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RU2003105463A - PEPTIDE STRUCTURES SUITABLE FOR COMPETITIVE MODULATION OF CATALYSIS BY DIPEPTIDYLPEPTIDASE IV - Google Patents

PEPTIDE STRUCTURES SUITABLE FOR COMPETITIVE MODULATION OF CATALYSIS BY DIPEPTIDYLPEPTIDASE IV

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Publication number
RU2003105463A
RU2003105463A RU2003105463/04A RU2003105463A RU2003105463A RU 2003105463 A RU2003105463 A RU 2003105463A RU 2003105463/04 A RU2003105463/04 A RU 2003105463/04A RU 2003105463 A RU2003105463 A RU 2003105463A RU 2003105463 A RU2003105463 A RU 2003105463A
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Prior art keywords
acid
amino acid
pro
gly
compound according
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RU2003105463/04A
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Russian (ru)
Inventor
Ханс Ульрих ДЕМУТ (DE)
Ханс Ульрих ДЕМУТ
Торстен ХОФФМАНН (DE)
Торстен Хоффманн
Зузанне МАНХАРТ (DE)
Зузанне МАНХАРТ
Маттиас ХОФФМАНН (DE)
Маттиас Хоффманн
Йохен ХАЙНС (DE)
Йохен ХАЙНС
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Пробиодруг Аг (De)
Пробиодруг Аг
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Publication of RU2003105463A publication Critical patent/RU2003105463A/en

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    • 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
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (19)

1. Соединение, представленное общей формулой (I)1. The compound represented by General formula (I)
Figure 00000001
Figure 00000001
 и его фармацевтически приемлемые соли, гдеand its pharmaceutically acceptable salts, where А представляет собой любую аминокислоту, кроме D-аминокислоты,A is any amino acid except D-amino acid, В представляет собой аминокислоту, выбранную из Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновой кислоты и пипеколиновой кислоты,B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid and pipecolinic acid, С представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина,C is any amino acid except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine, D представляет собой любую аминокислоту или отсутствует, иD represents any amino acid or is absent, and Е представляет собой любую аминокислоту или отсутствует, или гдеE is any amino acid or is absent, or where С представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина, и кроме D-аминокислоты,C is any amino acid except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine, and in addition to D-amino acid, D представляет собой аминокислоту, выбранную из Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновой кислоты и пипеколиновой кислоты, иD is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid and pipecolic acid, and Е представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина.E is any amino acid, except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine. 2. Соединение по п.1, отличающееся тем, что2. The compound according to claim 1, characterized in that А представляет собой любую аминокислоту, кроме D-аминокислоты,A is any amino acid except D-amino acid, В представляет собой аминокислоту, выбранную из Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновой кислоты и пипеколиноаой кислоты,B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid and pipecolinoic acid, С представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина,C is any amino acid except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine, D представляет собой любую аминокислоту или отсутствует, иD represents any amino acid or is absent, and Е представляет собой любую аминокислоту или отсутствует.E is any amino acid or is absent. 3. Соединение по п.1, отличающееся тем, что3. The compound according to claim 1, characterized in that А представляет собой любую аминокислоту, кроме D-аминокислоты,A is any amino acid except D-amino acid, В представляет собой аминокислоту, выбранную из Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновой кислоты и пипеколиновой кислоты,B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid and pipecolinic acid, С представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина, и кроме D-аминокислоты,C is any amino acid except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine, and in addition to D-amino acid, D представляет собой аминокислоту, выбранную из Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновой кислоты и пипеколиновой кислоты, иD is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid and pipecolic acid, and Е представляет собой любую аминокислоту, кроме Pro, Hyp, ацетидин-(2)-карбоновой кислоты, пипеколиновой кислоты, и кроме N-алкилированных аминокислот, например, N-метилвалина и саркозина.E is any amino acid, except Pro, Hyp, acetidine- (2) -carboxylic acid, pipecolinic acid, and in addition to N-alkylated amino acids, for example, N-methylvaline and sarcosine. 4. Соединение по любому из предшествующих пунктов, отличающееся тем, что4. The compound according to any one of the preceding paragraphs, characterized in that А представляет собой L-аминокислоту.A is an L-amino acid. 5. Соединение по любому из предшествующих пунктов, отличающееся тем, что5. The compound according to any one of the preceding paragraphs, characterized in that С представляет собой L-аминокислоту.C is an L-amino acid. 6. Соединение по любому из предшествующих пунктов, отличающееся тем, что6. The compound according to any one of the preceding paragraphs, characterized in that Е отсутствует.E is absent. 7. Соединение по любому из предшествующих пунктов, отличающееся тем, что7. The compound according to any one of the preceding paragraphs, characterized in that D и Е отсутствуют.D and E are absent. 8. Соединение по любому из предшествующих пунктов, отличающееся тем, что8. The compound according to any one of the preceding paragraphs, characterized in that А представляет собой т-бутил-Gly, Ile или Val.A is t-butyl-Gly, Ile or Val. 9. Соединение по любому из предшествующих пунктов, отличающееся тем, что9. The compound according to any one of the preceding paragraphs, characterized in that В представляет собой Pro.B is a Pro. 10. Соединение по любому из предшествующих пунктов, отличающееся тем, что10. The compound according to any one of the preceding paragraphs, characterized in that С представляет собой т-бутил-Gly, Ile или Val.C is t-butyl-Gly, Ile or Val. 11. Соединение по любому из предшествующих пунктов, отличающееся тем, что11. The compound according to any one of the preceding paragraphs, characterized in that А представляет собой Pro, Ala, Ser, Gly, Hyp, ацетидин-(2)-карбоновую кислоту или пипеколиновую кислоту.A is Pro, Ala, Ser, Gly, Hyp, acetidine- (2) -carboxylic acid or pipecolinic acid. 12. Соединение по п.1, а именно, т-бутил-Gly-Pro-Ile; т-бутил-Gly-Pro-Val; Val-Pro-т-бутил-Gly; Ile-Pro-т-бутил-Gly или т-бутил-Gly-Pro-т-бутил-Gly и их фармацевтически приемлемые соли.12. The compound according to claim 1, namely, t-butyl-Gly-Pro-Ile; t-butyl-Gly-Pro-Val; Val-Pro-t-butyl-Gly; Ile-Pro-t-butyl-Gly or t-butyl-Gly-Pro-t-butyl-Gly and their pharmaceutically acceptable salts. 13. Соединение по любому из предшествующих пп., отличающееся тем, что соединение представляет собой свободную ислую пептидную форму или пептидную форму с С-концевым амидом.13. A compound according to any one of the preceding claims, characterized in that the compound is a free isl peptide form or a peptide form with a C-terminal amide. 14. Соединение по п.13, отличающееся тем, что свободная кислая пептидная форма или пептидная форма с С-концевым амидом отличается модификацией боковой цепи, выбранной из следующей группы: добавление гомосерина, добавление пироглутаминовой кислоты, образование дисульфидной связи, дезамидирование остатков аспарагина или глутамина, метилирование, т-бутилирование, т-бутоксикарбонилирование, 4-метилбензилирование, тиоанизилирование, тиокрезилирование, бензилоксиметилирование, 4-нитрофенилирование, бензилоксикарбонилирование, 2-нитробензоилирование, 2-нитросульфенилирование, 4-толуолсульфонилирование, пентафторфенилирование, дифенилметилирование, 2-хлорбензилоксикарбонилирование, 2,4,5-трихлорфенилирование, 2-бромбензилоксикарбонилирование, 9-флуоренилметилоксикарбонилирование, трифенилметилирование, 2,2,5,7,8-пентаметилхроман-6-сульфонилирование, гидроксилирование, окисление метионина, формилирование, ацетилирование, анизилирование, бензилирование, бензоилирование, трифторацетилирование, карбоксилирование аспарагиновой кислоты или глутаминовой кислоты, фосфорилирование, сульфатирование, цистеинилирование, гликозилирование пентозами, дезоксигексозами, гексозаминами, гексозами или N-ацетилгексозаминами, фарнезилирование, миристолизирование, биотинилирование, пальмитоилирование, стеароилирование, геранилгеранилирование, глутатионилирование, 5’-аденозилирование, АДФ-рибозилирование, модификация с N-гликолилнейраминовой кислотой, N-ацетилнейраминовой кислотой, пиридоксальфосфатом, липоевой кислотой, 4’-фосфопантетеином или N-гидроксисукцинимидом.14. The compound according to item 13, wherein the free acid peptide form or the peptide form with a C-terminal amide is characterized by a modification of the side chain selected from the following group: addition of homoserine, addition of pyroglutamic acid, formation of a disulfide bond, deamidation of asparagine or glutamine residues , methylation, t-butylation, t-butoxycarbonylation, 4-methylbenzylation, thioanisylation, thiocresylation, benzyloxymethylation, 4-nitrophenylation, benzyloxycarbonylation, 2-nitrobenzoic irradiation, 2-nitrosulfenylation, 4-toluenesulfonylation, pentafluorophenylation, diphenylmethylation, 2-chlorobenzyloxycarbonylation, 2,4,5-trichlorophenylation, 2-bromobenzyloxycarbonylation, 9-fluorenylmethyloxycarbonylation, triphenylmethylmethane-6,5,5,5 sulfonylation, hydroxylation, methionine oxidation, formylation, acetylation, anisylation, benzylation, benzoylation, trifluoroacetylation, carboxylation of aspartic acid or glutamic acid, phosphorylated sulfation, cysteinylation, glycosylation of pentoses, deoxyhexoses, hexosamines, hexoses or N-acetylhexosamines, farnesylation, myristolization, biotinylation, palmitoylation, stearoylation, geranyl geranylation, glutathionylation, acidification, glutathionylation, 5'-acidification, -acetylneuraminic acid, pyridoxalphosphate, lipoic acid, 4'-phosphopanthetein or N-hydroxysuccinimide. 15. Пролекарства соединения по любому из предшествующих пунктов.15. Prodrugs of a compound according to any one of the preceding paragraphs. 16. Фармацевтическая композиция, включающая по меньшей мере одно соединение или пролекарство по любому из пп.1-15 и фармацевтически приемлемый носитель и/или разбавитель.16. A pharmaceutical composition comprising at least one compound or prodrug according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and / or diluent. 17. Способ получения фармацевтической композиции, включающий смешивание по меньшей мере одного соединения или пролекарства по любому из пп.1-15 и фармацевтически приемлемого носителя и/или разбавителя.17. A method of obtaining a pharmaceutical composition, comprising mixing at least one compound or prodrug according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and / or diluent. 18. Применение соединения, пролекарства или композиции по любому из пп.1-15 для получения лекарственного средства для профилактики или лечения состояния, опосредованного модулированием активности дипептидилпептидазы IV.18. The use of a compound, prodrug or composition according to any one of claims 1 to 15 for the manufacture of a medicament for the prophylaxis or treatment of a condition mediated by modulation of the activity of dipeptidyl peptidase IV. 19. Применение по п.17, отличающееся тем, что состояния выбирают из нарушенной толерантности к глюкозе, сахарного диабета, глюкозурии и метаболического ацидоза.19. The application of claim 17, wherein the conditions are selected from impaired glucose tolerance, diabetes mellitus, glucosuria and metabolic acidosis.
RU2003105463/04A 2001-06-27 2002-06-27 PEPTIDE STRUCTURES SUITABLE FOR COMPETITIVE MODULATION OF CATALYSIS BY DIPEPTIDYLPEPTIDASE IV RU2003105463A (en)

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