Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
  • C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

• This invention is related to new bradykinin-inhibiting tripeptide derivatives, especially amides and esters.
• Bradykinin exhibits strong pharmacodynamic activity. Also in extremely low doses BK causes vasodilation, bronchoconstriction, permeability increase in the capillary vessels, pain by influencing the nerve ends, contraction or relaxation of extravasal smooth muscles, e.g. in the intestines and uterus, accumulation of leucocytes.
• bradykinin is active, but probably there are several different receptors on the various target organs. Some of the effects of BK can probably also be mediated by the release of other active compounds, such as prostaglandines.
• BQ is probably involved in a number of different diseases, e.g. in inflammatory processes, shock by various causes, rheumatoid arthritis, gout, pane reatitis, carcinoid, migraine, hereditary angioneurotic oedema, burns, allergies.
• Boc t-butyloxy carbonyl
• DCCI dicyclohexyl carbodiimide
• Et 3 N triethylamine
• EtOAc ethyl acetate
• TFA trifluoroacetic acid
• TLC thin layer chromatography
• UV light (254 nm) and is then developed with chlorine/- o-toluidine reagens according to the conventional method.
• the HBr salt is ion exchanged on a column with QAE - 25 in chloride form in 90% EtOH-10% H 2 0 with the same medium for eluation.
• a fraction with the pure main product in chloride form is obtained, 496 mg (1.0 mmol), which is dissolved in 2 ml DMF and neutralized with 0.15 ml Et 3 N. Thereafter 215 mg (1.0 mmol Boc-D-Pro-OH, 135 mg (1.0 mmol) HBT and under cool conditions 250 mg (about 1.2 mmol) DCCI are added.
• the reaction is finished after 20 hours, and thereafter the reaction mixture is filtered and evaporated in vacuum to an oil which is kneeded with 2% NaHCO 3 in H 2 0 and pure H 2 0.
• the obtained mass is dissolved in MeOH and chromatographed on a column with Sephadex LH-20 in MeOH with MeOH as eluating agent.
• the fraction with pure lib is evaporated in vacuum och leached with H 2 O.
• the obtained crystal mass is dried in vacuum.
• IIIc 160 mg (0.28 mmol) of IIIc is deprotected with about 10 ml of
• Example Ila but with 130 mg (2.2 mmol) of isopropylamine as amine instead of heptylamine.
• Vlllb 300 mg (0.44 mmol) of Vlllb is deprotected, purified and ion exchanged in the same way as in Example I.
• Example Ila but with 218 mg (2.2 mmol) of cyclohexylamine as amine instead of heptylamine.
• the bradykinin-inhibiting activity of the new tripeptide derivatives is evident from the following disclosure of the biological evaluation on isolated organs.
• the bradykinin inhibiting activity is studied on isolated rat uterus.
• the rats are pretreated subcutanous with 0.2 mg/kg of diethyl stilbestrol, 12-15 hours prior to the experiment.
• the muscle from uterus which is longitudinally sectioned into halves is arranged in a smooth muscle bath with de Jalon's buffer (de Jalon et al., Farmacother.Acta, Vol. 3, p. 313, 1945), oxygenated with carbogene gas (5% carbon dioxide, 95% oxygen).
• the temperature is maintained at 35 C.
• the muscle is stretched with a tension corresponding to 0.5 g.
• the isometric tension is measured with Grass (FT 03C) force transmitter connected to a Grass polygraph.
• Muscle contractions for bradykinin in bath concentrations of 10 -1 1 - 10 -6 M (mole/litre) are registrated, and thereafter the concentration of bradykinin which induces 70% of maximum muscle contraction (ED 70 ) is evaluated.
• the bradykinin inhibiting activity is then tested with the tripeptide derivatives in bath concentrations of 10 -8 , 10 -7 , 10 - 6 and 10 -5 M, against the ED 70 for bradykinin of resp. muscle.
• the tripeptide derivatives are in cubated with the uterus tissue 5 and 10 minutes resp. before the addition of bradykinin.
• the bradykinin-inhibiting activity is expressed as the time in minutes required until bradykinin again gives the original contraction.
• Each addition of bradykinin is followed by washing with the buffer.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Genetics & Genomics (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

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Citations (3)

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• 1979
  • 1979-07-16 JP JP50113479A patent/JPS55500520A/ja active Pending
  • 1979-07-16 DE DE7979850071T patent/DE2964956D1/de not_active Expired
  • 1979-07-16 EP EP79850071A patent/EP0009010B1/en not_active Expired
  • 1979-07-16 WO PCT/SE1979/000157 patent/WO1980000252A1/en not_active Ceased
  • 1979-07-16 AT AT0905679A patent/AT387393B/de not_active IP Right Cessation
  • 1979-07-17 US US06/058,333 patent/US4242329A/en not_active Expired - Lifetime
• 1980
  • 1980-03-18 DK DK116380A patent/DK149630C/da not_active IP Right Cessation
  • 1980-08-21 SU SU802961995A patent/SU1034603A3/ru active

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