Glucagon-like peptide-1 (glp-1) derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel glucagons-like peptide-1 (GLP-1) derivatives which have a prolonged activity profile, their pharmaceutical compositions and use of the compounds in preparing a medicinal agent for treating or preventing hyperglycemia, diabetes 2 or obesity. The compound is a therapeutic GLP-1 polypeptide bonded to a residue bonded with albumin through a hydrophilic separator.

EFFECT: higher effectiveness of derivatives and treatment method.

26 cl, 66 ex

 

The text descriptions are given in facsimile form.

1. The compound having the formula (I)
,
where therapeutic polypeptide is a peptide GLP-1 containing the amino acid sequence of the formula (V)

where XAA7L - histidine, D-histidine, desamino-histidine, 2-amino-histidine, (3-hydroxy-histidine, homocysteine, Nα-acetyl-histidine, α-vermeil-histidine, α-methyl-histidine, 3-pyridylamine, 2-pyridylamine or 4-pyridylamine;
Xaa8- Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropane)carboxylic acid, (1-aminocinnamate)carboxylic acid, (1-aminocyclopent)carboxylic acid, (1-is monocyclohexyl)carboxylic acid, (1-aminocyclopent)carboxylic acid, or (1-aminocyclopent)carboxylic acid;
Xaa18Is Ser, Lys or Arg;
XAA22Is Gly, Glu or Aib;
XAA23Is Gln, Glu, Lys or Arg;
Xaa26Is Lys, Glu or Arg;
XAA30Is Ala, Glu or Arg;
XAA34Is Lys, Glu or Arg;
XAA35Is Gly or Aib;
XAA36Is Arg or Lys;
XAA37Is Gly, Ala, Glu or Lys;
XAA38- Lys, amide or is absent;
And is bound to albumin residue of a molecule selected from the group consisting of
,
,
,
,
,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms present is an independently from each other, or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
and

In represents -(CH2)l-O-[(CH2)n-O]m-(CH2)p-[C(O)NH-(CH2)l-O-[(CH2)n-O]m-(CH2)p]q-,
where l, m, n and p is independently equal to 1-5, and q is 05;
Y is a chemical group linking b and a therapeutic polypeptide selected from the group consisting of-C(O)NH-, -NHC(O)-, -C(O)NHCH2-, CH2NHC(O)-,
-OC(O)NH-, -NHC(O)O-, -C(O)NHCH2-, -CH2NHC(O)-, -C(O)CH2-, -CH2C(O)-,
-C(O)CH=CH-, -CH=CHC(O)-, -(CH2)s-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)- and-C(O)NH-, where s is 0 or 1, and
W is a chemical group linking a and b, selected from the group consisting of
-C(O)NH-, -NHC(O)-, -C(O)NHCH2-, -CH2NHC(O)-, -OC(O)NH-, -NHC(O)O-, -C(O)CH2-,
-CH2C(O)-, -C(O)CH=CH-, -CH=CHC(O)-, -(CH2)s-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)- and
-C(O)NH-, where s is 0 or 1,
or its pharmaceutically acceptable salt.

2. The compound having the formula (III)

where therapeutic polypeptide is a peptide GLP-1 containing the amino acid sequence of the formula (V)
,
where XAA7L - histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homocysteine, Nα-acetyl-histidine, α-vermeil-histidine, α-methyl-histidine, 3-pyridylamine, 2-pyridylamine or 4-pyridylamine;
XAA8- Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropane)carboxylic acid, (1-aminocinnamate)carboxylic acid, (1-aminocyclopent)carboxylic acid, (1-aminocyclohexane)carboxylic acid, (1-aminocyclopent)carboxylic acid, or (1-aminocyclopent)carboxylic acid;
Xaa8 Is Ser, Lys or Arg;
XAA22Is Gly, Glu or Aib;
XAA23Is Gln, Glu, Lys or Arg;
Xaa26Is Lys, Glu or Arg;
XAA30Is Ala, Glu or Arg;
XAA34Is Lys, Glu or Arg;
XAA35Is Gly or Aib;
XAA36Is Arg or Lys;
XAA37Is Gly, Ala, Glu or Lys;
XAA38- Lys, amide or is absent;
A and a' is bound to albumin remains of molecules selected from the group consisting of
,
,
,
,
,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where configuration is ia chiral carbon atom is a or R, or S,
,
where the configuration of the chiral carbon atom is a or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
where the configuration of the two chiral carbon atoms are independently from each other, or R, or S,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
and

In represents -(CH2)l-O-[(CH2)n-O]m-(CH2)p-[C(O)NH-(CH2)l-O-[(CH2)n-O]m-(CH2)p]q-,
where l, m, n and p is independently equal to 1-5, and q is 0-5;
Y is a chemical group linking b and a therapeutic polypeptide selected from the group consisting of-C(O)NH-and-NHC(O)-, -C(O)NHCH2-, -CH2NHC(O)-,
-OC(O)NH-, -NHC(O)O-, -C(O)NHCH2-, -CH2NHC(O)-, -C(O)CH2-, -CH2C(O)-,
-C(O)CH=CH-, -CH=CHC(O)-, -(CH2)s-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)- and-C(O)NH-, where s is 0 or 1, and
W is selected from the group consisting of
,,and,
where s is 0, 1 or 2,
or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, wherein q is 0 or 1.

4. The compound according to claim 1 or 2, wherein q is 1.

5. The compound according to claim 1 or 2, wherein q is 0.

6. The compound according to claim 1 or 2, characterized in that l is equal to 2.

7. The compound according to claim 1 or 2, characterized in that n is equal to 2.

8. The compound according to claim 1, wherein-W-B-Y - is selected from the group consisting of
,
,
,
,
,
,
and
.

9. The compound according to claim 2, wherein-W"-B-Y - is a
.

10. The compound according to claim 1 or 2, characterized in that the binding to albumin residue attached via a separator and bridges to the specified therapeutic polypeptide ε-and what kinogruppoy lysine residue.

11. The compound according to claim 1 or 2, characterized in that the binding to albumin residue attached via a separator and bridges to the specified therapeutic polypeptide by a bridge with the amino acid residue is selected from cysteine, glutamate and aspartate.

12. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 is selected from GLP-1(7-37), GLP-1(7-38), GLP-1(7-39), GLP-1(7-40), GLP-1(7-41) or their equivalent.

13. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 contains no more than 10 amino acid residues which have been substituted, inserted or delegated compared to GLP-1(7-37) (sequence SEQ ID NO: 1).

14. The connection according to claim 6, characterized in that the peptide GLP-1 contains no more than 6 amino acid residues which have been substituted, inserted or delegated compared to GLP-1(7-37) (sequence SEQ ID NO: 1).

15. The connection according to claim 6, characterized in that the peptide GLP-1 contains no more than 4 amino acid residues which are not encoded by the genetic code.

16. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 is protected from DPP-IV peptide GLP-1.

17. The compound according to claim 1 or 2, characterized in that the specified connection is resistant to DPP-IV.

18. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 contains the Aib residue in position 8.

9. The compound according to claim 1 or 2, characterized in that the amino acid residue in position 7 of the peptide GLP-1 is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homocysteine, Nα-acetyl-histidine, α-vermeil-histidine, α-methyl-histidine, 3-pyridylamino, 2-pyridylamine and 4-pyridylamine.

20. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 is selected from the group consisting of Arg34GLP-1(7-37),
Arg26,34Lys38GLP-1(7-38), Arg26,34Lys38GLP-1(7-38)-OH, Arg26,34Lys36GLP-1(7-36),
Aib8,22,35GLP-1(7-37), Aib8,35GLP-1(7-37), Aibby 8.22GLP-1(7-37),
Aib8,22,35Arg26,34Lys38GLP-1(7-38), Aib8,35Arg26,34Lys38GLP-1(7-38),
Aibby 8.22Arg26,34Lys38GLP-1(7-38), Aib8,22,35Arg26,34Lys38GLP-1(7-38),
Aib8,35Arg26,34Lys38GLP-1(7-38), Aib8,22,35Arg26Lys38GLP-1(7-38),
Aib8,35Arg26Lys38GLP-1(7-38), Aibby 8.22Arg26Lys38GLP-1(7-38),
Aib8,22,35Arg34Lys38GLP-1(7-38), Aib8,35Arg34Lys38GLP-1(7-38),
Aibby 8.22Arg34Lys38GLP-1(7-38),
Aib8,22,35Ala37Lys38GLP-1(7-38), Aib8,35Ala37Lys38GLP-1(7-38), Aibby 8.22Ala37Lys38GLP-1(7-38),
Aib8,22,35Lys37GLP-1(7-37), Aib8,35Lys37GLP-1(7-37), Aibby 8.22Lys37GLP-1(7-38),
Aib8Arg26,34Glu22,23,30Lys38GLP-1(7-38) Gly 8Arg26,34Lys38GLP-1(7-38),
Aib8,Arg26,34Lys38GLP-1(7-38), Aib8Lys38GLP-1(7-38), Aib8Arg26,34Lys36GLP-1(7-37), Gly8,Arg26,34,Lys36GLP-1-(7-37), Ala8Arg26,34Lys38GLP-1(7-38), Aib8,22,35Lys38GLP-1(7-38), Aib8Arg26,34Lys36GLP-1(7-37), Gly8Arg26,34Lys36GLP-1-(7-37), Aib8Arg34GLP-1-(7-37), Gly8Glu22,23,30Arg18,26,34GLP1(7-37), imidazolidinone acid7Aibto 22.35Lys38GLP1(7-38), 3-(5-imidazolyl)propionyl7Aib8Arg26,34Lys38GLP-1(7-38), and D-Ala8Lys37GLP-1-(7-37).

21. The compound according to claim 1 or 2, characterized in that the peptide GLP-1 attached to the specified hydrophilic separator amino acid residue at position 23, 26, 34, 36 or 38 in accordance with the amino acid sequence of SEQ ID NO: 1.

22. The compound according to claim 1 or 2, characterized in that one communicates with the albumin residue attached through the specified hydrophilic separator to the C-terminal amino acid residue of the indicated peptide GLP-1.

23. The compound according to claim 1 or 2, characterized in that the said compound is selected from the group consisting of
Nε37-(2-(2-(2-(dodecylamino)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys37]GLP-1(7-37)amide

Nε37-(2-(2-(2-(17-sulfosuccinimidyl)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys 37]GLP-1(7-37)amide

Nε37-{2-[2-(2-(15-carboxymethylamino)ethoxy)ethoxy]acetyl}-[Aib8,22,35,Lys37]GLP-1(7-37)amide

Nε37-(2-(2-(2-(17-carboxymethylamino)ethoxy)ethoxy)acetyl)-[Aib8,22,35,Lys37]GLP-1(7-37)amide

Nε37-(2-(2-(2-(19-carboxymethylamino)ethoxy)ethoxy)acetyl)-[Aib8,22,35,Lys37]GLP-1(7-37)amide

[Aib8,22,35,Arg26,34]GLP-1(7-37)Lys(4-(hexadecylamine)-4(S)-carboxybutyl)-HE

[Aib8,22,35,Arg26,34]GLP-1-(7-37)Lys(2-(2-(2-(hexadecylamine)ethoxy)ethoxy)-acetyl)-HE

Nε37-(2-[2-(2,6-(S)-bis-{2-[2-(2-(dodecanoyl)ethoxy)ethoxy]acetylamino}-hexanamine)ethoxy]ethoxy)acetyl-[Aib8,22,35]GLP-1(7-37)amide

Nε37-(2-[2-(2,6-(S)-bis-{2-[2-(2-(tetradecanoyl)ethoxy)ethoxy]acetylamino}-hexanamine)ethoxy]ethoxy)acetyl}-[Aib8,22,35]GLP-1(7-37)amide

[Aib8,22,35,Arg26,34]GLP-1(7-37)Lys(2-(2-(2-(4-(hexadecylamine)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetyl)-HE

[Aib8,22,35]GLP-1(7-37)Lys((2-{2-[4-[4-(4-amino-9,10-dioxo-3-sulfo-9,10-dihydro-anthracene-1-ylamino)-2-sulfo-phenylamino]-6-(2-sulfo-phenylamino)-[1,35]triazine-2-ylamino]ethoxy}ethoxy)acetyl))amide

[Aid8,22,35]GLP-1(7-37)Lys(({2-[2-(2-{2-[2-(2-{2-[2-(15-carboxymethylamino)-ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl))amide

Nε37-([2-(2-{3-[2,5-dioxo-3-(15-carboxypenicillins)-pyrrolidin-1-yl]-propionamide}ethoxy)ethoxy)acetyl] -, [D-Ala8,Lys37]GLP-1(7-37)amide

[Aib8,22,35Ala37]GLP-1(1-37)Lys((2-(2-(2-(11-(oxalylamino)undecanoate)ethoxy)ethoxy)acetyl)))amide

[Aib8,22,35Ala37]GLP-1(1-37)Lys({2-[2-(2-{2-[2-(2-(15-carboxy-pentadecanolide)-ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl)amide

[Aib8,22,35Ala37]GLP-1(1-37)Lys((2-{2-[11-(5-dimethylaminonaphthalene-1 sulfonylamino)undecanoyl]ethoxy}ethoxy)acetyl)amide

[Aib8,22,35Ala37]GLP-1(1-37)Lys(([2-(2-{2-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetylamino}ethoxy)ethoxy]acetyl))amide

[Aib8,Arg26,34Glu22,23,30]GLP-1H(7-37)Lys(2-(2-(2-(octadecylamino)ethoxy)ethoxy)acetyl)amide

[Aib8,Arg26,34Glu22,23,30]GLP-1(7-37)Lys(2-(2-(2-(eicosanoid)ethoxy)ethoxy)acetyl)amide

[Gly8,Arg26,34]GLP-1H(7-37)Lys(2-(2-(2-(2-(2-(2-(4-(octadec is noitamina)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetyl)ethoxy)ethoxy)acetyl)-HE

[Aib8,Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(octadecylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}HE

[Aib8]GLP-1(7-37)Lys(2-(2-(2-(4-(hexadecylamine)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetyl)-HE

[Aib8,Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(4-(octadecylamino)-4-carboxymethylamino)ethoxy)ethoxy] acetyl)ethoxy)ethoxy)acetyl)}HE

[Aib8,Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(17-carboxymethylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)acetyl)}HE

[Gly8Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(17-carboxymethylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}HE

[Aib8]GLP-1(7-37)Lys(2-(2-(2-(2-(2-(2-(4-(hexadecylamine)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-HE

Nε37-(2-(2-(2-(dodecanoyl)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys37]GLP-1H(7-37)amide

Nε37-(2-(2-(2-(tetradecanoyl)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys37]GLP-1H(7-37)amide

Nε37-(2-(2-(2-(hexadecylamine)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys]GLP-1(7-37)amide

Nε37 -(2-(2-(2-(octadecylamino)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys37]GLP-1(7-37)amide

Nε37-(2-(2-(2-(eicosanoid)ethoxy)ethoxy)acetyl)-[Aib8,22,35Lys37]GLP-1(7-37)amide

Nε36-(2-(2-(2-(2-(2-(2-(octadecylamino)ethoxy)ethoxy)acetylamino)-ethoxy)ethoxy)acetyl))-[Aib8,Arg26,34,Lys36]GLP-1(7-37)-HE

Nε36-(2-(2-(2-(2-(2-(2-(octadecylamino)ethoxy)ethoxy)acetylamino)ethoxy)-ethoxy)acetyl))-[Arg26,34,Lys36]GLP-1(7-37)-OH

Nε36-{2-(2-(2-(2-[2-(2-(octadecylamino)ethoxy)ethoxy]acetylamino)ethoxy)-ethoxy)acetyl)}-[Gly8,Arg26,34,Lys36]GLP-1(7-37)-OH

Nε37-(2-(2-(2-(4-4(4,4,5,5,6,6,7,7,8,8,9,9,9-criticalcarenurseseminar.html-amino)ethoxy)ethoxy)acetyl))-[Aib8,22,35,Lys37]GLP-1(7-37)-OH

Nε37-(2-(2-(2-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosanol-oxyacetylene)ethoxy)ethoxy)acetyl)-[Aib8,22,35,Lys37]GLP-1(7-37)-OH

Nε37-(2-(2-(2-(4-(hexadecanesulfonyl)bucillamine)ethoxy)ethoxy)acetyl)-[Aib8,22,35,Lys37]GLP-1(7-37)-OH

[Arg26,34]GLP-1(7-37)Lys({2-(2-(2-(2-[2-(2-(octadecylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)aceti is)})-HE

[Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(4-(octadecylamino)-4-carboxymethylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)acetyl)}HE

[Ala8,Arg26,34]GLP-1(7-37)Lys((2-[2-((2-oxalylamino-3-carboxy-2-4,5,6,7-tetrahydro-benzo[b]thiophene-6-yl-acetylamino)ethoxy]ethoxyacetic)amide

[Aib8,22,35]GLP-1(7-37)Lys((2-[2-((2-oxalylamino-3-carboxy-2-4,5,6,7-tetrahydro-benzo[b]thiophene-6-yl-acetylamino)ethoxy]ethoxyacetic)amide

Nε36-(2-(2-(2-(2-(2-(2-(4-(octadecylamino)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-[Aib8,Arg26,34,Lys36]GLP-1(7-37)-OH

Nε36-(2-(2-(2-(2-(2-(2-(4-(octadecylamino)-4(S)- carboxymethylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-[Gly8,Arg26,34,Lys36]GLP-1(7-37)-OH

Nε37-2-(2-(2-(4-(4-(heptadecanoyl)-4-(S)-carboxymethylamino)-4-(S)-carboxymethylamino)ethoxy)ethoxy)acetyl-[Aib8,22,35,Lys37]GLP-1(7-37)-NH2

Nε37-2-(2-[2-(2-[2-(4-[4-(heptadecanoyl)-4-(S)-carboxymethylamino]-4-(S)-carboxymethylamino)ethoxy]ethoxy)acetylamino)ethoxy]ethoxy)acetyl-[Aib8,22,35,Lys37]GLP-1(7-37)-NH2

Nε6 -(2-(2-(2-(4-(hexadecylamine)-4(S)-carboxymethylamino)ethoxy)ethoxy)acetyl)-[Aib8,Arg34]GLP-1(7-37)-OH

Nε26-2-(2-2-(2-(2-(2-(4-(octadecylamino)-4(S)-carboxymethylamino)ethoxy)-ethoxy)acetylamino)ethoxy)ethoxy)acetyl-[Aib8,Arg34]GLP-1(7-37)-OH

[Gly8,Arg26,34]GLP-1(7-37)Lys(2-(2-(19-(carboxy)nonadecanone)ethoxy)ethoxy)acetyl)-HE

[Gly8,Arg26,34]GLP-1(7-37)Lys(2-(2-(17-(carboxy)heptadecanoyl)ethoxy)ethoxy)acetyl))-HE

[Gly8,Arg26,34]GLP-1(7-37)Lys(2-(2-(2-(4-(19-(carboxy)nonadecanone)-4-carboxymethylamino)ethoxy)ethoxy)acetyl)-HE

[Gly8,Arg26,34]GLP-1(7-37)Lys((2-(2-(2-(2-(2-(2-(2-(2-(2-(hexadecylamine)ethoxy)-ethoxy)acetyl)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-HE

[Gly8,Arg26,34]GLP-1(7-37)Lys(2-(2-(2-(2-(2-(2-(octadecylamino)ethoxy)ethoxy)-acetylamino)ethoxy)ethoxy)acetyl)-NH2

Nε36-(2-(2-(2-(2-(2-(2-(17-carboxymethylamino)ethoxy)ethoxy)-acetylamino)ethoxy)ethoxy)acetyl)-[Aib8,Arg26,34,Lys36]GLP-1(7-37)

Nε36-(2-(2-(2-(2-(2-(2-(17-carboxymethylamino)ethoxy)ethoxy)-acetylamino)ethoxy)ethoxy)aceti is)-[Arg 26,34,Lys36]GLP-1(7-37)

Nε36-(2-(2-(2-(2-(2-(2-(17-carboxymethylamino)ethoxy)ethoxy)-acetylamino)ethoxy)ethoxy)acetyl)-[Gly8,Arg26,34,Lys36]GLP-1(7-37)

Nε36-(2-(2-(2-(2-(2-(2-(4-(octadecylamino)-4(S)-carboxymethylamino)ethoxy)-ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-[Arg26,34,Lys36]GLP-1(7-37)

Nε26-(2-[2-(2-[2-(2-[2-(17-carboxymethylamino)ethoxy]ethoxy)acetylamino]-ethoxy)ethoxy]acetyl)-[Arg34]GLP-1(7-37)-OH

Nε26-[2-(2-[2-(2-[2-(2-[4-(17-carboxymethylamino)-4(S)-carboxymethylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]-[Arg34]GLP-1(7-37)-OH

[Gly8Glu22,23,30,Argl8,26,34]GLP-1(7-37)Lys(2-(2-(2-(2-(2-(2-(17-carboxymethylamino)ethoxy)ethoxy)acetylamino)ethoxy))ethoxy)-acetyl)-NH2

[imidazolidinedione acid7,Aibto 22.35]GLP-1(7-37)LysNH((2-{[4-(17-carboxymethylamino)butylcarbamoyl]methoxy}ethoxy)ethoxy))

and
[3-(5-imidazolyl)propionyl7,Aib8,Arg26,34]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(17-carboxymethylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)acetyl)}HE

24. Pharmaceutical HDMI is required for the treatment or prevention of hyperglycemia, type 2 diabetes or obesity, which contains the compound as defined in any one of claims 1 to 23, in an effective amount and a pharmaceutically acceptable filler.

25. The pharmaceutical composition according to paragraph 24, characterized in that it is suitable for parenteral administration.

26. The use of compounds as defined in any one of claims 1 to 23, for preparing a medicinal product for the treatment or prevention of hyperglycemia, type 2 diabetes or obesity.



 

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6 cl, 7 dwg, 4 tbl, 14 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to method of acidifying of one or several amino groups of peptide which is selected from group including exendin-3, exendin-4, Arg34-GLP-1(7-37), Gly8-GLP-1(7-36)-amide, Gly8-GLP-1(7-37), Val8-GLP-1(7-36)-amide, Val8-GLP-1(7-37), Val8Asp22-GLP-1(7-36)-amide, Val8Asp22-GLP-1(7-37), Val8Glu22-GLP-1(7-36)-amide, Val8Glu22-GLP-1(7-37), Val8Lys22-GLP-1(7-36)-amide, Val8Lys22-GLP-1(7-37), Val8Arg22-GLP-1(7-36)-amide, Val8Arg22-GLP-1(7-37), Val8His22-GLP-1(7-36)-amide, Val8His22-GLP-1(7-37), des(B30)-human insulin and their analogues, in which reaction of acidifying is carried out in water mixture containing less than 10% wt/wt aprotonic polar solvent, and interaction of peptide with acidifying agent of general formula I is carried out, where n is 0-8; R1 represents COOR4; R2 represents lipophilic part of molecule; R3 together with carboxyl group, to which R3 is bound, represents reaction-able ester or reaction-able N-hydroxyimidoesther; and R4 is selected from group including hydrogen, C1-12-alkyl and benzyl; in base conditions in water solution, acidifying agent being added to reaction mixture in form of solution stabilised by adding acid.

EFFECT: obtaining efficient method of peptide acidifying.

17 cl, 2 tbl, 8 ex

FIELD: gene and protein- engineering, medicine, pharmaceutical industry.

SUBSTANCE: invention relates to recombinant plasmide DNA pER-Gl is constructed, which provides synthesis of hybrid polypeptide containing human glucagone and intein in Escerichia coli cells. Producer of said hybrid polypeptide is obtained by transformation of E.coli ER2566 with pER-Gl plasmide. Method for production of human recombinant glucagone includes providing and cultivation of hybrid polypeptide producer containing human glucagone and intein followed by isolation and cleavage of said hybrid protein.

EFFECT: increased yield of human recombinant glucagone; simplified technology.

3 cl, 3 ex, 3 dwg

Glp-1 analogs // 2288232

FIELD: peptides, medicine, pharmacy.

SUBSTANCE: invention relates to novel peptide analogs of glucagons-like peptide-1 and its pharmaceutically acceptable salts that are used in treatment of mammals.

EFFECT: valuable medicinal properties of analogs.

10 cl, 1 tbl, 411 ex

Glp-1 derivatives // 2214419
The invention relates to a derivative of GLP-1 parent peptide having one or two lipophilic substituent attached optionally via an amino acid or dipeptide spacer to amino acid residue that is not N-terminal or C-terminal amino acid residue, where the parent peptide has the sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG, or is in the amount of up to ten amino acid residues are replaced with any-amino acid residue which can be encoded using the genetic code

Analogues of glp-1 // 2214418
The invention relates to peptide analogs glucoheptonate peptide-1 formula

(R2R3)-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-AND23-AND24-AND25-AND26-AND27-AND28-AND29-AND30-AND31-AND32-AND33-AND34-AND35-AND36-AND37-AND38-AND39-R1the values of the radicals indicated in the claims

Analogues of glp-1 // 2208015
The invention relates to compounds of the formula (R2R3) AND7-AND8-AND9-AND10-AND11-AND12-AND13-AND14-AND15-AND16-AND17-AND18-AND19-AND20-AND21-AND22-AND23-AND24-AND25-AND26-AND27-AND28-AND29-AND30-AND31-AND32-AND33-AND34-AND35-AND36-AND37-R1,

where a7-AND37represent different amino acid residues, the values radicals cm

FIELD: medicine.

SUBSTANCE: invention relates to method of obtaining medication on the basis of biologically active substance, which includes binding biologically active substance to neutral carrier, as neutral carrier metal or semiconductor nanoparticles are used, and as biologically active substance used is bacteriorodopsin in therapeutically efficient amount, whose molecules are linked to nanoparticle surface with formation of ligand shell.

EFFECT: obtained nanoparticles ensure efficient transportation of bacteriorodopsin into cells and tissues.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cell biology, molecular biology, cancer biology and medicine and represents a pharmaceutical composition for targeting to the cells bearing BLyS receptor, containing an effective amount of fused protein consisting of BLyS polypeptide fused with cytotoxic polypeptide where said cytotoxic polypeptide is located on the N-end of fused protein, and BLyS polypeptide is located on the S-end of fused protein, and a pharmaceutically acceptable carrier.

EFFECT: invention provides treatment and prevention of B-cell proliferative disorder.

11 cl, 13 ex, 4 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivative of hyaluronic acid, where nonsteroid anti-inflammatory medical agent is joined to hyaluronic acid by means of covalent link, which contains partial structure of disaccharide unit of hyaluronic acid, to which anti-inflammatory medical agent is joined, being represented by the following formula (1): Y-CO-NH-R1-(O-R2)n (l) where Y-CO- represents one residue of disaccharide unit of hyaluronic acid; R2 represents a residue of nonsteroid anti-inflammatory medical agent represented by group Z-CO- or atom of hydrogen, provided that all R2 are not atom of hydrogen; -NH-R1-(O-)n represents spacer residue in compound-spacer represented by the formula H2N-R1-(OH)n, having hydroxyl groups in amount of n;R1 represents linear or ramified hydrocarbon group, containing from 2 to 12 atoms of carbon, which may have a substitute;-CO-NH- represents amide link of carboxyl group of hyaluronic acid as a component of hyaluronic acid saccharide with amides of compound-spacer;-O-CO- represents ester link of hydroxyl group of compound-spacer with carboxyl group in residue of nonsteroid anti-inflammatory medical agent, and n equals integer number from 1 to 3, where derivative of hyaluronic acid has an extent of susbstitution with nonsteroid anti-inflammatory medical agent from 5 to 50% mole per repeated unit of hyaluronic acid and carbonyl group in residue of hyaluronic acid, which represents component derivative of hyaluronic acid is available as participant in formation of amide link in process of binding with spacer-binding residue of nonsteroid anti-inflammatory medical agent or as free carboxyl group that does not participate in this process, according to extent of substitution of residue of nonsteroid anti-inflammatory medical agent. Invention also relates to solution and pharmaceutical agent for suppression of pain and/or suppression of inflammation and/or treatment of arthritis, derivative of hyaluronic acid, set and medical set for injection, including solution of hyaluronic acid derivative.

EFFECT: production of solution and pharmaceutical agent for suppression of pain and/or suppression of inflammation and/or treatment of arthritis.

26 cl, 12 dwg, 1 tbl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, more specifically to a delivered pharmaceutical composition with controlled release of biologically active compounds to a subject, containing: a) a complex biologically active compound containing at least one basic functional group, and polyanion which is a hexahydroxycyclohexane derivative, containing at least two negative functional groups; and a pharmaceutically acceptable carrier containing biodegradable water-insoluble polymer.

EFFECT: invention provides a delivery system which stabilises biologically active compounds, regulates polymer degradation, limits spurt effect and maintains drug release within therapeutic limits of treatment length.

29 cl, 19 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to conjugates of natriuretic compounds. In particular, conjugated forms of hBNP are proposed, which contain at least one modifying group attached thereto. The modified natriuretic compound conjugates retain activity for bonding with NPR-A receptor for stimulating cGMP production, and have longer half-life in blood flow compared to unmodified counterpart natriuretic compounds.

Class 1: Non-hydrolysable - conjugate medicinal agent remains unchanged Alky inside or PAG inside

Class 2: MicroPAGylated - the alkyl part remains splits in vivo

Class 3: Fully hydrolysable - the entire oligomer splits in vivo

= amphiphilic oligomer Nobex,

=bBNP.

EFFECT: pharmaceutical compositions which contain the disclosed conjugates and use of the disclosed conjugates to make medicinal agents.

13 cl, 13 dwg, 3 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.

EFFECT: increased output of the product under mild conditions.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of preparing a soluble inclusion compound which contains one or more active substances which are partially soluble in aqueous medium, included in one or more host molecules, distinguished by that it includes the following sequence of steps: one or more active substances are brought into contact with one or more host molecules which are cyclodextrins; molecular diffusion is carried out by bringing dense fluid medium which is carbon dioxide under pressure into contact with a mixture obtained at the previous step in static mode in the presence of one or more diffusion agents; the formed active substance/host molecule molecular complex is separated; an agent for reaction with a complex is added to the active substance/host molecule molecular complex and mixed and the solid inclusion compound formed is separated.

EFFECT: improvement of method.

8 cl, 17 dwg, 3 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly a liquid pharmaceutical composition containing ionite bound Pradofloxacine, and filled ionite is dispersed in a carrier medium containing water and one or more structurally viscous gelling agents, and the elastic ratio of the composition makes 5 to 50 Pa, and also to application thereof for making a medical product.

EFFECT: compositions shows improved physical stability and provide available intake of the preparation by animals.

5 cl, 1 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products, particularly to pharmaceutical tuberculosis composition containing isoniazid conjugate with oxidised dextrane of molecular weight 35-60 kDa purified from free isoniasid and cytotoxic impurities, e.g. by spirit sedimentation at temperature 60-80°C. Additionally, the pharmaceutical composition contains a liposome-forming agent, e.g. phosphatidylcholine, pharmaceutically acceptable excipient, e.g. water for injection, saline or buffer solution. The component ratio is as follows: isoniasid conjugate with oxidised dextrane - 0.4-4.0 wt %, the liposome-forming agent - 0.1-1.0 wt %, the pharmaceutically acceptable excipient - to 100 wt %. The pharmaceutical composition represents nanoliposome emulsions of liposome size 150-800 nm.

EFFECT: lower hepatotoxicity and improved biocompatibility.

5 cl, 2 tbl, 3 ex

FIELD: biotechnology.

SUBSTANCE: invention concerns biotechnology and conjugates of hydroxyalkyl starch and protein of factor (G-CSF) stimulating granulocyte colonies. The conjugates are formed by covalent link between hydroxyethyl starch or its derivative with molecular weight within 2 to 200 kD and protein.

EFFECT: methods of conjugate obtainment and application.

26 cl, 7 ex, 2 tbl, 21 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

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