Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/22—Tachykinins, e.g. Eledoisins, Substance P; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to new undecapeptides and to methods of producing the same, and more particularly to undecapeptides having blood pressure lowering activity, smooth muscles stimulating activity and other important activities.
• the present invention mainly comprises an undecapeptide of the formula:
• R is selected from the group consisting of L-glutamyl, L-glutaminyl, L-asparaginyl and glycyl and wherein R is selected from the group consisting of L-isoleucyl, L-leucyl and Lvalyl, and further wherein R in the case that R is L-leucyl or L-valyl can also be L-asparagyl.
• the synthesis of the new compounds of the present invention can be carried out by the usual method used in peptide coupling, for example as set forth in the monograph of Greenstein and Winitz in Chemistry of the Amino Acids, I. Wiley & Sons, New York, London (1961), preferably by the anhydride-, the azide-, the carbodiimideor the activated ester-method.
• the amino acid sequence is advantageously built up from small peptide units, for example as shown in Table 1 and in Table 2 below. If necessary, the functional groups which are not concerned with the condensation can intermediately be protected, for example by reductive or hydrolytically easily splittable radicals.
• the end products themselves are preferably obtained by coupling a heptapeptide and a tetrapeptide (note Table 1).
• the C-terminal carboxyl group of the heptapeptide thus exists first in the form of the methyl ester which is saponified to free the carboxyl group.
• the saponification can be carried out in normal manner in alkaline medium. It is particularly advantageous to free the Cterminal carboxyl group by enzymatic saponification, preferably with chymotrypsin or trypsin.
• the production of the new compounds of the present invention provides considerable preparation advantages as compared to the synthesis of eledoisin, which results from the choice of the substituted amino acids.
• glutamic acid exhibits much less of a tendency to form glutarimides than does the original aspartic acid to form succinimide.
• bradykinin note Table 3 below.
• the Glu -analog exhibits the advantage of greater solubility. Cons 7O quently it is possible to use higher doses, for example ent invention exhibit in their action on the smooth muscles 75 for the physiological building of the active agent.
• EXAMPLE 1 (a) Carbobenzoxy-L-glutamyl-v-terL-butyl ester-L-alanyl- L-phenylalanine-methyl ester (1) 10.5 g. of carbobenzoxy-Lglutamic acid-'y-tert-butyl ester-a-hydrazide [Ea Klieger and H. Gibian, Liebigs Ann. Chem. 655, 195 (1962)], are suspended in 39.6 cc. of 1.5% solution of hydrochloric acid in tetrahydrofurane at 20 C. and reacted with 3.65 cc. of tert.-butyl nitrite in 20 cc. of tetrahydrofurane.
• the same compound can be obtained, for example, from L-pyroglutamyl-L-prolyl-L-seryl-e-tert-butyloxycarbonyl-L-lysine-hydr-azide [Ed Sandrin and R. A. Boissonnas, Experientia XVIII, 77 (1962)] using the azide method.
• the above compound is obtained from 2 g. of the tert.- butyloxycarbonyl compound by splitting off of the protective groups with hydrochloric acid in glacial acetic acid in the above described manner.
• the yield is 1.6 g. (88%).

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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)
• Peptides Or Proteins (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=7433138

Family Applications (1)

Country Status (6)

Cited By (5)

Citations (5)

• 1964
  • 1964-01-09 DE DE19641518343 patent/DE1518343A1/de active Pending
  • 1964-12-09 NL NL6414277A patent/NL6414277A/xx unknown
  • 1964-12-23 US US420788A patent/US3268502A/en not_active Expired - Lifetime
  • 1964-12-24 CH CH1669864A patent/CH454161A/de unknown
• 1965
  • 1965-01-05 GB GB460/65A patent/GB1092682A/en not_active Expired
  • 1965-01-11 BE BE658146A patent/BE658146A/xx unknown

Patent Citations (5)

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