Azithromycin derivatives for use in the treatment of eosinophil-related diseases

Abstract

The current invention relates to the use of macrolide derivatives, for example, azithromycin derivatives for the treatment of eosinophil-associated pathologies, for example, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes. Furthermore, the invention relates to the use of macrolide derivatives, for example, azithromycin derivatives for the reduction of Type 2 inflammation. The invention also relates to the use of eosinophil number to directed therapeutic treatment.

Description

[0001] AZITHROMYCIN DERIVATIVES FOR USE IN THE TREATMENT OF EOSINOPHIL-RELATED DISEASES

[0002] Field of the invention

[0003] The current invention relates to the use of macrolide derivatives, for example, azithromycin derivatives for the treatment of eosinophil-associated pathologies.

[0004] Background

[0005] Macrolides have a range of physiological activities. The majority of macrolides have an antimicrobial effect as part of their therapeutic mode of action. The macrolides are not only classified in terms of activity but also based on structure. Erythromycin, the original naturally occurring macrolide, has a 14-membered macrolactone as a backbone. The 12-, 13-, 15- and 16-membered macrolides are mostly modified derivatives of erythromycin as well as the closely related ketolides, which are broad spectrum antimicrobials.

[0006] Many macrolides exhibit a range of disease modifying activities in various diseases of seemingly unrelated aetiology. In addition to antimicrobial activity, some macrolides have been proposed to possess alternative “non-antimicrobial” effects. Some of those effects have been proposed to manifest themselves in a disease modifying mode of action in humans that is primarily anti-inflammatory or immunomodulatory (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 macrolide compounds that have selective immunomodulatory effects (see Fecik el al., Current Opinion in Drug Discovery and Development, 2005, 8(6), 741-747).

[0007] In at least two double blind clinical trials azithromycin (“Azm”) has been shown to reduce the hospitalisation rate 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 defence against Pseudomonas aeruginosa, as well as increasing transepithelial resistance (“TER”) in epithelial cells in vitro ALI culture and increases cellular processing of tight junctions. Erythromycin and penicillin have been found not to exhibit similar effects (see Asgrimsson V et a\ (2006) Novel effects of azithromycin on tight junction proteins in human airway epithelia, Antimicrob Agents Chemother, 50: 1805-1812 and Halldorsson S et al. (2010) Azithromycin Maintains Airway Epithelial Integrity During Pseudomonas aeruginosa Infection. Am J Respir Cell Mol Biol. 2010, 42(1), 62-68.).

[0008] Eosinophils are tissue dwelling hematopoietic cell types that play a role in parasitic immunity and allergic disease (For a review see: Wechsler et al (2021) Mayo Clin. Proc. 96(10) 2694- 2707). Eosinophils develop in the bone marrow from hematopoietic stem cells and migrate mainly to the gut or to sites of inflammation. Eosinophils, neutrophils and monocytes have a common progenitor in the myeloid pathway of development. The eosinophil is an effector cell in the pathophysiology of a wide variety of diseases. Eosinophils possess and / or produce toxic basic proteins, e.g., major basic protein (MBP) and eosinophil-cationic protein (ECP), which they are able to deposit on their targets. They also possess and / or produce toxic oxygen metabolites, including H2O2, and hypohalous acids, including hypobromous acid. For example, hypobromous acid is a potent oxidant that is generated by the eosinophil peroxidase (EPOj+EECh+Br-. The ability of the eosinophil to kill targets can be increased by activators produced by other cells, such as T lymphocytes. These other cells can synthesise a series of glycoprotein hormones that regulate eosinophil function, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and IL-5. Information obtained over the past several years has indicated that eosinophils themselves have the ability to produce cytokines, such as GM-CSF, and IL-3. These cytokines can activate the eosinophil itself, in an autocrine fashion. Eosinophilia is the infiltration of eosinophils into tissues such as blood or lung, and the activation of those eosinophils, which results in the production of eosinophil-derived proteins that in turn mediate pathogenic effects.

[0009] Eosinophil levels in blood are used to select appropriate treatment regimens for chronic obstructive disease patients (COPD). Patients with greater than about 100 eosinophils per microlitre (pl) of blood are treated with inhaled corticosteroids, whilst patients with less than 100 eosinophil s / pl of blood can be treated with azithromycin (Azm) (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2024 Report); https: / / goldcopd.org / 2024-gold-report / ). We have found that compounds of formula (I) reduce eosinophil levels in blood which opens up the possibility of treating more COPD patients, i.e. extending the treatment group to those with higher eosinophil levels, as well as opening up the possibility of treating additional disease conditions.

[0010] Examples of azithromycin derivatives can be found in International application, WO 2017 / 085329. Summary of the Invention

[0011] In a first embodiment, the invention provides a compound according to formula (I) for use in the treatment of an eosinophil-associated pathology; wherein:

[0012] R1is selected from the group consisting of OH, carbamoyloxy, N-Ci-6-alkylcarbamoyloxy, N-(C6-i4-aryl-Ci-6-alkyl)carbamoyloxy, N,N-di-Ci-6-alkylcarbamoyloxy, N,N-di- alkylcarbamoyloxy with the two alkyl substituents together forming a 5- to 8- membered heterocycle together with the nitrogen atom of the carbamate moiety, Ci-6- alkylcarboxy and a moiety according to formula (II) wherein

[0013] R6is selected from the group consisting of H, OH and Ci-6-alkyl, whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to 6 halogen and / or CN; and R2is according to formula (III)

[0014] (Ill), wherein

[0015] R7is selected from the group consisting of Ci-6-alkyl, C6-i4-aryl-Ci-6-alkyl, C3-6- alkylcarbonyl, Ce-i 4-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl, Ce-w-arylsulfonyl, C1-6- alkyl-Ce-w-arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl, C6-i4-aryl-O-Ci-6-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-Ci-6-alkyl-carbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6,

[0016] C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and

[0017] Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN; and R8is selected from the group consisting of H; Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups; C3-6-alkylcarbonyl; H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being Ce-w-aryl and n, p and q being independently from 0 to 6; and heteroaryl carbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4- alkoxy, C2-4-alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen and / or CN;

[0018] R3is H; and

[0019] R4and R5are independently selected from H and Ci-6-alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and / or CN, or

[0020] R4and R5together form a single carbonyl group which forms a cyclic carbonate with both oxygen atoms it is bonded to; and with the proviso that the compound of formula (I) is not 2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-l l-[(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-l-oxa-6- azacyclopentadecan- 15 -one (Azithromycin); or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0021] In a further embodiment, the invention provides a compound according to formula (I), as defined herein, for use in the treatment of an eosinophil-associated pathology provided that if R6is H or methyl, then R8is not H, and provided that if R1is OH and R7is methyl, then R8is not H; and provided that if R8is C4 alkylcarbonyl, then R1is not a moiety according to formula (II); or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0022] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the treatment of the eosinophil-associated pathology.

[0023] The invention further provides method of treating an eosinophil-associated pathology comprising the administration of a compound of formula (I), as defined herein.

[0024] The invention further provides method of treating an eosinophil-associated pathology comprising the administration of an effective amount of a compound of formula (I), as defined herein.

[0025] In one embodiment the eosinophil-associated pathology is selected from eosinophilic asthma, chronic eosinophilic pneumonia, giant papillary conjunctivitis, vernal conjunctivitis, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, allergic asthma, and allergic gastroenteropathy, eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, episodic angioedema associated with eosinophilia, idiopathic hyper-eosinophilic syndrome, bullous pemphigoid, episodic angioedema associated with eosinophilia, urticaria, drug reactions, reactions to insect stings, cutaneous T-cell lymphoma (CTCL), Eosinophilia myalgia syndrome, eosinophilic esophagitis and toxic oil syndrome. In one embodiment, the eosinophil-associated pathology is not asthma, for example, not eosinophilic asthma.

[0026] The invention further provides a compound of formula (I), as defined herein, for the reduction of Type-2 inflammation.

[0027] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the treatment of Type-2 inflammation. The invention further provides a method of treating Type-2 inflammation comprising the administration of a compound of formula (I), as defined herein.

[0028] Disorders, conditions and diseases which are characterised by Type-2 inflammation include, atopic dermatitis, food allergy, allergic rhinitis, conjunctivitis, chronic idiopathic urticaria, Chronic rhinosinusitis with nasal polyps (CSwNP) and eosinophilic oesophagitis.

[0029] The invention further provides a method of treating Type-2 inflammation comprising the administration of an effective amount of a compound of formula (I), as defined herein.

[0030] The invention further provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, and at least one pharmaceutically acceptable excipient, for use in the treatment of an eosinophil-associated pathology.

[0031] The invention further provides a compound of formula (I) as defined herein, for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than about 100 eosinophil s / pl of blood.

[0032] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than about 100 eosinophil s / pl of blood.

[0033] The invention further provides a method of treating a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient, comprising the administration of a compound of formula (I), as defined herein, wherein the patient has more than about 100 eosinophil s / pl of blood.

[0034] Higher thresholds may be suitable for selecting patients for treating a disease, for example, chronic obstructive pulmonary disease (COPD) patients, with a compound of formula (I). Therefore, the invention further provides a compound of formula (I) as defined herein, for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than about 150 eosinophil s / pl of blood. In further embodiments the patient has more than about 200, about 250, about 300, about 350, about 400, about 450 or about 500 eosinophil s / pl of blood.

[0035] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than about 150 eosinophil s / pl of blood. In further embodiments the patient has more than about 200, about 250, about 300, about 350, about 400, about 450 or about 500 eosinophils / pl of blood.

[0036] The invention further provides a method of treating a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient, comprising the administration of a compound of formula (I), as defined herein, wherein the patient has more than about 150 eosinophil s / pl of blood. In further embodiments the patient has more than about 200, about 250, about 300, about 350, about 400, about 450 or about 500 eosinophil s / pl of blood.

[0037] 300 eosinophil s / pl of blood is equivalent to about 2% of total the leukocytes in blood (see Ramakrishnan et al (2024) The Lancet 12, 67-77, which is incorporated herein by reference). Therefore, the invention further provides a compound of formula (I) as defined herein, for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than about 0.6% eosinophils (as a percentage of total leukocytes in blood). In further embodiments the patient has more than about 1%, about 1.3%, about 1.6%, about 2%, about 2.3%, about 2.6%. about 3% or about 3.3% eosinophils (as a percentage of total leukocytes in blood).

[0038] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the treatment of a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient wherein the patient has more than 0.6% eosinophils (as a percentage of total leukocytes in blood). In further embodiments the patient has more than about 1%, about 1.3%, about 1.6%, about 2%, about 2.3%, about 2.6%. about 3% or about 3.3% eosinophils (as a percentage of total leukocytes in blood).

[0039] The invention further provides a method of treating a disease, for example, chronic obstructive pulmonary disease (COPD), in a patient, comprising the administration of a compound of formula (I), as defined herein, wherein the patient has more than about 0.6% eosinophils (as a percentage of total leukocytes in blood). In further embodiments the patient has more than about 1%, about 1.3%, about 1.6%, about 2%, about 2.3%, about 2.6%. about 3% or about 3.3% eosinophils (as a percentage of total leukocytes in blood).

[0040] The invention further provides a compound of formula (I) as defined herein, for the inhibition of eosinophils.

[0041] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the inhibition of eosinophils.

[0042] The invention further provides a method of inhibiting eosinophils in a patient, comprising the administration of a compound of formula (I), as defined herein.

[0043] The invention further provides a compound of formula (I) as defined herein, for the inhibition of eosinophil function.

[0044] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the inhibition of eosinophil function.

[0045] The invention further provides a method of inhibiting eosinophil function in a patient, comprising the administration of a compound of formula (I), as defined herein.

[0046] The invention further provides a compound of formula (I) as defined herein, for the inhibition of eosinophil numbers.

[0047] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the inhibition of eosinophil numbers.

[0048] The invention further provides a method of inhibiting eosinophil numbers in a patient, comprising the administration of a compound of formula (I), as defined herein.

[0049] The invention further provides a compound of formula (I) as defined herein, for the inhibition of eosinophil recruitment. The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the inhibition of eosinophil recruitment.

[0050] The invention further provides a method of inhibiting eosinophil recruitment in a patient, comprising the administration of a compound of formula (I), as defined herein.

[0051] The invention further provides a compound of formula (I) as defined herein, for reducing allergen-induced eosinophilia.

[0052] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for reducing allergen-induced eosinophilia.

[0053] The invention further provides a method of reducing allergen-induced eosinophilia in a patient, comprising the administration of a compound of formula (I), as defined herein.

[0054] The invention further provides a compound of formula (I) as defined herein, for the depletion of eosinophils.

[0055] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the depletion of eosinophils.

[0056] The invention further provides a method for the depletion of eosinophils, comprising the administration of a compound of formula (I), as defined herein.

[0057] The invention further provides a compound of formula (I) as defined herein, for the depletion of eosinophil number.

[0058] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for the depletion of eosinophil number.

[0059] The invention further provides a method for the depletion of eosinophil number, comprising the administration of a compound of formula (I), as defined herein. In a further embodiment the invention provides a compound of Formula (I), as defined herein, for a use as defined above; provided that if R6is H or methyl, then R8is not H, and provided that if R1is OH and R7is methyl, then R8is not H; and provided that if R8is C4 alkylcarbonyl, then R1is not a moiety according to formula (II);

[0060] Detailed Description

[0061] As described above, the invention provides compounds of Formula (I), as defined herein for use in the eosinophil-associated pathology. Preferred compounds of Formula (I) are the compounds according to the invention wherein R1is selected from the group consisting of OH, Ci-3-alkylcarboxy, a moiety according to formula (II) wherein R6is OH, and a moiety according to formula (IV) wherein R9and R10are independently selected from the group consisting of H, Ci-3-alkyl and C6-io-aryl-Ci-3-alkyl or are together alkyl forming a 5- or 6-membered aliphatic heterocycle together with the nitrogen atom they are both bonded to, whereby said heterocycle optionally contains one or two, preferably one further heteroatom(s) selected from the group consisting of N, O and S, preferably from the group consisting of N and O, more preferably optionally contains one or two further O atoms, yet more preferably optionally contains one further O atom, or said heterocycle is selected from the group consisting of piperidine, piperazine and morpholin, preferably is morpholin, whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to 6 halogen and / or CN.

[0062] Particularly preferred compounds according to the invention are those wherein R1is OH.

[0063] In Formula (I), R2is a group of formula (III)

[0064] In an embodiment, R7is selected from the group consisting of Ci-6-alkyl, Ce-i4-aryl-Ci-6- alkyl, G,.14-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl, Ce-u-arylsulfonyl, Ci-6-alkyl-C6-i4- arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl, C6-i4-aryl-O-Ci-6-alkylcarbonyl, Ce-i4-aryl-Ci-6- alkyl-O-Ci-6-alkyl-carbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and

[0065] Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN

[0066] In an another embodiment, R7is selected from the group consisting of Ci-6-alkyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl-carbonyl, Ce-io-aryl-Ci-3-alkylcarbonyl, Ce-io-aryl-O-Ci-3-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO- and a moiety according to formula (V.l) or formula (V.2).

[0067] More preferred compounds of the invention are those wherein R7is selected from the group consisting of Ci-3-alkyl, Ce-io-aryl-Ci-3-alkyl, linear or branched, preferably branched C3-4- alkylcarbonyl, Ce-io-arylcarbonyl, Ce-io-aryl-Ci-3-alkylcarbonyl, Ce-io-aryl-O-Ci-3- alkylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl-carbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, C6-io-aryl-Ci-3-alkyl-0-CO-NH-Ci-3-alkyl-CO-, Ce-io-arylsulfonyl, and Ci-3-alkyl-C6-io-arylsulfonyl.

[0068] Yet more preferably R7is selected from the group consisting of methyl, benzyl, benzoyl, naphthylsulfonyl, methylphenylsulfonyl, isopropylcarbonyl, succinyl, benzyl carbonyl, phenoxyethylcarbonyl, benzyloxymethylcarbonyl, benzyl-O-CO-NH-CIb-CO- and a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN.

[0069] In an embodiment, R8is selected from the group consisting of H, Ce-i 4-ary 1 carbonyl (optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups), H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, aryl and heteroaryl carbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4-alkoxy, C2-4-alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl, and / or CN;

[0070] Preferably R8is selected from the group consisting of H, Ce-io-arylcarbonyl, Ce-io- arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups), linear or branched, preferably branched C3-4-alkylcarbonyl, H00C-(CH2)m-(CO)- (with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2), a moiety according to formula (V.2) as depicted hereinbefore (wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3), Ci-3-alkylsulfonyl-bi- Ce-io-aryl-carbonyl, and heteroaryl carbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, most preferably 1 heteroatom, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, preferably from the group consisting of N and O, most preferably being N, the ring of the heteroaryl carbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of Ci-2-alkyl, Ci-2-alkoxy, C2-3-alkenyl, C2-3-alkenoxy, halogen, in particular F and Cl, and CN, preferably selected from the group consisting of methyl, methoxy, F and Cl, most preferably selected from the group consisting of methyl and Cl.

[0071] Preferably R8is selected from the group consisting of H, Ce-io-arylcarbonyl, Ce-io- arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups), bi-Ce-io-aryl-carbonyl (optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl and / or CN) and H00C-(CH2)m-(CO)- (with m being from 1 to 3, most preferably 1 or 2).

[0072] Yet more preferably R8is selected from the group consisting of isopropylcarbonyl, succinyl, benzoyl, iodobenzoyl, ethylphenylcarbonyl, methoxyphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl, a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, pyrazolyl carbonyl, dimethylpyrazolylcarbonyl, thiophenyl, chlorothiophenyl, pyridyl carbonyl and quinolylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN.

[0073] For particularly preferred compounds of the invention R1is OH; and / or

[0074] R7is selected from the group consisting of Ci-3-alkyl, in particular methyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-Ci-2-alkyl-O-CO-NH-Ci-2-alkyl-CO- and phenyl-O-Ci-3-alkylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R7is optionally substituted by 1 to 3 halogen and / or CN; and / or

[0075] R8is selected from the group consisting of H, H00C-(CH2)m-(CO)- with m being from 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthyl carbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 3 halogen and / or CN.

[0076] For particularly preferred compounds of the invention R1is OH; R8is H and R7is selected from the group consisting of Ci-3-alkyl, in particular methyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-Ci-2- alkyl-O-CO-NH-Ci-2-alkyl-CO- and phenyl-O-Ci-3-alkylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R7is optionally substituted by 1 to 3 halogen and / or CN. Preferably, the R7group contains at least one aromatic ring.

[0077] For particularly preferred compounds of the invention R1is OH; R7is Me and R8is selected from the group consisting of H, H00C-(CH2)m-(CO)- with m being from 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthylcarbonyl, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 3 halogen and / or CN. Preferably, the R8group contains at least one aromatic ring.

[0078] A particularly preferred group of compounds of the invention is the group in which R1is OH; R8is H and R7is selected from the group consisting of Ce-io-aryl-Ci-3-alkyl, Ce-io- arylcarbonyl, Ce-io-aryl-Ci-3-alkylcarbonyl, Ce-io-aryl-O-Ci-3-alkylcarbonyl, Ce-io-aryl-Ci-3- alkyl-O-Ci-3-alkyl-carbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, Ce-io- aryl-Ci-3-alkyl-O-CO-NH-Ci-3-alkyl-CO-, Ce-io-arylsulfonyl, and Ci-3-alkyl-Ce-io- arylsulfonyl; whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN groups.

[0079] A particularly preferred group of compounds of the invention is the group in which R1is OH; R8is H and R7is selected from the group consisting of benzyl, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl naphthyl carbonyl, naphthylsulfonyl, methylphenylsulfonyl, succinyl, and a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3. For R7benzyl, benzoyl, naphthyl sulfonyl, methylphenylsulfonyl, succinyl, and a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3 are especially preferred.

[0080] An alternative particularly preferred compounds of the invention is the group in which R1is OH; R7is Me and R8is selected from the group consisting of Ce-io-arylcarbonyl, Ce-io- arylcarbonyl substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups, branched C3-4-alkylcarbonyl, H00C-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) as depicted hereinbefore wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, Ci-3-alkylsulfonyl-bi-C6-io-aryl-carbonyl, and heteroaryl carbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, most preferably 1 heteroatom, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, preferably from the group consisting of N and O, most preferably being N, the ring of the heteroaryl carbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of Ci-2-alkyl, C1-2- alkoxy, C2-3-alkenyl, C2-3-alkenoxy, halogen, in particular F and Cl, and CN, preferably selected from the group consisting of methyl, methoxy, F and Cl, most preferably selected from the group consisting of methyl and Cl. Within the R8group, an alkyl, aryl and / or heterocyclic group may optionally be substituted by 1 to 6, preferably 1 to 3 halogen atoms and / or CN group(s).

[0081] A further particularly preferred compounds of the invention is the group in which R1is OH; R7is Me and R8is selected from the group consisting of isopropyl carbonyl, succinyl, benzoyl, halobenzoyl (for example iodobenzoyl), ethylphenylcarbonyl, methoxyphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthylcarbonyl, a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, pyrazolyl carbonyl, dimethylpyrazolylcarbonyl, thiophenyl, chlorothiophenyl, pyridyl carbonyl and quinolylcarbonyl.

[0082] A particularly preferred group of compounds of the invention are compounds of Formula (I) herein

[0083] R1is OH;

[0084] R2is according to formula (III) wherein

[0085] R7is Ci-6-alkyl; and R8is selected from the group consisting of Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from Ci-3-alkyl sulfonyl groups and / or Ci-3-alkyl groups; H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6;

[0086] R3is H; and

[0087] R4and R5are both H; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0088] In such a compound, for example R7is Me. For example, R7is Me and R8is selected from the group consisting of Ce-io-arylcarbonyl, Ce-io-arylcarbonyl substituted with 1 to 3 Ci^- alkyl sulfonyl groups or Cis-alkyl groups, H00C-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.l) as depicted hereinbefore wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3. Within the R8group, an alkyl, aryl and / or heterocyclic group may optionally be substituted by 1 to 6, for example 1 to 3 halogen atoms and / or CN group(s). For example, R7is Me and R8is selected from the group consisting of succinyl, benzoyl, halobenzoyl (for example iodobenzoyl), ethylphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl and a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2.

[0089] Further preferred compounds according to the invention are the following:

[0090] (2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-l l-{[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10, 13-tetrahydroxy-3,5,6,8, 10, 12, 14- heptamethyl- l-oxa-6-azacyclopentadecan- 15 -one;

[0091] (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl- 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan- 1 l-yl]oxy}-6-methyloxan-3-yl benzoate;

[0092] (3aR,4R,7R,8S,9S,10R,l lS,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-3- (benzoyloxy)-4-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-ethyl-l 1 -hydroxy-

[0093] 3 a, 7, 9,1 l,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[l,3]dioxolo[4,5-c]l-oxa-6- azacyclopentadecan-8-yl morpholine-4-carboxylate;

[0094] (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,l lS,13R,16R,16aR)-8- [(benzylcarbamoyl)oxy]-4-ethyl-l l-hydroxy-3a,7,9,l l,13,15,16-heptamethyl-2,6-dioxo- tetradecahydro-2H-[l,3]dioxolo[4,5-c]l-oxa-6-azacyclopentadecan-10-yl]oxy}-4- (dimethylamino)-6-methyloxan-3 -yl benzoate;

[0095] (2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-1 l-{[(2S,3R,4S,6R)-4- [benzyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-13- {[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,6,8,10,12,14- heptamethyl- l-oxa-6-azacyclopentadecan- 15 -one;

[0096] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 10R, 1 lR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}- 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6- methy 1 oxan-4-y 1 ] -N -methy lb enzami de;

[0097] N-[(2S,3R.4S,6R)-2-{[{2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl- 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-

[0098] 1 l-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzamide;

[0099] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-

[0100] 3.4.10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl] oxy}- 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6- methyloxan-4-yl]-N-methylnaphthalene-2-sulfonamide;

[0101] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 10R, 1 lR,12S,13S,14R)-2-ethyl-

[0102] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan- 1 l-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylnaphthalene-2-sulfonamide;

[0103] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0104] 3.4.10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}- 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l 1 -yl]oxy}-3-hydroxy-6- methyloxan-4-yl]-N,4-dimethylbenzene-l -sulfonamide;

[0105] (2S,3R,4S,6R)-2-{[(2R,3R,4R,5R,8R,10R,l lR,12S,13S,14R)-4,13- bis(acetyloxy)-2-ethyl-3,10-dihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-11 -yl]oxy }-4-(dimethylamino)-6-methyloxan-3-yl benzoate;

[0106] (2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptam ethyl- 15 -oxo- 1 -oxa-6-azacyclopentadecan-

[0107] 1 l-yl]oxy}-6-methyloxan-3-yl 4-(4-methanesulfonylphenyl)benzoate;

[0108] (2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}- 6-methyl-4-(N-methylnaphthalene-2-sulfonamido)oxan-3-yl benzoate;

[0109] {2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0110] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-

[0111] 1 l-yl]oxy}-6-methyloxan-3-yl 4-iodobenzoate; 1 -benzyl (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l 1R, 12S,13S,14R)-

[0112] 2-ethyl-3,4, 10, 13-tetrahydroxy-3,5,6,8, 10, 12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-1 l-yl]oxy}-6-methyloxan-3-yl (2R)-2- {[(benzyloxy)carbonyl]amino}pentanedioate; benzyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-

[0113] 2 { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0114] 3,5,6,8, l 0, 12, 14-heptamethyl- l 5-oxo-l-oxa-6-azacyclopentadecan- l l -yl]oxy J-3-hydroxy-6- methyloxan-4-yl](methyl)carbamoyl } butanoate;

[0115] 4-{ [(2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl]oxy}-4-oxobutanoic acid;

[0116] 3-{[(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahy droxy-3 ,5,6,8,10,12,14-heptam ethyl- 15 -oxo- 1 -oxa-6- azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6-methyloxan-4-yl](methyl)carbamoyl}propanoic acid; and

[0117] (2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptam ethyl- 15 -oxo- 1 -oxa-6- azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl pyridine-3 -carboxylate;

[0118] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0119] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-l 1- yl]°xy]-6-methyl-tetrahydropyran-3-yl] 2,5-dimethylpyrazole-3-carboxylate;

[0120] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0121] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-l 1- yl]°xy]-6-methyl-tetrahydropyran-3-yl] 5-chlorothiophene-2-carboxylate;

[0122] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0123] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-l 1- yl]°xy]-6-methyl-tetrahydropyran-3 -yl] 4-ethylbenzoate; [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0124] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-l 1- yl]°xy]-6-methyl-tetrahydropyran-3 -y 1 ] 4-methoxybenzoate;

[0125] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0126] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]°xy]-6-methyl-tetrahydropyran-3-yl] naphthalene-2-carboxylate;

[0127] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0128] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]°xy]-6-methyl-tetrahydropyran-3-yl] quinoline-3 -carboxylate;

[0129] 2-benzyloxy-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0130] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-acetamide; benzyl N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0131] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-2-oxo-ethyl]carbamate;

[0132] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll-yl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy-propanamide;

[0133] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll-yl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2-phenyl-acetamide;

[0134] (2R,3S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-3,4,10, 13 -tetrahydroxy- 11-[(2S,3R,4S,6R)- 3 -hy droxy-6-methyl-4-(methylamino)tetrahy dropyran-2-yl] oxy-3 ,5,6,8,10,12,14- heptam ethyl- 1 -oxa-6-azacyclopentadecan- 15-one;

[0135] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl- 3.4.10.13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]°xy]-6-methyl-tetrahydropyran-3-yl] 2-methylpropanoate; most preferably selected from the group consisting of

[0136] (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0137] 3.4.10.13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-

[0138] 1 l-yl]oxy}-6-methyloxan-3-yl benzoate;

[0139] (2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptam ethyl- 15 -oxo- 1 -oxa-6-azacyclopentadecan-

[0140] 1 l-yl]oxy}-6-methyloxan-3-yl 4-(4-methanesulfonylphenyl)benzoate;

[0141] 1 -benzyl (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l 1R, 12S,13S,14R)-

[0142] 2-ethyl-3,4, 10, 13-tetrahydroxy-3,5,6,8, 10, 12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-1 l-yl]oxy}-6-methyloxan-3-yl (2R)-2- {[(benzyloxy)carbonyl]amino}pentanedioate; benzyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-

[0143] 2 { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0144] 3,5,6,8, l 0, 12, 14-heptamethyl- l 5-oxo-l-oxa-6-azacyclopentadecan- l l -yl]oxy }-3-hydroxy-6- methyloxan-4-yl](methyl)carbamoyl } butanoate;

[0145] 4-{ [(2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl]oxy}-4-oxobutanoic acid;

[0146] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0147] 3.4.10.13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-l 1- yl]°xy]-6-methyl-tetrahydropyran-3 -yl] 4-ethylbenzoate;

[0148] [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl-

[0149] 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]°xy]-6-methyl-tetrahydropyran-3-yl] naphthalene-2-carboxylate; benzyl N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl- 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll- yl]°xy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl-amino]-2-oxo-ethyl]carbamate; and

[0150] N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll-yl]oxy]-3- hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy-propanamide.

[0151] The invention also provides a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable excipient, whereby this also includes compounds for which R8can be H if R1is OH and R7.

[0152] The invention also provides a method for the treatment or prophylaxis of any disease or condition as mentioned herein, which comprises administering to the subject (for example a mammal, typically a human) a therapeutically effective amount of a compound or composition according to the invention.

[0153] Depending upon the substituents present in compounds of the formula (I), the compounds may form esters, amides, carbamates and / or salts. Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein a counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non- pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of formula (I) and their pharmaceutically acceptable esters, amides or carbamates salts, or solvates thereof.

[0154] Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxy carboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cj-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.

[0155] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N- methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.

[0156] Compounds of formula (I) may have an appropriate group converted to an ester, an amide or a carbamate. Thus typical ester and amide groups formed from an acid group in the compound of formula (I) include -COORB, -C0NRB2, -SCh.OR6, or -SO2.NRB2, while typical ester and amide and carbamate groups formed from an -OH or -NHRBgroup in the compound of formula (I) include -O.CO.RB, -NRB.CO.RB, -NRB.C02RB-O.SO2RB, and -NRB.S02RB, wherein each RBis independently selected from the group consisting of hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs-scycloalkyl, Cs-scycloalkylCi-ealkyl, Ce-ioaryl and Ce-io arylCi-ealkyl, each optionally substituted by from 1 to 3 halogen atoms. Preferably, each RBis independently selected from the group consisting of hydrogen and Ci- 4alkyl. For example, in compounds of formula (I), one or more of the OH groups that are present when one or more of R3, R4and R5are H can be converted to an ester of formula -O.CO.RB; that is to say that the compound would have one or more of R3, R4and R5represented by CO.RB, RBbeing as given immediately above. A compound which, upon administration to the recipient, is capable of being converted into a compound of formula (I) as described above, or an active metabolite or residue thereof, is known as a “prodrug”. A prodrug may, for example, be converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Certain esters, amides and carbamates described above can be prodrugs. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, which are incorporated herein by reference.

[0157] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

[0158] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

[0159] As used herein, the term "alkyl" means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n- butyl, t-butyl, i-butyl, sec-butyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups. Among branched alkyl groups, there may be mentioned t-butyl, i-butyl, 1 -ethylpropyl and 1 -ethylbutyl groups.

[0160] As used herein, the term “alkoxy” means the group O-alkyl, where “alkyl” is used as described above. Examples of alkoxy groups include methoxy and ethoxy groups. Other examples include propoxy and butoxy.

[0161] As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Preferred alkenyl groups include ethenyl, 1- propenyl and 2- propenyl. As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Preferred alkynyl groups include ethynyl 1- propynyl and 2- propynyl.

[0162] As used herein, the term "cycloalkyl" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may, for example, be 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 bicyclo [2. 2.1]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

[0163] As used herein, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. A naphthyl group may be attached through the 1 or the 2 position. In a bicyclic aromatic group, one of the rings may, for example, be partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl. Specifically, the term C5-10 aryl is used herein to mean a group comprising from 5 to 10 carbon atoms in a monocyclic or bicyclic aromatic group. A particularly preferred C5-10 aryl group is phenyl.

[0164] As used herein, the term ‘eosinophil function’ refers to any of the effector functions of an eosinophil, for example, release of cationic proteins stored in cytoplasmic granules by degranulation and release cytokines, including IL-10 and IL-4.

[0165] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.

[0166] As used herein, the term "heterocyclyl" means an aromatic or a non-aromatic cyclic group of carbon atoms wherein from one to three of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. A heterocyclyl group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or only in one of the rings. A heteroatom is preferably O or N. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. Examples of monocyclic non-aromatic heterocyclyl groups (also referred to as monocyclic heterocycloalkyl rings) include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.

[0167] Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.

[0168] Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.

[0169] Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl and benzodroxazole.

[0170] Examples of preferred heterocyclyl groups include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrimidinyl and indolyl. Preferred heterocyclyl groups also include thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, isoxazolyl and imidazolyl.

[0171] As used herein the term “cycloalkylalkyl” means a group cycloalkyl-alkyl- attached through the alkyl group, “cycloalkyl” and “alkyl” being understood to have the meanings outlined above.

[0172] As used herein the term “eosinophil-associated pathology” means any pathology where eosinophil plays a significant, if not major role in the pathophysiology of a condition, disorder or disease. Examples of eosinophil-associated pathologies include eosinophilic asthma, chronic eosinophilic pneumonia, giant papillary conjunctivitis, vernal conjunctivitis, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, allergic asthma, and allergic gastroenteropathy, eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, episodic angioedema associated with eosinophilia, idiopathic hypereosinophilic syndrome, bullous pemphigoid, episodic angioedema associated with eosinophilia, urticaria, drug reactions, reactions to insect stings, cutaneous T-cell lymphoma (CTCL), eosinophilia myalgia syndrome, eosinophilic esophagitis and toxic oil syndrome. In a further embodiment, eosinophil-associated pathologies include chronic eosinophilic pneumonia, giant papillary conjunctivitis, vernal conjunctivitis, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, allergic asthma, and allergic gastroenteropathy, eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, episodic angioedema associated with eosinophilia, idiopathic hypereosinophilic syndrome, bullous pemphigoid, episodic angioedema associated with eosinophilia, urticaria, drug reactions, reactions to insect stings, cutaneous T-cell lymphoma (CTCL), eosinophilia myalgia syndrome, eosinophilic esophagitis and toxic oil syndrome.

[0173] As used herein the term “Type-2 inflammation” means any pathology where T-helper 2 (TH2) cells plays a significant, if not major role in the pathophysiology of a condition, disorder or disease. Examples of conditions, disorders or diseases wherein TH2 cells play a role include allergic and other inflammatory conditions, disorders and diseases.

[0174] The compounds of the invention contain several chiral (asymmetric) centers and the molecules as a whole are chiral. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.

[0175] The compounds of the invention can be prepared by methods well known in the art. Azithromycin (Azm) is widely available from commercial sources, including Sigma-Aldrich. The key intermediate Descladinose Azm (Example 1) can be prepared by selective acidic hydrolysis of Azm using methanol HCl(aq), following a published protocol as shown in Scheme 1. The key intermediates demethylated Azm (Intermediate A), and demethylated Descladinose Azm (Intermediate B) can be prepared by N-demethylation using iodine and NaOAc in MeOH or iPrOH, which method is set out in US3,725,385 and also described in European Journal of Medicinal Chemistry 49 (2012) 365-378, entry 5.1.3. That is also shown in Scheme 1 :

[0176]

[0177] Intermediate A Intermediate B

[0178] Scheme 1

[0179] The advanced intermediates shown in Scheme 1 can be derivatised to compounds of the invention using standard coupling techniques.

[0180] The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0181] Certain compounds of the invention have better oral bioavailability than others. A compound with particularly good bioavailability (particularly oral bioavailability) is especially useful in the treatment of conditions that are suited to treatment by systemic drug delivery. A compound with poorer bioavailability, on the other hand, lends itself to topical delivery (and systemic side effects will be minimised by the low bioavailability) and thus to the treatment of conditions that are suited to treatment by topical drug delivery (for example by inhalation or by dermal, buccal, sublingual or intraocular application.

[0182] Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 mg per kg of body weight per day (mg / kg / day) to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day, for adult humans. The typical daily dose is thus from about 1 mg to about 500 mg of the active ingredient, preferably from about 20 mg to about 500 mg of active ingredient, for example 50 mg to 500 mg, for example 100 mg to 400 mg, for example 200 mg to 300 mg, for example 250 mg of the active ingredient. For oral administration, the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units 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 the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

[0183] Intravenously, the most preferred doses will range from about 0.1 to about 10 mg / kg / minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0184] While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, the invention provides a pharmaceutical formulation comprising a compound according to the invention, and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as “carrier” materials). Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below. The pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators), rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

[0185] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0186] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0187] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally.

[0188] Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Moulded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

[0189] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-inj ection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0190] Exemplary compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0191] Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug.

[0192] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0193] Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

[0194] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

[0195] Whilst a compound of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further active agents. Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for example a further compound useful in the treatment of a respiratory condition or disease, for example a compound useful in the treatment of an eosinophil-associated pathology, Type-2 inflammation or COPD.

[0196] Compounds include inhaled corticosteroids (for example fluticasone (Flonase, Flovent HF A), budesonide (Pulmicort Flexhaler, Rhinocort), flunisolide (Aerospan HF A), ciclesonide (Alvesco, Omnaris, Zetonna), beclomethasone (Qnasl, Qvar), mometasone (Asmanex) or fluticasone furoate (Arnuity Ellipta)), Leukotriene modifiers(for example montelukast (Singulair), zafirlukast (Accolate) or zileuton (Zyflo); Long-acting beta agonists (for example salmeterol (Serevent) or formoterol (Foradil, Perforomist); Combination inhalers (for example fluticasone-salmeterol (Advair Diskus / Seretide), budesonide-formoterol (Symbicort) or formoterol-mometasone (Dulera) containing a long-acting beta agonist along with a corticosteroid); Theophylline (for example Theo-24 or Elixophyllin), Short-acting beta agonists (for example albuterol (ProAir HF A, Ventolin HF A, others) and levalbuterol (Xopenex)), Ipratropium (Atrovent) or oral or intravenous corticosteroids (for example prednisone or methylprednisolone)

[0197] Compounds further include short-acting bronchodilators (for example albuterol (ProAir HF A, Ventolin HF A, others), levalbuterol (Xopenex), and ipratropium (Atrovent)), long-acting bronchodilators (including tiotropium (Spiriva), salmeterol (Serevent), formoterol (Foradil, Perforomist), arformoterol (Brovana), indacaterol (Arcapta) and aclidinium (Tudorza)), Inhaled steroids (including Fluticasone (Flovent) and budesonide (Pulmicort), Combination inhalers (for example combining bronchodilators and inhaled steroids, for example Salmeterol and fluticasone (Advair) and formoterol and budesonide (Symbicort)), Oral steroids, Phosphodiesterase-4 inhibitors (for example roflumilast (Daliresp)) Theophylline and Antibiotics. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0198] Equivalents

[0199] The invention has been described broadly and generically herein. Those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention. Further, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0200] Incorporation by Reference

[0201] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[0202] The following Examples illustrate the invention, with the accompanying figures:

[0203] Figure 1 : Effect of Example 2 on ovalbumin (OVA)-induced pulmonary inflammation in Balb / C mice.

[0204] Figure 2: Effect of Example 2 on house dust mite induced pulmonary inflammation in guinea pigs

[0205] Examples

[0206] General methods

[0207] Methods for the preparation of compounds of formula (I) can, for example, be found in International application publication number: WO 2017 / 085329. Reversed phase chromatography was performed on X-bridge, prep Cl 8 (5 pm), 50mM ammonium bicarbonate / acetonitrile gradient.

[0208] Example 1: Descladinose Azithromycin: (2R,3S,4R,5R,8R,1OR,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-l-oxa-6- azacyclopentadecan- 15-one)

[0209] To a solution of Azithromycin ((2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-ll-[(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-l-oxa-6-azacyclopentadecan-15-one) (10 g, 13.35 mmol) in methanol (100 mL) HC1 (1 M) was added until pH was stabilized at 1.25 and the resulting solution was stirred for 24 h at room temperature. The mixture was again pH adjusted but using NaOH (1 M) to pH 10.75. The mixture was stirred for 1 h and portioned between NaHCO3 (5%) and DCM. The aqueous phase was washed with a second portion of DCM and the combined organic fractions were dried over magnesium sulphate and the solvent removed under reduced pressure giving the product as a white foam. A sample was purified by straight phase silica chromatography (DCM to 5% methanol in DCM, 0.1% triethylamine added to the mobile phase)

[0210] Example 2: (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,llR,12S,13S, 14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadec-ll-yl]oxy]-6-methyl-tetrahydropyran-3-yl] benzoate)

[0211] To a mixture of (2R,3 S,4R,5R,8R, 10R, 1 lR,12S,13S,14R)-ll-[(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13- tetrahy droxy-3 ,5,6,8,10,12,14-heptam ethyl- 1 -oxa-6-azacy clopentadecan- 15 -one (Example 1 ) (0.5 g, 0.8500 mmol) and Triethylamine (428.2 mg, 4.23 mmol) in DCM (5 ml), cooled on ice, was added benzoyl chloride (356.9 mg, 2.54 mmol). The reaction mixture was allowed to reach room temperature. After 3 days good conversion to the desired benzoylated product was obtained and the mixture was portioned between DCM and saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulphate and concentrated to a white foam. The product was purified using reversed phase chromatography. Example 3

[0212] Evaluation of the effect of Example 2 on ovalbumin (OVA)-induced pulmonary inflammation in Balb / C mice

[0213] Studies were conducted in male Balb / C mice (20-30 g on arrival, Charles Rivers, UK), which were acclimatized for a period of 7 days, before the start of experimental procedures. Mice had access to standard chow diet and water ad libitum. Mice were housed in cages of 5 on arrival based on weight (equal distribution of animal weights amongst each of the cages by the animal technician) with a 12-hour light dark cycle. Room temperature and humidity were maintained within home office guidelines (17-24°C and 40-70% respectively), environmental enrichment was provided in all cages.

[0214] During the study, animals were observed for adverse clinical signs on a daily basis and body weight was recorded. On a weekly basis, food consumption (based on weight change) per cage of n=5 animals was also recorded.

[0215] Dosing of animals with Example 2, budesonide or vehicle

[0216] Animals were treated by oral gavage (10 mL / Kg) once a day for 14 consecutive days with Example 2 or vehicle (citrate buffer, pH 4). First administration was on day 4 after the first ovalbumin (OVA) sensitisation on day 1 and the final dose 1 hour prior to the final OVA challenge on day 17. The positive control, budesonide, 10 mg / Kg, (p.o.) was administered once a day with the first dose administered 1 h before the first OVA challenge on day 15. See dosing scheme below.

[0217] Throughout the study dosing with Example 2, vehicle or budesonide was well tolerated in all animals.

[0218] Allergen exposure

[0219] Mice were actively sensitised with OVA (15 pg, s.c.) and 25 pL of Imject Alum on days 1 and 7. In order to elicit a local inflammatory response in the lungs, mice were repeatedly challenged on days 15, 16 and 17 with an aerosol of either 1% w / v OVA in phosphate buffered saline (PBS) or just PBS, generated with an ultrasonic nebuliser (Aerogen) for 20 min. Twenty -four h after the final challenge to OVA or PBS on day 18, bronchoalveolar lavage fluid (BALF) was collected. The sensitisation and dosing scheme is as follows:

[0220] S: sensitisation; C: challenge

[0221] Day 18: Sacrifice

[0222] BALF collection

[0223] 24 h after the final OVA or PBS challenge, the animals were overdosed with pentobarbitone. The trachea was then isolated by a midline incision in the neck and separation of the muscle layers. A small incision was made into the trachea and a plastic cannula was inserted and secured in place with a suture. The airway was then lavaged by flushing out the lungs using 1 mL of phosphate buffered saline. This procedure was repeated until the recovered volume is 1.6 mL. The isolated BALF was then centrifuged at 1500 rpm for 10 mins at 4°C and the supernatant was aliquoted (400 pL) at -80°C for cytokine analysis. The cell pellets were then re-suspended in 0.8 mL of 0.2% w / v NaCl to induce haemolysis of any erythrocytes. After isotonization with the same volume of 1.6% w / v NaCl, the BAL cells were analysed for total and differential numbers.

[0224] Total and differential cell counts of the BAL fluid samples were measured using a XT- 2000iV analyser (Sysmex, Milton Keynes, UK). Results were expressed as cells / mL (total and differential). Cell types differentially classified were neutrophils, eosinophils and mononuclear cells (monocytes, macrophages and lymphocytes).

[0225] Data is reported as total and differential number of cells per mL of BALF with provision of individual animal data and group means ± S.E.M. (standard error of the mean).

[0226] Inter-group deviations were statistically analysed by a one-way analysis of variance (ANOVA). In the case of significant difference in the mean values among the different levels of treatment, comparisons versus the vehicle group will be carried out using the Dunnett’s test. p< 0.05 was considered statistically significant.

[0227] Lung, GI tract and Skin sample collection

[0228] Following BALF collection, the thoracic cavity was opened to expose the lungs which were dissected free of the animal. The left lung lobe was separated from the right lobes and placed into a sterile container before being immersed in 10% neutral buffered formalin for 48 h before being transferred to 70% ethanol for tissue processing. Following the dissection of the lungs the peritoneum was opened to expose the gastrointestinal (GI) tract from which the large intestine was dissected and placed into sterile container. Each intestine sample was snap frozen and stored at -80°C. Finally, skin samples of the ear were collected from each animal. These were placed into a sterile Eppendorf and snap frozen before being stored at -80°C.

[0229] Tissue sample Processing

[0230] Left lung lobes were paraffin embedded and then shipped directly to EpiEndo, Iceland. The collected GI and skin samples were shipped to Recipharm, Sweden for bioanalysis.

[0231] Biomarker analysis

[0232] Cytokine levels (see below for details of cytokines evaluated) of BALF supernatant were measured in duplicate using magnetic multiplex assays as per the manufacturer’s instructions. Levels were measured using a Magpix system (Luminex Corp., Austin, USA).

[0233] Mouse cytokine magnetic 9 plex panel (Bio-Techne), Abingdon, UK

[0234] TNFa

[0235] IL- 13

[0236] IL-5

[0237] IL-6

[0238] IL- 10

[0239] IL-ip

[0240] IL- 17

[0241] CCL-2

[0242] MMP-12

[0243] Thymic stromal lymphopoietin (TSLP) of BALF supernatant was measured in duplicate using a commercial ELISA kit (Biotechne, UK) as per the manufacturer’s instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). Concentrations of TSLP were determined using SoftMax Pro v. 6.4 (Molecular Devices).

[0244] Results

[0245] Example 2 (1 and 2 mg / kg / day for 2 weeks) significantly reduced (p<0.001) total cell and eosinophil cell numbers in BALF when compared to vehicle treated animals (see Figure 1). Neutrophil numbers were also significantly reduced by Example treatment at all doses (p<0.01) (Table 1). Cytokine analysis of BALF included several key cytokines that were significantly reduced with Example 2 treatment (Table 2). The concentration of TSLP, an epithelial derived cytokine, was also significantly reduced with Example 2 treatment. The positive control budesonide was also significantly effective in reducing differential cell counts and the cytokines measured.

[0246] Two week’s oral treatment of mice with Example 2 at 2 mg / kg and 1 mg / kg could significantly reduce the number of eosinophils after OVA-induced pulmonary inflammation.

[0247] Tables 1

[0248] Table 2 Example 4

[0249] Evaluation of the effect of Example 2 on human dust mite-induced pulmonary inflammation in Guinea Pigs

[0250] The effect of Example 2 on inflammation involving predominantly eosinophils was not limited to the OVA model in mice. Similar effects of Example 2 are apparent in a model of house dust mite (HDM)-induced pulmonary allergic inflammation in guinea pigs. Animals were actively sensitised with the HDM extract containing Dermatophagoides pteronyssinus allergen on Days 1, 2 and 3, then again on Days 8, 9 and 10, and challenged intranasally on Day 15. Animals (n=5-7 / treatment) were treated with 2 mg / kg / day Example 2 by oral gavage once a day for 14 consecutive days (Days 3-17). The positive control budesonide (0.2 mg / kg) was administered i.n. once a day for 3 consecutive days (Days 14-16).

[0251] Treatment with Example 2 significantly reduced the total number of cells (p<0.05) and in the number of eosinophils in bronchoalveolar lavage (p<0.05) (see Figure 2).

[0252] Histology of the guinea pig lungs from this study showed that the challenge led to a robust accumulation of leukocytes around the airways with visible hypertrophy of the epithelial layer in HDM animals compared to sham animals. Treatment with Example 2 caused a reduction in the accumulation of cells around the airways and a better preservation of the epithelial integrity.

Claims

Claims1. A compound according to formula (I):for use in the treatment of an eosinophil-associated pathology; whereinR1is selected from the group consisting of OH, carbamoyloxy, N-Ci-6-alkylcarbamoyloxy, N-(C6-i4-aryl-Ci-6-alkyl)carbamoyloxy, N,N-di-Ci-6-alkylcarbamoyloxy, N,N-di-alkylcarbamoyloxy with the two alkyl substituents together forming a 5- to 8-membered heterocycle together with the nitrogen atom of the carbamate moiety, Ci-6-alkylcarboxy and a moiety according to formula (II)whereinR6is selected from the group consisting of H, OH and Ci-6-alkyl, whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to 6 halogen and / or CN; andR2is according to formula (III)whereinR7is selected from the group consisting of Ci-6-alkyl, C6-i4-aryl-Ci-6-alkyl, C3-6-alkylcarbonyl, Ce- 14-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl, Ce-w-arylsulfonyl, Ci-6-alkyl-C6-i4-arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl,C6-i4-aryl-O-Ci-6-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-Ci-6-alkyl-carbonyl,H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1)with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6,C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN; andR8is selected from the group consisting of H, Ce-i 4-ary 1 carbonyl (optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups), C3-6-alkylcarbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.l) as depicted hereinbefore with Ar being Ce-w-aryl and n, p and q being independently from 0 to 6, aryl, and heteroaryl carbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4-alkoxy, C2-4-alkenyl, C2-4- alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl and / or CN;R3is H; andR4and R5are independently selected from H and Ci-6-alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and / or CN, orR4and R5together form a single carbonyl group which forms a cyclic carbonate with both oxygen atoms it is bonded to; and with the proviso that the compound of formula (I) is not 2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-l l-[(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-heptam ethyl- 1 -oxa-6-azacyclopentadecan- 15 -one ; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

2. The compound for use, as claimed in claim 1, wherein the eosinophil-associated pathology is selected from eosinophilic asthma, chronic eosinophilic pneumonia, giant papillary conjunctivitis, vernal conjunctivitis, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, allergic asthma, and allergic gastroenteropathy, eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, episodic angioedema associated with eosinophilia, idiopathic hypereosinophilic syndrome, bullous pemphigoid, episodic angioedema associated with eosinophilia, urticaria, drug reactions, reactions to insect stings, cutaneous T-cell lymphoma (CTCL), eosinophilia myalgia syndrome, eosinophilic esophagitis and toxic oil syndrome.

3. The compound for use, as claimed in claim 1, wherein the eosinophil-associated pathology is selected from allergic asthma, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes.

4. A compound of formula (I) as defined in Claim 1 for the reduction of Type 2 inflammation.

5. The compound for use, as claimed in Claim 4 wherein the reduction of Type-2 inflammation is for the treatment of a disease, disorder or condition selected from atopic dermatitis, food allergy, allergic rhinitis, conjunctivitis, chronic idiopathic urticaria, Chronic rhinosinusitis with nasal polyps (CSwNP) and eosinophilic oesophagitis.

6. A compound of formula (I) as defined in Claim 1 for the inhibition of eosinophil numbers and / or eosinophil recruitment and / or eosinophil function.

7. A compound of formula (I), as defined in Claim 1, for use in the treatment of chronic obstructive pulmonary disease (COPD) in a patient wherein the patient has more than about 100 eosinophil s / pl of blood, for example, more than about 200 eosinophil s / pl of blood or more than about 300 eosinophil s / pl of blood.

8. The compound for use, as claimed in any one of claims 1 to 7, wherein R1is OH.The compound for use according to any one of claims 1 to 8, whereinR7is selected from the group consisting of Ci-3-alkyl, Ce-io-aryl-Ci-3-alkyl, linear or branched, preferably branched C3-4-alkylcarbonyl, Ce-io-arylcarbonyl, Ce-io-aryl-Ci-3- alkylcarbonyl, Ce-io-aryl-O-Ci-3-alkylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl- carbonyl, H00C-(CH2)m-(C0)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2)wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, C6-io-aryl-Ci-3-alkyl-0-CO-NH-Ci-3-alkyl-CO-, Ce-io-arylsulfonyl, and Ci-3-alkyl-Ce-io-arylsulfonyl; preferably R7is selected from the group consisting of methyl, succinyl, benzyl, benzoyl, naphthylsulfonyl, methylphenylsulfonyl, isopropyl carbonyl, succinyl, benzyl carbonyl, phenoxyethylcarbonyl, benzyloxymethylcarbonyl, benzyl-O-CO-NH- CH2-CO- and a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN; andR8is selected from the group consisting of H, Ce-io-aryl carbonyl, Ce-io-arylcarbonyl substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups,linear or branched, preferably branched C3-4-alkylcarbonyl, H00C-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) as depicted hereinbefore wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, Ci-3-alkylsulfonyl-bi-C6-io-aryl-carbonyl, and heteroaryl carbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, most preferably 1 heteroatom, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, preferably from the group consisting of N and O, most preferably being N, the ring of the heteroaryl carbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of Ci-2-alkyl, Ci-2-alkoxy, C2-3-alkenyl, C2-3-alkenoxy, halogen, in particular F and Cl, and CN, preferably selected from the group consisting of methyl, methoxy, F and Cl, most preferably selected from the group consisting of methyl and Cl; preferably R8is selected from the group consisting of isopropylcarbonyl, succinyl, benzoyl, iodobenzoyl, ethylphenyl carbonyl, methoxy phenyl carbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl, a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, pyrazolyl carbonyl, dimethylpyrazolylcarbonyl, thiophenyl, chlorothiophenyl, pyridyl carbonyl and quinolylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN.

10. The compound for use according to any one of claims 1 to 9, whereinR1is OH;R7is selected from the group consisting of Ci-3-alkyl, in particular methyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-Ci-2-alkyl-O-CO-NH-Ci-2-alkyl-CO- and phenyl-O-Ci-3- alkylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R7is optionally substituted by 1 to 3 halogen and / or CN; andR8is selected from the group consisting of H, HOOC-(CH2)m-(CO)- with m being from 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl andnaphthyl carbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 3 halogen and / or CN.

11. The compound for use according to any one of claims 1 to 10, wherein R1is OH;R2is according to formula (III)whereinR7is Ci-6-alkyl; andR8is selected from the group consisting of Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from Ci-3-alkyl sulfonyl groups and / or Ci-3-alkyl groups; H00C-(CH2)m-(C0)- with m being from 0 to 6, a substituent of formula (V.1)with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6;R3is H; andR4and R5are both H; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

12. The compound for use, as claimed in any one of claims 1 to 11, whereinR8is selected from the group consisting of H, Ce-io-aryl carbonyl, Ce-io-arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups), bi- Ce-io-aryl-carbonyl (optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl and / or CN) and H00C-(CH2)m-(CO)- (with m being from 1 to 3, most preferably 1 or 2).

13. The compound for use, as claimed in any one of claims 1 to 12, wherein R7is selected from the group consisting of Ci-6-alkyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl-carbonyl, C6-io-aryl-Ci-3-alkylcarbonyl, C6-io-aryl-0-Ci-3-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO- and a moiety according to formula (V.l) or formula (V.2).

14. The compound for use, as claimed in any one of claims 1 to 7, which is selected from the group consisting of:(2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-1 l-yl]oxy}-6-methyloxan-3-yl benzoate;(2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-1 l-yl]oxy}-6-methyloxan-3-yl 4-(4- methanesulfonylphenyl)benzoate; benzyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-2 { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-3- hydroxy-6-methyloxan-4-yl](methyl)carbamoyl } butanoate;4-{ [(2S,3R,4S,6R)-4-(dimethylamino)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)- 2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl]oxy}-4-oxobutanoic acid;[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadec-11 -yl]oxy]-6-methyl-tetrahydropyran-3-yl] 4-ethylbenzoate;[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadec-ll-yl]oxy]-6-methyl-tetrahydropyran-3-yl] naphthalene-2- carboxylate; benzyl N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptamethyl- 15 -oxo- 1 -oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl- amino]-2-oxo-ethyl]carbamate; andN-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahy droxy-3 ,5,6,8,10,12,14-heptamethyl- 15 -oxo- 1 -oxa-6-azacy clopentadec- 11- yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3-phenoxy- propanamide.

15. The compound for use, as claimed in any one of claims 1 to 7, which is(2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-1 l-yl]oxy}-6-methyloxan-3-yl benzoate;6. A pharmaceutical composition comprising a compound of Formula (I), as defined in any one of Claims 1, and 8 to 15 and at least one pharmaceutically acceptable excipient, for the use, as defined in any one of Claims 1 to 7:

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