- BIARYLMETHYL HETEROCYCLES
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The present invention provides compounds of Formula (I): wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are biased agonists, or β-Arrestin agonists of the angiotensin II receptor, which may be used as medicaments.
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- Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis
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GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.
- Miltz, Wolfgang,Velcicky, Juraj,Dawson, Janet,Littlewood-Evans, Amanda,Ludwig, Marie-Gabrielle,Seuwen, Klaus,Feifel, Roland,Oberhauser, Berndt,Meyer, Arndt,Gabriel, Daniela,Nash, Mark,Loetscher, Pius
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p. 4512 - 4525
(2017/07/22)
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- 2,6,8-Trisubstituted 1-deazapurines as adenosine receptor antagonists
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In this study we developed a refined pharmacophore model for antagonists of the human adenosine A1 receptor, based on features of known pyrimidine and purine derivatives. The adoption of these updated criteria assisted us in synthesizing a series of 1-deazapurines with consistently high affinity as inverse agonists for the adenosine A1 receptor. These 1-deazapurines (otherwise known as 3H-imidazo[4,5-b]pyridines) were substituted at their 2- and 6-positions, yielding a series with five of the derivatives displaying Ki values in the subnanomolar range. The most potent of these, compound 10 (LUF 5978), displayed an affinity of 0.55 nM at the human adenosine A1 receptor with > 300-fold and 45-fold selectivity toward A2A and A3 receptors, respectively. Compound 14 (LUF 5981, Ki = 0.90 nM) appeared to have the best overall selectivity with respect to adenosine A2A (> 200-fold) and A 3 (700-fold) receptors.
- Chang, Lisa C. W.,Von Frijtag Drabbe Künzel, Jacobien K.,Mulder-Krieger, Thea,Westerhout, Joost,Spangenberg, Thomas,Brussee, Johannes,Ijzerman, Adriaan P.
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p. 828 - 834
(2007/10/03)
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- Innovative approaches to the imidazo[4,5-b]pyridine ring system. Development of an efficient process for industrial-scale production of a key intermediate for potent angiotensin II receptor antagonists
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Two syntheses of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (3), an important intermediate for the synthesis of several potent angiotensin II antagonists, have been investigated. The first route involves conversion of 1,1-bis(methylthio)-2-nitroethene (17) to 2-ammo-4,6-dimethyl-3-nitropyridine (6); catalytic hydrogenation of 6 in propionic acid gave 3 in high yield. In the second synthesis, propionitrile is converted to imidate hydrochloride 15·HCl which is neutralised and reacted with aminoacetonitrile in the presence of acetylacetone to give 3 in 55% overall yield. The propionitrile route was scaled up to produce 3 in the pilot plant.
- Stucky, Gerhard C.,Roduit, Jean-Paul,Schmidt, Beat
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p. 280 - 282
(2007/10/03)
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- 3N-Methylbiphenylsulfonylurea and -carbamate substituted imidazo[4,5-b]pyridines. Potent antagonists of the ANG II AT1 receptors
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The synthesis and the SAR study of imidazo[4,5-b]pyridine biphenyl sulfonylureas and -carbamates as highly potent AT1-seIective ANG II receptor antagonists are described. Several members of this new class of antagonists efficiently inhibited the ANG II-induced presser response in pithed rats after iv and intraduodenal (id) administration.
- Heitsch, Holger,Becker, Reinhard H.A.,Kleemann, Heinz-Werner,Wagner, Adalbert
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p. 673 - 678
(2007/10/03)
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- Polymorphic forms of an angiotensin II antagonist
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Polymorphic forms of the angiotensin II receptor antagonist, 3-[2''-(N-benzoyl)sulfonamidobiphenyl-4-yl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine and a method for the preparation of these crystal forms.
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- IMIDAZOPYRIDINE DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS
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The present invention relates to new imidazopyridine derivatives of formula I STR1 wherein: one of A, B, C and D is N and the other are CR, wherein each R independently represents hydrogen, C 1-4 alkyl, COOH or halogen; R 1 represents C 1-4 alkyl or C 3-7 cycloalkyl; Ar 1 represents phenyl or pyridyl which can be optionally substituted; V represents C 1-4 alkyl, C 3-7 cycloalkyl, aryl, aryl-(C 1-4)alkyl or a 5-or 6-membered aromatic heterocycle; the group X-Y represents C=C or CH--CR 3 ; R 3 represents hydrogen, C 1-4 alkyl or aryl-(C 1-4)alkyl; Z represents among others--CO 2 R 4,--tetrazol-5-yl,--CONHSO 2 R 4,--CONR 4 R 5,--CH 2 NHSO 2 R 4 ; R 4 and R 5 independently represent hydrogen, C 1-4 alkyl, aryl, aryl-(C 1-4) alkyl or perfluoro-(C 1-4) alkyl; W represents hydrogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, aryl, aryl-(C 1-4)alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, C 1-4 alkylthio, C 1-4 alkoxy, C 1-4 alkylcarbonyl, halogen, hydroxymethyl or C 1-4 alkoxymethyl, or W can have any of the meanings disclosed for Z. These compounds are angiotensin II antagonists.
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- New approach to the imidazolutidine moiety of MK-996
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A highly effective, regio-selective synthesis of imidazolutidine (1) is described starting from readily available malonamamidine hydrochloride and 2,4-pentanedione.
- Senanayake, Chris H.,Fredenburgh, Laura E.,Reamer, Robert A.,Liu, Ji,Roberts, F. Edward,Humphrey, Guy,Thompson, Andrew S.,Larsen, Robert D.,Verhoeven, Thomas R.,Reider, Paul J.,Shinkai, Ichiro
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p. 821 - 830
(2007/10/03)
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- Substituted benzoxazole, benzthiazole, and benzimidazole derivatives as angiotensin II antagonists
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The invention concerns pharmaceutically useful compounds of the formula I, in which Q, X, Z and Ra have the various meanings defined herein, and their non-toxic salts, and pharmaceutical compositions containing them for treating conditions as hypertension and congestive heart failure.
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- Process for preparing imidazopyridine derivatives
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A process for preparing imidazopyridines of the general formula: STR1 wherein R1 is an alkyl, cycloalkyl, aryl or aralkyl group or is a heterocyclic radical, R2 and R4 are identical or different and are hydrogen, a hydroxy, a cyano, alkyl, cycloalkyl, aryl or aralkyl group or are an alkanoyl or an alkoxy-carbonyl group, and R3 is hydrogen, an alkyl, aryl or aralkyl group or a halogen atom. In the key step of the process, an amidine of the formula: STR2 is cyclized with a 1,3-dicarbonyl compound of the general formula: STR3 The imidazopyridines are valuable intermediates for the preparation of angiotensin II antagonists.
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- Process for preparing imidazopyridine derivatives
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A new process for preparing imidazopyridines of the general formula: STR1 wherein R1 is an alkyl, cycloalkyl, aryl or aralkyl group or is a heterocyclic radical, R2 and R4 are identical or different and are hydrogen, a hyd
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- Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogen atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- Angiotensin II antagonists incorporating a substituted thiophene or furan
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There are disclosed substituted thiophene and furan derivatives of Formula I which are useful as angiotensin II antagonists. STR1
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- ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED PYRIDOIMIDAZOLYL RING
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Substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives of the Formula I are useful as angiotensin II antagonists. STR1
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- SUBSTITUTED IMIDAZO-FUSED 6-MEMBERED HETEROCYCLCES AS ANGIOTENSIN II ANTAGONISTS
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogren atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle
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There are disclosed compounds, containing a pyridine, pyrazine or pyrimidine functionality on the lower ring of Formula I, which are useful as angiotensin II antagonists. STR1
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- Microbial transformation process for antihypertensive products
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Fermentation of the microorganism Streptomyces sp. MA6751 (ATCC No. 55043) in the presence of the Angiotensin II (A II) receptor antagonist yields an N2-tetrazole β-glucuronide analog which is also an A II antagonist useful in the treatment of hypertension and congestive heart failure and other indications known to respond to A II antagonists.
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- ANGIOTENSIN II ANTAGONISTS INCORPORATING AN INDOLE OR DIHYDROINDOLE
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There are disclosed substituted indoles and dihydroindoles of Formula I which are useful as angiotensin II antagonists. STR1
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- MICROBIAL TRANSFORMATION PROCESS FOR PREPARING ANTI-HYPERTENSIVE PRODUCTS
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Fermentation of the microorganism Streptomyces sp. (MA6750) ATTC No. 55042 in the presence of the Angiotensin II (A II) receptor antagonist STR1 yields three analogs, each having a shikimate sugar-like moiety attached to the tetrazole, which are also A II antagonists useful in the treatment of hypertension and congestive heart failure and other indications known to respond to A II antagonists.
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- Anti-hypersensitive N2-tetrazole-β-glucuronide analog
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Fermentation of the microorganism Streptomyces sp. MA6751 in the presence of STR1 yields an anti-hypertensive compound of the structure STR2
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