Patent EA-002058-B1 (EA)
Title: New bpc peptide salts with organo-protective activity, the process for their preparation and their use in therapy
IPC: A61K38/00
Filed: 1998-05-20
Abstract: 1. A salt of a BPC (Body Protection Compound) peptide comprising 8 amino acid residues wherein the anion of the salt is a negatively charged peptide having the general formula [Zaa Pro Pro Pro Xaa Yaa Pro Ala] <(-) or (2-)> wherein Xaa is a neutral aliphatic amino acid residue, Yaa is a basic amino acid residue and Zaa is an acidic amino acid residue and wherein the cation of the salt is the cation of an inorganic or organic non-toxic base. 2. The salt according to Claim 1 wherein the cation is selected from the group consisting of alkali metals, alkaline earth metals, Zn<+2>, primary, secondary and tertiary amines, in particular, Na<+>, K<+>, Li<+>, Cs<+>, Ca<2+>, NH4<+>, triethanolamine<+>, cyclohexylamine<+>, 2-AMP<+> (2-amino-1-propanol) and TRIS<+>(Tris-(hydroxymethyl)-aminomethan). 3. The salt according to Claim 1 or 2 wherein Xaa is Ala, bAla, Leu, Ile, Gly, Val, Nle or Nva, Yaa is Lys, Arg, Orn or His and Zaa is Glu, Asp, Aad or Apm. 4. The salt according to any one of the preceding claims, which furthermore comprises a pharmaceutically or diagnostically acceptable carrier. 5. The salt according to any one of the preceding claims, which furthermore comprises trehalose. 6. The salt according to any one of the preceding claims wherein the general formula is Xaa Zaa Pro Pro Pro Xaa Yaa Pro Ala Asp Zaa                              5                                       10 Ala Xaa Xaa Xaa                        15 7. The salt according to any one of the preceding claims wherein the peptide is selected from the group consisting of Leu Glu Pro Pro Pro Gly Lys Pro Ala Asp Asp                              5                               10 Ala Leu Gly Val;                       15 Gly Glu Pro Pro Pro Gly Lys Pro Ala Asp Asp                              5                               10 Ala Gly Leu Val;                       15 Leu Glu Pro Pro Pro Leu Lys Pro Ala Asp Asp                              5                               10 Ala Leu Gly Val;                       15 Leu Glu Pro Pro Pro Leu Lys Pro Ala Asp Ala                              5                               10 Leu Gly Val;                14 Gly Glu Pro Pro Pro Gly Lys Pro Ala Asp Ala                               5                              10 Gly Leu Val;                14 Glu Pro Pro Pro Leu Lys Pro Ala;                       5                         8 Asp Pro Pro Pro Ile Arg Pro Ala Asp;                             5                         9 Glu Pro Pro Pro Leu Lys Pro Ala Asp;                             5                         9 Leu Glu Pro Pro Pro Leu Lys Pro Ala Asp Ala                                     5                        10 Leu Gly Val;                14 Gly Glu Pro Pro Pro Gly Arg Pro Ala Asp and                              5                               10 Glu Pro Pro Pro Leu Lys Pro Ala Asn.                              5                          9 8. The salt according to any one of the preceding claims wherein the peptide is cyclized, in particular, by an amide bond between the first and the last amino acid residue. 9. The salt according to any one of the preceding claims wherein the salt is dissolved in an aqueous or aqueous/alcoholic solution, preferably at a pH of 6.0 to 8.5. 10. A compatible, storage-stable, pharmaceutical composition comprising a pharmaceutically effective amount of the BPC peptide salt according to any one of the preceding claims and optionally a physiologically acceptable carrier. 11. The pharmaceutical composition according to Claim 10 for peroral use admixed with trehalose. 12. A diagnostic storage-stable composition comprising a diagnostically effective amount of the BPC peptide salt according to any one of the preceding claims. 13. The use of a BPC peptide salt according to any of the claims 1 to 9 for the preparation of a compatible, storage-stable pharmaceutical composition according to Claim 10 for the treatment of: disturbances connected with either nitric oxide (NO) formation or impaired NO-system functions, in particular, hypertension, angina, impotence, circulatory and septic shock, stroke, inflammation, respiratory distress syndrome, adhesion and aggregation of platelets and leukocytes, endothelial dysfunction, gastrointestinal lesions, peristalsis disturbances, diabetes pancreatitis, hypotension and Parkinson's disease; dysfunctions or hyperfunctions of somatosensory nerves, in particular, sensory neuropathy, postherpetic neuralgia, atopic dermatitis, impaired healing of injured tissue, acquired cold and heat urticaria, psoriasis, bullous pemphigoid, eczema, photodermatoses, chronic arthritis, gastrointestinal lesions and specific or non-specific hyperreactivity of upper and lower respiratory tracts (asthma, rhinitis); endothelium disturbances; wounds, ulcers; conditions relating to acute and/or chronic inflammation, in particular, chronic arthritis, and disorders related with delayed type of hypersensitivity, and gastrointestinal lesions; liver disorders, organ lesions induced by free radicals specifically caused by irradiation; disorders connected with cathecholaminergic system disturbances, in particular, schizophrenia, amphetamine challenge effects, drug abuse; stress related conditions; acute pancreatitis; in particular with concomitant gastroduodenal pathology; cardiac disturbances; depressive disturbances; Parkinson's disease and Parkinson's disease-like pathology; temperature disturbances; bone impairments; hypertension-induced various organ damages; disturbances of coagulation; pain disturbances; convulsion disorders; spinal cord injury; alcohol injuries, induced by alcohol abuse or increased alcohol intake; brain ischemic disorders; peripheral nerve injuries; cataleptic disorders and neuroleptic disturbances; disorders related to abnormal or mutant lymphocytes; disturbances of fetuses; vaginal atrophy and osteoporosis development caused by ovariectomy conditions; tumors; viral diseases, in particular AIDS or ARC; gastrointestinal lesions; cognitive disorders; withdrawal disturbances; kidney disturbances and disturbances in cellular immune response. 14. The use of a BPC peptide salt according to any one of claims 1 to 9 for the preparation of a compatible, storage-stable pharmaceutical composition according to Claim 10 as a cyto-protective and organo-protective agent. 15. A process for the preparation of the BPC peptide salt according to anyone of claims 1 to 9 by mixing at least one BPC peptide in an aqueous or aqueous/alcoholic solvent with one or more bases and obtaining a BPC peptide salt wherein the cation of the salt is the cation of an inorganic or organic non-toxic base.