Cyclosporin derivatives

A cyclosporin derivative of general Formula I

• or a pharmaceutically acceptable salt thereof, wherein in Formula I
• A is an amino acid residue of Formula II,
• in which R1 corresponds to a residue of Formula III
• which is covalently bonded via the carbon atom a, or
• in which R1 corresponds to a residue of Formula V
• which is covalently bonded via the carbon atom a, or
• in which R1 corresponds to a residue of Formula VIII
• which is covalently bonded via the carbon atom a,
• wherein the C═O group in Formula II is covalently bonded to an alpha-amino group of B via an amide bond and the N—Ro group in Formula II is covalently bonded to a carboxyl group of K via an amide bond,
• B is an amino acid residue which is selected from the group consisting of:
• alpha-aminobutyric acid,
• alanine,
• threonine,
• valine,
• norvaline and
• alpha-aminobutyric acid, alanine, threonine, valine or norvaline modified in the side chain with a hydroxyl group,
• C is a sarcosine residue,
• D is an amino acid residue which is selected from the group consisting of:
• leucine,
• N-methyl leucine,
• valine,
• gamma-hydroxy-N-methyl leucine and
• gamma-hydroxy leucine,
• E is an amino acid residue which is selected from the group consisting of:
• valine,
• norvaline and
• a modified valine or norvaline in which a carbon atom in the side chain is substituted by a hydroxyl group,
• F is an amino acid residue which is selected from the group consisting of:
• leucine,
• N-methyl leucine,
• gamma-hydroxy-N-methyl leucine and
• gamma-hydroxy leucine,
• G is an alpha-aminobutyric acid residue or an alanine residue,
• H is a D-alanine residue,
• I and J are residues which are selected, independently of one another, from the group consisting of:
• leucine,
• N-methyl leucine,
• gamma-hydroxy-N-methyl leucine and
• gamma-hydroxy leucine,
• and
• K is an N-methyl valine residue or a valine residue,
• wherein in Formulae III, V and VIII
• Ro represents H or CH3,
• X represents H or
• hydroxyl or
• a hydroxyl group which is derivatized with an alkanoyl, aryloyl, alkylaminocarbonyl, arylaminocarbonyl, arylalkylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl group or a silyl protecting group,
• R2 represents
• a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl ring which is optionally substituted with R3,
• R3 is selected from the group consisting of:
• —Z—CO—Y, and
• —CO—Y,
• R4 represents H or
• a substituted or unsubstituted monocyclic, bicyclic or tricyclic aryl or heteroaryl ring which is optionally substituted with R3,
• Z is selected from the group consisting of:
• an unbranched, branched or cyclic alkyl group with 1 to 20 carbon atoms,
• an unbranched, branched or cyclic alkenyl group with 1 to 20 carbon atoms, and
• an unbranched, branched or cyclic alkinyl group with 1 to 20 carbon atoms,
• Y is selected from the group consisting of:
• the protected or unprotected amino acid residues Gly, D-Glu, D-Asp, D- and L-Cys(SO3H), and
• unprotected peptide residues with a chain length of from 2 to 200 amino acid residues, containing one amino acid type or a combination of different amino acid types selected from Gly, D-Glu, D-Asp, D- and L-Cys(SO3H),
• R5 is selected from the group consisting of:
• an alkyl, alkenyl, alkylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl group,
• the amino acid residues Gly, D-Glu, D-Asp, D- and L-Cys(SO3H),
• peptide residues with a chain length of from 2 to 200 amino acid residues, containing one amino acid type or a combination of different amino acid types selected from Gly, D-Glu, D-Asp, D- and L-Cys(SO3H),
• F, Cl, Br and I,
• and
• R7 is selected from the group consisting of:
• a carboxyl, amino, thiol, hydroxyl group,
• F, Cl, Br, I
• the protected or unprotected amino acid residues Gly, D-Glu, D-Asp, D- and L-Cys(SO3H), and
• peptide residues with a chain length of from 2 to 200 amino acid residues, containing one amino acid type or a combination of different amino acid types selected from Gly, D-Glu, D-Asp, D- and L-Cys(SO3H);
• wherein the cyclosporin derivative has a negative net charge at pH 6.