-10-18 Schering Corp Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia.
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7235543B2 (en) 2003-03-07 2007-06-26 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
EP1622898A1 (en) * 2003-05-13 2006-02-08 Synthon B.V. Processes for making thiazolidinedione derivatives and compounds thereof
EP1644368B1 (en) 2003-07-02 2008-08-27 F. Hoffmann-La Roche Ag Indolyl derivatives substituted with a thiazole ring and their use as ppar modulators
JP4767850B2 (en) 2003-08-20 2011-09-07 エミスフィアー テクノロジーズ インコーポレイテッド Compounds, methods and formulations for oral delivery of glucagon-like peptide (GLP) -1 compounds or melanocortin 4 receptor (MC4) agonist peptides
CA2530983C (en) * 2003-08-20 2012-09-25 Eli Lilly And Company Compounds, methods and formulations for the oral delivery of a glucagon like peptide (glp)-1 compound or an melanocortin 4 receptor (mc4) agonist peptide
US7223761B2 (en) 2003-10-03 2007-05-29 Amgen Inc. Salts and polymorphs of a potent antidiabetic compound
TW200526588A (en) * 2003-11-17 2005-08-16 Smithkline Beecham Corp Chemical compounds
JP4922615B2 (en) 2003-11-26 2012-04-25 武田薬品工業株式会社 Receptor function regulator
CA2549008A1 (en) 2003-12-15 2005-07-07 Eli Lilly And Company Selective peroxisome proliferator activated receptor modulators
EP1697339A1 (en) 2003-12-25 2006-09-06 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl)propanoic acid derivatives
JP4855777B2 (en) 2003-12-26 2012-01-18 武田薬品工業株式会社 Phenylpropanoic acid derivatives
CN100467463C (en) * 2004-03-09 2009-03-11 霍夫曼-拉罗奇有限公司 Pyrazolylindolyl derivatives as PPAR activators
DK2712617T3 (en) 2004-03-12 2017-02-13 Intercept Pharmaceuticals Inc Treatment of fibrosis with Fxr ligands.
US10987362B2 (en) 2004-03-12 2021-04-27 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using FXR ligands
CN101048367A (en) 2004-07-30 2007-10-03 萨尔瓦特实验室股份有限公司 New tyrosine derivative as ppar gamma regulator
WO2006016637A1 (en) * 2004-08-11 2006-02-16 Kyorin Pharmaceutical Co., Ltd. Novel cyclic aminobenzoic acid derivative
US7622491B2 (en) * 2004-08-13 2009-11-24 Metabolex Inc. Modulators of PPAR and methods of their preparation
PL371841A1 (en) * 2004-12-20 2006-06-26 ADAMED Sp.z o.o. New derivatives of 3-phenylpropionic acid
PL372332A1 (en) * 2005-01-19 2006-07-24 ADAMED Sp.z o.o. New compounds, derivatives of 3-phenylpropionic acid
PL372356A1 (en) 2005-01-20 2006-07-24 ADAMED Sp.z o.o. New compounds, derivatives of 3-phenylpropionic acid
WO2006082495A1 (en) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Peroxisome proliferator activated receptor modulators
ITMI20050912A1 (en) 2005-05-19 2006-11-20 Erregierre Spa PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI
CN101296914B (en) 2005-08-26 2012-07-18 盐野义制药株式会社 Derivatives with PPAR agonistic activity
JP4999923B2 (en) * 2006-06-13 2012-08-15 中国科学院上海薬物研究所 Heterocyclic non-nucleoside compounds, antiviral pharmaceutical compositions, and drugs for treating viral diseases
JP2010502670A (en) 2006-09-07 2010-01-28 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Combination therapy for diabetes mellitus
KR20090066289A (en) 2006-09-08 2009-06-23 로드아일랜드하스피틀 Treatment, prevention and retrograde alcohol-induced brain disease
MX2009007728A (en) 2007-01-19 2009-12-15 Intercept Pharmaceuticals Inc 23-substituted bile acids as tgr5 modulators and methods of use thereof.
JP2008239616A (en) * 2007-02-28 2008-10-09 Iyaku Bunshi Sekkei Kenkyusho:Kk HDL raising agent
WO2008117982A1 (en) * 2007-03-28 2008-10-02 Crystal Genomics, Inc. Heterocyclic carboxylic acid derivatives and pharmaceutical composition for inhibiting lipid accumulation containing same
JP5548120B2 (en) 2007-04-11 2014-07-16 オメロス コーポレーション Compositions and methods for prevention and treatment of addiction
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US20160331729A9 (en) * 2007-04-11 2016-11-17 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
EP2154131A4 (en) * 2007-04-26 2011-09-21 Pharmafrontier Co Ltd G protein-coupled receptor inhibitor and pharmaceutical product
ES2465216T3 (en) 2007-06-04 2014-06-05 Ben Gurion University Of The Negev Research And Development Authority Triaryl compounds and compositions comprising the same
WO2010014836A2 (en) 2008-07-30 2010-02-04 Intercept Pharmaceuticals, Inc. Tgr5 modulators and methods of use thereof
PL2698375T3 (en) 2008-11-19 2018-08-31 Intercept Pharmaceuticals, Inc. TGR5 modulators and method of use thereof
EP3398599A1 (en) 2009-03-11 2018-11-07 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US8581001B2 (en) 2010-04-16 2013-11-12 Codman & Shurtleff Metformin-cysteine prodrug
US20130156720A1 (en) 2010-08-27 2013-06-20 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US20120094959A1 (en) 2010-10-19 2012-04-19 Bonnie Blazer-Yost Treatment of cystic diseases
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
BR112014031556B1 (en) * 2012-06-19 2019-10-29 Schickaneder Helmut bendamustine derivatives and related compounds, and their medical use in cancer therapy
BR112014031828B1 (en) 2012-06-19 2021-12-21 Intercept Pharmaceuticals, Inc PHARMACEUTICAL COMPOSITIONS COMPRISING FORM 1 OF OBETICOLIC ACID
WO2014184104A1 (en) * 2013-05-17 2014-11-20 Boehringer Ingelheim International Gmbh Pyrrolidine derivatives, pharmaceutical compositions and uses thereof
WO2015068156A1 (en) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US10034868B2 (en) 2014-11-04 2018-07-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prevention and the treatment of rapidly progressive glomerulonephritis
WO2016100162A2 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. 5,5-bicyclic oxazole orexin receptor antagonists
CN104744282A (en) * 2015-02-17 2015-07-01 南通恒盛精细化工有限公司 Preparation process of insulin sensitizer
WO2019224393A1 (en) * 2018-05-25 2019-11-28 University Of Copenhagen Fenofibrate for reducing hypoglycemia in type 1 diabetes/lada

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative
US4367234A (en) 1980-07-28 1983-01-04 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4342771A (en) 1981-01-02 1982-08-03 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
RU1473300C (en) 1987-06-01 1995-02-09 Научно-производственное объединение "Витамины" Method of synthesis of 4-benzoylamino-3-oxotetrahydrothiophene
US5220023A (en) 1989-07-18 1993-06-15 Janssen Pharmaceutica N.V. Glycine derivatives
DE3941438A1 (en) 1989-12-15 1991-06-20 Hoechst Ag NEW 2-SUBSTITUTED 4- (3-ALKYL-5-TERT.-BUTYL-4-HYDROXY-PHENYL) -THIAZOLE, PROCESS FOR THEIR MANUFACTURE, THE MEDICAMENT CONTAINING THEIR AND ITS USE
US5089514A (en) 1990-06-14 1992-02-18 Pfizer Inc. 3-coxazolyl [phenyl, chromanyl or benzofuranyl]-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
WO1993021166A1 (en) 1992-04-10 1993-10-28 Smithkline Beecham Plc Heterocyclic compounds and their use in the treatment of type ii-diabetes
US6048883A (en) 1992-07-03 2000-04-11 Smithkline Beecham P.L.C. Heterocyclic compounds as pharmaceutical
US5232945A (en) * 1992-07-20 1993-08-03 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives
GB9225386D0 (en) 1992-12-04 1993-01-27 Smithkline Beecham Plc Novel compounds
US5556977A (en) 1993-03-29 1996-09-17 Zeneca Limited Heterocyclic derivatives
GB9311661D0 (en) * 1993-06-05 1993-07-21 Smithkline Beecham Plc Novel compounds
GB9311644D0 (en) 1993-06-05 1993-07-21 Smithkline Beecham Plc Novel compounds
SE9302332D0 (en) 1993-07-06 1993-07-06 Ab Astra NEW COMPOUNDS
GB9315148D0 (en) 1993-07-22 1993-09-08 Smithkline Beecham Plc Novel compounds
JPH08325264A (en) 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd Novel 2-aromatic ring-substituted-3-phenylpropionic acid or acrylic acid derivative
JPH08325263A (en) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd Novel 2-amino-3-phenylpropionic acid derivative
JPH08325564A (en) 1995-06-05 1996-12-10 Nec Corp Organic thin film EL device
CA2259487A1 (en) * 1996-07-01 1998-01-08 Margaret Mary Faul Hypoglycemic and hypolipidemic compounds

Non-Patent Citations (1)

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

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