Peptide derivatives

 

(57) Abstract:

The proposed peptide derivatives of General formula I: P-R1-R2-R3-R4or their pharmaceutically acceptable salts, in which R is an organic hydrophobic group comprising from 5 to 20 carbon atoms of the formula RCO-; R represents aryl(2-10)alkyl or heteroaryl(2-10C)alkyl, where aryl or heteroaryl group, R is optionally substituted by one or more (1-4C)alkyl, halogeno, cyano or (1-4C)alkoxy; R1is a sequence of 5 L-amino acids represented as AA1-AA2-AA3-AA-AA, and R3represents a single L-amino acid selected from Ala, Gly, azalina or utilizin; or R1is a sequence of 3 L-amino acids represented as A-AA-AA, and R3is a sequence of 3 L-amino acids represented as A-AA-AA; and AA1 is selected from Ala, Ile, Arg, Gap, GapMe4 and Lys(= C(NMe2)2); AA2 is selected from Ala, Lys, Ile, and Arg; AA3 is selected from Ala and Asn; AA4 is selected from Ala, Asn, Lys, Arg and His; AA5 is selected from Val and Thr; AA6 is selected from Ala, Arg and Ile; AA7 is selected from Lys, Arg, Ala, and Ile; AA8 is an Ala; AA9 is selected from Ala and Leu; AA10 is selected from Ala and Arg; AA11 is an Ala; R2Dorada and (1-4C) alkyl, And represents methylene; R4is a HE, NH2or NRcRd, where Rc is selected from (1-4C)alkyl, 3-carbamoylethyl, 4-carbamoylethyl, 4-(carbamoylmethyl)phenyl, 4-(carboxymethyl)phenyl, 4-(methoxycarbonylmethyl)-phenyl, 2-morpholinoethyl and a group of the formula-A1-G1where AND1represents (3C)alkylene or AND1represents a group of formula-A2IN2- where AND2represents a p-phenylene and2represents (1-4C)alkylene; and G1represents a group of formula-N=C[N(Rp)2]2in which each Rp is a hydrogen; or a1represents a group of formula-A4IN4- where AND4represents a p-phenylene, and IN the4represents-CH2-CO-, and G1is a 2-morpholinoethyl or 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-yl; and Rd represents hydrogen or (1-4)alkyl; or R4represents a 4-(2-(2-hydroxyethoxy)ethyl)-1-piperazinil, 1-piperidyl or 4-substituted-1-piperidyl where this 4-assistant selected from carboxy and carbamoyl; method for obtaining compounds of formula I on p. 1 proposed pharmaceutical composition having the ability inhib is the initial formula I or its pharmaceutically acceptable salt; the method of treatment is dependent on MHC class II T-cell mediated autoimmune or inflammatory diseases. The described invention provides peptides with minimal losses associated with the degradation with release of the drug. 4 C. and 11 C.p. f-crystals, 1 table.

Description text in facsimile form (see drawings)and

1. Peptide derivatives of General formula I

P-R1-R2-R3-R4< / BR>
or its pharmaceutically acceptable salt,

in which R is an organic hydrophobic group comprising from 5 to 20 carbon atoms of the formula RCO-; R represents aryl(2-10)alkyl or heteroaryl(2-10C)alkyl, where aryl or heteroaryl group, R is optionally substituted by one or more (1-4C)alkyl, halogeno, cyano or (1-4C)alkoxy;

R1is a sequence of 5 L-amino acids represented as AA1-AA2-AA3-AA-AA, and R3represents a single L-amino acid selected from Ala, Gly, azalina or utilizin; or R1is a sequence of 3 L-amino acids represented as A-AA-AA, and R3is a sequence of 3 L-aminolysis la, Lys, Ile, and Arg; AA3 is selected from la and Asn; AA4 is selected from la, Asn, Lys, Arg and His; AA5 is selected from Val and Thr; AA6 is selected from la, Arg and Ile; AA7 is selected from Lys, Arg, Ala, and Ile; AA8 is a la; AA9 is selected from la and Leu; AA10 is selected from la and Arg; AA11 is a la;

R2represents a group of formula II or formula III

< / BR>
< / BR>
in which Ra and Rb are independently selected from hydrogen and (1-4C)alkyl;

And represents methylene;

R4is a HE, NH2or NRcRd, where Rc is selected from (1-4C)alkyl, 3-carbamoylethyl, 4-carbamoylethyl, 4-(carbamoylmethyl)phenyl, 4-(carboxymethyl)phenyl, 4-(methoxycarbonylmethyl)-phenyl, 2-morpholinoethyl and a group of the formula-A1-G1where AND1represents (3C)alkylene or AND1represents a group of formula-A2IN2- where AND2represents a p-phenylene and2represents (1-4C)alkylene; and G1represents a group of formula-N=C[N(Rp)2]2in which each Rp is a hydrogen; or a1represents a group of formula-A4IN4- where AND4represents a p-phenylene, and IN the4represents-CH2-CO-, and G1is a 2-morpholinoethyl or 4-[2-(2-hydro is 2-(2-hydroxyethoxy)ethyl)-1-piperazinil, 1-piperidyl or 4-substituted-1-piperidyl where this 4-assistant selected from carboxy and carbamoyl.

2. Peptide derivative or its pharmaceutically acceptable salt under item 1, in which R4represents the NHRc, where Rc is selected from 4-(carbamoylmethyl)phenyl, 4-(2-guanidinate)phenyl, 2-morpholinoethyl, 3-guanidinopropionic and 4-[4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-yl-carbonylmethyl] phenyl; or R4represents a 4-(2-(2-hydroxyethoxy)ethyl)-1-piperazinil or 4-carbarnoyl-1-piperidyl.

3. Peptide derivative or its pharmaceutically acceptable salt p. 1, where R1is a sequence of 5 L-amino acids represented as AA1-AA2-AA3-AA-AA in which A-AA selected from Lys-Val, Arg-Val, Lys-Thr, Arg-Thr, Ala-Val, and Ala-Thr; and R3represents a single L-amino acid selected from Ala, Gly and Azgly.

4. Peptide derivative or its pharmaceutically acceptable salt under item 1, in which R1is a sequence of 5 L-amino acids represented as AA1-AA2-AA3-AA-AA selected from Ala-Ala-Ala-Lys-Val, Ile-Ala-Ala-Arg-Thr, Arg-Ala-Ala-Ala-Val-Arg-Ala-Ala-Ala-Thr, Ala-Ala-Ala-Arg-Val, Ala-Arg-Ala-Arg-Val, Ala-Ile-Ala-Arg-Val Ala-Arg-Ala-His-Val, Ala-Ala-Asn-Arg-Val, Ala-Arg-Ala-Ala-Thr, Ala-Arg-Ala-Arg-Thr, Gap-Ala-Ala-Ala-Thr, GapMe4-Ala-Ala-Ala-Thr, Ala-Ala-Ala-Arg-Thr ly.

5. Peptide derivative or its pharmaceutically acceptable salt under item 1, in which R1is a sequence of 3 L-amino acids represented as A-AA-AA selected from Ala-Arg-Ala, Arg-Ala-Ala, Arg-Ile-Ala, Ile-Arg-Ala and Ala-Lys-Ala; and R3is a sequence of 3 L-amino acids represented as A-AA-AA selected from Ala-Arg-Ala, Leu-Arg-Ala and Ala-Ala-Ala.

6. Peptide derivative or its pharmaceutically acceptable salt according to any one of paragraphs.1-5, where R2represents a group of formula IIb

< / BR>
7. Peptide derivative or its pharmaceutically acceptable salt according to any one of paragraphs.1-5, where the hydrophobic group R represents a 5-phenylvaleric.

8. Peptide derivative or its pharmaceutically acceptable salt according to any one of paragraphs. 1-5, where R4is a 4-carbarnoyl-1-piperidyl, 4-(carbamoylmethyl)aniline or 4-(2-guanidinate)of aniline.

9. Peptide derived under item 1 or its pharmaceutically acceptable salt, which is selected from

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or its pharmaceutically acceptable salt, in which the Phv is 5-phenylvaleric group.

10. The peptide derivative of the formula I or its pharmaceutically acceptable salt according to moleculo MHC class II.

11. The peptide derivative of the formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1-9, is capable of inhibiting the binding of antigen molecules MHC class II associated with the disease.

12. The pharmaceutical composition capable of inhibiting T-cell immune response, mediated through the molecule MHC class II, which includes the peptide derivative of General formula I or its pharmaceutically acceptable salt PP.1-9, in Association with a pharmaceutically acceptable diluent or carrier.

13. A method of obtaining a peptide derivative of General formula I on PP.1-9 or its pharmaceutically acceptable salt, namely, that (I) bind correspondingly protected amino acid, which is the C-terminal amino acid peptide derived from solid media; (II) then provide a serial link in a specific order correspondingly protected amino acids and therefore protected groups of the formula H-II-OH or H-III-OH, as defined in paragraph 1, and the functional group of the N-terminal amino acids of the peptide derivative may be optionally modified to introduce hydrophobic R-group; (III) remove tendenoy group of the formula R4-H, where R4defined as in point 1, does not necessarily modify the N-terminal amino group for the introduction of hydrophobic groups R and remove the remaining protective group; and then secrete the peptide derivative of the formula I or its pharmaceutically acceptable salt.

14. Treatment-dependent MHC class II T-cell mediated autoimmune or inflammatory diseases, which includes the introduction of warm-blooded mammal in need of such treatment, an effective amount of a peptide derivative of formula I or its pharmaceutically acceptable salt.

15. The method of treatment under item 14 of rheumatoid arthritis.

 

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