Azithromycin derivatives with enhanced epithelial barrier enhancement properties

Abstract

The present invention provides novel compounds which are derivatives of azithromycin and which have been found by the present inventors to have low antimicrobial activity, but significant epithelial barrier enhancing properties. The present invention further provides the use of the compounds as medicaments, in particular in the treatment or prevention of diseases or conditions caused by defects in epithelial cells or tissues or diseases or conditions which would benefit from enhancing or re-establishing epithelial barrier function, such as diseases of the respiratory tract.

Description

[0001] This application is a divisional application of application number 201680067151.6, filed on November 21, 2016, entitled "Azithromycin Derivative with Epithelial Barrier Enhancement Properties". Technical Field

[0002] This invention relates to macrocyclic lactone derivatives with particularly beneficial pharmacological properties. The compounds have been found to treat a variety of conditions, including respiratory conditions such as asthma, COPD, diffuse panbronchiolitis (DPB), and cystic fibrosis (CF). Background Technology

[0003] Macrocyclic lactones possess a range of physiological activities. Most macrocyclic lactones exhibit antimicrobial activity as part of their therapeutic mechanism of action. Macrocyclic lactones are classified not only according to their activity but also based on their structure. Erythromycin (the original, naturally occurring macrocyclic lactone) has a 14-membered macrocyclic lactone as its backbone. 12-, 13-, 15-, and 16-membered macrocyclic lactones are primarily modified derivatives of erythromycin and closely related ketolides; they are broad-spectrum antimicrobial agents.

[0004] Many macrocyclic lactones exhibit a range of disease-modifying activities against a variety of diseases with seemingly unrelated pathologies. In addition to antimicrobial activity, some macrocyclic lactones have been proposed to have alternative "non-antimicrobial" effects. Some of these effects have been proposed to manifest themselves in disease-modifying mechanisms primarily of anti-inflammatory or immunomodulatory action in humans (Kanoh, S. and Rubin, B.K., Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications, Clinical Microbiology Reviews, 2010, 23(3), 590-615). The term "immunolides" has been used to describe macrocyclic lactone compounds with selective immunomodulatory effects (see Fecik et al., Current Opinion in Drug Discovery and Development, 2005, 8(6), 741-747).

[0005] In at least two double-blind clinical trials, azithromycin (“Azm”) has been shown to reduce hospitalization rates and disease-related exacerbations by 30% in patients with COPD (see Uzun et al., *Lancet Respiratory Medicine*, 2014, 2(5), 361-368 and Albert et al., *New England Journal of Medicine*, 2011, 365(8), 689-698). Azm has also been shown to increase host defense against *Pseudomonas aeruginosa* and increase transepithelial impedance (“TER”) in in vitro ALI cultures of epithelial cells, as well as increase tight junction cell handling. Erythromycin and penicillin have not been found to have similar effects. (See Asgrimsson V et al. (2006), Novel effects of azithromycin on tight junction proteins in human airway epithelial cells, Antimicrob Agents Chemother, 50:1805-1812 and Halldorsson S et al. (2010), Azithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infection, American Journal of Respiratory Cell and Molecular Biology, 2010, 42(1), 62-68.)

[0006] TER, also known as TEER ("transmembrane resistance"), is a measure of the electrical impedance of the cell layer. It is used as an indicator of the formation and functional tight junctions; see, for example, Rezaee F and Georas SN, 2014, *American Journal of Respiratory Cell and Molecular Biology*, 857-869. Increased TER is a parameter of good barrier properties and is associated with healthy polarized epithelial tissue, while diseased or inadequately effective epithelial tissue is associated with poor barrier function (see, for example, Marchiando et al., *Annu. Rev. Pathol. Mech Dis.*, 2010, 5, 119-144) and higher permeability.

[0007] Overuse of antibiotics is one of the reasons for the rise in antibiotic-resistant bacterial strains. Therefore, the use of macrocyclic lactones in treating conditions that are not bacterial infections is limited by the need to avoid the unnecessarily widespread use of antibiotic compounds. Thus, there is a clinical need for macrocyclic lactone compounds that possess clinically useful immunomodulatory activity but are sufficiently low in antimicrobial activity to not pose a risk of promoting resistance. Despite considerable interest in developing such immunolactones, suitable compounds have not yet been developed. Some compounds described in WO2014 / 166503 have good non-antibiotic properties but reduced antimicrobial activity. In practice, the compounds described therein do not possess clinically useful sufficient activity.

[0008] A limited number of derivatives of azithromycin are known, for example, through patent publications WO2006 / 087644, WO2004 / 005310, WO2004 / 139821, WO03 / 070174 and CN1837225. Summary of the Invention

[0009] In a first embodiment, the present invention provides a compound according to formula (I).

[0010]

[0011] in

[0012] R 1 Choose from the following groups: OH, carbamoyloxy, NC 1-6 Alkyl carbamoyloxy, N-(C 6-14 Aryl-C 1-6 Alkyl)carbamoyloxy, N,N-di-C 1-6 Alkylcarbamoyloxy, N,N-dialkylcarbamoyloxy having two alkyl substituents forming a 5- to 8-membered heterocycle together with the nitrogen atom of the carbamate moiety, C 1-6 alkyl carboxyl groups and the part according to formula (II)

[0013]

[0014] in

[0015] R 6 Choose from the following groups: H, OH, and C 1-6 Alkyl, wherein in R 1 The alkyl, aryl, and / or heterocyclic groups are optionally substituted with 1 to 6 halogens and / or CN; and

[0016] R 2 According to formula (III)

[0017]

[0018] in

[0019] R 7 Choose from the following groups: C 1-6 Alkyl, C 6-14 Aryl-C 1-6 Alkyl, C 3-6 alkyl carbonyl, C 6-14 aryl carbonyl, C 1-6 Alkyl-C 6-14 aryl carbonyl, C 6-14 Arylsulfonyl, C 1-6 Alkyl-C 6-14 arylsulfonyl, C 6-14 Aryl-C 1-6 alkyl carbonyl, C 6-14 Aryl-OC 1-6 alkyl carbonyl, C 6-14 Aryl-C 1-6 Alkyl-OC 1-6 Alkyl-carbonyl, HOOC-(CH2) m -(CO)-, where m is between 0 and 6.

[0020] Substituents of formula (V.1)

[0021]

[0022] Where Ar is C 6-14 The aryl group has n, p, and q that are independently between 0 and 6.

[0023] C 6-14 Aryl-C 1-6 Alkyl-O-CO-NH-C 1-6 Alkyl-CO-, and

[0024] C 6-14 arylsulfonyl group, and C 1-6 Alkyl-C 6-14 arylsulfonyl,

[0025] Among them, in R 7 The alkyl and / or aryl groups are optionally substituted with 1 to 6 halogens and / or CN; and

[0026] R 8 Choose from the following groups: H; optionally selected from halogen atoms, C 1-3 alkylsulfonyl, C 1-3 Alkyl and / or C 1-3 C with 1 to 5 alkoxy groups substituted 6-14 aryl carbonyl; C 3-6Alkyl carbonyl; HOOC-(CH2) m -(CO)-, where m is 0 to 6, as in the substituents of formula (V.1) described above, where Ar is C 6-14 Aryl group and n, p, and q independently being 0 to 6; and heteroarylcarbonyl group having a 5 to 10-membered ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S, wherein the ring of the heteroarylcarbonyl group is optionally selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 The group consisting of 1 to 3 substituents of olefin, halogen, and CN is substituted.

[0027] Among them, in R 8 The alkyl and / or aryl groups are optionally replaced by 1 to 6 halogens and / or CN;

[0028] R 3 For H; and

[0029] R 4 and R 5 Independently selected from H and C 1-6 Alkyl carbonyl, wherein the alkyl group is optionally substituted with 1 to 6 halogens and / or CN, or

[0030] R 4 and R 5 Together they form a single carbonyl group, which, together with the two oxygen atoms it is bonded to, forms a cyclic carbonate; and

[0031] The condition is if R 6 If it is H or methyl, then R 8 Not H, and

[0032] The condition is if R 1 It is OH and R 7 If it is methyl, then R 8 Not H; and

[0033] The condition is if R 8 If it is a C4 alkyl carbonyl group, then R 1 Not the part according to formula (II);

[0034] Or a pharmaceutically acceptable ester, amide, carbamate, solvate, or salt thereof, including salts of such esters, amides, or carbamates, and solvates of such esters, amides, carbamates, or salts.

[0035] The present invention further provides pharmaceutical compositions comprising at least one compound as defined above and at least one pharmaceutically acceptable excipient. In such pharmaceutical compositions, if R 1 It is OH and R 7If it is methyl, then R 8 It can be H.

[0036] The present invention further provides compounds or compositions according to the invention for use as pharmaceutical agents.

[0037] The present invention further provides compounds or compositions for treating diseases or conditions caused by defects in epithelial cells or tissues, or for which enhancement or reconstruction of epithelial barrier function may be beneficial.

[0038] The present invention further provides a method for treating or preventing diseases or conditions caused by defects in epithelial cells or tissues, or diseases or conditions that would benefit from enhanced or reconstructed epithelial barrier function, comprising administering a therapeutically effective amount of the compound or composition of the present invention to a mammal.

[0039] The inventors have found that the compounds of this invention exhibit good activity in a human respiratory epithelial regeneration model and reduced antimicrobial activity in a series of tests against various bacteria. The compounds of this invention have been tested in an in vivo model of barrier attack in the lungs and have been found to provide significant benefits in enhancing lung epithelial barrier function.

[0040] The present invention further provides a compound of formula (I) for use as a pharmaceutical agent. Attached Figure Description

[0041] Figure 1 This is a bar graph showing that, for azithromycin and the compound in Example 2, compared with the control group, HSA penetration into the lungs was reduced after SO2 injury. Detailed Implementation

[0042] As described above, the present invention provides compounds of formula (I). Preferred compounds of formula (I) are those according to the present invention, wherein R... 1 Choose from the following groups: OH, C 1-3 alkyl carboxyl group, part according to formula (II)

[0043]

[0044] Where R 6 For OH, and according to the part of formula (IV)

[0045]

[0046] Where R 9 and R 10 Independently select H and C 1-3 Alkyl and C 6-10 Aryl-C 1-3The group consisting of alkyl groups, or alkyl groups together forming a 5- or 6-membered aliphatic heterocycle with nitrogen atoms to which they are all bonded, wherein the heterocycle optionally contains one or two selected from the group consisting of N, O, and S, preferably one additional heteroatom, more preferably optionally containing one or two additional O atoms, but more preferably optionally containing one additional O atom, or the heterocycle is selected from the group consisting of piperidine, piperazine, and morpholine, preferably morpholine, wherein in R 1 The alkyl, aryl, and / or heterocyclic groups are optionally substituted with 1 to 6 halogens and / or CN.

[0047] Particularly preferred compounds according to the invention are those wherein R 1 Those that are OH.

[0048] In equation (I), R 2 Groups of formula (III)

[0049]

[0050] In one embodiment, R 7 Choose from the following groups: C 1-6 Alkyl, C 6-14 Aryl-C 1-6 Alkyl, C 6-14 aryl carbonyl, C 1-6 Alkyl-C 6-14 aryl carbonyl, C 6-14 arylsulfonyl, C 1-6 Alkyl-C 6-14 arylsulfonyl, C 6-14 Aryl-C 1-6 alkyl carbonyl, C 6-14 Aryl-OC 1-6 alkyl carbonyl, C 6-14 Aryl-C 1-6 Alkyl-OC 1-6 Alkyl-carbonyl, HOOC-(CH2) m -(CO)-, where m is between 0 and 6.

[0051] Substituents of formula (V.1)

[0052]

[0053] Where Ar is C 6-14 The aryl group has n, p, and q that are independently between 0 and 6.

[0054] C 6-14 Aryl-C 1-6 Alkyl-O-CO-NH-C 1-6 Alkyl-CO-, and

[0055] C 6-14 arylsulfonyl and C 1-6 Alkyl-C 6-14 arylsulfonyl,

[0056] Among them, in R 7 The alkyl and / or aryl groups are optionally replaced by 1 to 6 halogens and / or CN;

[0057] A more preferred compound of the present invention is one in which R 7 Choose those groups consisting of: straight chains or branches C 1-3 Alkyl, C 6-10 Aryl-C 1-3 Alkyl group, preferably branched C 3-4 alkyl carbonyl, C 6-10 aryl carbonyl, C 6-10 Aryl-C 1-3 alkyl carbonyl, C 6-10 Aryl-OC 1-3 alkyl carbonyl, C 6-10 Aryl-C 1-3 Alkyl-OC 1-3 Alkyl-carbonyl, HOOC-(CH2) m -(CO)-, where m is 0 to 3, preferably 1 to 3, most preferably 1 or 2, according to part of formula (V.2).

[0058]

[0059] Where Ar is C 6-10 The aryl group, n, p, and q, are each independently 0 to 3, preferably n and p are each independently 1 or 2 and q is 2 or 3, most preferably n and p are the same and are 1 or 2 and q is 2 or 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 group.

[0060] Furthermore, more preferably, R 7 Choose from the group consisting of: methyl, benzyl, benzoyl, naphthalenesulfonyl, methylbenzenesulfonyl, isopropylcarbonyl, succinyl, benzylcarbonyl, phenoxyethylcarbonyl, benzyloxymethylcarbonyl, benzyl-O-CO-NH-CH2-CO- and the part according to formula (V.2), where Ar is phenyl, n = p = 1 and q = 2.

[0061] Among them, in R 7The alkyl and / or aryl groups are optionally substituted with 1 to 6, preferably 1 to 3 halogens and / or CN.

[0062] In one embodiment, R 8 Choose from the following groups: H; optionally selected from halogen atoms, C 1-3 alkylsulfonyl, C 1-3 Alkyl and / or C 1-3 C with 1 to 5 alkoxy groups substituted 6-14 Aryl carbonyl; HOOC-(CH2) m -(CO)- where m is 0 to 6, as described above in formula (V.1), where Ar is C 6-14 Aryl group and n, p, and q independently being 0 to 6; and heteroarylcarbonyl group having a 5 to 10-membered ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S, wherein the ring of the heteroarylcarbonyl group is optionally selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 The group consisting of 1 to 3 substituents of olefin, halogen, and CN is substituted.

[0063] Among them, in R 8 The alkyl and / or aryl groups are optionally replaced by 1 to 6 halogens and / or CN;

[0064] Preferably R 8 Choose from the following groups: H, C 6-10 Aryl carbonyl group, with 1 to 3 halogen atoms, C 1-2 Alkyl and / or C 1-2 alkoxy-substituted C 6-10 Aryl carbonyl, straight-chain or branched, preferably branched C 3-4 Alkyl carbonyl, HOOC-(CH2) m -(CO)- where m is 0 to 3, preferably 1 to 3, most preferably 1 or 2, according to part of formula (V.2) as described above, where Ar is C 6-10 The aryl group, n, p, and q, are each independently 0 to 3, preferably n and p are each independently 1 or 2 and q is 2 or 3, most preferably n and p are the same and are 1 or 2 and q is 2 or 3, C 1-3 alkylsulfonyl-bis-C 6-10 The aryl-carbonyl group and the heteroarylcarbonyl group having a 5, 6, or 10-membered ring containing 1, 2, or 3 heteroatoms, more preferably 1 or 2 heteroatoms, and most preferably 1 heteroatom, wherein the heteroatom(s) are selected from the group consisting of N, O, and S in each case, preferably from the group consisting of N and O, and most preferably N, and the ring of the heteroarylcarbonyl group is optionally selected from C. 1-2 Alkyl, C1-2 Alkoxy, C 2-3 alkenyl, C 2-3 The group consisting of olefins, halogens (especially F and Cl) and CN, preferably the group consisting of free methyl, methoxy, F and Cl, and most preferably the group consisting of free methyl and Cl, is substituted with one or two substituents.

[0065] Furthermore, R is even more preferred. 8 Choose from the group consisting of: isopropyl carbonyl, succinyl, benzoyl, iodobenzoyl, ethylphenyl carbonyl, methoxyphenyl carbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl, the part according to formula (V.2), where Ar is phenyl, n = p = 1 and q = 2, pyrazolyl carbonyl, dimethylpyrazolyl carbonyl, phenylthio, chlorophenylthio, pyridyl carbonyl, and quinolinyl carbonyl, where R 8 The alkyl, aryl and / or heterocyclic groups are optionally substituted with 1 to 6, preferably 1 to 3 halogens and / or CN.

[0066] For particularly preferred compounds of the present invention, R 1 For OH; and / or

[0067] R 7 Choose from the following groups: C 1-3 Alkyl group, particularly methyl group; according to the part of formula (V.2), wherein Ar is phenyl, n and p are each the same and are 1 or 2 and q is 2 or 3; phenyl-C 1-2 Alkyl-O-CO-NH-C 1-2 Alkyl-CO- and phenyl-OC 1-3 alkyl carbonyl, wherein in R 7 The alkyl, aryl, and / or heterocyclic groups are optionally substituted with 1 to 3 halogens and / or CN; and / or

[0068] R 8 Choose from the following groups: H, HOOC-(CH2) m -(CO)-, where m is 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl, and naphthylcarbonyl, wherein in R 8 The alkyl, aryl, and / or heterocyclic groups are optionally substituted with 1 to 3 halogens and / or CN.

[0069] For particularly preferred compounds of the present invention, R 1 For OH; R 8 For H and R 7 Choose from the following groups: C 1-3Alkyl groups, particularly methyl groups, according to a portion of formula (V.2), where Ar is phenyl, n and p are each the same and are 1 or 2, and q is 2 or 3, phenyl-C 1-2 Alkyl-O-CO-NH-C 1-2 Alkyl-CO- and phenyl-OC 1-3 alkyl carbonyl, wherein in R 7 The alkyl, aryl, and / or heterocyclic groups are optionally substituted with one to three halogens and / or CN. Preferably, R 7 The group contains at least one aromatic ring.

[0070] For particularly preferred compounds of the present invention, R 1 For OH; R 7 For Me and R 8 Choose from the following groups: H, HOOC-(CH2) m -(CO)- where m is 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl chloride, methylsulfonylphenylbenzoyl, and naphthylcarbonyl, wherein in R 8 The alkyl and / or aryl groups are optionally substituted with 1 to 3 halogens and / or CN. Preferably, R 8 The group contains at least one aromatic ring.

[0071] A particularly preferred group of compounds of the present invention is the group in which R 1 For OH; R 8 For H and R 7 Choose from the following groups: C 6-10 Aryl-C 1-3 Alkyl, C 6-10 aryl carbonyl, C 6-10 Aryl-C 1-3 alkyl carbonyl, C 6-10 Aryl-OC 1-3 alkyl carbonyl, C 6-10 Aryl-C 1-3 Alkyl-OC 1-3 Alkyl-carbonyl, HOOC-(CH2) m -(CO)- where m is 0 to 3, preferably 1 to 3, most preferably 1 or 2, according to part of formula (V.2), where Ar is C 6-10 The aryl group, n, p, and q, are each independently 0 to 3, preferably n and p are each independently 1 or 2 and q is 2 or 3, most preferably n and p are the same and are 1 or 2 and q is 2 or 3, C 6-10 Aryl-C 1-3 Alkyl-O-CO-NH-C 1-3 Alkyl-CO-, C 6-10arylsulfonyl and C 1-3 Alkyl-C 6-10 arylsulfonyl; wherein in R 7 The alkyl and / or aryl groups are optionally substituted with 1 to 6, preferably 1 to 3 halogen and / or CN groups.

[0072] A particularly preferred group of compounds of the present invention is the group in which R 1 For OH; R 8 For H and R 7 Choose from the group consisting of: benzyl, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl, naphthylcarbonyl, naphthalenesulfonyl, methylbenzenesulfonyl, succinyl, and the part according to formula (V.2), wherein Ar is phenyl, n and p are each the same and are 1 or 2, and q is 2 or 3. For R 7 Particularly preferred are benzyl, benzoyl, naphthalenesulfonyl, methylbenzenesulfonyl, succinyl and the part according to formula (V.2), wherein Ar is phenyl, n and p are each the same and are 1 or 2 and q is 2 or 3.

[0073] The particularly preferred alternatives to the compounds of the present invention are the group consisting of R. 1 For OH; R 7 For Me and R 8 Choose from the following groups: C 6-10 Aryl carbonyl group, with 1 to 3 halogen atoms, C 1-2 Alkyl and / or C 1-2 alkoxy-substituted C 6-10 Aryl carbonyl, branched C 3-4 Alkyl carbonyl, HOOC-(CH2) m -(CO)- where m is 0 to 3, preferably 1 to 3, most preferably 1 or 2, according to part of formula (V.2) as described above, where Ar is C 6-10 The aryl group, n, p, and q, are each independently 0 to 3, preferably n and p are each independently 1 or 2 and q is 2 or 3, most preferably n and p are the same and are 1 or 2 and q is 2 or 3, C 1-3 alkylsulfonyl-bis-C 6-10 The aryl-carbonyl group and the heteroarylcarbonyl group having a 5, 6, or 10-membered ring containing 1, 2, or 3 heteroatoms, more preferably 1 or 2 heteroatoms, and most preferably 1 heteroatom, wherein the heteroatom(s) are selected from the group consisting of N, O, and S in each case, preferably from the group consisting of N and O, and most preferably N, and the ring of the heteroarylcarbonyl group is optionally selected from C. 1-2 Alkyl, C 1-2 Alkoxy, C 2-3 alkenyl, C2-3 The group consisting of olefins, halogens (especially F and Cl), and CN is preferred, and the group consisting of free methyl, methoxy, F, and Cl is most preferably the group consisting of free methyl and Cl, with one or two substituents. In R 8 Within the group, alkyl, aryl and / or heterocyclic groups may optionally be substituted by 1 to 6, preferably 1 to 3 halogen atoms and / or (one or more) CN groups.

[0074] Furthermore, particularly preferred compounds of the present invention are those from the group consisting of R 1 For OH; R 7 For Me and R 8 Choose from the group consisting of: isopropyl carbonyl, succinyl, benzoyl, halobenzoyl (e.g., iodobenzoyl), ethylphenyl carbonyl, methoxyphenyl carbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl, the part according to formula (V.2), where Ar is phenyl, n = p = 1 and q = 2, pyrazolyl carbonyl, dimethylpyrazolyl carbonyl, phenylthio, chlorophenylthio, pyridyl carbonyl, and quinolinyl carbonyl.

[0075] The particularly preferred group of compounds of the present invention is the compound of formula (I) herein.

[0076] R 1 It is OH;

[0077] R 2 According to formula (III)

[0078]

[0079] in

[0080] R 7 C 1-6 Alkyl; and

[0081] R 8 Choose from the following groups: (Optionally selected from C) 1-3 alkylsulfonyl and / or C 1-3 C1- to C2-substituted alkyl groups 6-14 Aryl carbonyl; HOOC-(CH2) m -(CO)- where m is 0 to 6, the substituents in formula (V.1)

[0082]

[0083] Where Ar is C 6-14 The aryl group has n, p, and q that are independently 0 to 6.

[0084] R 3 For H; and

[0085] R 4 and R 5 Both are H;

[0086] Or a pharmaceutically acceptable ester, amide, carbamate, solvate, or salt thereof, including salts of such esters, amides, or carbamates, and solvates of such esters, amides, carbamates, or salts.

[0087] In these types of compounds, for example R 7 For Me. For example, R 7 For Me and R 8 Choose from the following groups: C 6-10 aryl carbonyl, via 1 to 3 carbons 1-2 alkylsulfonyl or C 1-2 Alkyl-substituted C 6-10 Aryl carbonyl, HOOC-(CH2) m -(CO)-, where m is 0 to 3, preferably 1 to 3, most preferably 1 or 2, according to part of formula (V.1) as described above, where Ar is C 6-10 The aryl group, n, p, and q, are each independently 0 to 3, preferably n and p are each independently 1 or 2 and q is 2 or 3, and most preferably n and p are the same and are 1 or 2 and q is 2 or 3. In R 8 Within the group, alkyl, aryl, and / or heterocyclic groups may optionally be substituted with 1 to 6, for example 1 to 3 halogen atoms and / or (one or more) CN groups. For example, R 7 For Me and R 8 Choose from the group consisting of: succinyl, benzoyl, halobenzoyl (e.g., iodobenzoyl), ethylphenylcarbonyl, methanesulfonylphenylbenzoyl, naphthylcarbonyl and the part according to formula (V.2), where Ar is phenyl, n = p = 1 and q = 2.

[0088] The preferred compounds according to the present invention are as follows:

[0089] (2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-11-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxacyclohexyl-2-yl]oxy}-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1);

[0090] Benzoic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 2);

[0091] Morpholine-4-carboxylic acid (3aR,4R,7R,8S,9S,10R,11S,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyloxacyclohexyl-2-yl]oxy}-4-ethyl-11-hydroxy-3a,7,9,11,13,15,16-heptamethyl-2,6-dioxo-tetradecyl-2H-[1,3]dioxacyclopenta[4,5-c]1-oxa-6-azacyclopentadecane-8-yl ester (Example 3);

[0092] Benzoic acid (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-tetradecyl-2H-[1,3]dioxacyclopenta[4,5-c]1-oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxacyclohexyl-3-yl ester (Example 4);

[0093] (2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-11-{[(2S,3R,4S,6R)-4-[benzyl(methyl)amino]-3-hydroxy-6-methyloxacyclohexyl-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxacyclohexyl-2-yl]oxy}-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 5);

[0094] 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-dimethyloxacyclohexyl-2-yl]oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl]-N-methylbenzamide (Example 6);

[0095] N-[(2S,3R.4S,6R)-2-{[{2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohex-4-yl]-N-methylbenzamide (Example 7);

[0096] 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-dimethyloxacyclohexyl-2-yl]oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl]-N-methylnaphthalene-2-sulfonamide (Example 8);

[0097] N-[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohex-4-yl]-N-methylnaphthalene-2-sulfonamide (Example 9);

[0098] 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-dimethyloxacyclohexyl-2-yl]oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl]-N,4-xylene-1-sulfonamide (Example 10);

[0099] Benzoic acid (2S,3R,4S,6R)-2-{[(2R,3R,4R,5R,8R,10S,11R,12S,13S,14R)-4,13-bis(acetoxy)-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-methyloxacyclohexyl-3-yl ester (Example 11);

[0100] 4-(4-Methanesulfonylphenyl)benzoic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 12);

[0101] Benzoic acid (2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyl-4-(N-methylnaphthalene-2-sulfonamide)oxacyclohexyl-3-yl ester (Example 13);

[0102] 4-Iodobenzoic acid {2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 14);

[0103] (2R)-2-{[(benzyloxy)carbonyl]amino}glutaric acid 1-benzyl ester (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 15);

[0104] (2R)-2-{[(benzooxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-2{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl](methyl)carbamoyl} benzoyl butyrate (Example 16);

[0105] 4-{[(2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl]oxy}-4-oxobutyric acid (Example 17);

[0106] 3-{[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl](methyl)carbamoyl}propionic acid (Example 18); and

[0107] Pyridine-3-carboxylic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 19);

[0108] 2,5-Dimethylpyrazol-3-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 20);

[0109] 5-Chlorothiophene-2-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 21);

[0110] 4-Ethylbenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 22);

[0111] 4-Methoxybenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 23);

[0112] Naphthalene-2-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 24);

[0113] Quinoline-3-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 25);

[0114] 2-Benzoxy-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methylacetamide (Example 26);

[0115] N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-2-oxo-ethyl]carbamate (Example 27);

[0116] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy-propionamide (Example 28);

[0117] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide (Example 29);

[0118] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 30);

[0119] 2-Methylpropionic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 31);

[0120] The most preferred option is to select from the following groups.

[0121] Benzoic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 2);

[0122] 4-(4-Methanesulfonylphenyl)benzoic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10S,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 12);

[0123] (2R)-2-{[(benzyloxy)carbonyl]amino}glutaric acid 1-benzyl ester (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl ester (Example 15);

[0124] (2R)-2-{[(benzooxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-2{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxacyclohexyl-4-yl](methyl)carbamoyl} benzoyl butyrate (Example 16);

[0125] 4-{[(2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-6-methyloxacyclohexyl-3-yl]oxy}-4-oxobutyric acid (Example 17);

[0126] 4-Ethylbenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 22);

[0127] Naphthalene-2-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 24);

[0128] N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-2-oxo-ethyl]carbamate (Example 27); and

[0129] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy-propionamide (Example 28).

[0130] The present invention also provides pharmaceutical compositions comprising at least one compound of the present invention and at least one pharmaceutically acceptable excipient, wherein this further comprises wherein, in R 1 For OH and R 7 In the case of R 8 Compounds that can be H.

[0131] The compounds or compositions of the present invention are suitable as pharmaceutical agents, wherein this further includes the presence of R 1 For OH and R 7 In the case of R 8 Compounds that can be H.

[0132] As mentioned above, the inventors have found that the compounds of the present invention exhibit good activity in a human respiratory epithelial regeneration model and reduced antimicrobial activity in a series of tests against various bacteria. Various in vitro and in vivo tests exist for evaluating the epithelial barrier function of the compounds of the present invention. In vivo tests include challenge with pathogen SO2, challenge with rhamnolipids, and challenge with high-pressure trauma. The compounds of the present invention have been tested in vivo in SO2 challenge experiments, and it has been found that said compounds provide a significant role in protecting the lung epithelial barrier function.

[0133] The compounds or pharmaceutical compositions according to the invention are effective in treating diseases or conditions caused by defects in epithelial cells or tissues, or in benefiting from enhanced or restored epithelial barrier function. The disease or condition may be a respiratory disease, and the epithelial tissue may be in the respiratory epithelial tissue, specifically selected from a portion of the respiratory tract comprising: the nose, nasal cavity, sinuses, larynx, trachea, bronchi, bronchioles, terminal respiratory tract, and alveoli.

[0134] The compounds or compositions according to the invention are effective in treating congenital, chronic, persistent, or long-term respiratory diseases. For example, they are effective in treating conditions including: asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, chronic sinusitis, diffuse panbronchiolitis (DPB), chronic bronchitis, obstructive bronchiolitis with organifying pneumonia (BOOP) primary or secondary to chemotherapy or transplantation status, infant respiratory distress syndrome (IRDS) and its long-term complications, bronchopulmonary dysplasia, neuromuscular respiratory depression and / or failure, pneumonia (specifically, community-acquired pneumonia), and conditions caused by and associated with respiratory syncytial virus (RSV) and related viruses (e.g., human metapneumovirus), such as chronic infantile wheezing and associated childhood asthma with bronchial hyperresponsiveness.

[0135] The compounds or compositions according to the invention are also effective in enhancing or restoring epithelial barrier function in many diseases and conditions commonly associated with inflammation, preferably selected from the group consisting of: systemic inflammatory distress syndrome (SIRS), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0136] The present invention also provides a method for treating or preventing any disease or condition as mentioned herein, the method comprising administering a therapeutically effective amount of a compound or composition according to the invention to a subject (e.g., a mammal, typically a human).

[0137] Depending on the substituents present in the compound of formula (I), the compound may form esters, amides, carbamates, and / or salts. Salts and solvates of compounds of formula (I) suitable for use in pharmaceuticals are those in which the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates or associated solvents having non-pharmaceutically acceptable counterions are within the scope of this invention, for example, as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable esters, amides, or carbamates or solvates thereof.

[0138] Suitable salts according to the invention include those formed with organic or inorganic acids or bases. Specifically, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids (such as unsubstituted or halogenated alkylcarboxylates of 1 to 4 carbon atoms, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids) or with organic sulfonic acids (such as unsubstituted or halogenated (C1-C4) alkyl or aryl-sulfonic acids). Pharmaceutically acceptable acid addition salts include those formed from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid and glutamic acid, lysine and arginine. Other acids such as oxalic acid (although not in their own pharmaceutically acceptable form) may be used as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0139] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as those of potassium and sodium), alkaline earth metal salts (such as those of calcium and magnesium), and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-alkylamines (such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethyl-propylamine) or mono-, di-, or trihydroxyalkylamines (such as mono-, di-, or triethanolamine). Furthermore, corresponding inner salts may be formed.

[0140] Compounds of formula (I) may have suitable groups that convert to esters, amides, or carbamates. Therefore, typical ester and amide groups formed from acid groups in compounds of formula (I) include -COOR. B -CONR B 2. -SO2.OR B or -SO2.NR B 2, although the -OH or -NHR in the compound of formula (I) B Typical ester, amide, and carbamate groups formed by these groups include -O, CO, and R. B -NR B .CO.R B -NR B .CO2R B -O.SO2R B and -NR B .SO2R B , where each R B Choose independently from the following groups: hydrogen, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl groups, each optionally substituted with 1 to 3 halogen atoms. Preferably, each R... B Choose independently the following groups: hydrogen and C 1-4 Alkyl group. For example, in compounds of formula (I), when R... 3 R 4 and R 5 When one or more of the components are H, one or more of the OH groups present can be converted into the formula -O.CO.R. B The ester; that is, the compound will have the properties of CO.R. B R represents 3 R 4 and R 5 One or more of them, R B As given immediately above.

[0141] A compound that, upon administration to an acceptor, can be converted into a compound of formula (I) as described above, or its active metabolite or residue, is called a "prodrug." A prodrug can, for example, be converted in the body, for example, by hydrolysis in the blood, into its active form with pharmaceutical effects. Certain of the aforementioned esters, amides, and carbamates can be prodrugs. Pharmaceutically acceptable descriptions of prodrugs are found in: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Conference Series, Vol. 14 (1976); "Design of Prodrugs," H. Bundgaard, Elsevier, 1985; and Edward B. Roche (eds.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference.

[0142] Those skilled in the art of organic chemistry should understand that many organic compounds can form complexes with solvents, in which the organic compound reacts or precipitates or crystallizes through the solvent. These complexes are called "solvents." For example, complexes with water are called "hydrates."

[0143] Unless otherwise restricted in specific examples, the following definitions apply to the terms used throughout this specification.

[0144] As used herein, the term "alkyl" refers to both straight-chain and branched saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, and hexyl. Among non-branched alkyl groups, methyl, ethyl, n-propyl, isopropyl, and n-butyl are preferred. Among branched alkyl groups, the aforementioned tert-butyl, isobutyl, 1-ethylpropyl, and 1-ethylbutyl may be present.

[0145] As used herein, the term "alkoxy" refers to an O-alkyl group, where "alkyl" is used as described above. Examples of alkoxy groups include methoxy or ethoxy. Other examples include propoxy and butoxy.

[0146] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, and hexenyl. Preferred alkenyl groups include vinyl, 1-propenyl, and 2-propenyl.

[0147] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having at least one carbon-carbon linkage. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentyynyl, and hexynyl. Preferred alkynyl groups include ethynyl-1-propynyl and 2-propynyl.

[0148] As used herein, the term "cycloalkyl" refers to a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group can be, for example, fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl, and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclic [2.2.1]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

[0149] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. The naphthyl group can be linked at the 1- or 2-position. In bicyclic aromatic groups, one of the rings may, for example, be partially saturated. Examples of such groups include indenyl and tetrahydronaphthyl. Specifically, the term C... 5-10 In this document, aryl is used to refer to a group containing 5 to 10 carbon atoms in a monocyclic or bicyclic aromatic group. Particularly preferred C 5-10 The aryl group is phenyl.

[0150] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, and bromine are particularly preferred.

[0151] As used herein, the term "heterocyclic group" refers to an aromatic or non-aromatic cyclic group of carbon atoms, wherein one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. Heterocyclic groups can be, for example, monocyclic or bicyclic. In bicyclic heterocyclic groups, one or more heteroatoms may be present in each ring or only in one of the rings. The heteroatoms are preferably O or N. Heterocyclic groups containing suitable nitrogen atoms include corresponding N-oxides.

[0152] Examples of monocyclic nonaromatic heterocyclic groups (also known as monocyclic heterocyclic alkyl groups) include acridinel, acridinel, pyrrolidinel, tetrahydroimidazolyl, pyrazolidinel, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and nitrogen-containing heterocyclic heptyl.

[0153] Examples of bicyclic heterocyclic groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indololinyl, isoindololinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and benzozaheptanyl.

[0154] Examples of monocyclic aromatic heterocyclic groups (also known as monocyclic heteroaryl groups) include furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

[0155] Examples of bicyclic aromatic heterocyclic groups (also known as bicyclic heteroaryl groups) include quinolinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiopheneyl, benzoimidazolyl, naphridyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzoxazole.

[0156] Examples of preferred heterocyclic groups include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, and indoleyl. Preferred heterocyclic groups also include thiopheneyl, thiazolyl, furanyl, pyrazolyl, pyrroleyl, isoxazolyl, and imidazoleyl.

[0157] As used herein, the term “cycloalkylalkyl” means cycloalkyl-alkyl-linked by an alkyl group, and “cycloalkyl” and “alkyl” should be understood to have the meanings outlined above.

[0158] The compounds of the present invention contain several chiral (asymmetric) centers and the molecule as a whole is chiral. Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the present invention.

[0159] The compounds of the present invention can be prepared by methods well known in the art. Azithromycin is widely available from commercial sources, including Sigma-Aldrich. The key intermediate, descladinose azithromycin (Example 1), can be prepared by selective acid hydrolysis of azithromycin using methanol and hydrochloric acid (aqueous solution) according to the scheme shown in Procedure 1. The important intermediates, demethylated azithromycin (intermediate A) and demethylated descladinose azithromycin (intermediate B), can be prepared by N-demethylation using iodine and NaOAc in MeOH or iPrOH, a method stated in US 3,725,385 and also described in the European Journal of Medicinal Chemistry, 49(2012) 365-378, entry 5.1.3. This is also shown in Procedure 1:

[0160]

[0161] The advanced intermediates shown in process 1 can be derived into the compounds of this invention using standard linking techniques.

[0162] The compounds of this invention are suitable as pharmaceutical agents. Specifically, they are suitable as agents for treating diseases or conditions caused by defects in epithelial cells or tissues, or for which enhancement or restoration of epithelial barrier function may be beneficial. The disease or condition may be a respiratory disease and the epithelial tissue may be in the respiratory epithelial tissue, specifically selected from a portion of the respiratory tract consisting of: the nose, nasal cavity, sinuses, larynx, trachea, bronchi, bronchioles, terminal respiratory tracts, and alveoli.

[0163] The compounds or compositions according to the invention are suitable agents for treating congenital, chronic, persistent, or long-term respiratory diseases. For example, they are effective in treating conditions including: asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, chronic sinusitis, diffuse panbronchiolitis (DPB), chronic bronchitis, obstructive bronchiolitis with organifying pneumonia (BOOP) primary or secondary to chemotherapy or transplantation status, infant respiratory distress syndrome (IRDS) and its long-term complications, bronchopulmonary dysplasia, neuromuscular respiratory depression and / or failure, pneumonia (specifically, community-acquired pneumonia), and conditions caused by and associated with respiratory syncytial virus (RSV) and related viruses (e.g., human metapneumovirus), such as chronic infantile wheezing and associated childhood asthma with bronchial hyperresponsiveness.

[0164] The compounds of the present invention are suitable agents for treating or preventing diseases and conditions that are generally associated with inflammation that benefits from enhanced or reconstructed epithelial barrier function, preferably selected from the group consisting of: systemic inflammatory distress syndrome (SIRS), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0165] The present invention also provides methods for treating or preventing diseases or conditions caused by defects in epithelial cells or tissues, or diseases or conditions that would benefit from enhanced or reconstructed epithelial barrier function. Conditions and diseases treatable by the methods of the present invention are preferably those described above. The present invention also provides methods for treating or preventing conditions associated with inflammation that benefit from enhanced or reconstructed epithelial barrier function. Such conditions and diseases are preferably those described above.

[0166] The present invention also provides the use of compounds according to the invention in the manufacture of pharmaceutical agents for treating or preventing diseases or conditions caused by defects in epithelial cells or tissues, or for which enhancement or reconstruction of epithelial barrier function would benefit. Treatable conditions and diseases are preferably those described above. The present invention also provides the use of compounds according to the invention in the manufacture of pharmaceutical agents for treating or preventing conditions associated with inflammation that benefit from enhancement or reconstruction of epithelial barrier function. Such conditions and diseases are preferably those described above.

[0167] The amount of active ingredient required to achieve a therapeutic effect will vary depending on the specific compound, route of administration, the subject being treated (including the subject's type, species, age, weight, sex, medical condition, and renal and hepatic function), and the specific condition or disease being treated and its severity. Generally, a skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of drug required to prevent, counteract, or halt the progression of a condition.

[0168] Compared to others, certain compounds of the present invention have better oral bioavailability. Compounds with particularly good bioavailability (specifically, oral bioavailability) are especially suitable for treating conditions suitable for treatment by systemic drug delivery. On the other hand, compounds with poor bioavailability are suitable for topical delivery (and systemic side effects will be minimized by the low bioavailability) and are therefore suitable for treating conditions suitable for treatment by topical drug delivery (e.g., by inhalation or administration via the skin, buccally, sublingually, or intraocularly).

[0169] When used for a specified effect, the oral dosage range of the present invention for adults is from about 0.01 mg / kg body weight / day to about 100 mg / kg / day, preferably from 0.01 mg / kg body weight / day to 10 mg / kg / day, and most preferably from 0.1 to 5.0 mg / kg / day. Therefore, a typical daily dose is from about 1 mg to about 500 mg of the active ingredient, preferably from about 20 mg to about 500 mg of the active ingredient, for example from 50 mg to 500 mg, for example from 100 mg to 400 mg, for example from 200 mg to 300 mg, for example from 250 mg of the active ingredient. For oral administration, the composition is preferably provided in tablet form or other presentation form containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, 250 or 500 mg of active ingredient in a discrete unit for symptomatic adjustment of the dose to a patient being treated.

[0170] The most preferred dose, administered intravenously at a constant rate, will be in the range of about 0.1 to about 10 mg / kg / min. Advantageously, the compounds of the present invention can be administered as a single daily dose, or the total daily dose can be administered in divided doses two, three, or four times daily. Furthermore, preferred compounds for use in the present invention can be administered intranasally via topical application of a suitable intranasal medium or via a percutaneous route, using those forms of percutaneous epidermal patches well known to those skilled in the art. For administration via a percutaneous delivery system, the dose will naturally be administered continuously rather than intermittently throughout the dosing regimen.

[0171] While it is possible to administer the active ingredient alone, it is preferred that the active ingredient be present in a pharmaceutical formulation or composition. Therefore, the present invention provides pharmaceutical formulations comprising the compounds according to the invention and pharmaceutically acceptable diluents, excipients, or carriers (collectively referred to herein as “carrier” materials). The pharmaceutical compositions of the present invention may be in the form of pharmaceutical formulations as described below.

[0172] Pharmaceutical formulations according to the invention include those suitable for oral, non-enteric (including subcutaneous, intradermal, intramuscular, intravenous (push or infusion) and intra-articular) administration, inhalation (including fine particulate dust or mist generated by various types of metered-dose pressurized sprays, nebulizers or blowers), rectal, intraperitoneal and topical (including skin, buccal, sublingual and intraocular) administration, but most suitable routes may depend on, for example, the recipient's condition and illness.

[0173] Formulations may suitably be in unit dosage form and may be prepared by any method well known in the pharmaceutical field. All methods involve the step of associating the active ingredient with a carrier constituting one or more secondary components. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely powdered solid carrier, or both, and then (if necessary) shaping the product into the desired formulation.

[0174] Formulations of the present invention suitable for oral administration may be in the form of discrete units, such as capsules, granules, pills, or tablets, each containing a predetermined amount of the active ingredient; in the form of powders or granules; in the form of solutions or suspensions in aqueous or non-aqueous liquids, for example as elixirs, tinctures, suspensions, or syrups; or in the form of oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be in the form of pellets, scoops, or pastes.

[0175] Tablets can be prepared by compression or molding, optionally with one or more byproducts. Compressed tablets can be prepared by compressing a free-flowing active ingredient, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. The compounds of the present invention can be administered, for example, in a form suitable for immediate or prolonged release. Immediate or prolonged release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or, particularly in the case of prolonged release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of the present invention can also be administered via liposomes.

[0176] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for imparting bulk, alginate or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavorings, as those known in the art; and immediately-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, supplements, disintegrants, diluents, and lubricants, as those known in the art. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Compounds of formula (I) may also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that may be used. Exemplary compositions include those formulated with one or more of the compounds of the present invention in conjunction with rapidly dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. High molecular weight excipients such as cellulose (Avitol) or polyethylene glycol (PEG) may also be included in such formulations. Such formulations may also include excipients that contribute to mucosal adhesion (such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez)) and controlled-release agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, flow aids, flavoring agents, coloring agents, and stabilizers may also be added to facilitate manufacture and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral pharmaceutical component may be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.

[0177] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. Formulations may be available in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to use. Ready-to-use injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable nontoxic, non-enteric-acceptable diluents or solvents (such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution) or other suitable dispersants or wetting agents and suspending agents (including synthetic mono- or diglycerides and fatty acids including oleic acid or Cremaphor).

[0178] Exemplary compositions for nasal, aerosol, or inhalation administration include a solution in saline solution that may contain, for example, benzyl alcohol or other suitable preservatives, bioavailability enhancers, and / or other solubilizers or dispersants, as known in the art.

[0179] Formulations intended for rectal administration may be presented as suppositories with a common carrier (such as cocoa butter, synthetic glycerides, or polyethylene glycol). These carriers are typically solid at normal temperatures but liquefy and / or dissolve in the rectal lumen to release the drug.

[0180] Formulations for oral (e.g., buccal or sublingual) topical application include lozenges containing active ingredients in a flavoring matrix such as sucrose and gum arabic or tragacanth, and tablets containing active ingredients in a matrix such as gelatin and glycerol or sucrose and gum arabic. Exemplary compositions for topical application include topical carriers such as Plastibase (mineral oil gelled with polyethylene).

[0181] Preferred unit dose formulations are those containing an effective dose or appropriate fraction of the active ingredient as listed above.

[0182] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art in view of the type of formulations discussed, such as those suitable for oral administration, which may include flavoring agents.

[0183] Although the compounds of the present invention may be used as the sole active ingredient in a pharmaceutical preparation, they may also be used in combination with one or more other active agents. These other active agents may be other compounds according to the present invention, or they may be different therapeutic agents, such as compounds suitable for treating respiratory conditions or diseases, such as compounds suitable for treating asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis (CF).

[0184] Compounds suitable for treating asthma include inhaled corticosteroids (such as fluticasone (Flonase, Flovent HFA), budesonide (Pulmicort Flexhaler, Rhinocort), flunisolide (Aerospan HFA), ciclesonide (Alvesco, Omnaris, Zetonna), beclomethasone (Qnasl, Qvar), mometasone (Asmanex), or fluticasone furoate (Arnuity Ellipta)) and leukotriene modifiers (such as montelukast (Singulair), zafirlukast (Accolate), or zileuton). (Zyflo); long-acting beta-boosters (e.g., salmeterol (Serevent) or formoterol (Foradil, Perforomist); combination inhalers (e.g., fluticasone-salmeterol (Advair Diskus / Seretide), budesonide-formoterol (Symbicort), or formoterol-mometasone (Dulera) containing a long-acting beta-booster and a corticosteroid); theophylline (e.g., Theo-24 or Elixophyllin), short-acting beta-boosters (e.g., albuterol (ProAir HFA, Ventolin HFA, others) and levalbuterol (Xopenex)), ipratropium (Atrovent), or oral or intravenous corticosteroids (e.g., prednisone or methylprednisolone)).

[0185] Compounds suitable for treating COPD include short-acting bronchodilators (such as salbutamol (ProAir HFA, Ventolin HFA, others), levosalbutamol (Xopenex), and ipratropium (ipratropine bromide (Atrovent))) and long-acting bronchodilators (including tiotropium (Spiriva), salmeterol (Serevent), formoterol (Foradil, Perforomist), artooterol (Brovana), and indacaterol). (indacaterol)(Arcapta and aclidinium)(Tudorza)), inhaled steroids (including fluticasone and budesonide), combination inhalers (e.g., combination bronchodilators and inhaled steroids, such as salmeterol and fluticasone (Advair) and formoterol and budesonide (Symbicort)), oral steroids, phosphodiesterase-4 inhibitors (e.g., roflumilast (Daliresp)), theophylline, and antibiotics.

[0186] Compounds suitable for treating CF include antibiotics, mucolytics, bronchodilators, and oral pancreatic enzymes.

[0187] If the compounds of the present invention are used to treat conditions associated with inflammation that would benefit from enhanced or reconstructed epithelial barrier function, then the additional active agent is selected from reagents suitable for the condition in question.

[0188] When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by a person skilled in the art.

[0189] The following examples illustrate the present invention.

[0190] Example

[0191] General Method

[0192] Preparative reversed-phase chromatography was performed on an X-bridge, prepC18 (5 μm) with a 50 mM ammonium bicarbonate / acetonitrile gradient. All compounds were analyzed by analytical HPLC / LCMS. The analyses were performed using an Agilent 1100 Series HPLC / MTU-selective detector (MSD) (single quadrupole) equipped with an electrospray interface and a UV diode array detector. The prepared compounds were named using the IUPAC names obtained from MarvinSketch 5.2.6 software.

[0193] The starting materials were obtained from conventional, readily available sources.

[0194] For all compounds, MS / ESI yields [M+H] by positive ionization. + Since the conversion yield is a better indicator of purification than the yield to the desired product, the conversion yield is omitted. The isolated yield of each compound exceeded the expected 50 mg, with a few exceptions.

[0195] Example 1: Sciglioside azithromycin: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one)

[0196]

[0197] Add hydrochloric acid (1M) to a methanol (100 mL) solution of azithromycin ((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one) (10 g, 13.35 mmol) until the pH stabilizes at 1.25 and the resulting solution is stirred at room temperature for 24 hours. Again, the pH of the mixture was adjusted to pH 10.75 using NaOH (1M). The mixture was stirred for 1 hour and partitioned between NaHCO3 (5%) and DCM. The aqueous phase was washed with a second fraction of DCM, and the combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure to give a white, foamy product. The sample was purified by straight-phase silica gel chromatography (DCM in DMC, 5% methanol, 0.1% triethylamine added to the mobile phase).

[0198] Example 2: Benzoic acid (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester)

[0199]

[0200] Benzoyl chloride (356.9 mg, 2.54 mmol) was added to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (0.5 g, 0.8500 mmol) and triethylamine (428.2 mg, 4.23 mmol) in DCM (5 ml). The reaction mixture was allowed to reach room temperature. After 3 days, good conversion of the desired benzoylation product was obtained and the mixture partitioned between DCM and a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated into a white foam. The product was purified using reversed-phase chromatography (see General Information).

[0201] Example 3: Morpholine-4-carboxylic acid (1R,2R,5R,7R,8R,9S,10S,11R,14R,15R)-8-[(2S,3R,4S,6R)-3-benzoyloxy-4-(dimethylamino)-6-methyl-tetrahydropyran-2-yl]oxy-14-ethyl-7-hydroxy-2,3,5,7,9,11,15-heptamethyl-12,17-dioxo-13,16,18-trioxa-3-azabicyclo[13.3.0]octadecane-10-yl] ester)

[0202]

[0203] Benzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadeca-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 2) (250 mg, 0.3600 mmol) was mixed with carbonyl diimidazole (466.73 mg, 2.88 mmol) and triethylamine (291.27 mg, 2.88 mmol) in THF (2.5 mL). After stirring for 2 days, the intermediate product was separated by partitioning between DCM and a saturated sodium bicarbonate solution. The DCM phase was dried over magnesium sulfate and concentrated under reduced pressure. DMF (1 mL) was added, followed by morpholine (37.61 mg, 0.4300 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (65.73 mg, 0.4300 mmol). When no starting material remained, the material was again partitioned between DCM and a saturated sodium bicarbonate solution. The DCM phase was again dried over magnesium sulfate and concentrated under reduced pressure. The material was dissolved in acetonitrile and purified by reversed-phase chromatography (see General Methods). The clean fraction was concentrated and lyophilized to a solid.

[0204] Example 4: Benzoic acid [(2S,3R,4S,6R)-2-[[(1R,2R,5R,7R,8R,9S,10S,11R,14R,15R)-10-(benzylcarbamoyloxy)-14-ethyl-7-hydroxy-2,3,5,7,9,11,15-heptamethyl-12,17-dioxo-13,16,18-trioxa-3-azabicyclo[13.3.0]octadecane-8-yl]oxy]-4-(dimethylamino)-6-methyl-tetrahydropyran-3-yl] ester

[0205]

[0206] Benzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadeca-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 2) (250 mg, 0.3600 mmol) was mixed with carbonyl diimidazole (466.73 mg, 2.88 mmol) and triethylamine (291.27 mg, 2.88 mmol) in THF (2.5 mL). After stirring for 2 days, the intermediate product was separated by partitioning between DCM and a saturated sodium bicarbonate solution. The DCM phase was dried over magnesium sulfate and concentrated under reduced pressure. DMF (1 mL) was added, followed by benzylamine (46.26 mg, 0.4300 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (65.73 mg, 0.4300 mmol). When no starting material remained, the material was again partitioned between DCM and a saturated sodium bicarbonate solution. The DCM phase was again dried over magnesium sulfate and concentrated under reduced pressure. The material was dissolved in acetonitrile and purified by reversed-phase chromatography (see General Methods). The clean fraction was concentrated and lyophilized to a solid.

[0207] Example 5: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[phenylmethyl(methyl)amino]-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one

[0208]

[0209] Intermediate A is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one. The compound was prepared by N-demethylation of azithromycin using the method described in US 3,725,385 (also described in the European Journal of Medicinal Chemistry, 49(2012)365-378, entry 5.1.3).

[0210] Benzyl bromide (43.63 mg, 0.2600 mmol) was added to ((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-11-[(2S,3R,4S, A mixture of 6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Intermediate A) (125 mg, 0.1700 mmol) and N,N-diisopropylethylamine (32.97 mg, 0.2600 mmol) in IPA (1 mL) was reacted. When no starting material was observed, the reactants partitioned between DCM and a saturated sodium bicarbonate solution. The DCM was removed under reduced pressure, and the residue was dissolved in acetonitrile and purified using reversed-phase chromatography (see General Methods). The clean fractions were combined and concentrated, followed by lyophilization to obtain the product as a solid.

[0211] Example 6: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-benzamide

[0212]

[0213] Benzoyl chloride (27.83 mg, 0.2000 mmol) was added to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (97 mg, 0.1300 mmol) (intermediate A) and sodium bicarbonate (16.63 mg, 0.2000 mmol) in IPA (1 mL). When no starting material remained, the mixture was partitioned between saturated sodium bicarbonate and DCM. The solvent was removed under reduced pressure, and the residue was diluted with acetonitrile and purified by reversed-phase chromatography (see General Methods), concentrated, and lyophilized to give the product as a solid.

[0214] Example 7: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methylbenzamide

[0215]

[0216] Intermediate B is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one. The compound was prepared by N-demethylation of azithromycin by scristinose (Example 1) using the method described in US 3,725,385 (also described in the European Journal of Medicinal Chemistry, 49(2012) 365-378, entry 5.1.3).

[0217] Benzoyl chloride (20.96 mg, 0.1500 mmol) was added to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (57.33 mg, 0.1000 mmol) and sodium bicarbonate (12.53 mg, 0.1500 mmol) in IPA (1.25 mL). The mixture was partitioned between saturated sodium bicarbonate and DCM when no starting material remained. The solvent was removed under reduced pressure and the residue was diluted with acetonitrile and purified by reversed-phase chromatography (see General Methods). The product was then concentrated and lyophilized to obtain a solid product.

[0218] Example 8: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-naphthalene-2-sulfonamide

[0219]

[0220] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8, 10,12,14-Heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Intermediate A) (195 mg, 0.2700 mmol) 200 mg (containing approximately 50% of the desired starting material and undemethylated material), sodium bicarbonate (33.43 mg, 0.4000 mmol), and 2-naphthalenesulfonyl chloride (90.21 mg, 0.4000 mmol) were reacted with THF (1 mL) and IPA (1 mL). The reaction mixture was stirred overnight and good conversion to the desired product was obtained. The reaction mixture was treated by adding DCM and a saturated sodium bicarbonate solution. The organic phase was collected and concentrated into a yellow oil. The crude product was dissolved in approximately 4 mL of ACN and filtered and separated by preparative LC (see General Information) to obtain a purified fraction, which was concentrated and lyophilized into a solid material.

[0221] Example 9: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-naphthalene-2-sulfonamide

[0222]

[0223] IPA (2 mL) was added to (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (175 mg, 0.3000 mmol) (containing approximately 50% of the desired starting material and the undemethylated material), sodium bicarbonate (38.24 mg, 0.4600 mmol), and 2-naphthalenesulfonyl chloride (103.17 mg, 0.4600 mmol). The reaction mixture was stirred overnight. The reaction mixture was treated by adding DCM and a saturated sodium bicarbonate solution. The organic phase was collected and concentrated. The crude product was dissolved in approximately 4 ml of ACN and filtered and separated by preparative LC (see General Information) to obtain a pure product fraction, which was concentrated and lyophilized into a solid material.

[0224] Example 10: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N,4-dimethyl-benzenesulfonamide

[0225]

[0226] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3, 5,6,8,10,12,14-Heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Intermediate A) (199.98 mg, 0.2700 mmol) (containing approximately 50% of the desired starting material and undemethylated material), sodium bicarbonate (34.29 mg, 0.4100 mmol), and p-toluenesulfonyl chloride (77.81 mg, 0.4100 mmol) were reacted with IPA (2 mL). The reaction mixture was stirred overnight (conversion and purity were not as good as with the 2-naphthyl analogue). The reaction mixture was treated by adding DCM and a saturated sodium bicarbonate solution. The organic phase was collected and concentrated. The crude product was dissolved in approximately 4 mL of ACN and filtered and separated by preparative LC (see General Information) to obtain a purified fraction, which was concentrated and lyophilized into a solid material.

[0227] Example 11: Benzoic acid [(2S,3R,4S,6R)-2-[[(2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-4,13-diacetoxy-2-ethyl-3,10-dihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-4-(dimethylamino)-6-methyl-tetrahydropyran-3-yl] ester

[0228]

[0229] To a solution of benzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadeca-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester (Example 2) (200 mg, 0.2900 mmol) in DCM (2 mL), acetic anhydride (146.91 mg, 1.44 mmol) and pyridine (113.82 mg, 1.44 mmol) were added. The mixture was stirred until the major product was diacetylated. The mixture was treated by adding approximately the same volume of saturated sodium bicarbonate solution as the reaction mixture. The organic phase was concentrated and dissolved in acetonitrile (approximately 4 ml). The solution was filtered and purified by reversed-phase chromatography (see General Methods). The clean fraction was collected, concentrated under reduced pressure, and lyophilized to give the product as a solid.

[0230] Example 12: Benzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl]4-(4-methylsulfonylphenyl) ester)

[0231]

[0232] 4-Iodobenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran- Add 0.2 mL of water and 2 mL of DME to an inert (nitrogen-purged) mixture of 3-yl] ester (Example 14) (200 mg, 0.2400 mmol), potassium carbonate (101.05 mg, 0.7300 mmol), dichlorobis(triphenylphosphine)palladium(II) (8.55 mg, 0.0100 mmol), and (4-methylsulfonylphenyl)boronic acid (73.12 mg, 0.3700 mmol). Heat the mixture to 60°C. When no starting material remains, treat the reactants by partitioning between a saturated sodium bicarbonate solution and DCM. Concentrate the DCM phase and dissolve the mixture in acetonitrile, filter, and purify by reversed-phase chromatography (see General Methods). Concentrate the clean fraction and lyophilize to give the product as a solid.

[0233] Example 13: Benzoic acid [(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-4-[methyl(2-naphthalenesulfonyl)amino]tetrahydropyran-3-yl] ester)

[0234]

[0235] Benzoic acid [(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-4-(methylamino)tetrahydropyran-3-yl] ester (Example 2) (150 mg, 0.2200 mmol) was mixed with 2-naphthalenesulfonyl chloride (59.93 mg, 0.2600 mmol) in IPA (1.5 mL). Sodium bicarbonate (24.06 mg, 0.2900 mmol) was added as an antacid. The reaction was very rapid, and after approximately 30 minutes, the mixture partitioned between DCM and a saturated sodium bicarbonate solution. The organic phase was concentrated and diluted with acetonitrile. The mixture was filtered and purified by reversed-phase chromatography (see General Information). The clean fraction was concentrated and lyophilized to give the product as a solid.

[0236] Example 14: 4-Iodobenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester)

[0237]

[0238] 4-Iodobenzoyl chloride (270.61 mg, 1.02 mmol) was added to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (500 mg, 0.8500 mmol) and N,N-diisopropylethylamine (164.07 mg, 1.27 mmol) in THF (5 mL) cooled on ice. The mixture was allowed to reach room temperature after the addition. The reactants were stirred for approximately 3 hours and then partitioned between DCM and saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated to a grayish-white solid. A portion of the crude product was purified by reversed-phase chromatography (see General Information) and the remaining material was used as the crude product in the palladium-catalyzed cross-coupling reaction.

[0239] Example 15: O1-Benzyl glutarate O5-[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl](2R)-2-(benzyloxycarbonylamino) ester

[0240]

[0241] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (250 mg, 0.4200 mmol) was added to a mixture of ZD-glutamic acid 1-benzyl ester (235.71 mg, 0.6300 mmol), 4-(dimethylamino)pyridine (5.17 mg, 0.0400 mmol), and DCC (130.96 mg, 0.6300 mmol) in DCM (2.5 mL). The reaction mixture was stirred overnight and 0.1 ml of water was added. The reaction mixture was concentrated and diluted with acetonitrile to about 4 ml, filtered, and the product was purified by reversed-phase chromatography. (See General Methods) The purified fraction was concentrated and water was removed by lyophilization to give the title compound in solid form.

[0242] Example 16: (2R)-2-(benzyloxycarbonylamino)-5-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-5-oxo-pentacarbonylbenzyl ester

[0243]

[0244] ZD-glutamic acid 1-benzyl ester (282.88 mg, 0.7600 mmol) was added in a single dose to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (300 mg, 0.5100 mmol), EDC hydrochloride (113.93 mg, 0.7600 mmol), and 4-(dimethylamino)pyridine (6.2 mg, 0.0500 mmol) in DCM (3 mL). Stir the mixture until the starting material has disappeared (approximately 2 hours). Add 0.1 ml of water. Concentrate the reaction mixture and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the purified fraction and remove water by lyophilization to give the product as a white solid.

[0245] Example 17: 4-[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl]oxy-4-oxo-butyric acid

[0246]

[0247] Succinic anhydride (63.52 mg, 0.6300 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (250 mg, 0.4200 mmol) and 4-(dimethylamino)pyridine (5.17 mg, 0.0400 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was diluted with acetonitrile to a volume of approximately 4 mL. The mixture was filtered and purified by reversed-phase chromatography (see General Methods). The clean fraction was concentrated and lyophilized to give a product as a white solid.

[0248] Example 18: Scicladinose, Azithromycin N-succinyl

[0249] 4-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-4-oxo-butyric acid

[0250]

[0251] Succinic anhydride (78.07 mg, 0.7800 mmol) was added in a single-part ratio to a solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (300 mg, 0.5200 mmol), (N-demethylscrodactyl azithromycin) and 4-(dimethylamino)pyridine (6.35 mg, 0.0500 mmol) in DCM (3 mL) at RT. After stirring the mixture for approximately 2 hours and observing no starting material (LC), water (0.1 mL) was added to the mixture. The solution was concentrated under reduced pressure and acetonitrile was added to a volume of approximately 4 mL. The mixture was filtered and purified by reversed-phase chromatography (see General Methods). The clean fraction was collected and concentrated, then lyophilized to give the product as a white solid.

[0252] Example 19: Pyridine-3-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester)

[0253]

[0254] DCC (130.98 mg, 0.6300 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (250 mg, 0.4200 mmol), nicotinic acid (78.15 mg, 0.6300 mmol), and 4-(dimethylamino)pyridine (12.93 mg, 0.1100 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was diluted with acetonitrile to a volume of approximately 4 ml. The mixture was filtered and purified by reversed-phase chromatography (see General Methods). The clean fraction was concentrated and lyophilized to give the product as a white solid.

[0255] Example 20: 2,5-Dimethylpyrazol-3-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0256]

[0257] (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15 1,3-Dimethyl-1H-pyrazole-5-carboxylic acid (74.73 mg, 0.5300 mmol) was added in a single batch to a mixture of 4-(dimethylamino)pyridine (21.72 mg, 0.1800 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by adding approximately 0.1 mL of water, the reactants were concentrated, and diluted with acetonitrile to approximately 4 mL. The mixture was filtered and the product was purified by reversed-phase chromatography (see General Methods). The purified fraction was concentrated under reduced pressure (to remove the major fraction of acetonitrile) and water was removed by lyophilization to give a product as a white solid.

[0258] Example 21: 5-Chlorothiophene-2-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0259]

[0260] 5-Chlorothiophene-2-carboxylic acid (86.7 mg, 0.5300 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (210 mg, 0.3600 mmol), EDC hydrochloride (79.76 mg, 0.5300 mmol), and 4-(dimethylamino)pyridine (21.72 mg, 0.1800 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. Add 0.1 ml of water. Concentrate the reaction mixture and dilute with acetonitrile to approximately 4 ml. Filter the material and then purify it using reversed-phase chromatography (see General Methods). Concentrate the purified fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0261] Example 22: 4-Ethylbenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0262]

[0263] 4-Ethylbenzoic acid (92.27 mg, 0.6100 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (242 mg, 0.4100 mmol), EDC hydrochloride (91.9 mg, 0.6100 mmol), and 4-(dimethylamino)pyridine 25.02 mg, 0.2000 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. Add water (0.1 ml) to quench the reaction. Concentrate the reactants and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the purified fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0264] Example 23: 4-Methoxybenzoic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0265]

[0266] 4-Methoxybenzoic acid (87.3 mg, 0.5700 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (226 mg, 0.3800 mmol), EDC hydrochloride (85.82 mg, 0.5700 mmol), and 4-(dimethylamino)pyridine (23.37 mg, 0.1900 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. Water (0.1 ml) was added to the reaction. The reactants were then concentrated and diluted with acetonitrile to approximately 4 ml, filtered, and the product was purified by reversed-phase chromatography (see General Methods). The purified fraction was concentrated under reduced pressure to remove acetonitrile, and the remaining water was removed by lyophilization to give the product as a white solid.

[0267] Example 24: Naphthalene-2-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0268]

[0269] Add 2-naphthoic acid (100.98 mg, 0.5900 mmol) in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (231 mg, 0.3900 mmol), EDC hydrochloride (87.72 mg, 0.5900 mmol), and 4-(dimethylamino)pyridine (23.88 mg, 0.2000 mmol) in DCM (2.5 mL). Stir the mixture overnight at room temperature. Add approximately 0.1 ml of water. Concentrate the reaction mixture and dilute with acetonitrile to approximately 4 ml. Filter the mixture and purify the product using reversed-phase chromatography (see General Methods). Concentrate the purified fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0270] Example 25: Quinoline-3-carboxylic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0271]

[0272] 3-Quinolinecarboxylic acid (95.85 mg, 0.5500 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (218 mg, 0.3700 mmol), EDC hydrochloride (82.79 mg, 0.5500 mmol), and 4-(dimethylamino)pyridine (22.54 mg, 0.1800 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. Add 0.1 ml of water. Concentrate the reaction mixture and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the pure fraction under reduced pressure to remove acetonitrile and remove water by lyophilization to give the product as a white solid.

[0273] Example 26: 2-Benzoxy-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methylacetamide

[0274]

[0275] To a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (254 mg, 0.4400 mmol), EDC hydrochloride (98.8 mg, 0.6600 mmol), and 4-(dimethylamino)pyridine (26.9 mg, 0.2200 mmol) in DCM (2.5 mL), benzooxyacetic acid (109.77 mg, 0.66 mmol) was added in a single step. The mixture was stirred overnight at room temperature. Add 0.1 ml of water to quench any excess reagent. Concentrate the reactants and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the purified fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0276] Example 27: N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-2-oxo-ethyl]carbamate

[0277]

[0278] Z-glycine (131.12 mg, 0.6300 mmol) was added in a single step to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (241 mg, 0.4200 mmol), EDC hydrochloride (93.75 mg, 0.6300 mmol), and 4-(dimethylamino)pyridine (25.52 mg, 0.2100 mmol) in DCM (2.5 mL) cooled on ice. Allow the mixture to reach room temperature and stir overnight. Add 0.1 ml of water. Concentrate the reaction mixture and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the purified fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0279] Example 28: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy-propionamide

[0280]

[0281] Add 3-phenoxypropionic acid (123.6 mg, 0.7400 mmol) in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (286 mg, 0.5000 mmol), EDC hydrochloride (111.25 mg, 0.7400 mmol), and 4-(dimethylamino)pyridine (30.29 mg, 0.2500 mmol) in DCM (2.5 mL) (cooled on ice). Stir the mixture overnight at room temperature. Add water (approximately 0.1 ml) to quench the reaction. Concentrate the reactants and dilute with acetonitrile to approximately 4 ml, filter, and purify the product using reversed-phase chromatography (see General Methods). Concentrate the pure fraction under reduced pressure and remove water by lyophilization to give the product as a white solid.

[0282] Example 29: N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide

[0283]

[0284] To an ice-cooled solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (246 mg, 0.4300 mmol) in DCM (2.5 mL), phenylacetyl chloride (98.9 mg, 0.6400 mmol) was carefully added. The resulting mixture was allowed to reach room temperature and, after approximately 1 hour, the reaction was quenched by adding a few drops of water. The solvent was removed and acetonitrile was added to approximately 4 mL of total volume. The mixture was filtered and purified by reversed-phase chromatography (see General Methods). The solvent was removed under reduced pressure and the resulting water was removed by freeze drying, resulting in a product that was a white solid.

[0285] Example 30: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one

[0286]

[0287] To an ice-cooled solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (intermediate B) (249 mg, 0.4300 mmol) in DCM (2.5 mL), isobutyryl chloride (69 mg, 0.6500 mmol) was carefully added. The resulting mixture was allowed to reach room temperature and, after approximately 1 hour, the reaction was quenched by adding a few drops of water. The solvent was removed and acetonitrile was added to approximately 4 mL of total volume. The mixture was filtered and purified by reversed-phase chromatography (see General Methods). The solvent was removed under reduced pressure and the resulting water was removed by freeze drying, resulting in a product that was a white solid.

[0288] Example 31: 2-Methylpropionic acid [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecano-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] ester

[0289]

[0290] Isobutyryl chloride (62.49 mg, 0.5900 mmol) was added in a single batch to a mixture of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one (Example 1) (231 mg, 0.3900 mmol) and 4-(dimethylamino)pyridine (23.88 mg, 0.2000 mmol) in DCM (2.5 mL). The mixture was stirred overnight at room temperature. 0.1 mL of water was added. The reactants were concentrated and diluted with acetonitrile to approximately 4 ml, filtered, and the product was purified by reversed-phase chromatography (see General Methods). The purified fraction was concentrated under reduced pressure and water was removed by lyophilization to give the product as a white solid.

[0291] Compound testing

[0292] Example A: Antimicrobial activity

[0293] The antimicrobial activity of each example compound was investigated. The minimum inhibitory concentration (MIC – the minimum dose required to inhibit bacterial growth) and minimum bactericidal concentration (MBC – the minimum dose required to kill bacteria) of each compound against *Streptococcus pneumoniae* (ATCC49619), *Staphylococcus aureus* (ATCC29213), *Bacillus megaterium* (BM-11), and *Escherichia coli* (D-21) were measured on microtiter plates using an antimicrobial culture dilution method. The MIC of each example compound and azithromycin was also measured using the *Mycobacterium avium* complex (MAC). The *Mycobacterium avium* complex (MAC) is a term encompassing both *M. avium* and *M. intracellulare*.

[0294] Experiment 1:

[0295] The antimicrobial activity of example compounds 1 to 31 and azithromycin was investigated. The minimum inhibitory concentration (MIC – the minimum dose required to inhibit bacterial growth) and minimum bactericidal concentration (MBC – the minimum dose required to kill bacteria) of each compound against Streptococcus pneumoniae (ATCC49619), Staphylococcus aureus (ATCC29213), Bacillus megaterium (BM-11), and Escherichia coli (D-21) were measured on 96-well microtiter plates using the antimicrobial culture dilution method.

[0296] A 256 μg / mL stock solution of each compound was prepared in Mueller-Hinton medium and then further diluted by 2-fold serial dilutions. Serial dilutions were performed on 96-well microtiter plates to maintain 50 μL of the diluted compound per well. Each compound was diluted in duplicate. Compounds to be cultured with Streptococcus pneumoniae (ATCC49619) were diluted in Mueller-Hinton medium containing 5% horse blood and 20 mL / L βNAD.

[0297] The bacterial culture was diluted with sterile saline to obtain a solution with a value of 0.5 on the McFarland turbidity standard. This solution was then further diluted in Mueller-Hinton medium (1:100). 50 μl of the diluted culture was added to each well of a 96-well plate to obtain approximately 10 6 Cell densities of 100 cells / mL and a final test volume of 100 μl were used. Final compound concentrations after adding bacterial solution ranged from 128, 64, 32, 16, 8, 4, 2, 1, 0.5, and 0.25 μg / mL. Compounds were tested at higher concentrations of 500 and 1000 μg / mL. Control groups included wells containing only culture medium and bacteria, and wells containing only culture medium.

[0298] After adding the bacterial solution, the plate was incubated at 35°C for 18 hours. Bacterial growth was then recorded for each well, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MIB) were subsequently determined.

[0299] Experiment 2:

[0300] The minimum inhibitory concentration (MIC) of the example compound and azithromycin was measured using the Mycobacterium avium complex (MAC). The Mycobacterium avium complex (MAC) is a term encompassing both Mycobacterium avium and intracellular Mycobacteria. The sensitivity of the MAC to the test compound was assessed using a 2,3-diphenyl-5-thienyl-(2)-tetraazole chloride (STC) colorimetric microplate assay described by Park et al. (J. Korean Med Sci. 2009, 24(3), 511-2).

[0301] Each compound was tested in duplicate using two different strains: Mycobacterium avium (S1002170205 and S1003050114) and Mycobacterium intracellulare (S1005200018 and S1303150028). All strains were sensitive to clarithromycin (CLR), the selected drug for anti-MAC infection, but sensitivity to other drugs (amikacine, clofazimine, clarithromycin, ethambutol, ofloxacin, rifabutin, rifampin, and isoniazid) varied.

[0302] A 256 μg / mL stock solution of each compound was prepared in Middlebrook medium and then further diluted by 2-fold serial dilutions. Serial dilutions were performed on 96-well microtiter plates to maintain 50 μL of the diluted compound per well. Each compound was diluted in duplicate. Middlebrook medium was supplemented with STC to obtain a final experimental concentration of 50 μg / mL.

[0303] MAC strains in The culture was propagated in the medium for 10 days and then transferred to Middlebrook medium and incubated for another 5 days at 37°C. The bacterial strain was then diluted to obtain a reading of 1 on the McFarlane turbidity standard. The culture was then further diluted, and a total of 50 μl was added to each well of a 96-well plate to obtain a cell density of approximately 102. 6 Cells / mL and a final test volume of 100 μl. Final compound concentrations after adding bacterial solution ranged from 128, 64, 32, 16, 8, 4, 2, 1, 0.5, and 0.25 μg / mL. Control groups included wells containing only culture medium and bacteria, and wells containing only culture medium. Compounds were also tested at higher concentrations of 250, 500, and 1000 μg / mL against strains S1002170205 (Mycobacterium avium) and S1303150028 (Mycobacterium intracellulare).

[0304] After 7 days, bacterial growth was determined by recording changes in STC colorimetric analysis. This data was then used to determine the minimum inhibitory concentration (MIC) for each compound.

[0305] result:

[0306] For the antibacterial study in Experiment 1, azithromycin was found to have the following MIC and MBC concentrations:

[0307]

[0308] For each of the four bacteria studied, all example compounds of the present invention exhibited higher MIC or MBC concentrations compared to azithromycin. For example compounds 2, 3, 4, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31, for each of the four bacteria studied, the MIC or MBC concentrations exceeded those of azithromycin by more than 16 times. For each of the four bacteria studied, the MIC and MBC concentrations of example compounds 2, 3, 4, 7, 8, 9, 10, 11, 16, 18, 22, 24, 26, 27, 28, 29, and 30 exceeded those of azithromycin by more than 32 times.

[0309] In Experiment 2, azithromycin was found to have the following MIC (μg / ml) concentration:

[0310]

[0311] For each of the mycobacteria studied, all example compounds of the present invention exhibited higher MIC concentrations compared to azithromycin. For compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31, for each of the mycobacteria studied, the MIC concentration was more than four times that of azithromycin. For Mycobacterium avium S1002170205 and Mycobacterium intracellulare S1305150028, the MIC concentration for each compound was more than 15 times that of azithromycin, for example compounds 2, 3, 4, 7, 9, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 and 31.

[0312] Example B: Measurement of transepithelial drug resistance in immortalized VA10 or BCI-NS1.1 cells cultured at the air-liquid interface (ALI) in the presence of the test compound:

[0313] Prepare the stock solution as follows:

[0314] DMEM / F12 + FBS solution: Add 2.5 ml of Pen / Strep (Gibco 15070) to 500 ml of DMEM / F12 solution (Gibco 11330-032). Take 45 ml of the sample aliquot and add 5 ml of FBS solution to obtain a final FBS concentration of 10%.

[0315] DMEM / F12 + Ultroser G (UG) solution: Add 20 ml of sterile cell culture grade water to one vial of UG and allow it to dissolve in the dark at room temperature for 30 minutes. Add 10 ml of the UG mixture to 500 ml of DMEM / F-12. Add 2.5 ml of Pen / Strep (Gibco 15070) and store the solution in the dark at 4°C. Store another 10 ml of UG in the dark at -20°C.

[0316] Collagen: Combine 166 μl of acetic acid with 83.3 ml of cell culture grade water. Dissolve the collagen in 3–5 ml of this mixture. Add one whole vial of collagen (human type IV collagen (Sigma C7521-50 mg)) to the acetic acid / water mixture. Store this 10× stock solution at -20°C. Dilute a small portion in cell culture grade water for use as a 1× working solution. Filter both the working and stock solutions through a 0.2 μm pore size filter membrane.

[0317] ALI wells: Use ALITranswell filter membranes: 6.5 mm (Corning 3470), 12 mm (Corning 3460). Add enough 1× collagen to the wells to cover the membranes, and then incubate them at room temperature or 37°C for at least one hour. Aspirate the collagen. Wash the membranes with 1×PBS, and then completely dry the membranes (~30 minutes) using the cap portion before use.

[0318] program:

[0319] On day 2, BCI-NS1.1 / VA10 cells suspended in DMEM / F-12+FBS were transferred to the upper chamber of each membrane, as shown below:

[0320] -6.5 mm well: 15 × 10⁻⁶ BCI-NS1.1 cells in 200 μl of culture medium 4 individual cells

[0321] -6.5mm well: VA10 cells in 200μl of culture medium, 6×10 4 individual cells

[0322] -12mm well: 0.5 × 10⁻¹² BCI-NS1.1 cells in 500 μl of culture medium 6 individual cells

[0323] -12mm well: 0.2 × 10⁻¹² VA10 cells in 500 μl of culture medium 6 individual cells

[0324] DMEM / F-12+FBS culture medium was added to the lower chamber as follows:

[0325] -6.5mm well: 1ml culture medium

[0326] -12mm well: 1.5ml culture medium

[0327] The cells were stored at 37°C and 5% CO2.

[0328] On day 1, aspirate the culture medium from the lower chamber, then from the upper chamber. The culture medium in both chambers is then replaced with DMEM / F-12+UG, as follows:

[0329] -6.5mm orifice: 1 ml in the lower chamber; 200 μl in the upper chamber

[0330] -12mm orifice: 1.5ml in the lower chamber; 500μl in the upper chamber.

[0331] The membrane was stored at 37°C and 5% CO2.

[0332] On day 0, transepithelial impedance (TER) was measured. Culture medium was then aspirated from the lower chamber and replaced in the lower chamber with the studied test sample from DMEM / F-12+UG (the same volume as previously applied). Culture medium in the upper chamber was then aspirated. The chamber was flushed once with PBS, followed by aspiration until the upper chamber was free of liquid.

[0333] The membrane was stored at 37°C and 5% CO2.

[0334] The culture medium in the lower chamber is changed every 2 days, and any liquid is aspirated from the upper chamber. TER is measured every 2 days.

[0335] For each compound, the ratio of TER in the presence of the test compound to TER in the presence of only culture medium and diluent was calculated.

[0336] For example compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, and 30, the TER impedance of immortalized VA10 cells cultured at the air-liquid interface (ALI) was measured. In each case, the ratio of TER in the presence of the test compound to TER in the presence of culture medium + diluent only was greater than 1.0. For example compounds 1, 2, 5, 8, 9, 11, 12, 14, 15, 16, 17, 19, 20, 22, 23, 24, 25, 27, and 28, the ratio was greater than 2.0. For example compounds 2, 5, 9, 11, 16, 17, 19, 20, 22, 23, 24, and 25, the ratio was greater than 3.0. These data indicate that the compounds of the present invention enhance the barrier function of epithelial cells.

[0337] TER impedance was measured in immortalized BCI-NS1.1 cells cultured at the air-liquid interface (ALI) for example compounds 1, 2, 3, 5, 6, 11, 12, 14, 16, 23, 24, and 25. The ratio between TER in the presence of the test compound and TER in the presence of culture medium + diluent only was calculated. For example compounds 1, 2, 11, 14, 16, 23, and 25, the ratio was greater than 2.0. For example compounds 1, 2, 11, and 16, the ratio was greater than 3.0. These data indicate that the compounds of the present invention enhance the barrier function of epithelial cells.

[0338] Example C: Solubility and Stability

[0339] For certain compounds, their solubility and stability in plasma were measured. The method is as follows:

[0340] Solubility in 10 mM phosphate buffer (pH 7.4):

[0341] Solubility tests of compounds were performed using HPLC-MS in phosphate buffer (pH 7.4). For each compound, a 10 M stock solution in DMSO was prepared. For the solubility test sample, 100 μL of the stock solution was diluted to a final concentration of 250 mM with 3.9 mL of 10 mM phosphate buffer (pH 4.7). The buffer solution was allowed to stand at room temperature for 60 min and then filtered. The filtrate was analyzed using HPLC-MS relative to two calibration points of the same analyte prepared at 250 mM and 25 mM. These calibration points were prepared from the same stock solution as the solubility sample by diluting it with DMSO:H₂O (1:1) at a 1:40 ratio and then again with a 1:10 ratio. The chromatographic signal area of ​​the analyte in the solubility sample was then compared with the chromatographic signal areas of the two calibration samples.

[0342] Using a 50×2.1mm x BridgeC HPLC system on a Waters HPLC-MS system 18 Chromatographic separation was performed using a column and gradient elution with water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. (M+H) was recorded in a single ion. + The analytes were analyzed using positive electrode electrospray mode.

[0343] Stability in mouse and human plasma:

[0344] The stability of compounds in mouse and human plasma was performed using protein precipitation as sample purification and HPLC-MS detection. Plasma stability studies of the compounds were performed at room temperature for up to 4 hours. For each compound, a 10M stock solution in DMSO was prepared. For plasma stability samples, 100 μL of the stock solution was diluted to a final concentration of 250 mM with 3.9 mL of mouse or human plasma. The plasma was allowed to equilibrate at room temperature for 10 minutes prior to the first analysis. For each analytical time point (0, 30, 60, 120, 240, and 360 minutes), 100 μL of plasma aliquots were taken and protein precipitation (PPT) was performed on the aliquots by adding 900 μL of (ACN:DMSO) 95:5. The precipitated sample was shaken for 60 seconds and then centrifuged. The supernatant was transferred to an HPLC vial and analyzed using HPLC-MS. The chromatographic signal area of ​​the samples at different time points was then compared with each other by setting the initial analysis at t = 0 minutes as 100% and then calculating the % value for each subsequent time point.

[0345] Using a 50×2.1mm x BridgeC HPLC system on a Waters HPLC-MS system 18 Chromatographic separation was performed using a column and gradient elution with water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. (M+H) was recorded in a single ion. + The analytes were analyzed using positive electrode electrospray mode.

[0346] The results are as follows:

[0347]

[0348]

[0349] Example D: Enhanced barrier integrity in the lungs

[0350] The effects of the compounds of this invention on maintaining the barrier integrity in the lungs of mice exposed to sulfur dioxide damage were investigated.

[0351] method:

[0352] 1. Fifteen female mice were randomly divided into three groups of five mice each. The three groups were as follows:

[0353] a) Control group

[0354] b) Azithromycin treatment group

[0355] c) Research Compound Treatment Group

[0356] 2. Mice were pretreated with the following method for three consecutive days:

[0357] a) Placebo (phosphate-buffered saline-PBS) was administered intravenously at a dose of 10 mg / kg three times a week.

[0358] b) Azithromycin: 100 μl is administered intravenously three times a week at a dose of 10 mg / kg.

[0359] c) The compound of Example 2: 100 μl was administered intravenously three times a week at a dose of 10 mg / kg.

[0360] 3. One mouse in each group was placed on one side as a control. Four mice were then exposed to 200 ppm sulfur dioxide gas in the air for 60 minutes. Mice were placed in cages inserted into 45L treatment boxes with removable lids, gas feed lines, and exhaust outlets. The gas was fed into the middle box at a rate causing approximately 7 volume changes per hour. The gas was premixed in the first box from bottled air and bottled 200 ppm SO2, and then fed into the treatment box. The level of SO2 fed into the treatment box could be varied by adjusting the relative flow rates of air and SO2 from the two source gas canisters. Because the sulfur dioxide concentration was 200 ppm in this experiment, pure sulfur dioxide was used without additional air mixing. Mice received food and water during the duration of the treatment.

[0361] 4. Twenty-four hours after treatment, 1 mg of human serum albumin (HSA) in 100 μl of saline was injected into the tail vein of each mouse, and fluorescent glucosamine (FD) was injected into the respiratory tract. The mice were then sedated for 90 minutes.

[0362] 5. After 90 minutes, the mice were euthanized by exsanguination. Plasma and bronchoalveolar lavage fluid (BAL) were collected, and the lungs were processed for paraffin embedding.

[0363] 6. Quantify the HSA level in BAL by ELISA. The ELISA assay used was an ELISA assay available from Antibody Cambridge (Human Serum Albumin Kit AB179887). Absorbance was measured at 600 nm according to the kit manufacturer's instructions. Fluorescent glucan was quantified using a fluorescent plate reader.

[0364] The level of HSA that leaks into the lungs (as found in BAL) is a measure of the integrity of the lung epithelial barrier.

[0365] result:

[0366] In the placebo group, experimental difficulty was observed in two out of four mice; in the azithromycin group, it was observed in one out of four mice; and in the investigational compound group, it was observed in two out of four mice. Therefore, results were obtained from two mice in each of the placebo and investigational compound groups, and from three mice in the azithromycin group. HSA data were read as follows:

[0367]

[0368] Data in Figure 1 The bar chart is shown in the image.

[0369] It is evident that, compared to the control group, azithromycin and the compound from Example 2 reduced HSA leakage into the lungs after SO2 injury. This suggests that azithromycin and the compound from Example 2 enhance the resilience of the barrier function of epithelial cells in the lungs.

Claims

1. A compound according to formula (I), wherein R 1 OH, N-(C 6-14 aryl-C 1-6 alkyl)carbamoyloxy, N,N-di-alkylcarbamoyloxy of two alkyl substituents which form, together with the nitrogen atom of the carbamoyl moiety, a 5- to 8-membered heterocyclic ring and C 1-6 alkylcarboxy, wherein the alkyl, aryl and / or the heterocycle in R 1 are optionally substituted with 1 to 6 halogen and / or CN; and R 2 According to formula (III) wherein R 7 selected from the group consisting of C 6-14 aryl-C 1-6 alkyl, 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-(CH2) m -(CO)-, wherein m is 0 to 6, substituents of formula (V.1) wherein Ar is C 6-14 aryl and n, p and q are independently 0 to 6, and C 6-14 aryl-C 1-6 alkyl-O-CO-NH-C 1-6 alkyl-CO-, wherein the alkyl in R 7 is optionally substituted with 1 to 6 halogen and / or CN; and wherein the aryl group in R 7 is substituted with 1 to 6 halogen and / or CN; and R 8 is selected from the group consisting of H; optionally substituted C 1-3 alkylsulfonyl, C 1-3 alkyl and / or C 1-3 alkoxy; C 6-14 arylcarbonyl; C 3-6 alkylcarbonyl; HOOC-(CH2) m -(CO)-, wherein m is 0 to 6; a substituent of formula (V.1) as depicted above, wherein Ar is C 6-14 aryl and n, p and q are independently 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, which ring of the heteroarylcarbonyl is optionally substituted with 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 alkenyloxy, halogen and CN, wherein the alkyl and / or aryl groups in R 8 are optionally substituted with 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, wherein alkyl is optionally substituted by 1 to 6 halogen and / or CN, or R 4 and R 5 together form a single carbonyl group which forms a cyclic carbonate with the two oxygen atoms to which it is bonded; or pharmaceutically acceptable hydrates or salts thereof, including salts of such hydrates.

2. The compound of claim 1, wherein R 1 is selected from the group consisting of OH and C 1-3 alkylcarboxyl.

3. The compound of claim 1 or 2, wherein R 1 is OH.

4. The compound according to claim 1 or 2, wherein R 7 is selected from the group consisting of C 6-10 aryl-C 1-3 alkyl, 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-(CH2) m -(CO)-, wherein m is 0 to 3, a moiety according to formula (V.2) wherein Ar is C 6-10 aryl and each of n, p and q is independently 0 to 3, C 6-10 aryl-C 1-3 alkyl-O-CO-NH-C 1-3 alkyl-CO-, C 6-10 arylcarbonyl and C 1-3 alkyl-C 6-10 arylcarbonyl; wherein the alkyl in R 7 is optionally substituted with 1 to 6 halogen and / or CN; and wherein the aryl group in R 7 is substituted with 1 to 6 halogen and / or CN; and R 8 is selected from the group consisting of H, C 6-10 arylcarbonyl, 1 to 3 halogen atoms, C 1-2 alkyl and / or C 1-2 alkoxy-substituted C 6-10 arylcarbonyl, straight-chain or branched C 3-4 alkylcarbonyl, HOOC-(CH2) m -(CO)-, wherein m is 0 to 3, According to moieties of the formula (V.2) as depicted above, wherein Ar is C 6-10 aryl and n, p and q are each independently 0 to 3, C 1-3 alkylsulfonyl-di-C 6-10 aryl-carbonyl, and heteroarylcarbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are in each case selected from the group consisting of N, O and S, which ring of the heteroarylcarbonyl is optionally 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 alkenyloxy, halogen.

5. The compound according to claim 1 or 2, wherein R 7 is selected from the group consisting of benzyl, benzoyl, naphthalenesulfonyl, methylphenylsulfonyl, isopropylcarbonyl, succinyl, benzylcarbonyl, phenyloxyethylcarbonyl, benzyl- oxymethylcarbonyl, benzyl-O-CO-NH-CH2-CO- and a moiety according to formula (V.2), wherein Ar is phenyl, n = p = 1 and q = 2, wherein the alkyl in R 7 is optionally substituted with 1 to 6 halogen and / or CN; and wherein the aryl group in R 7 is substituted with 1 to 6 halogen and / or CN.

6. The compound according to claim 1 or 2, wherein R 8 is selected from the group consisting of isopropylcarbonyl, succinyl, benzoyl, iodo- benzoyl, ethylphenylcarbonyl, methoxyphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthylcarbonyl, a moiety according to formula (V.2), wherein Ar is phenyl, n = p = 1 and q = 2, pyrazolylcarbonyl, dimethylpyrazolylcarbonyl, phenylthio, chloro- phenylthio, pyridylcarbonyl and quinolylcarbonyl, wherein the alkyl, aryl and / or the heterocycle in R 8 is optionally substituted with 1 to 6 halogen and / or CN.

7. The compound according to claim 1 or 2, wherein R 1 is OH; R 7 is selected from the group consisting of moieties according to formula (V.2), wherein Ar is phenyl, n and p are each identical 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, wherein alkyl, aryl and / or the heterocycle in R 7 are optionally substituted by 1 to 3 halogen and / or CN; and R 8 is selected from the group consisting of H, HOOC-(CH2) m -(CO)-, wherein m is 1 to 3, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthylcarbonyl, wherein the alkyl, aryl and / or heterocycle in R 8 is optionally substituted by 1 to 3 halogen and / or CN.

8. The compound of claim 1 or 2, wherein R 8 is H.

9. The compound according to claim 1 selected from the group consisting of: N-[(2S,3R,4S,6R)-2-{[{2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy}- 3-hydroxy-6-methyloxan-4-yl]-N-methylbenzamide; N-[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy}- 3-hydroxy-6-methyloxan-4-yl]-N-methylnaphthalene-2-sulfonamide; (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-2{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6- azacyclopentadec-11-yl]oxy}-3-hydroxy-6-methyloxan-4-yl](methyl)carbamoyl}butyric acid benzyl ester; 3-{[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy}- 3-hydroxy-6-methyloxan-4-yl](methyl)carbamoyl}propanoic acid; 2-benzyloxy-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]- 3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-acetamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecyl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecyl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecyl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide.

10. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 or 9 and at least one pharmaceutically acceptable excipient.

11. Use of a compound according to claim 1 or 9 for the manufacture of a medicament for the treatment of a disease or condition caused by a defect in epithelial cells or tissue or a disease or condition that would benefit from enhanced or reconstituted epithelial barrier function.

12. Use according to claim 11, wherein the disease or condition is a disease of the respiratory tract and the epithelial tissue is in respiratory tract epithelial tissue.

13. Use according to claim 12, wherein the disease or condition is a disease of the respiratory tract and the epithelial tissue is in respiratory tract epithelial tissue of the nasal cavity, sinuses, larynx, bronchi, bronchioles, distal airways or alveoli.

14. Use according to claim 12, wherein the disease or condition is a disease of the respiratory tract and the epithelial tissue is in respiratory tract epithelial tissue of the nose, trachea.

15. The use of claim 11 or 12, wherein the condition is a congenital, chronic, persistent or long-term respiratory disease selected from the group consisting of 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-transplant status, bronchopulmonary dysplasia, pneumonia, and conditions caused by and associated with respiratory syncytial virus (RSV) and related viruses.

16. The use of claim 11 for treating diseases or disorders generally associated with inflammation that would benefit from enhanced or reestablished epithelial barrier function.

17. The use of claim 15 for treating diseases or disorders generally associated with inflammation that would benefit from enhanced or reestablished epithelial barrier function, wherein the disease or disorder is selected from the group consisting of adult respiratory distress syndrome (ARDS), inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

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