ABSTRACT
Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.
Subject(s)
Arginine Vasopressin/antagonists & inhibitors , Azepines/chemical synthesis , Azepines/pharmacology , Animals , Arginine Vasopressin/metabolism , Azepines/chemistry , Azepines/metabolism , Rats , Receptors, Vasopressin/metabolism , Structure-Activity RelationshipSubject(s)
Arginine Vasopressin/antagonists & inhibitors , Receptors, Vasopressin/metabolism , Administration, Oral , Animals , Arginine Vasopressin/deficiency , Azepines/administration & dosage , Azepines/chemical synthesis , Azepines/metabolism , Azepines/pharmacology , Benzamides/administration & dosage , Benzamides/chemical synthesis , Benzamides/metabolism , Benzamides/pharmacology , Blood Platelets/metabolism , Body Water/metabolism , Cell Line , Cell Membrane/metabolism , Dogs , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Kidney/metabolism , Liver/metabolism , Osmolar Concentration , Pyrroles , Rats , Sodium/blood , Structure-Activity Relationship , Urine/chemistrySubject(s)
Arginine Vasopressin/antagonists & inhibitors , Azepines/pharmacology , Benzamides/pharmacology , Receptors, Vasopressin/metabolism , Animals , Antidiuretic Hormone Receptor Antagonists , Blood Pressure/drug effects , Cyclic AMP/metabolism , Dogs , Heart Failure/physiopathology , Humans , Hyponatremia/etiology , Hyponatremia/physiopathology , Inappropriate ADH Syndrome/physiopathology , Kidney/drug effects , Kidney/physiology , Kidney/physiopathology , PyrrolesABSTRACT
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.
Subject(s)
Histamine Antagonists/chemical synthesis , Imidazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Basophils/drug effects , Basophils/metabolism , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Lethal Dose 50 , Macaca mulatta , Male , Mice , Passive Cutaneous Anaphylaxis/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Reaction of estradiol-17 beta with triethylamine-sulfur trioxide in pyridine gives exclusively monosulfation at the C17-hydroxyl group with the preparation of 17 beta-sulfooxyestra-1,3,5(10)-trien-3-ol triethylammonium salt (V). The structural assignment suggested by spectroscopic measurements was confirmed by synthetic studies. (Formula: see text) A synthesis of 3-sulfooxyestra-1,3,5(10)-trien-17 beta-ol triethylammonium salt (II) has been accomplished based on the preparation of 17 beta-formyloxyestra-1,3,5(10)-trien-3-ol (XIII). Fusion of the 3-sulfate triethylammonium salt II gives rise to the 17-sulfate triethylamine salt V. The preparation of estradiol-17 beta disulfate has also been achieved.
Subject(s)
Estradiol/analogs & derivatives , Chemical Phenomena , Chemistry , Estradiol/chemical synthesis , Ethylamines , Indicators and Reagents , Magnetic Resonance Spectroscopy , Optical Rotation , Spectrophotometry, Infrared , Sulfur OxidesABSTRACT
A method for the preparation of steroid triethylammonium sulfates is outlined which involves the fusion of triethylamine-sulfur trioxide and steroids. Experimental details are presented which define the process as a thermal equilibrium resulting in the preferential sulfation of aliphatic hydroxyl groups. Sulfation of an aromatic hydroxyl group can be achieved in the absence of an aliphatic hydroxyl group. With excess reagent both types of hydroxyl groups in the same molecule can be sulfated.
