Patent EP-2471806-A2 (EP)
Inventor: FISCHER GUNTER
IPC: A61K38/00
Filed: 2010-08-17
Abstract: Cyclosporin derivatives (I) and their salts are new. Cyclosporin derivatives of formula (I) and their salts are new. A : amino acid residue of formula (II), where C=O in (II) is covalently bonded to alpha -amino group of B 1over an amide bond and the group N-R ois covalently bonded to carboxyl group of K 1over an amide bond; R 1 : (R 2)(CH 3)C=C(R 4)-, R 6-Z-R 7-CH 2-CH=CH-, N(R 5)(Z-R 7)-CH 2-, N(R 5)(R 8)-CH(COOH)-, CH(OH)(C?=R 3)-, a group of formula (VIII) or CH(R 5NH)(R 3)-CH(OH)-; B 1 : an amino acid comprising alpha -amino butyric acid, alanine, threonine, valine, norvaline, or hydroxyl group modified alpha -amino butyric acid, alanine, threonine, valine or norvaline (where the hydroxyl group is in the side chain); C 1 : sarcosine residue; D 1 : an amino acid comprising leucine, N-methyl leucine, valine, gamma -hydroxy-N-methylleucine or gamma -hydroxyleucine; E : an amino acid residue comprising valine, norvaline or modified valine or norvaline (whose side chain is substituted with OH); F 1 : an amino acid residue comprising leucine, N-methyl leucine, gamma -hydroxy-N-methylleucine or gamma -hydroxyleucine; G : alpha -aminobutyric acid residue or alanine; Ha 1 : D-alanine; I 1, J : leucine, N-methyl leucine, gamma -hydroxy-N-methylleucine or gamma -hydroxyleucine; K 1 : N-methyl valine or valine; R o : H or CH 3; X : H or OH (optionally derivatized with an alkanoyl-, aryloyl-, alkylaminocarbonyl-, arylaminocarbonyl-, arylalkylaminocarbonyl-, alkoxycarbonyl-, aryloxycarbonyl-, arylalkyloxycarbonyl or a silyl protecting group); R 2, R 4 : H or monocyclic, bicyclic or tricyclic (hetero)aryl (all optionally substituted with R 3); R 3 : -Z-NY 1-Y 2, -Z-CO-Y 1, -Z-S-Y 1, Y 3, -NY 1-Y 2, -CO-Y 1, -S-Y 1, -Z-O-Y 1or -O-Y 1; Z : cyclic 1-20C-alkyl, 1-20C-alkenyl, 1-20C-alkynyl, optionally substituted monocyclic, bicyclic or tricyclic (hetero)aryl or -[(CH 2) m-O-(CH 2) n] o-; m, n, o : 1-20; Y 1, Y 2 : H, protected or deprotected amino acid residue comprising Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), deprotected peptide residue with a chain length of 2-200 amino acid containing an amino acid type, or a combination of different amino acid types of Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), an alkyl-, alkenyl-, aryl-, alkylaminocarbonyl-, arylaminocarbonyl-, arylalkylaminocarbonyl-, alkylcarboxyl-, alkoxycarbonyl-, aryloxycarbonyl- or arylalkyloxycarbonyl-group; Y 3 : H, F, Cl, Br or I; R 5, R 8 : alkyl-, alkenyl-, aryl-, alkylaminocarbonyl-, arylaminocarbonyl-, arylalkylaminocarbonyl-, alkylcarboxyl-, alkoxycarbonyl-, aryloxycarbonyl-, arylalkyloxycarbonyl-group, amino acid residue comprising Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), peptide residue with a chain length of 2-200 amino acid containing an amino acid type, or a combination of different amino acid types of Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), F, Cl, Br or I; R 6 : O, N, S, protected or deprotected amino acid residue comprising Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), peptide residue with a chain length of 2-200 amino acid containing an amino acid type, or a combination of different amino acid types of Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H); and R 7 : carboxyl, amino, thiol, OH, F, Cl, Br, I, protected or deprotected amino acid residue comprising Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H), alkyl-, alkenyl-, aryl-, alkylaminocarbonyl-, arylaminocarbonyl-, arylalkylaminocarbonyl-, alkylcarboxyl-, alkoxycarbonyl-, aryloxycarbonyl-, arylalkyloxycarbonyl-group, peptide residue with a chain length of 2-200 amino acid containing an amino acid type, or a combination of different amino acid types of Gly, D-Glu, D-Asp, D- or L-Cys(SO 3H). An independent claim is included for enriching (I) in an extracellular room of multicellular objects, comprising providing (I) and contacting (I) with multicellular objects. [Image] ACTIVITY : Antiinflammatory; Antiasthmatic; Antiarthritic; Antirheumatic; Neuroprotective; Antipsoriatic; Antiulcer; Gastrointestinal-Gen.; Immunosuppressive. MECHANISM OF ACTION : Calcineurin inhibitor; Lymphokine synthesis inhibitor.