Azithromycin derivatives with epithelial barrier enhancement properties
AssigneeEpiendo Pharmaceuticals Ehf
InventorsFridrik Runar Gardarsson, Fredrik Lehmann, Peter Teodorovic
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Abstract
The invention provides novel compounds that are derivatives of Azithromycin and that have been found by the current inventors to have low antimicrobial activity but significant epithelial barrier enhancement properties. The invention further provides use of the compounds as a medicament, in particular in the treatment or prophylaxis of a disease or condition that is caused by a defect in epithelial cells or tissue, or a disease or condition that benefits from enhancement or restoration of epithelial barrier function, for example diseases of the respiratory tract.
Claims18
A compound according to formula (I)
- wherein
- R1 is selected from the group consisting of OH, carbamoyloxy, N—C1-6-alkylcarbamoyloxy, N—(C6-14-aryl-C1-6-alkyl)carbamoyloxy, N,N-di-C1-6-alkylcarbamoyloxy, N,N-di-alkylcarbamoyloxy with the two alkyl substituents together forming a 5- to 8-membered heterocycle together with the nitrogen atom of the carbamate moiety, and C1-6-alkylcarboxy, whereby alkyl, aryl and/or the heterocycle in R1 is optionally substituted by 1 to 6 halogen and/or CN;
- and
- R2 is according to formula (III)
- wherein
- R7 is selected from the group consisting of C3-6-alkylcarbonyl, C6-14-arylcarbonyl, C1-6-alkyl-C6-14-arylcarbonyl, C6-14-arylsulfonyl, C1-6-alkyl-C6-14-arylsulfonyl, C6-14-aryl-C1-6-alkylcarbonyl, C6-14-aryl-O—C1-6-alkylcarbonyl, C6-14-aryl-C1-6-alkyl-O—C1-6-alkyl-carbonyl, HOOC—(CH2)m—(CO)— with m being from 0 to 6,
- a substituent of formula (V.1)
- with Ar being C6-14-aryl and n, p and q being independently from 0 to 6,
- C6-14-aryl-C1-6-alkyl-O—CO—NH—C1-6-alkyl-CO—, and
- C6-14-arylsulfonyl, and C1-6-alkyl-C6-14-arylsulfonyl,
- whereby alkyl in R7 is unsubstituted or substituted by 1 to 6 halogen and/or CN, and aryl in R7 is optionally substituted by 1 to 6 halogen and/or CN;
- and
- R8 is selected from the group consisting of H;
- C6-14-arylcarbonyl optionally substituted with 1 to 5 groups selected from halogen atoms, C1-3-alkyl sulfonyl groups, C1-3-alkyl groups and/or C1-3-alkoxy groups;
- C3-6-alkylcarbonyl;
- HOOC—(CH2)m—(CO)— with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being C6-14-aryl and n, p and q being independently from 0 to 6;
- and heteroarylcarbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroarylcarbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of C1-4-alkyl, C1-4-alkoxy, C2-4-alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and/or aryl in R8 is optionally substituted by 1 to 6 halogen and/or CN;
- R3 is H;
- and
- R4 and R5 are independently selected from H and C1-6-alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and/or CN, or
- R4 and R5 together form a single carbonyl group which forms a cyclic carbonate with both oxygen atoms it is bonded to;
- or a pharmaceutically acceptable solvate or salt thereof.
Dependencies are inferred from the claim text.