US3579494A - C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin (cck-pz) - Google Patents

C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin (cck-pz) Download PDF

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Publication number
US3579494A
US3579494A US745688A US3579494DA US3579494A US 3579494 A US3579494 A US 3579494A US 745688 A US745688 A US 745688A US 3579494D A US3579494D A US 3579494DA US 3579494 A US3579494 A US 3579494A
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United States
Prior art keywords
aspartyl
tyrosyl
sulfonyl
arginyl
methionyl
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Expired - Lifetime
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US745688A
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English (en)
Inventor
Miguel A Ondetti
John T Sheehan
Josip Pluscec
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • 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
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel peptide amides of the general formula wherein R represents L-aspartyl-3-sulfonyl-L-tyrosyl,
  • Peptide salts encompassed by the above include pharmaceutically acceptable acid addition salts, such as hydrochlorides, hydrobromides, acetates, fluoroacetates, such as trifluoroacetate, chloroacetates such as dichloroacetate, and the like, as well as ammonium salts such as dicyclohexylammonium, triethylammonium, morpholinium, pyridinium, and the like, and inorganic salts, such as alkali or alkaline earth metal salts, e.g., sodium, potassium, calcium, barium, and the like.
  • pharmaceutically acceptable acid addition salts such as hydrochlorides, hydrobromides, acetates, fluoroacetates, such as trifluoroacetate, chloroacetates such as dichloroacetate, and the like
  • ammonium salts such as dicyclohexylammonium, triethylammonium, morpholinium, pyridinium, and
  • the final products of this invention are peptide amides containing amino acid residues of L-isoleucine (Ileu), L-serine (Ser), L-arginine (Arg), L-tyrosine (Tyr), L-aspartic acid (Asp), L-methionine (Met), glycine (Gly), L-tryptophane (Trp) and L-phenylalanine (Phe).
  • cholecystokinin activity that is, they have the ability to stimulate the contraction of the gall bladder.
  • they find utility as diagnostic aids in X-ray examination of the gall bladder in the same manner as cholecystokinin.
  • they may be administered either intravenously or subcutaneously to an animal species (e.g., cats or dogs) in a single dosage of about 0.008 to 0.012 mg./kg. of body weight.
  • Met-Gly-Trp-Met-Asp-Phe-NH X-ASID-TYI-NHNHQ (V)
  • the starting material L-methionyl-glycyl L tryptophyl-L-methionyl-L-aspartyl-L-phenylalaninamide may be prepared by reacting glycyl-L-tryptophyl L methionyl L-aspartyl-L-phenylalaninamide trifluoroacetate with tertiary butyloxycarbony1-L-methionyl-2,4,S-trichlorophenyl ester.
  • the peptide sequences indicated in the above reaction schema may be joined by any known coupling method of peptide synthesis to form the indicated polypeptides as shown. Partial sequences are first formed by joining together the amino acids one at a time and then joining the resulting sequences one with another to obtain the desired polypeptide product.
  • the peptides of this invention may be prepared by the sequential addition of the appropriate amino acids one at a time to the L-methionyl-glycyl-L-tryptophyl-L-rnethionyl-L-aspar-tyl-L-phenylalanine amide.
  • Such additions are accomplished, for example, by activating the carboxylic acid group in the amino acid to be added after protecting the amino group in such amino acid, for instance, by converting it to its tertiary-butyloxycarbonyl derivative, converting this derivative into, for example, a nitrophenyl ester and then reacting this active ester with another amino acid or peptide as desired.
  • any group which causes the acid function to become more reactive such as mixed anhydrides (which normally involves the acylation of an amine with the mixed anhydrides of, for instance, an acyl amino acid and isovaleric acid), azides, acid chlorides, reaction products with carbodiimides, reactive N-acyl compounds, O-acyl hydroxylamine derivatives, and active esters, such as alkyl esters with electron attracting (negative) substituents, vinyl esters, enol esters, phenyl esters, halophenyl esters, thiophenyl esters, nitrophenyl esters, 2,4-dinitrophenyl esters, and nitrophenylthiol esters.
  • mixed anhydrides which normally involves the acylation of an amine with the mixed anhydrides of, for instance, an acyl amino acid and isovaleric acid
  • azides such as alkyl esters with electron attracting (negative) substituents, vinyl esters, enol esters, pheny
  • the hydroxyl protecting group employed may be benzyl, tertiary butyl, tetrahydropyranyl, and the like
  • the carboxyl protecting groups may be methyl, ethyl, tertiary butyl, benzyl, and the like
  • the guanidino protecting groups may be nitro, tosyl, p-nitrobenzyloxycarbonyl, protonation, and the like
  • the amino protecting groups (X and Y in the above formulae) may be benzyloxycarbonyl, t-butyloxycarbonyl, trifiuoroacetyl or o-nitrophenylsulfenyl, except that t-butyloxycarbonyl may not be employed in combination with o-nitrophenylsulfenyl.
  • X represents trifiuoroacetyl
  • a nucleophile e.g., hydrazine in methanol, sodium hydroxide in methanol or an alkoxide such as sodium methoxide or sodium ethoxide, and the like
  • X is o-nitrophenylsulfenyl
  • mild acid e.g., a hydrohaloacid (such as hydrobromic or hydrochloric acids) in a solvent such as ethyl acetate, ether, or other alkyl ester or alkyl ether solvents]
  • sulfur nucleophile such as sodium thiophenoxide, nitrothiophenoxide, and the like.
  • the hydroxyl, carboxyl and guanidino protecting groups may be removed by known reactions, such as hydrogenolysis, treatment with acids such as hydrochloric acid, hydrobromic acid, trifiuoroacetic acid, and the like, treatment with alkali, such as sodium or potassium hydroxide, and the like, or by treatment with sodium in liquid ammonia.
  • reactions such as hydrogenolysis, treatment with acids such as hydrochloric acid, hydrobromic acid, trifiuoroacetic acid, and the like, treatment with alkali, such as sodium or potassium hydroxide, and the like, or by treatment with sodium in liquid ammonia.
  • the sulfonation of the peptides of this invention containing tyrosine may be achieved by the reaction of the peptide with concentrated sulfuric acid in the cold.
  • the reaction is conducted for a period of time of about 24 to 72 hours at temperatures below 20 C., preferably below 0 C.
  • Glycyl-L-tryptophyl-L-methionyl L aspartyl-L- phenylalanine amide trifiuoroacetate (3.8 g.) is dissolved in a mixture of dimethylformamide (45 ml.) and triethylamine (1.4 ml.) and tert.-butyloxycarbonyl-L-methionine 2,4,5-trichlorophenyl ester (2.5 g.) added. After stirring for three hours at room temperature, the reaction mixture is diluted with ethyl acetate and the precipitate is filtered, washed with ethyl acetate and ether and dried. Yield is 3.4 g.; M.P. ISO-182.
  • Triethylamine (0.28 ml.) and tert.-butyloxycarbonylnitro L arginine N-hydroxysuccinimide ester (915 mg.) were added.
  • the reaction mixture was stored at room temperature and three more portions (83 mg. each) of active ester were added after 2, 3 and 6 hours.
  • ethyl acetate 200 ml. was added and the solution was washed with 20% aqueous citric acid and water. After drying (MgSO the solvent was removed in vacuo and the residue crystallized from ethyl acetate ether. Yield 1.31 g.
  • EXAMPLE 7 Tert.-butyloxycarbonyl L aspartyl-L-tyrosyl-L-methionylglycyl-L-tryptophyl L methionyl-L-aspartyl-L- phenylalanine amide (VI) Concentrated hydrochloric acid (0.12 ml.) was added to a solution of V (100 mg.) in dimethylformamide (4 ml.), cooled in a Dry Ice-acetone bath at 20. The temperature of the bath was allowed to rise to 15 and an aqueous 14% sodium nitrite solution (0.125 ml.) was added.
  • This material was purified by ion exchange chromatography on DEAE sephadex [(NH CO buffer] or by countercurrent distribution (n-butanol, pyridine, acetic acid, water system).
  • the temperature of the bath was allowed to rise to 15 and an aqueous 14% solution of sodium nitrite (0.50 ml.) was added. After minutes the temperature was lowered to 25 and N-ethylpiperidine (0.6 ml.) was added, followed by a solution of IX (1 g.) in dimethylformamide (4 ml.). After 24 hours standing at 5, the reaction mixture was concentrated to dryness and the resulting tert.- butyloxycarbonyl dodecapeptide (XIV) was dissolved in cold trifluoroacetic acid (6 ml.). The solution was kept under nitrogen for 15 minutes. Ether was added and the precipitate filtered, washed with ether and dried.
  • the desired dodecapeptide sulfonate was isolated by ion-exchange chromatography on DEAE sephadex. Yield 50 mg.
  • the title compound may also be obtained from benzyloxycarbonyl L isoleucyl L seryl L aspartyl L- arginyl L aspartyl 3 sulfonyl L tyrosyl L- methionylglycyl L tryptophyl L methionyl L aspartyl-L- phenylalanine amide.
  • EXAMPLE 17 Tert. butyloxycarbonyl L arginyl L aspartyl L- tyrosyl L methionylglycyl L tryptophyl L- methionyl L aspartyl L phenylalanine amide (XVII) Concentrated hydrochloric acid (0.12 ml.) was added to a solution of XVI (138 mg.) in dimethylformamide (1.2 m1.) and cooled in a Dry Ice-acetone bath at 20". The temperature of the bath was allowed to rise to 15 and an aqueous 14% sodium nitrite solution (0.125 ml.) was added.
  • the temperature of the bath was allowed to rise to 15 and an aqueous 14% solution of sodium nitrite (0.25 ml.) was added. After 5 minutes the temperature was lowered to 25 and N- ethylpiperidine (0.6 ml.) was added, followed by a solution of IX (500 mg.) in dimethylformamide (2 ml.). After 24 hours standing at 5 the reaction mixture was concentrated to dryness and the residue was triturated with water and then filtered and washed with ethanol. Yield 290 mg.
  • X is benzyloxycarbonyl, t-butyloxycarbonyl, trifiuoroacetyl or o-nitrophenylsulfenyl.
  • a compound in accordance with claim 1 having the name 3 sulfonyl L tyrosyl L methionylglycyl-L- tryptophyl-L-methionyl-L-aspartyl-L-phenylalanine amide.
  • a compound in accordance with claim 1 having the name L aspartyl L arginyl L aspartyl 3' sulfonyl L tyrosyl L methionylglycyl L tryptophy1- L-methionyl-L- aspartyl-L-phenylalanine amide.
  • a compound in accordance with claim 1 having the name benzyloxycarbonyl L isoleucyl L seryl L- aspartyl L arginyl L aspartyl 3' sulfonyl-L- tyrosyl L methionylglycyl L tryptophyl L methionyl L aspartyl L phenylalanine amide.
  • a compound in accordance with claim 1 having the name L isoleucyl L seryl L aspartyl L arginyl- L aspartyl 3' sulfonyl L tyrosyl L methionylglycyl L tryptophyl L methionyl L aspartyl L- phenylalanine amide.
  • a compound in accordance with claim 1 having the name t-butyloxycarbonyl L isoleucyl L seryl L- aspartyl L arginyl L aspartyl 3' sulfonyl L- 10 tyrosyl L methionylglycyl L tryptophyl L methionyl L aspartyl L phenylalanine amide.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US745688A 1968-07-18 1968-07-18 C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin (cck-pz) Expired - Lifetime US3579494A (en)

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US74568868A 1968-07-18 1968-07-18

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US (1) US3579494A (enrdf_load_stackoverflow)
JP (1) JPS4813115B1 (enrdf_load_stackoverflow)
CA (1) CA959830A (enrdf_load_stackoverflow)
CH (1) CH513127A (enrdf_load_stackoverflow)
DE (1) DE1935402B2 (enrdf_load_stackoverflow)
FR (1) FR2013212B1 (enrdf_load_stackoverflow)
GB (1) GB1281383A (enrdf_load_stackoverflow)
HU (1) HU163786B (enrdf_load_stackoverflow)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705140A (en) * 1967-10-05 1972-12-05 Luigi Bernardi Peptides related to the c-terminal sequence of cck-pz and caerulein
US3723406A (en) * 1969-12-23 1973-03-27 Squibb & Sons Inc Novel peptides having cholecystokinin activity and intermediates therefor
US3839315A (en) * 1968-05-03 1974-10-01 Squibb & Sons Inc Novel peptides having cholecystokinin activity and intermediates therefor
US3875137A (en) * 1973-04-20 1975-04-01 Searle & Co N-Substituted aspactyl peptide amids
US3892726A (en) * 1969-05-27 1975-07-01 Squibb & Sons Inc Tyrosine-O-sulfate containing peptides
USRE29324E (en) * 1973-04-20 1977-07-26 G. D. Searle & Co. N-Substituted aspartyl peptide amides
DE2751026A1 (de) 1976-11-29 1978-06-01 Akad Wissenschaften Ddr Verfahren zur herstellung von peptiden, die tyrosinsulfat enthalten
US4330466A (en) * 1980-06-10 1982-05-18 Amano Pharmaceutical Co., Ltd. Process for the production of cholecystokinin-pancreozymin C-terminal peptide amide sulfate esters
US4368192A (en) * 1979-04-30 1983-01-11 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Peptides
US4769445A (en) * 1985-03-04 1988-09-06 Pennwalt Corporation Process for the solid phase synthesis of peptides which contain sulfated tyrosine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE754248R (fr) * 1969-08-01 1971-02-01 Farmaceutici Italia Polypeptides a activite
GB0105069D0 (en) * 2001-03-01 2001-04-18 Univ Ulster The Modified peptide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705140A (en) * 1967-10-05 1972-12-05 Luigi Bernardi Peptides related to the c-terminal sequence of cck-pz and caerulein

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705140A (en) * 1967-10-05 1972-12-05 Luigi Bernardi Peptides related to the c-terminal sequence of cck-pz and caerulein
US3839315A (en) * 1968-05-03 1974-10-01 Squibb & Sons Inc Novel peptides having cholecystokinin activity and intermediates therefor
US3892726A (en) * 1969-05-27 1975-07-01 Squibb & Sons Inc Tyrosine-O-sulfate containing peptides
US3723406A (en) * 1969-12-23 1973-03-27 Squibb & Sons Inc Novel peptides having cholecystokinin activity and intermediates therefor
US3875137A (en) * 1973-04-20 1975-04-01 Searle & Co N-Substituted aspactyl peptide amids
USRE29324E (en) * 1973-04-20 1977-07-26 G. D. Searle & Co. N-Substituted aspartyl peptide amides
DE2751026A1 (de) 1976-11-29 1978-06-01 Akad Wissenschaften Ddr Verfahren zur herstellung von peptiden, die tyrosinsulfat enthalten
FR2372146A1 (fr) * 1976-11-29 1978-06-23 Akad Wissenschaften Ddr Procede de preparation de peptides contenant le sulfate de tyrosine
US4368192A (en) * 1979-04-30 1983-01-11 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Peptides
US4507235A (en) * 1979-04-30 1985-03-26 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method for preparing peptides and intermediate products
US4330466A (en) * 1980-06-10 1982-05-18 Amano Pharmaceutical Co., Ltd. Process for the production of cholecystokinin-pancreozymin C-terminal peptide amide sulfate esters
US4769445A (en) * 1985-03-04 1988-09-06 Pennwalt Corporation Process for the solid phase synthesis of peptides which contain sulfated tyrosine

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Publication number Publication date
CA959830A (en) 1974-12-24
DE1935402A1 (de) 1970-01-22
CH513127A (fr) 1971-09-30
HU163786B (enrdf_load_stackoverflow) 1973-10-27
JPS4813115B1 (enrdf_load_stackoverflow) 1973-04-25
DE1935402C3 (enrdf_load_stackoverflow) 1974-11-07
FR2013212B1 (enrdf_load_stackoverflow) 1974-05-24
FR2013212A1 (enrdf_load_stackoverflow) 1970-03-27
DE1935402B2 (de) 1974-04-04
GB1281383A (en) 1972-07-12

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