US3761461A - D-ser1-nle4-lys17-lys18-val-nh2 25-alpha-1-25 acth and derivatives thereof - Google Patents

D-ser1-nle4-lys17-lys18-val-nh2 25-alpha-1-25 acth and derivatives thereof Download PDF

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Publication number
US3761461A
US3761461A US00608448A US3761461DA US3761461A US 3761461 A US3761461 A US 3761461A US 00608448 A US00608448 A US 00608448A US 3761461D A US3761461D A US 3761461DA US 3761461 A US3761461 A US 3761461A
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lys
lysyl
val
ctb
valyl
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J Pless
S Guttmann
R Boissonnas
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Sandoz AG
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Sandoz AG
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    • 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
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/695—Corticotropin [ACTH]
    • C07K14/6955—Corticotropin [ACTH] with at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention provides the pentacosapeptides of general formula D-seryl-L-tyrosyl-L-seryl-L-norleucyl- X L histidyl L phenylalanyl L arginyl L-tryptophanyl glycyl L lysyl L prolyl L valyl-glycyl- L lysyl L lysyl L lysyl L prolyl-L- valyl L lysyl L lysyl L prolyl-L- valyl L lysyl L valyl L tyrosyl-L-prolyl-L-valinamide, in which X signifies an L-glutamyl or L-glutaminyl radical, their therapeutically active acid addition salts and heavy metal complexes.
  • the present invention relates to new polypeptides and a process for their production.
  • the present invention provides the pentacosapeptides of general formula D-seryl-L-tyrosyl-L-seryl-L-norleucy1- X L histidyl L phenylalanyl L arginyl-L-tryptophanyl glycyl L lysyl L prolyl L valyl-glycyl-L- lysyl L lysyl L lysyl L prolyl-L-valyl- L-lysyl L valyl L tyrosyl L prolyl-L-valinamide, in which X signifies an L-glutamyl or L-glutaminyl radical, their therapeutically active acid addition salts and heavy metal complexes.
  • the pentacosapeptides of the above formula are hereinafter named as follows: D Ser Nle Lys Lys Val-NH pentacosapeptide and D Ser -Nle -Gln -Lys -Lys -Val- NH -pentacosapeptide.
  • Nle -Lys -Lys -Val-NH -pentacosapeptide over natural ACTH is that the former has no antigenic effects.
  • a further advantage is that it is devoid of a methionine radical in the 4-position, which methionine radical is easily oxidized whereby the hormone becomes inactive;
  • Nle Lys -Lys -Val-NH -pentacosapeptide contains a norleucine radical in place of the methionine radical present in ACTH, which norleucine radical has the same steric properties as the methionine radical, but is stable to oxidation.
  • Nle -Lys -Lys Val-NH -pentacosapeptide has two lysine radicals in the 17- and 18-positions in place of the arginine radicals present in these positions in natural ACTH. This simplifies the synthetic production of Nle -Lys -Lys Val-NH -pentacosapeptide and, surprisingly, no lowering of the biological activity has been ascertained in the new compound.
  • Nle Lys" Lys Val-NH -pentacosapeptide has a valinamide radical in the 25-position
  • This valinamide radical protects the peptide chain from enzymatic degradation.
  • this compound has the disadvantage that it is easily affected by aminopeptidase degradation.
  • the other compound of the invention has been produced by replacing the glutaminic acid radical in the 5-position of D-ser -Nle Lys Lys Val NH pentacosapeptide by a glutamine radical. Surprisingly this may be done without a loss of the biological activity so that D-ser -Nle -Gln Lys Lys Val NH -pentacosapeptide has all the advantages of D ser Nle 4 Lys" Lys -Val-N'H cosapeptide.
  • the pentacosapeptides of the invention may be produced by methods for the synthesis of compounds of this type in actual use of described in the literature on the subject, it being possible to join together the amino acids in the order indicated in the above formula one at a time or by first forming constituent peptide units and joining these together.
  • One method of producing the pentacosapeptides of the invention consists in that L-valyl-glycyl-e-N-R-L-lysyl-e- N-R-L-lysyl-e-N-R-L-lysyl-e-N-R-L-lysyl prolyl-L-valyle-N-R-L-lysyl-L-valyl-L-tyrosyl-L-prolyl-L-valinamide, in which R signifies a carbo-tert-butoxy or carbo-tert-amyloxy radical, is condensed with N-triphenylmethyl-L-glutaminyl (or 'y-O-tert-butyl-L-glutamyl) Im triphenylmethyl-L-histidyl-L-phenylalanyl-L-arginyl L tryptophanyl-glycyl-e-N-R-L-
  • the starting materials for producing the pentacosapeptides of the invention may be obtained by methods for the synthesis of peptides in actual use or described in the literature, it being possible to join together the amino acids one at a time or by first forming constituent peptide units and joining these together.
  • pentacosapeptides of the invention may likewise be obtained or used in the form of their salts.
  • acids for acid addition salt formation are: acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, tartarc, citric, benzoic, cinnamic, salicylic, 2-phenoxyor 2-acetoxy-benzoic, mandelic, methanesulphonic, ethauesulphonic, hydroxyethanesulphonic, benzeneor toluenesulphonic, naphthalenesulphonic and sulphanilic acid, polymeric acids, e.g.
  • tannic alginic or polygalacturonic acid
  • polyphloretinic phosphate or carboxymethyl cellulose and halogen hydracids, e.g. hydrochloric or hydrobromic acid, nitric, thiocyanic, sulphuric and phosphoric acid.
  • Zinc may, for example, be used for the heavy metal complex.
  • a major advantage of the synthetic pentacosapeptides over the natural hormone extracted from animal material is that the former have no antigenic effects. Absence of antigenic effect in a substance indicates no objection to its use even in the face of an earlier allergic reaction to natural ACIH.
  • the pentacosapeptides of the invention have the following biological activity:
  • the pentacosapeptides of the invention were tested in ac cordance with the third International Standard for corticotropin which is available in the form of an International Standard for Corticotropin and permits the standardization of ACTH preparations in International Units.
  • the dose of the pentacosapeptides of the invention ranges between about 40 and 60 IU daily, in exceptional cases between and 100 IU daily.
  • the pentacosapeptides of the invention may be used as medicaments, for example in the form of pharmaceutical preparations. These may contain the said compounds in mixture with an organic or inorganic carrier material which is suitable for parenteral administration.
  • Appropriate carrier materials are substances which do not react with the new compounds, e.g. gelatin, lactose, starch, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gum arabic, polyalkylene glycols, Vaseline, cholesterol and other known pharmaceutical carrier materials.
  • the pharmaceutical preparations may, for example, be used in the liquid form as solutions, suspensions or emulsions.
  • the new compounds may be sterilized and/or they may contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents. However, they may contain other therapeutically valuable substances.
  • the new compounds may also be administered in the form of depot preparations as is the case with natural ACTH.
  • radicals for blocking the amino radical of the serine radical during the synthesis of the new pentacosapeptides are the triphenylmethyl, the carbo-tertbutoxy and the carbo-tert-amyloxy radical, but other suitable protective radicals, e.g. the carbobenzoxy, the trifiuoroacetyl, the acetyl, the chloroacetyl and the formyl radical, may likewise be used.
  • Suitable radicals for blocking the e-amino radical of the lysine radical are the carbo-tert-butoxy and the carbotert-amyloxy radical, but other suitable protective radicals, e.g. the carbobenzoxy, toluenesulphonyl, phthalyl, formyl and trifiuoroacetyl radical, may likewise be used.
  • a suitable radical for blocking the 'y-carboxyl radical of the glutaminic acid radical is the tert-butyloxy radical, but other suitable protective radicals, e.g. the methoxy, the ethoxy, the tert-amyloxy, the amide or the benzyloxy radical, may likewise be used.
  • a suitable radical for the blocking of the imidazole radical of the histidine radical is the triphenylmethyl radical, but other suitable protective radicals, e.g. the carbo-tert-butoxy, carbo-tert-amyloxy, carbobenzoxy or benzyl radical, may likewise be used.
  • EXAMPLE 1 Carbo tert butoxy D seryl L tyrosyl L seryl- L-norleucine hydrazide.
  • CTB D Ser Tyr Ser-Nle- NHNH 54 g. of H-Ser-Nle-Ome-HCl and 63 g. of CBO-Tyr- OH are dissolved in 860 ml. of acetonitrile, cooling is effected to 28 ml. of triethylamine are added, cooling is effected to --10 and 41 g. of dicylohexyl carbodiimide are added. The mixture is stirred at 0 for 16 hours and is then filtered. The precipitate is washed with 1400 ml.
  • D-serine methyl ester hydrochloride 60 g. of D-serine methyl ester hydrochloride are dissolved in 200 ml. of dimethyl formamide and 54 ml. of triethylamine, cooling is effected to 0 and the triethylamine hydrochloride is filtered oif.
  • Dimethyl formamide is evaporated in a high vacuum and the residue dissolved in 150 ml. of pyridine.
  • 100 g. of tert-butyl-oxy-carbonyl azide are added dropwise and the mixture is allowed to stand at 20 for 2 days. The solvent is evaporated and the product is taken up in ethyl acetate. After washing with water, dilute hydrochloric acid and potassium bicarbonate solution, drying is effected over sodium sulphate.
  • CTB-D-Ser-OMe After evaporating the ethyl acetate CTB-D-Ser-OMe results as an oil.
  • the ester is dissolved in 500 ml. of methanol and is allowed to stand at 20 with 50 ml. of hydrazine hydrate for 2 days. After evaporating the methanol, the hydrazide crystallizes. After recrystallization from hot ethyl acetate, 53 g. of CTB-D-ser-NHNH having a melting point of 114, [u] -3 in dimethyl formamide, are obtained. 10 g. of CTB-D-serine hydrazide are dissolved at -10 in 136 ml. of 1 N hydrochloric acid containing 15 g.
  • the tripeptide obtained above is dissolved in 3 litres of methanol, hydrogenation is effected in the presence of 50 g. of 10% palladium/charcoal, filtration and evaporation are effected, the residue is dissolved in 1.5 litres of methylene chloride, cooling is effected to 0, ml. of triethylamine and then 270 g. of triphenylchloromethane are added, the mixture is allowed to stand at 20 for 16 hours, washing is effected with dilute acetic acid, water and 1 N sodium bicarbonate solution, drying and evaporation are effected. The residue is dissolved in diethyl ether and precipitation is effected with petroleum ether. 480 g.
  • Trit-Gln-(Trit)His-Phe-OMe melting point 90 with decomposition
  • 50 ml. of hydrazine are added, the mixture is allowed to stand at 20 for 24 hours, concentration is effected to 500 ml., 5 litres of diethyl ether are added, washing with 0.1 N common salt solution, drying, concentrating to 500 ml. and precipitating with petroleum ether are effected.
  • 380 g. of Trit-Gln- (Trit)His-Phe-NHNH having a melting point of 100 with decomposition, [a] 12 in dimethyl formamide, are obtained.
  • the peptide obtained above is dissolved in 200 ml. of pyridine, cooling is effected to '20, 30 ml. of a 1 N solution of hydrochloric acid in dioxane are added, stirring is effected at -20 for minutes, 7.8 ml. of triethylamine are added, the mixture is concentrated to half its volume, 30 g. of Tri-(trichlorophenyl)-phosphite are added, the mixture is allowed to stand at 20 for 16 hours, is evaporated, the residue is treated with diethyl ether and dissolved in ethyl acetate. Precipitation with diethyl ether, filtration and drying are effected. 51 g. of Trit-Gln-(Trit)His-Phe-Arg-Try-Gly (CTB)Lys Pro- OCRHCI, having a melting point of 180 with decomposition, are obtained.
  • CTB Trit-Gln-(Trit)His-

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
US00608448A 1966-01-12 1967-01-10 D-ser1-nle4-lys17-lys18-val-nh2 25-alpha-1-25 acth and derivatives thereof Expired - Lifetime US3761461A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH39266A CH488663A (de) 1966-01-12 1966-01-12 Verfahren zur Herstellung bisher unbekannter Polypeptide

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US (1) US3761461A (enrdf_load_stackoverflow)
BE (1) BE692420A (enrdf_load_stackoverflow)
CH (1) CH488663A (enrdf_load_stackoverflow)
DE (1) DE1593974A1 (enrdf_load_stackoverflow)
FR (1) FR1513597A (enrdf_load_stackoverflow)
GB (1) GB1173437A (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3954975A (en) * 1972-02-17 1976-05-04 Ciba-Geigy Corporation Salts of ACTH-peptides and processes for their manufacture
US4018753A (en) * 1974-07-30 1977-04-19 Shionogi & Co., Ltd. Polypeptides with ACTH-like activities
US4018754A (en) * 1974-07-30 1977-04-19 Shionogi & Co., Ltd. Novel polypeptides having ACTH-like action
US4089821A (en) * 1976-03-31 1978-05-16 Armour Pharmaceutical Company Synthesis of peptide amides
US4250086A (en) * 1979-11-19 1981-02-10 Ortho Pharmaceutical Corporation Method and composition for preparation of H-SAR-LYS-SAR-GLN-NH2
US4297270A (en) * 1978-09-15 1981-10-27 Hoechst Aktiengesellschaft Manufacture and use of non-ionogenic interface-active agents based on modified rosins

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3954975A (en) * 1972-02-17 1976-05-04 Ciba-Geigy Corporation Salts of ACTH-peptides and processes for their manufacture
US4018753A (en) * 1974-07-30 1977-04-19 Shionogi & Co., Ltd. Polypeptides with ACTH-like activities
US4018754A (en) * 1974-07-30 1977-04-19 Shionogi & Co., Ltd. Novel polypeptides having ACTH-like action
US4089821A (en) * 1976-03-31 1978-05-16 Armour Pharmaceutical Company Synthesis of peptide amides
US4297270A (en) * 1978-09-15 1981-10-27 Hoechst Aktiengesellschaft Manufacture and use of non-ionogenic interface-active agents based on modified rosins
US4250086A (en) * 1979-11-19 1981-02-10 Ortho Pharmaceutical Corporation Method and composition for preparation of H-SAR-LYS-SAR-GLN-NH2

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Publication number Publication date
FR1513597A (fr) 1968-02-16
DE1593974A1 (de) 1971-03-04
CH488663A (de) 1970-04-15
GB1173437A (en) 1969-12-10
BE692420A (enrdf_load_stackoverflow) 1967-07-10

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