Rational Development of Practical Catalysts for Aromatic Carbon−Nitrogen Bond Formation

A series of C2-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1‘-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid−liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in...

Design of N-Spiro C2-Symmetric Chiral Quaternary Ammonium Bromides as Novel Chiral Phase-Transfer Catalysts: Synthesis and Application to Practical Asymmetric Synthesis of α-Amino Acids

Orally-active angiotensin-converting enzyme inhibitors are rapidly establishing themselves in the therapy of hypertension and congestive heart failure. Concerted efforts in a number of laboratories have now led to the discovery or synthesis of an unparalleled variety of potent inhibitors. The manner in which several of these inhibitors bind to ACE is beginning to be understood. It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well. The success of ACE inhibitors as pharmacological tools and in the clinic will also quite certainly encourage future efforts to develop new enzyme inhibitor approaches to drug therapy.

Recent developments in the design of angiotensin-converting enzyme inhibitors.

Towards control of χ-space: Conformationally constrained analogues of Phe, Tyr, Trp and His

Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 A) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation. Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.

A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies.

The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described The above compounds were tested for inhibition of angiotensin converting enzyme The structure-activity relationship of the series is also discussed Compound 6u, the most potent member of the series, had an in vitro IC50 of 48 X 10(-9) M Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg

Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.

1-Carboxy-(alkanoyl or aralkanoyl)-indoline-2-carboxylic acids, e.g., those of the formula ##STR1## R=H, alkyl, alkoxy, halogeno or CF 3 ; R'=H or R-phenyl; m=0 or 1; p,q=0 to 2; and functional derivatives thereof, are antihypertensive and cardioactive agents.

1-Carboxyalkanoylindoline-2-carboxylic acids

The synthesis of N-(3-mercaptopropionyl)-N-arylglycines (14a-x),- N-arylalanines (15a,b),-N-cycloalkylglycines (16a-k), and -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (17a-d), -1,2,3,4-tetrahydroquinoline-2-carboxylic acids (18a-f), and -indoline-2-carboxylic acids (19a-k) is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure--activity relationship for each series is discussed. The in vivo inhibition of ACE and antihypertensive effects of representative compounds from each series are discussed. The most potent compound, 19d, had an in vitro ACE IC50 of 2.6 X 10(-9) M and lowered blood pressure in spontaneous hypertensive rats 85 mm at a dose of 10 mg/kg po.

Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.

Substituted pyridyl-2-imidazolones and their acid addition salts which are analgesic, anti-inflammatory, and antipyretic agents. An illustrative embodiment is 1-methyl-5-(2-pyridyl)-2-imidazolone.

Norbert Gruenfeld

Papers

Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.

1-Carboxyalkanoylindoline-2-carboxylic acids

Angiotensin converting enzyme inhibitors: N-substituted monocyclic and bicyclic amino acid derivatives.

Pyridyl-2-imidazolones

O-(substituted benzamido)phenylacetic acids