- Alcohols
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Novel alcohols of the formula STR1 wherein Ra is azido or phthalimido, R4 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, R7 and R8 together are a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one --CH2 -- group is replaced by --NH--, --N(alkoxycarbonyl)-, --N(acyl)- or --S-- or which carries a fused cycloalkane, aromatic or heteroaromatic ring, and R9 is alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula STR2 in which R10 and R11 each is alkyl, are described along with a process for their manufacture. These alcohols are useful as intermediates, for example in the manufacture of amino acid derivatives having antiviral activity.
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- Structure-Activity Study of Tripeptide Thrombin Inhibitors Using α-Alkyl Amino Acids and Other Conformationally Constrained Amino Acid Substitutions
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In our continuing effort to design novel thrombin inhibitors, a series of conformationally constrained amino acids (e.g. α-alkyl, N-alkyl cyclic, etc.) were utilized in a systematic structure-activity study of the P3, P2, and P1 positions of tripeptide arginal thrombin inhibitors.Early examples of this effort include: D-MePhe-Pro-Arg-H (15), Boc-D-Phg-Pro-Arg-H (18), D-1-Tiq-Pro-Arg-H (23, D-1-Tiq = D-1,2,3,4-tetrahydroisoquinolin-1-ylcarbonyl), and Boc-D-Phe-Pro-Arg-H (25).10a,20 The current work clarifies the contribution of each residue of the tripeptide arginals toward the potent and selective inhibition of thrombin relative to that of t-PA and plasmin.The α-methylarginal modification in the P1 residue resulted in analogs 30 (D-MePhe at P3) and 32 (D-1-Tiq at P3) which had lower potency toward thrombin while exhibiting improved selectivity.Analogs modified at the P2 site were found to be very sensitive to the conformational changes induced by variations in side chain ring size with the flexible pipecolinic acid 31 being 2 orders of magnitude less potent at thrombin inhibition than the conformationally constrained azetidine analog 20.Examination of the P3 binding region indicated that α-alkylphenylglycine residues resulted in a tendency to exhibit substantional improvements in selectivity over the nonalkylated residues.Combinations of optimal P3 and P2 changes led to compounds TFA-D-Phg(αEt)-Azt-Arg-H (16), TFA-D-Phg(αMe)-Azt-Arg-H (17), Ac-D-Phg(αMe)-Azt-Arg-H (21), TFA-D-Phg(αMe)-Pro-Arg-H (27), 30, and 32, which are clearly more selective for thrombin versus plasmin than the nonconformationally constrained compounds.
- Shuman, Robert T.,Rothenberger, Robert B.,Campbell, Charles S.,Smith, Gerald F.,Gifford-Moore, Donetta S.,et al.
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p. 4446 - 4453
(2007/10/03)
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- Amino acid derivatives
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Compounds having the formula STR1 wherein R is benzyloxycarbonyl or 2-quinolylcarbonyl, and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and can be used as medicaments for the treatment of prophylaxis of viral in
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- Bicyclic α-iminocarboxylic acid compounds having hypotensive activity
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What are disclosed are indole, quinoline and isoquinoline compounds of the formula STR1 in which n denotes 0 or 1, m denotes 1 or 2, but (n+m)≤2, A together with the bridgehead carbon atoms denotes a benzene or a cyclohexane ring, Y1 denotes hy
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