Pharmaceutical agents for the treatment of sickle cell disease

• US 4,390,526 A
• Filed: 06/06/1980
• Issued: 06/28/1983
• Est. Priority Date: 06/21/1979
• Status: Expired due to Term

• Current Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Original Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Inventors: Wilchek, Meir, Gorecki, Marian, Rich, Alexander, Acquaye, Clemenceau T. A.
• Primary Examiner(s): Rosen, Sam
• Application Number:
  US06/157,107
• Time in Patent Office: 1,117 Days
• Field of Search: 424/309, 424/177, 424/275, 424/320, 424/248.54, 424/263, 424/273, 424/274, 424/248.55, 424/324, 424/248.5, 424/248.52, 424/248.53
• US Class Current: 514/13.5
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic

Abstract

The present invention relates to novel compounds selected from R₁ --COO(CH₂)_n --R₂ and ##STR1## wherein R₁ is selected from heterocyclic aromatic and hydrophobic naturally occuring and modified amino acids in the D- and in the L-form, and from peptides, wherein n is an integer of from 1 to 5 and R₂ is selected from unsubstituted and substituted phenyl rings, and from heterocyclic rings, as well as to pharmaceutical compositions for preventing sickling of erythrocytes during sickle cell crisis and for desickling of sickle cells of patients afflicted by sickle cell disease, the active ingredient of which is a compound as defined above.

Claims

1. A pharmaceutical composition for preventing the sickling of erythrocytes during sickle cell crises, and for desickling of sickle cells of patients afflicted by sickle cell disease, comprising a pharmaceutical excipient, and, as active ingredient, an effective amount of the formula ##STR3## wherein R₁ is a residue selected from the group consisting of naturally occurring and modified amino acids and from peptides containing said amino acids;

n is an integer of 1 to 5; and

R₂ is selected from the group consisting of unsubstituted thienyl, morpholine, pyridine, and pyrrolidone rings.

2. A composition in accordance with claim 1, wherein said active ingredient is L-Phe-(2-thienyl)ethyl ester, L-Phe-(2-morpholine)ethyl ester, L-Phe-(2-pyridine)ethyl ester, or L-Phe-(2-pyrrolidone)ethyl ester.

3. A method for preventing the sickling of erythrocytes during sickle cell crises, and for desickling of sickle cells of patients afflicted by sickle cell disease, comprising administering to such patients an effective amount of a compound of the formula ##STR4## wherein R₁ is a residue selected from the group consisting of naturally occurring and modified amino acids and from peptides containing said amino acids;

n is an integer of 1 to 5; and

R₂ is selected from the group consisting of unsubstituted or para-nitro substituted phenyl, thienyl, morpholine, pyridine and pyrrolidone rings.

4. A method in accordance with claim 3, wherein said compound is a benzyl ester and the moiety R₁ is selected from the group consisting of phenylalanine, tyrosine, thyroxine, tryptophan, proline, hydroproline, histidine, and from peptides containing such residue.

5. A method in accordance with claim 3, wherein said compound is selected from the group consisting of L-Phe-OBz.HCl, L-Tyr-OBz.HCl, L-Try-OBz.HCl, L-Pro-OBz.HCl, L-Phe-OBz-(pNO₂).HBr, L-Pro-OBz(pNO₂).HBr, L-His-OBz(pNO₂)-pTs, L-Ala-L-Phe-OBz.HBr, L-Gly-L-Phe-OBz.HBr, L-Phe-Benzyl amide, L-Val-OBz, L-Leu-OBz, L-Phe-L-Ala-OBz.HBr, L-Try-Lys-OBz.HBr, D-Phe-OBz.HCl, D-Tyr-OBz.HCl, D-Try-OBz.HCl, L-Phe-(2-thienyl)ethyl ester, L-Phe-(2-morpholine)ethyl ester, L-Phe-(2-pyridine)ethyl ester, L-Phe-(2-pyrrolidone)ethyl ester, L-Phe-(2-phenyl)ethyl ester, L-Phe-(3-phenyl)propyl ester, and L-Phe-(4-phenyl)butyl ester.