Azithromycin derivatives with epithelial barrier enhancement properties

1. A compound according to compound according to formula (I)

wherein

R 1 is selected from the group consisting of carbamoyloxy, N—C 1-6 -alkylcarbamoyloxy, N—(C 6-14 -aryl-C 1-6 -alkyl)carbamoyloxy, N,N-di-C 1-6 -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 C 1-6 -alkylcarboxy;

and

R 2 is according to formula (III)

wherein

R 7 is selected from the group consisting of C 1-6 -alkyl, C 6-14 -aryl-C 1-6 -alkyl, C 3-6 -alkylcarbonyl, C 6-14 -arylcarbonyl, C 1-6 -alkyl-C 6-14 -arylcarbonyl, C 6-14 -arylsulfonyl, C 1-6 -alkyl-C 6-14 -arylsulfonyl, C 6-14 -aryl-C 1-6 -alkylcarbonyl, C 6-14 -aryl-O—C 1-6 -alkylcarbonyl, C 6-14 -aryl-C 1-6 -alkyl-O—C 1-6 -alkyl-carbonyl, HOOC—(CH 2 ) m -(CO)- with m being from 0 to 6,

a substituent of formula (V.1)

with Ar being C 6-14 -aryl and n, p and q being independently from 0 to 6,

C 6-14 -aryl-C 1-6 -alkyl-O—CO—NH—C 1-6 -alkyl-CO—, and

C 6-14 -arylsulfonyl, and C 1-6 -alkyl-C 6-14 -arylsulfonyl,

whereby alkyl and/or aryl in R 7 is optionally substituted by 1 to 6 halogen and/or CN; and

R 8 is selected from the group consisting of H; C 6-14 -arylcarbonyl optionally substituted with 1 to 5 groups selected from halogen atoms, C 1-3 -alkyl sulfonyl groups, C 1-3 -alkyl groups and/or C 1-3 -alkoxy groups; C 3-6 -alkylcarbonyl; HOOC—(CH 2 ) m -(CO)- with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being C 6-14 -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 C 1-4 -alkyl, C 1-4 -alkoxy, C 2-4 -alkenyl, C 2-4 -alkenoxy, halogen and CN,

whereby alkyl and/or aryl in R 8 is optionally substituted by 1 to 6 halogen and/or CN;

R 3 is H; and

R 4 and R 5 are independently selected from H and C 1-6 -alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and/or CN;

and

or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of C 1-3 -alkylcarboxy, and a moiety according to formula (IV)

wherein R 9 and R 10 are independently selected from the group consisting of H, C 1-3 -alkyl and C 6-10 -aryl-C 1-3 -alkyl or are together alkyl forming a 5- or 6-membered aliphatic heterocycle together with the nitrogen atom they are both bonded to, whereby said heterocycle optionally contains one or two further heteroatom(s) selected from the group consisting of N, O and S, or said heterocycle is selected from the group consisting of piperidine, piperazine and morpholin,

whereby alkyl, aryl and/or the heterocycle in R 1 is optionally substituted by 1 to 6 halogen and/or CN.

3. The compound according to claim 1 , wherein

R 7 is selected from the group consisting of C 1-3 -alkyl, C 6-10 -aryl-C 1-3 -alkyl, linear or branched C 3-4 -alkylcarbonyl, C 6-10 -arylcarbonyl, C 6-10 -aryl-C 1-3 -alkylcarbonyl, C 6-10 -aryl-O—C 1-3 -alkylcarbonyl, C 6-10 -aryl-C 1-3 -alkyl-O—C 1-3 -alkyl-carbonyl, HOOC—(CH 2 ) m -(CO)-with m being from 0 to 3, a moiety according to formula (V.2)

wherein Ar is C 6-10 -aryl and n, p and q each are independently from 0 to 3,

C 6-10 -aryl-C 1-3 -alkyl-O—CO—NH—C 1-3 -alkyl-CO—,

C 6-10 -arylsulfonyl, and C 1-3 -alkyl-C 6-10 -arylsulfonyl;

and

R 8 is selected from the group consisting of H, C 6-10 -arylcarbonyl, C 6-10 -arylcarbonyl substituted with 1 to 3 halogen atoms, C 1-2 -alkyl groups and/or C 1-2 -alkoxy groups, linear or branched, C 3-4 -alkylcarbonyl, HOOC—(CH 2 ) m -(CO)- with m being from 0 to 3,

a moiety according to formula (V.2) as depicted hereinbefore wherein Ar is C 6-10 -aryl and n, p and q each are independently from 0 to 3,

C 1-3 -alkylsulfonyl-bi-C 6-10 -aryl-carbonyl, and

heteroarylcarbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, the ring of the heteroarylcarbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of C 1-2 -alkyl, C 1-2 -alkoxy, C 2-3 -alkenyl, C 2-3 -alkenoxy, halogen and CN;

whereby alkyl, aryl and/or the heterocycle in R 8 is optionally substituted by 1 to 6 halogen and/or CN.

4. The compound according to claim 1 , wherein

R 1 is N—(C 6-14 -aryl-C 1-6 -alkyl)carbamoyloxy, 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 C 1-6 alkylcarboxy;

R 7 is selected from the group consisting of C 1-3 -alkyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-C 1-2 -alkyl-O—CO—NH—C 1-2 -alkyl-CO—and phenyl-O—C 1-3 -alkylcarbonyl, whereby alkyl, aryl and/or the heterocycle in R 7 is optionally substituted by 1 to 3 halogen and/or CN; and

R 8 is selected from the group consisting of H, HOOC—(CH 2 ) m -(CO)- with m being from 1 to 3, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthylcarbonyl, whereby alkyl, aryl and/or the heterocycle in R 8 is optionally substituted by 1 to 3 halogen and/or CN.

5. The compound according to claim 1 , wherein

R 1 is N—(C 6-14 -aryl-C 1-6 -alkyl)carbamoyloxy, 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 C 1-6 alkylcarboxy;

R 2 is according to formula (III)

wherein

R 7 is C 1-6 -alkyl; and

R 8 is selected from the group consisting of C 6-14 -arylcarbonyl optionally substituted with 1 to 5 groups selected from C 1-3 -alkyl sulfonyl groups and/or C 1-3 -alkyl groups; HOOC—(CH 2 ) m -(CO)- with m being from 0 to 6, a substituent of formula (V.1)

with Ar being C 6-14 -aryl and n, p and q being independently from 0 to 6;

R 3 is H; and

R 4 and R 5 are both H;

or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

6. The compound according to claim 1 , which is selected from the group consisting of

(3aR,4R,7R,8S,9S, 10R, 11S, 13R, 16R, 16aR)-10-{[(2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-ethyl-11-hydroxy-3a, 7,9,11, 13, 15, 16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1,3]dioxolo[4,5-c]1-oxa-6-azacyclopentadecan-8-yl morpholine-4-carboxylate (Example 3);

(2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S, 10R, 11S, 13R, 16R, 16aR)-8-[(benzylcarbamoyl)oxy]-4-ethyl-11-hydroxy-3a,7,9,11,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1,3]dioxolo[4,5-c]1-oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl benzoate (Example 4);

(2R,3S,4R,5R,8R, 10S, 11R, 12S, 13S, 14R)-11-{[(2S,3R,4S,6R)-4-[benzyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,6,8, 10, 12, 14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 5);

N-[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S, 13S, 14R)-2-ethyl-3,4, 10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,6,8,10,12, 14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzamide (Example 6);

N-[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R, 10S, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl] oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylnaphthalene-2-sulfonamide (Example 8);

N-[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R, 10S, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,6,8,10,12, 14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N,4-dimethylbenzene-1-sulfonamide (Example 10);

(2S,3R,4S,6R)-2-{[(2R,3R,4R,5R,8R, 10S, 11R, 12S, 13S, 14R)-4, 13-bis(acetyloxy)-2-ethyl-3,10-dihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl benzoate (Example 11).

7. A pharmaceutical composition comprising at least one compound of Formula (Ia) and at least one pharmaceutically acceptable excipient:

wherein

R 1 is selected from the group consisting of carbamoyloxy, N—C 1-6 -alkylcarbamoyloxy, N—(C 6-14 -aryl-C 1-6 -alkyl)carbamoyloxy, N,N-di-C 1-6 -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 C 1-6 -alkylcarboxy;

and

R 2 is according to formula (III)

wherein

R 7 is selected from the group consisting of C 1-6 -alkyl,

and

R 8 is selected from the group consisting of H; C 6-14 -arylcarbonyl optionally substituted with 1 to 5 groups selected from halogen atoms, C 1-3 -alkyl sulfonyl groups, C 1-3 -alkyl groups and/or C 1-3 -alkoxy groups; C 3-6 -alkylcarbonyl; HOOC—(CH 2 ) m -(CO)- with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being C 6-14 -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 C 1-4 -alkyl, C 1-4 -alkoxy, C 2-4 -alkenyl, C 2-4 -alkenoxy, halogen and CN,

whereby alkyl and/or aryl in R 8 is optionally substituted by 1 to 6 halogen and/or CN;

R 3 is H; and

R 4 and R 5 are independently selected from H and C 1-6 -alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and/or CN;

or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

8. A method for the treatment of a disease or condition that benefits from enhancement or restoration of epithelial barrier function, said method comprising administering to a mammal a therapeutically effective amount of the compound of claim 1 .

9. The method according to claim 8 , wherein the disease or condition is an airways disease and the epithelial tissue is in the respiratory tract epithelial tissue.

10. The method according to claim 8 wherein the condition is asthma, chronic obstructive pulmonary disease (COPD), Cystic Fibrosis (CF), non-CF Bronchiectasis, chronic rhinosinusitis, diffuse panbronchiolitis (DPB), chronic bronchitis, Bronchiolitis Obliterans Organizing Pneumonia (BOOP) primary or secondary to chemotherapy or post-transplantation status, infantile respiratory distress syndrome (IRDS) and its long term complication, bronchopulmonary dysplasia, neuromuscular respiratory depression and/or failure, pneumonia and conditions caused by and associated with Respiratory Syncytial Virus (RSV) and related viruses.

11. The method according to claim 8 wherein the treatment of a disease or disorder is systemic inflammatory distress syndrome (SIRS), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, ulcerative colitis or Crohn's disease.

12. A method for the treatment or prophylaxis of a disease or condition that benefits from enhancement or restoration of epithelial barrier function, which comprises administering to the mammal a therapeutically effective amount of a compound or composition as defined in claim 1 .