Technical Field

The present invention relates to 1 1 , 12-dtde ydro-1 1 , 12-dideoxy 14-membered macrolides and 1 5-membered azalide macrolides useful in the treatment of inflammatory diseases. More particularly, the invention relates to (E)-1 1 , 12-didehydro-1 1 ,12-dideoxy 14- membered macrolides and 15-membered azalide macrolides useful in the treatment of neutrophil dominated inflammatory diseases, especially in the treatment of neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils, to intermediates for their preparation, to methods for their preparation, to their use as therapeutic agents, and to salts thereof.

Background inflammation is the final common pathway of various insults, such as infection, trauma, and allergies to the human body. It is characterized by activation of the immune system with recruitment and activation of inflammatory ceils and production of pro-inflammatory mediators.

Most inflammatory diseases are characterized by enhanced accumulation of differing proportions of inflammatory cells, including monocytes/macrophages, granulocytes, plasma cells, lymphocytes and platelets. Along with tissue endothelial ceils and fibroblasts, these inflammatory ceils release a complex array of lipids, growth factors, cytokines and destructive enzymes that cause local tissue damage.

One form of inflammatory response is neutrophilic inflammation which is characterized by infiltration of the inflamed tissue by neutrophilic polymorphonuclear leukocytes (PMN, i.e. neutrophils), which are a major component of host defence. Neutrophils are activated by a great variety of stimuli and are involved in a number of clinical conditions and diseases where they play a pivotal role. Such diseases may be classified according to the major neutrophi!-activating event (Table 3, page 638 of V. Witko-Sarsat et al. , Laboratory Investigation (2000) 80(5), 617-653). Tissue infection by extracellular bacteria represents the prototype of this inflammatory response. On the other hand, various non-infectious diseases are characterized by extravascular recruitment of neutrophils. These noninfectious inflammatory diseases may be the result of an intermittent resurgence (e.g. flare in autoimmune diseases such as rheumatoid arthritis), or continuous generation (e.g. chronic obstructive pulmonary disease (COPD)) of inflammatory signals arising from underlying immune dysfunction. Non-infectious inflammatory diseases include chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, emphysema, adult respiratory distress syndrome (ARDS, known also as acute respiratory distress syndrome or respiratory distress syndrome, RDS), as well as glomerulonephritis, rheumatoid arthritis, gouty arthritis, ulcerative colitis, certain dermatoses such as psoriasis and vasculitis. In these conditions neutrophils are thought to play a crucial role in the development of tissue injury which, when persistent, can lead to the irreversible destruction of the normal tissue architecture with consequent organ dysfunction. Consequently, correlation between neutrophil number in sputum or bronchoalveolar lavage fluid and disease severity and decline in lung function is demonstrated in patients with chronic obstructive pulmonary disease (Di Stefano et al., Am J Respir Crit Care Med. (1998), 158(4): 1277-1285), cystic fibrosis (Sagel SD et al., J Pediatr. (2002), 141 (6): 81 1 - 817), diffuse panbronchiolitis (Yanagihara K et al., Int J Antimicrob Agents. (2001 ), 18 Suppl 1 : S83-87), bronchiolitis obliterans (Devouassoux G et al., Transpl Immunol. (2002), 10(4): 303-310), bronchitis (Thompson AB et ai„ Am Rev Respir Dis. (1989), 140(6): 1527-1537), bronchiectasis (Sepper R et al., Chest (1995), 107(6): 1641 -1647), adult respiratory distress syndrome (Weiland JE et a!. , Am Rev Respir Dis. (1986), 133(2): 218- 225), to name a few. In addition, there is increasing evidence of neutrophil inflammation in asthmatics, particularly in patients with severe disease and patients who smoke (Chalmers GW et a!., Chest (2001 ), 120: 1917-1922). Evidence of the importance of neutrophils in several lung diseases has prompted a search for drugs that inhibit neutrophilic infiltration into lungs and consequent inflammation (reviewed in Barnes PJ, J Allergy Clin Immunol. (2007), 1 19(5): 1055-1062).

Summary of the Invention

The present invention relates to (E)-1 1 , 12-didehydro-1 1 , 12-dideoxy 14-membered macrolides and 15-membered azalide macrolides represented by Formula (I):

wherein,

R ¹ is hydrogen or CH ₃ ;

R ² is a β-D-desosaminyl group of Formula (a);

R is:

i) an a-L-cladinosy of Formula (b)

and A is a bivalent radical -C(0)-, -N(R ⁵ )CH _r , -CH ₂ N(R ⁵ )-, -C(=NOR ⁶ )-, -CH(OH)-, -NHC(O)- or -C(0)NH-, or ii) hydroxy! and A is a bivalent radical -N(R ^S )CH ₂ -, -CH ₂ N(R ⁵ )-, -NHC(O)- or -C(0)NH-;

R ⁴ is hydrogen;

R ⁵ is hydrogen or -Ci. ₄ alkyl; R ⁶ is hydrogen or wherein -C _h alky! may be optionally interrupted by one or two oxygen atoms, and/or is unsubstituted or substituted by one or two substituents independently selected from -C^alkoxy or -C ₃ . ₇ cycloaikyl, with the proviso thai when the -C _-4 alkyl is interrupted by two oxygen atoms, the two oxygen atoms are not adjacent one another;

R ⁷ is hydroxy!, hydroxyl protecting group or -0-(CH ₂ ) ₂ CN;

R ⁸ is independently selected from:

ai) hydrogen,

bi) -Ci. _e alkyl, unsubstituted or substituted at the terminal carbon atom by a substituent selected from the group consisting of:

(aii) hydroxy!,

(bii) -(5-oxotetrahydro-2-furanyl),

(cii) -Ci- ₃ alkoxy, and

(dii) -C(0)Ci. ₃ alkyl, or

ct) -C(=0)-R ¹⁰ ; R is hydroxyl or hydroxyl protecting group;

R ¹⁰ is independently selected from:

(aiii) -Ci- ₄ alkyl, unsubstituted or substituted at the terminal carbon atom by a substitutent selected from the group consisting of hydroxyl, -C _M alkoxy , -C{0)OC _1-4 alkyl, -N(R ⁵ )(R ¹¹ ) and -S-R ¹² ,

(biii) a 5-6 membered heteroaromatic ring, unsubstituted or substituted by one or two substituents independently selected from the group consisting of halo, hydroxyl, -C _h alky!, -C _1-3 alkoxy, -CF _3l -OCF ₃ and -NH ₂ ,

(ciii) phenyl, unsubstituted or substituted by one or two subsituents independently selected from the group consisting of halo, hydroxyl,

-C _1-3 alkyl, -C _1-3 alkoxy, -CF ₃ , -OCF ₃ and -NH ₂ ,

(diii) a 4-6-membered heterocyclic ring, unsubstituted or substituted by one or two -C _1-3 alkyl, or

(eiii) -C ₃ . ₇ cycloalkyl, unsubstituted or substituted by one or two subsiituents independently selected from the group consisting of hydroxy, -C^alkoxy and -C(0)OCi- ₃ alkyl;

R is -C^alkyl;

R ¹² is a 5-6 membered heteroaromatic ring, unsubstituted or substituted by one or two substituents independently selected from the group consisting of halo, hydroxyl, -C _1-3 alkyS, -C _1-3 alkoxy, -CF _3l -OCF ₃ and -NH ₂ ; or a salt thereof.

The present invention also relates to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention also relates to methods of treating neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils comprising administration of a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

According to another aspect, the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medical therapy.

In another aspect, the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils.

In another aspect, the invention relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils.

Brief Description of the Figures

Figure 1 shows correlation of inhibition of IL-6 production in vitro and inhibition of cell infiltration into BALF in vivo.

Description of the Embodiments It will be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.

The term "alkyl" as used herein, refers to a saturated, straight or branched-chain hydrocarbon radical containing the stated number of carbon atoms, for example, C _h alky! contains between one and four carbon atoms. Examples of "C _h alky!" radicals include: methyl, ethyl, propyl and isopropyl. Examples of "C _h alky!" radicals include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of "C _h alky!" radicals include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, hexyl and the like.

The term "alkoxy" as used herein, refers to an -O-alkyl group wherein alkyl is as defined above. Examples of "-Ci. ₃ a!koxy" radicals include: methoxy, ethoxy, propoxy and isopropoxy. Examples of "-C _1-4 alkoxy" radicals include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

The term "-C^alkyl substituted by phenyl" as used herein, refers to alkyl as defined above, substituted by phenyl . Examples of "-C _-4 alky! substituted by phenyl" radicals include benzyl, phenyl-2-ethyl, phenyl-1 -ethyl, phenyl-3-propyl, phenyi-2-propyl and the like.

The term "ary!" as used herein refers to a C ₆ .io monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl, tetrahydronaphthalenyl and the like. The term "comprise", and variations such as "comprises" and "comprising", throughout the specification and the claims which follow, unless the context requires otherwise, will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The term "cycloaikyi" as used herein, refers to a saturated monocyclic hydrocarbon ring containing the stated number of carbon atoms, for example, 3 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobuty!, cyclopentyl, cyclohexy!, cycloheptyl and the like.

The term "halogen" or "halo" refers to a fluorine, chlorine, bromine or iodine atom.

The term "heteroaromatic ring" or "heteroaryl ring" as used herein refers to a 5-6 membered monocyclic aromatic ring containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur. Examples of such monocyclic aromatic rings include thienyl, furyl, pyrrolyl, furazanyl, triazolyl, imidazoly!, oxazo!yl, thiazoiyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridaziny!, pyrazinyl, pyridyi, triazinyi and the like.

The term "heterocyclic ring" refers to a 4-6 membered monocyclic ring which may be saturated or partially unsaturated containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen or sulphur. Examples of such monocyclic rings include pyrroiidinyl, azetidinyl, pyrazolidinyl, oxazo!idinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, thiazolidinyi, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathioianyl, oxathianyi, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyrtdinyl, tetrahydropyrimidinyi, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

The term "hydroxy! protecting group" refers to a substituent on an functional hydroxyl group which prevent undesired reactions and degradations during synthetic procedures, and which may be selectively removed after certain synthetic step. Examples of "hydroxyl protecting group" include: ester and ether hydroxy! protecting group. Examples of ester hydroxyl protecting group include: formyl, -OC(0)C _1-4 alkyl such as acetyl (Ac or -C(0)CH ₃ ), methoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacety!, trifluoroacetyl, triphenylmethoxyacetyl, phenoxyacetyl, benzoylformy!, benzoyl (Bz or -C(0)C ₆ H ₅ ), benzyloxycarbonyl (Cbz or -C(0)-0-CH ₂ C ₆ H ₅ ) ₁ methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbony! or 2-(trimethylsily!)ethoxycarbonyl and the like. Examples of ether hydroxyl protecting group include: alky! silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl, triethylsilyl, triisopropylsi!yi and the like. Examples of suitable "hydroxyl protecting group" include; -OC(0)Ci. ₄ alkyl such as acetyl (Ac or -C(0)CH ₃ ), benzoyl (Bz), benzyloxycarbonyl (Cbz) and trimethylsilyl (TMS). Suitably, "hydroxyl protecting group" is: acetyl (Ac or -C(0)CH ₃ ), benzoyl (Bz) or benzyloxycarbonyl (Cbz). Conveniently, "hydroxyl protecting group" is: acetyl (Ac or -C(0)CH ₃ ). The term "inert solvent" or "solvent inert to the reaction", as used herein, refers to a solvent that cannot react with the dissolved compounds including non-polar solvents such as hexane, toluene, diethyl ether, diisopropylether, chloroform, ethyl acetate, THF, dichloromethane; polar aprotic solvents such as acetonitrile, acetone, N,N- dimethylformamide, Ν,Ν-dimethy!acetamide, dimethyl sulfoxide, pyridine, and polar protic solvents such as lower alcohol, acetic acid, formic acid and water.

The term "lower alcohol", as used herein, refers to a C _1-4 alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, t-butano!, and the like.

In one aspect the present invention relates to a compound of Formula (I) or a salt thereof wherein the salt is a pharmaceutically acceptable salt. For a review on suitable salts see Berge ef a/., J. Pharm. Sci. (1977) 66: 1-19. Suitable pharmaceutically acceptable salts can include acid or base addition salts.

Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trifiuoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, salicylate, propionate, pyruvate, hexanoate, oxalate, oxaloacetate, trifiuoroacetate, saccharate, g!utamate, aspartate, benzoate, aikyl or ary! sulphonates (eg methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate) and isethionate. For example, hydrochloride or acetate salt.

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". Solvates of the compounds of the invention are within the scope of the invention. The salts of compounds of Formula (I) may form solvates (e.g. hydrates) and the invention also includes all such solvates.

In one aspect, compounds of the present invention may be in the form of pharmaceutically acceptable salts, solvates or solvates of salts. In a further aspect, a compound of Formula (I) of the present invention may be in the form of a pharmaceutically acceptable salt.

References hereinafter to "a compound according to the invention" or "compounds of the present invention" include both a compound of Formula (I) or its pharmaceutically acceptable salts.

With regard to stereoisomers, the compounds of Formula (I) have more than one asymmetric carbon atom. In the general Formula (I) as drawn, the solid wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.

It will be appreciated that the substituents on the macro!ide may also have one or more asymmetric carbon atoms. Thus, the compounds of Formula (I) may occur as individual diastereomers or mixtures thereof. All such isomeric forms are included within the present invention, including mixtures thereof.

Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. An individual stereoisomer may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C, of the corresponding mixture using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate.

It will be appreciated that compounds of the invention may exist as geometric isomers (cis/trans or (E)/(Z)). The present invention includes the individual geometric isomers of the compounds of the invention and, where appropriate, mixtures thereof, unless otherwise stated.

The compounds of Formula (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of Formula (I) may exist as polymorphs, which are included in the present invention. In one aspect of the invention A is a bivalent radical -N(R ⁵ )CH ₂ - wherein R ⁵ is -C _1-4 alkyl and R ¹ is hydrogen. In a further aspect of the invention A is a bivalent radical -N(R ⁵ )CH ₂ - wherein R ⁵ is methyi and R is hydrogen.

In one aspect of the invention A is a bivalent radical -NHC(O)- and R ¹ is CH ₃ .

In one aspect of the invention A is a bivalent radical -N(R ^S )CH ₂ - wherein R ⁵ is methyl and R ¹ is hydrogen or A is a bivalent radical -NHC(O)- and R is CH ₃ .

In one aspect of the invention R ¹ is hydrogen.

In one aspect of the invention R ¹ is CH ₃ .

In one aspect of the invention R ³ is a-L-cladinosyl group of Formula (b). In one aspect of the invention R ³ is hydroxy!.

In one aspect of the invention R ³ is a-L-cladinosyl group of Formula (b) or hydroxyl and A is a bivalent radical -N(R ⁵ )CH ₂ -, -CH ₂ N(R ⁵ )-, -NHC(O)- or -C(0)Nhk In a further aspect of the invention R ³ is a-L-cladinosyl group of Formula (b) or hydroxyl and A is a bivalent radical -N(R ^S )CH ₂ - or -NHC(O)-. I n even further aspect of the invention R is a-L- cladinosyi group of Formula (b) and A is a bivalent radical -N(R ⁵ )CH ₂ - or -NHC(O)-. In one aspect of the invention R ⁵ is methyl.

In one aspect of the invention R ⁷ is hydroxyl.

In one aspect of the invention R ⁷ is a hydroxyl protecting group. In a further aspect of the invention the hydroxyl protecting group is -OC(0)C _1- a!kyl. In another aspect of the invention the hydroxyl protecting group is -OC(0)CH ₃ (acetyl).

In one aspect of the invention R ⁸ is hydrogen. In one aspect of the invention R ⁸ is unsubstituted -Ci. ₆ alkyl. In a further aspect of the invention R ⁸ is unsubstituted methyl.

In one aspect of the invention R ⁸ is -C _h alky! substituted at the terminal carbon atom by hydroxy!. In a further aspect of the invention R ⁸ is ethyi or n-propyl substituted at the terminal carbon atom by hydroxy!.

In one aspect of the invention R ⁸ is ~C _1-6 alkyl substituted at the terminal carbon atom by -[(2R)-5-oxotetrahydro-2-furanyl] or -[(2S)-5-oxotetrahydro-2-furanyl]. In a further aspect of the invention R ⁸ is methyl substituted at the terminal carbon atom by -[(2R)-5- oxotetrahydro-2-furanyl]. In another aspect of the invention R ⁸ is methyl substituted at the terminal carbon atom by -[(2S)-5-oxotetrahydro-2-furanyl]. in one aspect of the invention R ⁸ is -C(=0)-R ¹⁰ and R ¹⁰ is -C _h alky! substituted at the terminal carbon atom by -C _1-4 alkoxy. In a further aspect of the invention R ¹⁰ is methyl, ethy! or n-propy! substituted at the terminal carbon atom by methoxy. In another aspect of the invention R ¹⁰ is methyl substituted by methoxy.

In one aspect of the invention R ⁸ is -C(=0)-R ¹⁰ and R ¹⁰ is -C _-4 atkyl substituted at the terminal carbon atom by -C(0)OCi. ₄ alkyl. In a further aspect of the invention R ¹⁰ is methyl, ethyl or n-propyl substituted at the terminal carbon atom by -C(0)OCH ₃ . In another aspect of the invention R ¹⁰ is ethyl substituted at the terminal carbon atom by -C(0)OCH ₃ .

!n one aspect of the invention R ⁸ is -C(=O)-R ⁱ⁰ and R ¹⁰ is -Ci. ₄ alkyl substituted at the terminal carbon atom by -N(R ⁵ )(R ¹¹ ). In a further aspect of the invention R ¹⁰ is methyl, ethyl or n-propyl substituted at the terminal carbon atom by -N(CH ₃ ) ₂ . In another aspect of the invention R ¹⁰ is methyl substituted by -N(CH ₃ ) ₂ . in one aspect of the invention R ⁸ is -C(=0)-R ¹⁰ and R ⁰ is -d^alkyl substituted at the terminal carbon atom by -S-R ¹² . in a further aspect of the invention R ¹⁰ is methyl, ethyl or n-propyl substituted at the terminal carbon atom by a six membered unsubstituted heteroaromatic ring. In another aspect of the invention R ¹⁰ is methyl and R ¹² is pyridyl. In a yet further aspect R ¹² is 4-pyridyl.

In one aspect of the invention R ⁸ is -C(=0)-R ¹⁰ and R ¹⁰ is 5-6 membered unsubstituted heteroaromatic ring. In a further aspect of the invention R ¹⁰ is six membered monocyclic unsubstituted heteroaromatic ring containing two heteroatoms. In another aspect of the invention R ¹⁰ is pyrazinyl. In a yet further aspect of the invention R ⁰ is 2-pyrazinyl,

In one aspect of the invention R ⁹ is hydroxyl. In one aspect of the invention R ⁹ is a hydroxyl protecting group. In a further aspect of the invention the hydroxyl protecting group is -OC(0)Ci. alkyl. In another aspect of the invention the hydroxy! protecting group is -OC(0)CH ₃ (acetyl).

In one aspect of the invention R ¹¹ is methyl, ethyl or n-propyl. In a further aspect of the invention R ¹ is methyl.

In one aspect of the invention R ² is 5-6 membered unsubstituted heteroaromatic ring. In a further aspect of the invention R ¹² is six membered unsubstituted heteroaromatic ring containing one heteroatom. in another aspect of the invention R ¹² is pyridyl. In a yet further aspect R ¹² is 4-pyridyl.

In a further aspect of the invention, there is provided a compound of Formula (I) represented by Formula (IA):

wherein,

A is a bivalent radical -N(R ⁶ )CH ₂ -, -CH ₂ N(R ⁵ )-, -NHC(O)- or -C(0)NH-;

R is hydrogen or CH ₃ ; R ² is a β-D-desosaminyl group of Formula (a);

R ³ is an a-L-cladinosyl group of Formula (b) or hydroxy I;

R ⁴ is hydrogen;

R ⁵ is hydrogen or -C _1-4 alkyl;

R is hydroxy!, hydroxyl protecting group or -0-(CH ₂ ) ₂ CN;

R ^s is independently selected from:

ai) hydrogen,

bi) -C ea!kyl, unsubstituted or substituted at the terminal carbon atom by hydroxyl or ~(5~oxotetrahydro-2-furanyl), or

ci) -C(=0)-R ¹⁰ ;

R ⁹ is hydroxy! or hydroxyl protecting group;

R ¹⁰ is independently selected from:

-C _-4 alky!, unsubstituted or substituted at the terminal carbon atom by a substitueni selected from the group consisting of hydroxyl, -C _1-4 alkoxy , -C(0)OC _1-4 alkyl, -N(R ⁵ )(R ¹¹ ) and -S-R ¹² , or

5-6 membered unsubstituted heteroaromatic ring; R ¹ is -C _1-4 alkyl; R ¹² is 5-6 membered unsubstiiuted heteroaromatic ring; or a salt thereof. In one aspect, the present invention comprises a compound of Formula (I) selected from: (Ey^' T-O-diacetyl-l 1 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A,

(£)-4"- O-acetyl-11 , 2-didehydro-1 1 ,12-dideoxy-6-0-methyl-9a-a2a-9a-homoerythromycin A,

(£ 11 , 12-didehydro-11 , 12-dideoxy-6-0-methyl-9a-aza-9a-homoerythromycin A,

(E)-4"-0-acetyl-3'-/V-demethyH 1 ,12-didehydro-11 ,12-dideoxy-6-0-met yI-9a-aza-9a- homoerythromycin A,

(E)-3'-/V-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A,

(£)-4"-0-acetyl-3'-W-demethyl-11 , 2-didehydro-1 1 , 12-dideoxy-3'-W-(methoxy)acetyi-6-0- methyl -9a-aza-9a-homoerythromycin A,

(£)-4"-0-acetyl-3'-W-demethyl-11 ,12-didehydro-l 1 ,12-dideoxy-6-0-methy]-3'-/V-(4- pyridinylthio)acetyl-9a-aza-9a-homoerythromycin A,

(E)-4"-0-acetyl-3'-/V-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0~methyl-3'-/V-(2- pyrazinyl)carbonyl-9a-aza-9a-homoerythromycin A,

(£)-3'-/V-demethyl-1 1 , 12-didehydro-1 1 , 12-dideoxy-3'-/V-(methoxy)acetyl-6-0-methyl-9a- aza-9a-homoerythromycin A,

(E)-3'-/V-demethyl-1 1 _I 12-didehydro-11 ,12-dideoxy-6-0-methyi-3'-W-(4-pyridinylth

9a-aza-9a-homoerythromycin A,

(E)-2\4"-0-diacetyl-11 , 12-didehydro-9-deoxo-1 1 , 12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A,

(£)-4"-0-acetyl-1 1 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyi-9a-aza-9a- homoerythromycin A,

(£)-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a-homoerythromycin A, (_E)-4"-0-acetyj-3'-A/"demethyl-11 , 12-didehydro-9-deoxo-1 1 ,12-dideoxy-9a-methyl-9a-aza- 9a-homoerythromycin A,

(E)-3'-/V-demethyl-1 1 , 12-didehydro-9-deoxo-11 , 12-dideoxy-9a-methy1-9a-aza-9a- homoerythromycin A,

(£)-4"-0-acetyl-3'-/V-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3'-W- (methoxy)acetyl-9a-methyl-9a-aza-9a-homoerythromycin A,

(£)-4"-0-acetyl-3'-W-demethyl-11 ,12-didehydro-9-deoxo-1 1 ,12-dideoxy-3'-/V-(4-methoxy-

4-oxobutanoyi)-9a-methy[-9a-aza-9a-homoerythromycin A,

(E)-4''-0-acetyl-3'-/V-demethyl-1 1 , 12-didehydro-9-deoxo-11 , 12-dideoxy-3'-/V-(/V,/V- dimethylglycy!)-9a-methyl-9a-aza-9a-homoervthromycin A,

(E)-3'-W-demethyl-1 1 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3'-W-(methoxy)acetyl-9a- methyl-9a-aza-9a-homoerythromycin A,

(£)-3'-/V-demethyl-11 ,12-dide ydro-9-deoxo-11 ,12-dideoxy-3 ^, -/V-(/V,/V-dimethylglycy!)-9a- methyi-9a-aza-9a-homoerythromycin A,

(£)-3'-/V-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3'-/V-(4-methoxy-4- oxobutanoy[)-9a-methyl-9a-aza-9a-homoerythromycin A,

(£)-3'-/\/-demethy!-1 1 ,12-didehydro-9-deoxo-11.^-dideoxy-ga-methyW-W^- hydroxyethyl)-9a-aza-9a-homoerythromycin A,

(E)-3'-/V-demethyl-11 ,12-didehydro-9-deoxo-11 _l 12-dideoxy-9a-methyl-3'-/V-(3- hydroxypropyi)-9a-aza-9a-homoerythromycin A,

(£)-3'-W-demethyl-11 , 12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-3'-/V-{[(2F?)-5- oxotetrahydro-2-furany!]methyl}-9a-aza-9a-homoerythrornycin A,

(E)-3'-W-demethyl-1 1 ,12-didehydro-9-deoxo-11 _l 12-dideoxy-9a-methyl-3 ^, -W-E(2S)-5- oxotetrahydro-2-furanyl]methyl}-9a-aza-9a-homoerythromycin A,

(£)-4"-0-acetyl-2 ^, -0-{2-cyanoethyl)-11 ,12-didehydro-9-deoxo-1 1 ,12-dideoxy-9a-methyl- 9a-aza-9a-homoerythromycin A, or

(E)-3-0-decladinosyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A;

or a salt thereof.

In one aspect the present invention also relates to 11 2-(W,A/-di-substituted-formamide) acetai intermediates of Formula (ii) useful for the preparation of compounds of Formula (I)

(ii)

wherein,

A is a bivalent radical -C(O)-, -N(R ⁵ )CH ₂ -, -CH ₂ N(R ⁵ )-, -C(=NOR ⁶ )-, -CH(OH)-, -NHC(O)- or -C(0)NH;

R ¹ is hydrogen or CH ₃ ; R ² is a β-D-desosaminyl group of Formula (a),

R ³ is an a-L-cladinosyl group of Formuia (b)

R ⁴ is hydrogen;

R ⁵ is hydrogen or -d- alkyl;

R ⁶ is hydrogen or -C - aikyl, wherein -C _1-4 aikyl may be optionally interrupted by one or two oxygen atoms, and/or is unsubstituted or substituted by one or two substituents independently selected from -C-|. ₄ a!koxy or -C ₃ . ₇ cyc!oalky!, with the proviso that when the - C _1-4 alkyl is interrupted by two oxygen atoms, the two oxygen atoms are not adjacent one another; R ⁷ is hydroxy!, hydroxyl protecting group or -0-(CH ₂ ) ₂ CN; R ⁸ is CH ₃ ;

R ⁹ is hydroxyl or hydroxyl protecting group;

R ^q and R ^l independently are -C _-4 alkyl or -C _h alky! substituted by phenyl, or a salt thereof. In a further aspect of the invention, there is provided 11 ,12-(/V,/V-disubstituted-formamide) acetal intermediate of Formula (II) useful for the preparation of compounds of Formula (I) represented by Formula (MA):

a) CH ₃ and A is a bivalent radical -0(0)-, -N(R ^S )CH ₂ - ₁ -CH ₂ N(R ^S )- ₁ -C(=NOR ⁶ )-, -CH(OH)-, -NHC(O)- or -C(0)NH-; or

b) hydrogen and A is a bivalent radical -C(0)-, -C(=NOR ⁶ )-, -CH(OH)-, -NHC(O)- or -C(0)NH- ;

R ² is a β-D-desosaminyl gro

R ³ is an cc-L-cladinosyl group of Formula (b)

R ⁴ is hydrogen;

R ⁵ is hydrogen or -C _1-4 alkyl;

R is hydrogen or -C _1- alkyl, wherein -C _h alky! may be optionally interrupted by one or two oxygen atoms, and/or is unsubstituted or substituted by one or two substituents independently selected from -Ci _-4 aikoxy or -C _3-7 cycloalkyl, with the proviso that when the - C _1- alkyl is interrupted by two oxygen atoms, the two oxygen atoms are not adjacent one another;

R ⁷ is hydroxyl, hydroxyl protecting group or -0-(CH ₂ ) ₂ CN;

R ⁸ is CH ₃ ;

R ⁹ is hydroxyl or hydroxyl protecting group; R ^q and R' independently are -C _-4 alkyl or -Ci _-4 aikyl substituted by phenyl, or a salt thereof, in one aspect the present invention relates to 1 1 , 12-(/V, A/-disubstituted-formamide) acetal intermediates of Formula (II), wherein, R ^q and R' independently are -C _1-4 alkyl. In a further aspect of the invention R ^q and R ¹ independently are methyl.

In one aspect the present invention relates to 1 1 ,12-(W,W-disubstituted-formamide) acetal intermediates of Formula (!!), wherein A is a bivalent radical -NHC(O)- and R ¹ is CH ₃ .

Compounds of the present invention inhibit infiltration of neutrophils into inflamed lung tissue (as demonstrated hereinafter). Therefore these compounds may have utility in acute and chronic treatment of inflammatory pathologies, especially of those pathologies associated with extensive neutrophil infiltration into the lung tissue, for example chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS, known also as acute respiratory distress syndrome or respiratory distress syndrome, RDS), severe or steroid-resistant asthma (Simpson JL et al. (2008) Am J Respir Crit Care Med, 177: 148-155), and emphysema or into the respiratory tract, for example chronic rhinosinusitis (with or without nasal polyposis) (Wal!work B et at. (2006) Laryngoscope, 1 16: 189-193). In addition, compounds of the present invention may be used for the treatment of other diseases associated with aitered cellular functionality of neutrophils, for example rheumatoid arthritis (Kitsis E and, Weissmann G, Clin Orthop Relat Res. (1991 ), 265: 63-72), gouty arthritis, inflammatory bowel diseases (such as ulcerative colitis and Chron's disease), glomerulonephritis (Heinzelmann M et al., Am J Kidney Dis. (1999), 34(2): 384-399), damage from ischemic reperfusion (Kaminski KA et al., Int J Cardiol. (2002), 86(1 ): 41 -59), atherosclerosis (Henriksen PA and Sal!enave JM. Int J Biochem Cell (2008), 40: 1095-1 100), dermatoses such as psoriasis (Terui T et al., Exp Dermatol. (2000), 9(1 ): 1-10) and vasculitis, systemic lupus erythematodes (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome. The induction of lung neutrophil infiltration in rodents by the local application of bacterial lipopolysaccharide (LPS) is widely used as a test model for neutrophilic infiltration of human lungs during pulmonary inflammatory disease. We have observed a correlation between the inhibitory activity of compounds on cell infiltration into broncho-alveolar iung fluid (BALF) of mice treated intranasally with LPS and their inhibition of interleukin-6 (IL-6) production by LPS-stimulated mouse splenocytes in vitro (Figure 1 ). Therefore, inhibition of IL-6 production in LPS-stimuiated murine spleen cells may be a suitable in-vitro mode! (biomarker) for the in-vivo activity of compounds in treating inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils.

"Treating" or "treatment" of neutrophil dominated inflammatory diseases, especially those resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils means the alleviation of the symptoms and/or retardation of progression of the disease, and may include the suppression of symptom recurrence in an asymptomatic patient.

Inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils include chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS), severe or steroid-resistant asthma, emphysema, chronic rhinosinusitis (with or without nasal polyposis), rheumatoid arthritis, gouty arthritis, inflammatory bowel disease (ulcerative colitis and Chron's disease), glomerulonephritis, damage from ischemic reperfusion, atherosclerosis, dermatoses such as psoriasis and vasculitis, systemic lupus erythematosus (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome. In one aspect, the present invention provides a method of treating chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS), severe or steroid-resistant asthma, emphysema, chronic rhinosinusitis (with or without nasal polyposis), rheumatoid arthritis, gouty arthritis, inflammatory bowel disease (ulcerative colitis and Chron's disease), glomerulonephritis, damage from ischemic reperfusion, atherosclerosis, dermatoses such as psoriasis and vasculitis, systemic lupus erythematosus (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, bronchitis, bronchiectasis, adu!t respiratory distress syndrome, severe or steroid-resistant asthma, emphysema and chronic rhinosinusitis (with or without nasal polyposis) in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. in one aspect, the present invention provides a method of treating chronic obstructive pulmonary disease in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treating bronchiolitis obliterans in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (!) or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treating severe or steroid- resistant asthma in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treating cystic fibrosis in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (!) or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a method of treating chronic rhinosinusitis (with or without nasal polyposis) in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

In one aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS), severe or steroid-resistant asthma, emphysema, chronic rhinosinusitis (with or without nasal polyposis), rheumatoid arthritis, gouty arthritis, inflammatory bowel disease (u!cerative colitis and Chron's disease), glomerulonephritis, damage from ischemic reperfusion, atherosclerosis, dermatoses such as psoriasis and vasculitis, systemic lupus erythematosus (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome.

In another aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease, cystic fibrosis, diffuse panbronchitis, bronchiolitis obliterans, bronchitis, bronchiectasis, adult respiratory distress syndrome, severe or steroid-resistant asthma, emphysema and chronic rhinosinusitis (with or without nasal polyposis).

In a further aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease.

In a further aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of bronchiolitis obliterans.

In a further aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of severe or steroid- resistant asthma. In a further aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of cystic fibrosis. in a further aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic rhinosinusitis (with or without nasal polyposis).

In a further aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceuticaiiy acceptabie salt thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS), severe or steroid-resistant asthma, emphysema, chronic rhinosinusitis (with or without nasal polyposis), rheumatoid arthritis, gouty arthritis, inflammatory bowel disease (ulcerative coiitis and Chron's disease), glomerulonephritis, damage from ischemic reperfusion, atherosclerosis, dermatoses such as psoriasis and vasculitis, systemic iupus erythematosus (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome. In a further aspect of the invention, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease, cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, bronchitis, bronchiectasis, adult respiratory distress syndrome, severe or steroid-resistant asthma, emphysema and chronic rhinosinusitis (with or without nasal polyposis).

Sn a further aspect, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.

In a further aspect, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bronchiolitis obliterans.

In a further aspect, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of severe or steroid-resistant asthma. in a further aspect, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis. In a further aspect, the present invention provides the use of a compound of Formula (I) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic rhinosinusitis (with or without nasal polyposis).

The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

"Subject" refers to an animal, in particular a mammal and more particularly to a human or a domestic animal or an animal serving as a model for a disease (e.g., mouse, monkey, etc.). in one aspect, the subject is a human.

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a neutrophil dominated inflammatory disease resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated and will ultimately be at the discretion of the attendant physician. Pharmaceutical Compositions

While it is possible that, for use in the methods of the invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with at least one pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Accordingly, the present invention provides a pharmaceutical composition comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof and b) one or more pharmaceutically acceptable carriers.

The term "carrier" refers to a diluent, excipient, and/or vehicle with which an active compound is administered. The pharmaceutical compositions of the invention may contain combinations of more than one carrier. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions, Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18th Edition. The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or so!ubilizsng agent(s).

The phrase "pharmaceutically acceptable", as used herein, refers to salts, molecular entities and other ingredients of compositions that are generally physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Suitably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or fisted in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.

A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

The present invention is further related to a pharmaceutical composition for the treatment of a neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils comprising a compound of Formula (I) or a pharmaceutically acceptabie salt thereof. The present invention is further related to a pharmaceutical composition for the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), diffuse panbronchio!itis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, adult respiratory distress syndrome (ARDS), severe or steroid-resistant asthma, emphysema, chronic rhinosinusitis (with or without nasal polyposis), rheumatoid arthritis, gouty arthritis, inflammatory bowel disease (ulcerative colitis and Chron's disease), glomerulonephritis, damage from ischemic reperfusion, atherosclerosis, dermatoses such as psoriasis and vasculitis, systemic lupus erythematosus (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention is further related to a pharmaceutical composition for the treatment of chronic obstructive pulmonary disease, cystic fibrosis, diffuse panbronchitis, bronchiolitis obliterans, bronchitis, bronchiectasis, adult respiratory distress syndrome, severe or steroid-resistant asthma, emphysema and chronic rhinosinusitis (with or without nasal polyposis), comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The present invention is even further related to a pharmaceutical composition comprising a) 10 to 2000 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) 0.1 to 2 g of one or more pharmaceutically acceptable excipients.

It will be appreciated that pharmaceutical compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosatly administered) suspensions, solutions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients. In one aspect, the pharmaceutical composition is formulated for oral administration.

The compounds of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. In one aspect, oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules. This release profile can be achieved, for example, by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the Gl tract wherein a lesion or inflammation site has been identified. Or a delayed release can be achieved by a coating that is simply slow to disintegrate. Or the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.

Suitable compositions for delayed or positioned release and/or enteric coated oral formulations include tablet formulations film coated with materials that are water resistant, pH sensitive, digested or emulsified by intestinal juices or sloughed off at a slow but regular rate when moistened. Suitable coating materials include, but are not limited to, hydroxypropyl methyicellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellu!ose phthalate, polymers of metacrylic acid and its esters, and combinations thereof. Plasticizers such as, but not limited to polyethylene glycol, dibutytphthalate, triacetin and castor oil may be used. A pigment may also be used to color the film. Suppositories are be prepared by using carriers like cocoa butter, suppository bases such as Suppocire C, and Suppocire NA50 (supplied by Gattefosse Deutschland GmbH, D-Weil am Rhetn, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C ₈ - C-ie triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides, and whitepsol (hydrogenated plant oils derivatives with additives). Enemas are formulated by using the appropriate active compound according to the present invention and solvents or excipients for suspensions. Suspensions are produced by using micronized compounds, and appropriate vehicle containing suspension stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof; propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropyimethylcellulose, hydroxyethylceilu!ose, ethylcellulose, methyicellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinylacetamide polymer, polyvinyl methacry!ate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrated caster oil, polyoxyethylene alkyl ethers, and pluronic and appropriate buffer system in pH range of 6.5 to 8. The use of preservatives, masking agents is suitable. The average diameter of micronized particles can be between 1 and 20 micrometers, or can be less than 1 micrometer, Compounds can also be incorporated in the formulation by using their water-soluble salt forms.

Alternatively, materials may be incorporated into the matrix of the tablet e.g. hydroxypropyl methyicellulose, ethyl cellulose or polymers of acryiic and metacrylic acid esters. These latter materials may also be applied to tablets by compression coating. Pharmaceutical compositions can be prepared by mixing a therapeutically effective amount of the active substance with a pharmaceutically acceptable carrier that can have different forms, depending on the way of administration. Pharmaceutical compositions can be prepared by using conventional pharmaceutical excipients and methods of preparation. The forms for oral administration can be capsules, powders or tablets where usual solid vehicles including lactose, starch, glucose, methylcellulose, magnesium stearate, di- calcium phosphate, mannitol may be added, as well as usual liquid oral excipients inciuding, but not limited to, ethanol, glycerol, and water. All excipients may be mixed with disintegrating agents, solvents, granulating agents, moisturizers and binders. When a solid carrier is used for preparation of oral compositions (e.g., starch, sugar, kaolin, binders disintegrating agents) preparation can be in the form of powder, capsules containing granules or coated particles, tablets, hard gelatin capsules, or granules without limitation, and the amount of the solid carrier can vary (between 1 mg to 1g). Tablets and capsules are the preferred oral composition forms.

Pharmaceutical compositions containing the compounds of the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.

Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the present invention include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycoiate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and cross!inked polyvinylpyrrolidone.

Examples of pharmaceutically acceptable binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethyScellulose; gelatin, glucose, dextrose, xylitol, polymethacryiates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.

Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro- calcium phosphate, calcium carbonate and calcium sulfate.

Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryt sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

Examples of suitable pharmaceutically acceptable flavourings for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.

Examples of suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel. Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylito!, mannitol, sorbitol, lactose and sucrose.

Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.

Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.

Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).

Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisoie.

The compounds of the invention may also, for example, be formulated as suppositories e.g., containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g., containing conventional pessary bases.

The compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g., eye ear or nose drops) or pour- ons.

For application topically to the skin, the compound of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropytene compound, emulsifying wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyidodecanol, benzyl alcohol, and water. Such compositions may also contain other pharmaceutically acceptable excipients, such as polymers, oils, iiquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and flavourings.

Examples of pharmaceutically acceptable polymers suitable for such topical compositions include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methy!ce!iulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.

As indicated, the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., a hydrofluoroaikane such as 1 ,1 ,1 ,2- tetrafluoroethane (HFA 134AT) or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EA), or a mixture thereof. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch. For topical administration by inhalation the compound according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.

If the compound of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intraarterialiy, intraperitoneally, intratheca!iy, intraventriculariy, intraurethraliy, intrasterna!ly, intracranial!y, intramuscularly or subcutaneously administering the agent, and/or by using infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

The compounds according to the invention may be formulated for use in human or veterinary medicine by injection (e.g. by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative. The compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain fo mulatory agents such as suspending, stabilising, so!ubilising and/or dispersing agents. Alternatively the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The pharmaceutical compositions of the invention may contain from 0,01 to 99% weight per volume of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1 % of the active compound.

A therapeutically effective amount of the compound of the present invention can be determined by methods known in the art. The therapeutically effective quantities will depend on the age and on the general physiological condition of the subject, the route of administration and the pharmaceutical formulation used. The therapeutic doses will generally be between about 10 and 2000 mg/day and suitably between about 30 and 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day. The daily dose as employed for acute human treatment will range from 0.01 to 2 mg/kg body weight, suitably 2 to 20 mg/kg body weight, or suitably 5 to 10 mg/kg body weight, which may be administered in one to four daily doses, for example, depending on the route of administration and the condition of the subject. When the composition comprises dosage units, each unit will contain 10 mg to 2 g of active ingredient, suitably 200 mg to 1 g of active ingredient. Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead of every day or twice a day. The dose and the administration frequency will depend on the clinicai signs with the reduction or absence of at least one or more, preferably more than one, clinical signs of the acute phase known to the person skilled in the art. fn one aspect of the present invention, administration is once daily oral dosing.

In one aspect, the present invention provides a combination comprising a) a compound of Formula (!) or a pharmaceutically acceptable salt thereof and b) one or more further therapeutically active agents.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers thereof represent a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

Methods of preparation:

Compounds of Formula (!) and sa!ts thereof may be prepared by the general methods outlined hereinafter or any method known in the art, said methods constituting a further aspect of the invention. In the following description, the groups A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^s , R ¹⁰ , R ¹¹ and R ¹² have the meaning defined for the compounds of Formula (i) unless otherwise stated. It will be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of the compounds of Formula (I). Protection and deprotection of functional groups may be performed by methods known in the art. Hydroxyl, amino or keto groups may be protected with any hydroxy), amino or keto protecting group (for example, as described in Green and Wuts. Protective Groups in Organic Synthesis. John Wiley and Sons, New York, 1999). The protecting groups may be removed by conventional techniques. For example, acyl groups (such as alkanoy!, alkoxycarbonyl and aryloyl groups) may be removed by sotvolysis (e.g. , by hydrolysis under acidic or basic conditions). Benzyl group may be cleaved by hydrogenolysis in the presence of a catalyst such as palladium-on-carbon. Hydroximino group may be converted to keto group by reaction with Na ₂ S ₂ 0 ₅ as described in WO2006/087644. 1 ,2 diol groups may be protected as aceta! by reaction with dimethyl acetal of N,N- dimethylacetamide (DMADMA) or dimethyl acetal of Ν,Ν-dimethylformamide (DMFDMA) which may be removed by hydrogenoiysis or methanolysis at reflux {Tetrahedron Lett. 12 (1971 ), 813-816, Collection Czech. Chem. Commun. 32 (1967), 3159).

The synthesis of the compounds of Formula (I) may be completed, if appropriate, by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are we!l-known to those skilled in the art. The compounds of Formula (I) may be purified by conventional methods known in the art. For example, the compounds may be purified using standard techniques such as silica gel chromatography, HPLC on silica gel, HPLC using an aqueous solution of an acid such as formic acid or trifluoroacetic acid, or an ammonium salt of carbonic acid, such as ammonium bicarbonate with an organic co-solvent such as acetonitrile or methanol, and the like. Alternatively, compounds of Formula (I) may be purified by differential partition between aqueous and organic solvents and/or crystallisation. Compounds of Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b), R ⁸ is hydrogen, methyl or -C{=0)-R ¹ °, R ⁷ and R ⁹ are hydroxyl, may be prepared from compounds of Formula (I) wherein R ³ is an α-L-c!adinosyl group of Formula (b), R ⁸ is hydrogen, methyl or -C(=0)-R ¹⁰ , R ⁷ is hydroxyl and R ⁹ is hydroxy! protecting group (suitably acetyl), by using suitable base, for example K ₂ C0 ₃ or LiOH in a suitable solvent, such as methanol or mixture of methanol and water.

The reaction may be carried out for example using excess of a suitable base, such as K ₂ C0 ₃ , suitably 5-10 equivalents of base, in a suitable solvent, such as methanol or a mixture of methanol and water at room temperature.

Alternatively, compounds of Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b), R ⁸ is -C(=0)-R ¹⁰ , R ⁷ and R ^s are hydroxyl, may be prepared by reaction of compounds of Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b), R ^s is hydrogen, R ^? and R ⁹ are hydroxyl with suitable acid of Formula (II!)

HOOCR ¹⁰ (I!I)

in the presence of carbodiimides such as polymer-supported carbodiimide (PS CDl), 1-{3- dimethylaminopropy!)-3-ethylcarbodiimide (EDC), dicyc!ohexylcarbodiimide (DCC) or 1 ,8- diazabicycio[5.4.0.]undec-7-ene (D8U) in the presence of hydroxybenzotriazole monohydrate (HOBt) in a suitable inert organic solvent such as a halohydrocarbon (e.g. dichioromethane), Ν,Ν-dimethylformamide or mixture thereof optionally in the presence of a tertiary organic base such as triethylamine or dimethySaminopyridine or in the presence of an inorganic base (eg. sodium hydroxide) and at a temperature in the range 0° to 120°C.

Compounds of Formula (I) wherein R ³ is an α-L-cladinosyl group of Formula (b), R ⁸ is -Ci„ ₆ alkyl, R ⁷ and R ⁹ are hydroxy!, may be prepared by N-alkylation of compounds of Formula (I) wherein R ⁸ is hydrogen using suitable halo derivative of Formula (IV) Hal-C _1-6 alkyl (IV)

wherein Hal is chloro, bromo or iodo (suitably iodo).

The N-aikylation is suitably carried out in a presence of an organic base {suitably N,N- diisopropylethylamine) in an inert organic solvent such as lower alcohol (suitably methanol) or acetonitrile.

Alternatively, compounds of Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b), R ⁸ is -Ci _-6 alkyl, R ⁷ and R ⁹ are hydroxyl, may be prepared by reductive amination of compounds of Formula (I) wherein R ⁸ is hydrogen, using suitable aldehyde of Formula (V)

J-C(0)H (V)

wherein J represents the group R but comprises one carbon atom less than the R group (for example if R ⁸ is n-butyl, then J is n-propyl). The reductive amination reaction is suitably carried out in a solvent such as methanol, dichloromethane, chloroform, Ν,Ν-dimethylformamide or a mixture thereof, in the presence of asuitabie reducing agent, for example sodium t iacetoxyborohydride or sodium cyanoborohydride, Specifically, compounds of Formula (I), wherein R ³ is an α-L-c!adinosyI group of Formula (b), R ⁸ is methyl, R ⁷ and R ⁹ are hydroxyl, may be prepared from compounds of Formula (I) wherein R ^s is hydrogen, by the Eschweiler-Clarke procedure using formaldehyde and formic acid. Specifically, compounds of Formula (I) wherein R ³ is an α-L-c!adinosyl group of Formula (b), R ⁸ is -Ci. ₆ alkyl substituted at the terminal carbon atom by a -(5-oxotetrahydro-2- furanyl) group, R ⁷ and R ⁹ are hydroxyl, may be prepared by N-alkylation of compounds of Formula (i) wherein R ⁸ is hydrogen, using a suitable tosylate derivative of Formula (VI), wherein R ⁸ is -Ci. ₆ alkyl substituted at the terminal carbon atom by a -(5-oxotetrahydro-2- furanyl) group.

in the presence of tertiary organic base such as diisopropylethylamine (DSPEA), triethylamine (TEA), or mixture thereof.

The reaction is suitably carried out in a lower alcohol solvent such as methanol, in a presence of a base such as diisopropylethylamine (DIPEA) at room or elevated temperature (suitably at about 50 °C).

Compounds of Formula (I) wherein R ³ is an a-L-ciadinosyl group of Formula (b), R ⁸ is - C(=0)-R ¹⁰ , R ⁷ is hydroxyl and R ⁹ is hydroxyl protecting group (suitably acetyl), may be prepared by reaction of compounds of Formula (I) wherein R ³ is an a-L-ciadinosyl group of Formula (b), R ⁸ is hydrogen, R ⁷ is hydroxyl and R ⁹ is hydroxyl protecting group (suitably acetyl) with suitable acid of Formula (III)

HOOCR ⁰ (IM)

in the presence of carbodiimides such as polymer-supported carbodiimide (PS CDI), 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC) or 1 ,8- diazabicyclo[5.4.0.]undec-7-ene (DBU) in the presence of hydroxybenzotriazole monohydrate (HOBt) in a suitable inert organic solvent such as a halohydrocarbon (e.g. dichloromethane), Ν,Ν-dimethy!formamide or mixture thereof optionally in the presence of a tertiary organic base such as triethy!amine or dimethylaminopyridine or in the presence of an inorganic base (eg. sodium hydroxide) and at a temperature in the range 0° to 120°C, Compounds of Formula (I) wherein R ³ is an -L-cladinosyl group of Formula (b), R ⁸ is hydrogen, R ⁷ is hydroxy!, and R ⁹ is hydroxy! or hydroxyl protecting group (suitably acetyl), may be prepared by reaction of compounds of Formula (I), wherein R ^s is C^alkyl (suitably methyl), R ³ is an α-L-c!adsnosyl group of Formula (b), R ⁷ is hydroxyl and R ⁹ is hydroxy! or hydroxy! protecting group (suitably acetyl), by conventional techniques for mono- demethy!ation of the 3'-NMe ₂ group, for example by reaction with azodicarboxy!ic acid esters, suitably DEAD in D F (E. E. Smissman, et al. J. Org. Chem. 38 (1973) 1652- 1657), or with iodine under UV radiation (preferably with 500 W halogen lamp), in the presence of sodium acetate (US 3,725,385 and WO2004/013153), or by reaction of compound of Formula (I) with N-iodosuccinimide in acetonttrile at room temperature (J. Org. Chem. 65 (2000) 3875-3876), or with iodine in presence of morpholine or with benzy!chloroformate, followed by elimination of benzyloxycarbonyl groups at position and 3' as described in US 5,250,518.

Compounds of Formula (I) wherein R ³ is hydroxyl may be prepared by acid hydrolysis of compounds of Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b) using diluted hydrochloric acid at a temperature within the range of 20° to 40°C.

Compounds of Formula (I) wherein R ³ is an -L-cladinosyl group of Formula (b), R ⁸ is methyl, R ⁷ is hydroxy! and R ⁹ is hydroxyl protecting group (suitably acetyl), may be prepared by selective solvolysis of C/2'-hydroxyl protecting group from compounds of Formula (I) wherein R ³ is an α-L-c!adinosyl group of Formula (b), R ⁸ is methyl, R ⁷ and R ⁹ are hydroxyl protecting group (suitably acetyl) according to the methods known in the art, such as J. Med. Chem. (1972) 1 5, 631-634 and J. Antibiotics (1987) 40, 1006-1015. The reaction may be carried out for example using methanol at a temperature in the range from room temeperature to 60 °C. Alternatively compounds Formula (I) wherein R ³ is an a-L-cladinosyl group of Formula (b), R ⁸ is methyl, R ⁷ is hydroxyl and R ⁹ is hydroxy! protecting group (suitably acetyl), may be prepared by reaction of compounds of Formula (I!) wherein R ⁷ and R ⁹ are hydroxyl with the appropriate carboxy!ic acid anhydride (suitably acetanhydride) in a suitable inert organic solvent such as toluene or halohydrocarbon (e.g. dichioromethane), in the presence of tertiary organic base such as triethylamine (TEA), diisopropyiethylamine (DIPEA) or mixture thereof, and catalytic amount of dimethylaminopyridine (DMAP) at a temperature in the range from room to reflux, followed by solvoiysis with methanol. The reaction may be carried out for example using excess of carboxylic acid anhydride (sutably acetanhydride), suitably 5 to 10 equivalents, in a suitable solvent, such as toluene, at reflux temperature in the presence of triethylamine and dimethylaminopyridine, followed by treatment with methanol. Compounds of Formula ([) wherein R ³ is an a-L-ciadinosyl group of Formula (b), R ⁸ is methyl, R ⁷ is hydroxy! protecting group (suitably acetyl) or -0-(CH ₂ ) ₂ CN and R ⁹ is hydroxy! protecting group (suitably acetyl), may be prepared by decarboxylation reaction of compounds of Formula (II), wherein R ⁷ is hydroxy! protecting group (suitably acetyl) or -0-(CH ₂ ) ₂ CN, and R ⁹ is hydroxyl protecting group (suitably acetyl) with the appropriate carboxy!ic acid haisde (suitably benzoyl chloride) or with the appropriate carboxylic acid anhydride (sutably acetanhydride) in a suitable inert organic solvent such as halohydrocarbon (e.g. dichioromethane) or to!uene, in the presence of tertiary organic base such as triethylamine (TEA), diisopropy!ethy!amine (DIPEA) or mixture thereof, and catalytic amount of dimethylaminopyridine (DMAP) at a temperature in the range from room to reflux.

The reaction may be carried out for example using excess of carboxylic acid halide (suitably benzoyl chloride) suitably 5 to 10 equivalents, in a suitable solvent, such as a halohydrocarbon (e.g. dichioromethane) at room temperature in the presence of a suitable base, such as triethylamine.

Compounds of Formula (II), wherein R ⁷ is hydroxy! protecting group (suitably acetyl) or -0-(CH ₂ ) ₂ CN, and R ⁹ is hydroxyl protecting group (suitably acetyl), may be prepared from compounds of Formula (II) wherein R ⁷ is hydroxyl or -0-(CH ₂ ) ₂ CN, and R ⁹ is hydroxyl, by reaction with (Ci. ₄ alky!CO) ₂ 0 carboxylic acid anhydride (suitably acetanhydride) in a suitable aprotic solvent such as halohydrocarbon (e.g. dichioromethane) or N,N- dimethylformamide and in the presence of organic base such as dimethlyamino pyridine, triethylamine, mixture thereof or pyridine, and at a temperature range from 0° C to room temperature.

Compounds of Formula (II) wherein R ⁷ and R ⁹ are hydroxyl may be prepared by reaction of compounds of Formula (VII).

with the /V,W-substituted formamide acetal of formula (VIII)

wherein R ^l and R ^q independently are substituted by phenyl and R ^w is -C _1- a!kyl (suitably methyl), in a suitable inert organic solvent such as halohydrocarbon (e.g. chloroform or DCM), Λ/,/V-dimethy!formamide (DMF) or toluene at a temperature in the range from room to reflux.

The reaction may be carried out for example using excess of Λ/,/V-substituted formamide acetal (suitably Λ/,/V-dimethySformamide dimethylacetal (DMF-DMA)) suitably 2 to 6 equivalents, in a halohydrocarbon (e.g. chloroform) or in DMF at 60-70 °C. Compounds of Formula (VI I) are known compounds or may be prepared by processes known in the art.

Compounds of Formula (VI!) wherein A represents -C(O)- and R is methyl, may be prepared according to J. Antibiotics (1984) 37, 187-189.

Compounds of Formula (VII) wherein A represents -C(=NOR ⁶ )- and R ¹ is hydrogen or methyl, may be prepared according to US patent 3,478,014 or J. Antibiotics (1991 ), 44, 313-330.

Compounds of Formula (VII) wherein A represents -CH(OH)- may be prepared from compounds of Formula (VII) where A is -C(0)~ using a suitable reducing agent, for instance a hydride (sodium borohydride lithium borohydride, sodium cyano borohydride or lithium aluminium hydride) according to J. Antibiotics (1990) 1334-1336. Compounds of Formula (VII) wherein A represents -N(R ⁵ )CH ₂ - or -NCH ₂ (R ⁵ )- may be obtained by reduction of the corresponding 9a- or 8a-imino ether followed by reductive N- alkylation according to the procedure described in J. Chem. Soc. Perkin Trans (1986) 1881-1890, J. Chem Res. S (1988) 152-153; (M) (1988) 1239-1261 , EP0508725 and EP0507595.

Compounds of Formula (VI !) wherein A is -NHC(O)- or -C(0)NH- and R ¹ is methyl are known compounds or they may be prepared from the corresponding 6-O-methyl erythromycin A oxime by Beckman rearrangement according to the procedure described in W09951616.

Compounds of Formula (VII) wherein A is -C(0)NH- and R ¹ is hydrogen are known compounds or they may be prepared from the corresponding erythromycin A (9Z)-oxime by Beckman rearrangement according to the procedure described in Bioorg. Med. Chem, Lett. (1993) 3, 1287-1292.

Compounds of Formulae III, IV, V, Vi and VIII are commercially available or may be readily prepared by methods well known in the art, Pharmaceuticaliy acceptable acid addition salts, which also represent an object of the present invention, may be obtained by reaction of a compound of Formula (I) with an at least equimolar amount of the corresponding inorganic or organic acid such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, benzenesulfonic acid, methane sulfonic acid, jaurySsulfonic acid, stearic acid, palmitic acid, succinic acid, ethylsuccinic acid, lactobionic acid, oxalic acid, salicylic acid and similar acid, in a solvent inert to the reaction. Addition salts are isolated by evaporating the solvent or, alternatively, by filtration after a spontaneous precipitation or a precipitation by the addition of a non-polar cosolvent. Biological Assays

The potential for a compound of the present invention to have an advantageous profile for providing therapeutic benefit in the treatment of neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils may be demonstrated, for example, using the foi!owing assays.

In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described in the experimental section. A test compound from one batch may have been combined with other batch(es) for the assay(s).

A compound analysed using biological assays defined herein is considered to be active if it exhibits at least one of the following results; a) 40% or more, suitably 50% or more, inhibition in the in vitro Inhibition of IL-6 production in LPS-stimulated murine spleenocytes assay; and/or

b) 30% or more, suitably 50% or more, inhibition in the in vivo Lung neutrophilia induced by bacterial lipopoly 'saccharide in mice assay.

The following abbreviations are used in the text: DMSO for dimethyl sulfoxide, PBS for phosphate buffered saline, DME for Dulbecco's modified Eagle medium, FBS for fetal bovine serum, LPS for bacterial lipopolysaccharide, and BALF for bronchoa!veolar lavage fluid.

In vitro screening protocol

Compound preparation

Test and reference substances used in an in vitro assay are dissolved in dimethyl sulfoxide (DMSO) (Sigma Chemicai Co., USA) at a concentration of 50 mM and are further diluted to final concentrations of 50 μΜ, 25 μΜ, 12.5 μΜ, 6.3 μΜ and 3.1 μΜ in Dulbecco's modified Eagle medium (DMEM) (Gibco, USA) supplemented with 1 % heat inactivated fetal bovine serum (FBS) (BioWest, Ringmer, United Kingdom), inhibition of IL-6 production in LPS-stimulated murine spleenocytes in vitro

After cervical dislocation, mouse spleens are removed using sterile dissection tools. Spleens are transferred to a pre-wetted cell strainer in a 50 ml_ sterile conical tube and cell suspension was made by gentle puddle. Cells are centrifuged (20 min, 300xg) and resuspended in 2 mL of sterile phosphate buffered saline (PBS) (Sigma Chemical Co., USA). Red blood cells are lysed by addition of 3 mL of sterile water and occasionally gentle shaking for 1 minute. Afterwards, the tube is filled to 40 mL with DMEM medium and centrifuged (20 min, 300xg). Cells are resuspended in DMEM supplemented with 1 % FBS and seeded in a 24-well plate, 1 x10 ⁶ cells per mL medium.

Cells are pre-incubated with the test compounds for 3 h at 37°C, in an atmosphere of 5% C0 ₂ and 90% humidity. Afterwards, ceils are stimulated with 1 pg/mL lipopolysaccharide (LPS, E. coli 01 1 1 ;B4, Sigma Chemical Co. , USA) and incubated overnight. Concentration of IL-6 is determined in cell supernatants by sandwich ELISA using capture and detection antibodies (R&D Systems, USA) according to the manufacturer's recommendations. Inhibition (as percentage) is calculated using the following formula:

% inhibition = [1 - (concentration of IL-6 in sample - concentration of !L-6 in negative control) / (concentration of IL-6 in positive control - concentration of IL-6 in negative control)] 100.

The positive control refers to LPS-stimulated samples that were not preincubated with the compounds.

The negative control refers to unstimulated and untreated samples. in vivo screening protocol

Lung neutrophilia induced by bacterial iipopolysaccharide (LPS) in mice

For intraperitoneal administration (i.p.) compounds are dissolved in a final concentration of 10mg/mL The required amount of compound is first dissolved in dimethylsulfoxide (DMSO, Sigma) and then diluted with 0.5% (w/v) methyl-cellulose so that the final DMSO concentration was 5% (v/v). The obtained solution is applied in a dose volume of 0.1 mL per 10g of animal. Therefore, the compound dose is 10Qmg/kg. Maie BALB/c mice (Charles River, Germany), with an average weight of ~25g are randomly grouped (n=8 in testing group, 10 in positive control and 6-8 in negative control). Mice received intraperitoneally (i.p.) a single dose of 100 mg/kg of test compound. Two hours after administration, 0.4 pg of LPS (from Escherichia coli serotype 01 1 1 :B4, Sigma), dissolved in sterile saline (0.9% NaCI) in a volume of 50 μΙ_, is intranasally administered to all experimental groups except the negative control group, which received the same volume of vehicle (saline). Animals are sacrificed approximately 24 hours after application of LPS in order to obtain bronchoalveolar lavage fluid (BALF), which is used to determine absolute number of cells and the percentage of neutrophils. Results are expressed as percentage decrease in total cell number and number of neutrophils in BALF of treated animals compared to positive control (LPS challenged, but untreated animals), as revealed by cytospine evaluation. In some experiments neutrophil levels in BALF are assessed by measurement of concentration of a neutrophil-specific enzyme myeloperoxidase (MPO). Results are then expressed as percentage of decrease in myeloperoxidase (MPO) concentration measured in BALF lysates of treated animals compared to positive control (Mouse MPO EL!SA Kit, Hycult biotechnology, Nederlands). For this purpose, BALF is sonicated after addition of 1.5% Triton-X-100 (Pharmacia Biotech) in Milli-Q water and frozen at -80°C until analysed. Examples

The foliowing abbreviations are used in the text: DMF-DMA for Λ/,/V-dimethylformamide dimethylaceta!, DCM for dichloromethane, DMAP for dimethylaminopyridine, TEA or Et ₃ N for triethylamine, DEA or Et ₂ N for diethylamine, MeOH for methanol, DMF for N,N- dimethyiformamide, Ac ₂ 0 for acetic anhydride, EtOAc for ethyl acetate, DEAD for diethyl azodicarboxytate, DIPEA for diisopropy!ethylamine, HOBt for 1 -hydroxybenzotriazole hydrate, PS-CD! for polymer-supported carbodiimide, PS-trisamine for polymer-supported trisamine, DMSO for dimethyl sulfoxide, and THF for tetrahydrofurane.

The compounds and processes of the present invention will be better understood in connection with the foliowing examples, which are intended as an illustration only and not limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same, Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities, determined unless otherwise stated as area percentage by LC-MS, ranging from for example 73% to 99.6%. However, calculations of number of moles and yield are generally not adjusted for this. In the procedures that follow, reference to the product of an Intermediate or Example by number is typically provided. This is provided merely for assistance to the skilled chemist to identify the starting material used. The starting material may not necessarily have been prepared from the batch referred to.

The compounds of Formula (I) and derivatives thereof may be purified by conventional methods known in the art. For example, the compounds may be purified by reverse phase preparative HPLC, such as reverse phase mass directed automatic preparative HPLC using an aqueous solution of an acid, such as formic acid (HCOOH) or an ammonium salt of carbonic acid, such as ammonium bicarbonate (NH4HCO ₃ ), with an organic co-solvent such as acetonitrile. Alternatively, said compounds may be purified by crystallisation, chromatography and/or differential partition between aqueous and organic solvents.

Reverse phase mass directed automatic preparative HPLC refers to the use of Waters Mass Directed AutoPurification System using XBridge MS C18 column (19 x 100 mm, 5μηι) and isocrat technique, using mixture of eluents 10mM NH HC0 ₃ /pH 10 and CH ₃ CN. Unless otherwise stated, column chromatography was conducted on silica gel.

9-Deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, may be prepared by the procedure as described in J. Chem. Res. (S) 1988, page 152. 6-0-Methyl-9a-aza-9a- homoerythromycin A may be prepared according to procedure of W099/51616, example 2, page 1 5. 2'-0-(2-Cyanoethyt-4"-0-acetyl-9-deoxo-9a-methyi-9a-aza-9a- homoerythromycin A 1 1 , 12-(/V, /V-dimethylformamide) acetal may be prepared by the procedure as described in WO2009/016142, Intermediate 1 , Procedure B, Step 4, compound 1 1 b. INTERMEDIATES

Intermediate 1

6-0-Methyl-9a-aza-9a-homoerythromycin A 11 ,12-(W,W-dimethylformamide) acetal

To a solution of 6-0-methyl-9a-aza-9a-homoerythromycin A (10 g, 1 3.1 mmol, calculated based on 100% purity of starting macrolide) in chloroform (50 mL), DMF-DMA (5.74 mL, 40.6 mmol) was added, the reaction mixture was warmed at 60 °C and stirred for 12 hours. Then, additional amount of DMF-DMA (0.5 mL, 3.5 mmol) was added and stirring continued at 60 °C for 8 hours. After that, additional amount of reagent DMF-DMA (0.5 mL, 3.5 mmol) was added and stirring continued at 60 °C for a further 20 hours. The solvent was evaporated to afford crude title product (1 1 .20 g, purity; 73 %) as a yellow foam which was used in the next step without further purification; MS (ES\ m/z): 818.42 [M] ⁺ .

Intermediate 2

2',4"-0-Diacetyl-6-0-methyl-9a-aza-9a-homoerythrornycin A 11 ,12-{N,N- dimethylform

To a solution of DMAP (0.12 g, 1.00 mmol) in DCM (150 mL) cooled at 0 °C, TEA (4.76 mL, 34.0 mmol) and Ac ₂ 0 (2.08 mL, 22.01 mmol), followed by Intermediate 1 (1 1.20 g, 10.00 mmol, calculated based on 73% purity of Intermediate 1 ) solution in DCM (60 mL) were added. Reaction mixture was stirred at 0 °C for 1 hour, and at room temperature for 15 hours. Then, additional amount of TEA (1 .0 mL, 7.1 mmol) and Ac ₂ 0 (0.5 mL, 5.3 mmol) were added and stirring continued for 20 hours. Reaction mixture was washed with saturated aqueous NaHC0 ₃ solution (2 χ 200 mL) and with brine (200 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and evaporated to afford Intermediate 2 (1 1 .25 g, purity: 79 %) which was used in the next step without futher purification; MS (ES ⁺ , m/z): 902.56 [Mf.

Intermediate 3

9-deoxo-9a-methy!-9a-aza-9a-homoerythromycin A 11 ,12-{W,W-dimethylformamide) acetal

To a solution of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (100 g, 32 mmol, calculated based on 99% purity of starting macrolide) in DMF (150 mL), DMF-DMA (84 mL, 595 mmol) was added and the reaction mixture stirred at 70 °C for 20 hours. To the reaction mixture water (1000 mL) was added and product extracted by DCM (400 mL, 2 x 200 mL). Combined organic layers were washed with water (4 x 300 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, evaporated and dried in a vacuum oven at 50 °C over night to afford crude title product (101 g, purity: 87 %) which was used in the next step without further purification; MS (ES ⁺ , m/z): 804.40 [M] ⁺ .

Intermediate 4

2',4"-0-Diacetyl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromyci n A 11 ,12-(N,N- dimethylformamide) acetal

To a solution of intermediate 3 (101 g, 109 mmol, calculated based on 87% purity of Intermediate 3) in DCM (500 mL), TEA (94 mL, 678 mmol) and DMAP (1 .335 g, 10.9 mmol) were added, and the reaction mixture was cooled to 0 °C. Ac ₂ 0 (56.7 mL, 601 mmol) was added dropwise and stirring continued at 0 °C for 5 hours. Temperature was allowed to reach room temperature and reaction mixture stirred further 12 hours. Reaction mixture was washed with saturated aqueous NHC0 ₃ solution (4 x 300 mL) and with water (500 mL). Organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered, evaporated and dried in a vacuum oven at 50 °C over night to afford Intermediate 4 (103.25 g, purity: 82.5 %) which was used in the next step without futher purification; MS (ES ⁺ , m/z): 888.40 [M] ⁺ . Example 1

(E)-2',4"-0-Diacetyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromyctn A

A solution of TEA (3.48 mL, 24.99 mmol) and benzoyl chloride (2.64 mL, 22.71 mmol) in DCM (150 mL) was stirred for 10 minutes. Then solution of Intermediate 2 (5.2 g, 4.54 mmol, calculated based on 79% purity of Intermediate 2) in DCM (100 mL) was added dropwise over 2 hours and stirring continued for 4 hours. Reaction mixture was quenched with saturated aqueous NaHC0 ₃ solution (200 mL). Organic layer was washed with saturated aqueous NaHC0 ₃ solution (250 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude title product (6.42 g) which was purified by column chromatography (using solvent system 0-100% (DCM/MeOH/NH ₄ OH = 90/5/0.5) in DCM) to afford two fractions of crude title product: fraction A (1 .982 g, purity 80%), which was used in next step without further purification and fraction B (596.9 mg, purity 85%), which was further purified by precipitation from acetonitriie to afford title product (126.6 mg, purity 96.36%); MS (ES ⁺ , m/z): 813.71 [MH] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 0,78 (m, 3Η), 0.79 (m, 3Η), 0.93 (d, 3Η), 1.06 (m, 3H), 1 .06 (m, 3H), 1 .08 (m, 3H), 1 .14 (m, 3H), 1 .16 (m, 3Η), 1 .1 8 (m, 1 H), 1 .22 (m, 1 H), 1.24 <s, 3H), 1.41 (m, 1 H), 1 .50 (s, 3H), 1.54 (m, 1 Η), 1 .65 (m, 1 H), 1 .72 (m, 1 H), 1 .75 (m, 1 H), 1 .78 (m, 1 H), 1 .93 (s, 3H), 2.07 (s, 3H), 2.17 (s, 6H), 2.23 (m, 1 H), 2.40 (d, 1 H), 2.62 (m, 1 H), 2.74 (m, 1 H), 3.20 (s, 3H), 3.26 (s, 3H), 3.67 (m, 1 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.26 (m, 1 H), 4.44 (m, 1 H), 4.54 (m, 1 H), 4.57 (m, 1 H), 4.70 (d, 1 H), 4.91 (m, 2H), 5.38 (d, 1 H), 6.55 (d, 1 H). Example 2

(E)-4"-0-Acetyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methy1-9a-aza-9a- homoerythromycin A

Method A:

A solution of (E)-2',4''-0-diacetyl-11,12-didehydro-11,12-dtdeoxy-6-0-meth yl-9a-aza- 9a-homoerythromycin A, Example 1 (1.98 g, 1.95 mmol, calculated based on 80% purity of Example 1) in MeOH (40 mL) was stirred at 60 °C for 15 hours. Solvent was evaporated, the crude product dissolved in DC (3 mL), and precipitated by addition of diisopropylether (200 mL) to afford after filtration title product (1.01 g, purity: 94 %); MS (ES ⁺ , m/z): 771.70 [MH] ⁺ .

¹ H NMR (500 MHz, CDCI ₃ ) δ ppm: 0.86 (t, 3H), 1.05 (d, 3H), 1.13 (m, 3H), 1.14 (m, 3H), 1.17 (m, 3H), 1.18 (m, 3H), 1.20 (m, 3H), 1.24 (d, 3H), 1.30 (m, 1H), 1.35 (s, 3H), 1.53 (s, 3H), 1.59 (m, 2H), 1.60 (m, 1H), 1.68 (m, 1H), 1.70 (m, 1H), 1.75 (m, 1H), 1.92 (m, 1H), 2.12 (s, 3H), 2.33 (m, 1H), 2.32 (s, 6H), 2.44 (m, 1H), 2.56 (m, 1H), 2.92 (m, 1H), 3.20 (dd, 1H), 3.32 (s, 3H), 3.37 (s, 3H), 3.78 (dd, 1H), 3.84 (m, 1H), 3.86 (d, 1H), 4.39 (m, 1H), 4.62 (m, 1H), 4.68 (m, 1H), 4.69 (m, 1H), 4.94 (t, 1H), 5.03 (d, 1H), 5.58 (d, 1H), 6.44 (d, 1H).

Mother liqour was evaporated, obtained residue dissolved in DCM (2 mL) and precipitated by addition of diisopropylether (150 mL), which after filtration gave additional amount of title product (157.8 mg, purity: 92 %).

Method B:

To a solution of 6-0-methyl-9a-aza-9a-homoerythromycin A (7.63 g, 10 mmol) in toluene (40 mL), DMF-DMA (5.36 mL, 40.0 mmol) was added, reaction mixture heated to reflux temperature and stirred overnight. Volati!es were removed under reduced pressure. The residue was dissolved in toluene (40 mL), then Ac ₂ 0 (5.66 mL, 60.0 mmol) and TEA (8.36 mL, 60.0 mmol), followed by DMAP (0.122 g, 1.0 mmol) were added, and the reaction mixture was stirred at reflux temperature overnight. To the reaction mixture EtOAc (40 mL) and water (40 mL) were added and pH was adjusted to 4. Layers were separated and the organic one was washed with water (2 χ 20 mL). The combined aqueous layers were extracted with EtOAc (2 χ 20 m!_). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , solvent was removed under reduced pressure, to the obtained brown sticky residue MeOH (20 mL) was added and mixture stirred at 40 °C overnight. Solvent was removed under reduced pressure and brown residue purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/9/1 .5) to afford title product in three fractions: fraction A (1.08 g, purity: 78 %), fraction B {2.76 g, purity: 93 %) and fraction C (0.62 g, purity: 87 %), all of which, according to LC-MS profile, conform to the reference. Example 3

(E)-11 ,12-Didehydro _" 11 ,12-dideoxy-6-0-methyl-9a-aza-9a-homoerythromycin A

To a solution of (E)-4"-0-acetyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A, Example 2 (457.3 mg, 0.49 mmol, calculated based on 87% purity of Example 2) in MeOH (10 mL), potassium carbonate (676 mg, 4.89 mmol) was added, and the reaction mixture shaked at room temperature for 60 hours. Solvent was evaporated, the obtained residue dissolved in DCM (50 mL) and washed with brine (2 ^χ 50 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered, and evaporated to yield crude product (313.4 mg), which was purified by precipitation using DCM (1 mL) and diisopropylether (50 mL), giving stil! crude product (156.8 mg), which was further purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/9/0.5), to afford title product (85.1 mg) which was precipitated from DCM and diisopropylether and dried to afford title product (53 mg, purity: 95 %); MS (ES ⁺ , m/z): 729.35 [M] ⁺ .

1H NMR (500 MHz, CDCI ₃ ) δ ppm: 0.86 (t, 3H), 1 .05 (d, 3H), 1 .13 (d, 3H), 1 .19 (d, 3H), 1.22 (m, 3H), 1 .24 (m, 3H), 1 .27 (s, 3H), 1 .30 (m, 1 H), 1.34 (d, 3H), 1.36 (s, 3H), 1 .53 (s, 3H), 1 .59 (m, 2H), 1.60 (m, 1 H), 1 .68 (m, 1 H), 1 .70 (m, 1 H), 1 .75 (m, 1 H), 1 .90 (m, 1 H), 2.22 (m, 1 H), 2.31 (s, 6H), 2.37 (d, 1 H), 2.45 (m, 1 H), 2.91 (m, 1 H), 3.07 (m, 1 H), 3.21 (dd, 1 H), 3.34 (s, 3H), 3.37 (s, 3H), 3.54 (m, 1 H), 3.77 (m, 1 H), 3.77 (m, 1 H), 3.89 (d, 1 H), 4.08 (m, 1 H), 4.54 (d, 1 H), 4.63 (m, 1 H), 4.94 (t, 1 H), 4.98 (d, 1 H), 5.58 (d, 1 H), 6.45 (d, 1 H).

Example 4

(E)-4"-0-Acetyl-3'-W-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A

Method A:

To a solution of (E)-4"-0-acetyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A, Example 2 (436.7 mg, 0.53 mmol, calculated based on 93% purity of Example 2) in DMF (20 mL), DEAD (0.083 mL, 0.53 mmol) was added and reaction mixture stirred at room temperature for 3 hours. After solvent was evaporated, yelow residue was dissolved in MeOH (15 mL), saturated aqueous NH ₄ C! (4 mL) was added and mixture refluxed for 2 hours. Reaction mixture was cooled to room temperature, concentrated under reduced pressure, water (50 mL) and DCM (50 mL) were added and pH adjusted to 9.5 (1 M NaOH). Layers were separated and aqueous one extracted with DCM (3 x 15 mL). Combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product (885.8 mg), which was purified by column chromatography (using solvent system (0 - 100% (DCM/ eOH/NH ₄ OH = 90/9/1.5) in DCM) to afford title product in three fractions: fraction A (52.4 mg), fraction B (154,8 mg, purity determined by TLC: 80 %) and fraction C (153.4 mg, purity determined by TLC: 75 %),

Fraction A (52.4 mg) was further purified by precipitation from DCM (0.5 mL) and diisopropylether (50 mL) to afford title product (40.8 mg, purity: 91 %); MS (ES ⁺ , m/z): 757.35 [M] ⁺ .

1 ³ C NMR (125 MHz, CDCI ₃ ) δ ppm: 9.81 , 9.95, 10.50, 16.44, 17.95, 18.38, 18.92, 20.83, 21.00, 21.52, 22.00, 24.22, 32.97, 33.04, 35.29, 36.70, 37.31 , 39.95, 41.28, 44.12, 49.21 , 51.36, 59.56, 63.29, 66.93, 72.47, 75.13, 78.24, 78.39, 79.11 , 79.67, 81.62, 96.48, 100.50, 134.72, 135.83, 170.45, 174.20, 176.02. Method B:

To a solution of (£)-4"-0-acetyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A, Example 2 (2.74 g, 3.25 mmol, calculated based on 93% purity of Example 2) in DMF (125 mL), DEAD (0.849 mL, 4.88 mmol) was added and reaction mixture stirred at room temperature for 3 hours. After solvent was evaporated, yellow residue was dissolved in MeOH (75 mL), saturated aqueous NH ₄ Ci (25 mL) was added and mixture refluxed for 2 hours. Reaction mixture was cooled to room temperature, concentrated under reduced pressure, water (100 mL) and DCM (100 mL) were added and pH adjusted to 9.5 using 1 M NaOH. Layers were separated and aqueous one extracted with DCM (3 ^χ 55 mL). Combined organic layers were washed with brine (2 100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product (3.48 g), which was purified by precipitation from DCM/diisopropylether to afford title product (2.164 g, purity: 91 .5 %). Example 5

(EJ-S'-W-Demethyl-I I .I -didehydro-I I .I Z-dideoxy-e-O-methyl-Sa-aza-Sa- homoerythromycin A

To a solution of (£)-4"-0-acetyl-3'-W-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0- methyl-9a-aza-9a-homoerythromycin A, Example 4 (154.8 mg, 0.16 mmol, calculated based on 80% purity of Example 4, in MeOH (15 mL), potassium carbonate (226 mg, 1 .64 mmol) was added, and the reaction mixture stirred at room temperature for 10 days. TLC showed that conversion is not completed therefore reaction mixture was heated to 80 °C and stirred for 2 hours. Solvent was evaporated, the obtained residue dissolved in DCM (20 mL) and washed with saturated aqueous NaHC0 ₃ solution (2 x 20 mL). The organic layer was dried over anhydrous Na ₂ SCXi, filtered, and evaporated to yield crude product (51 .4 mg), which was putified by column chromatography (using solvent system: DCM/MeOH/ΝΗ,ΟΗ = 90/9/0.5), to afford crude product (36.9 mg, purity: 82%), which was further purified by precipitation using DCM and diisopropylether to afford title product (14.7 mg, purity: 94 %); MS (ES ⁺ , m/z): 715.99 [MH] ⁺ .

3C NMR (1 50 MHz, CDCI ₃ ) δ ppm: 9.86, 9.90, 10.62, 16.42, 18.07, 18.68, 18.97, 21 .1 5, 21 .49, 22.09, 24.34, 32.26, 33.18, 35.34, 36.81 , 37.00, 40.00, 41 .40, 44.25, 49.31 , 51.35, 60.16, 66.74, 67.86, 72.95, 73.00, 77.48, 79.66, 79.76, 79.96, 81.71 , 96.64, 101 .42, 134.76, 134.96, 174.00, 176.09. EXAMPLES 6-8

General procedure for Examples 6-8:

Dry PS-Carbodiimide resin (PS-CDI, loading: 1 .25 mmo!/g, 1 equivalent) was added to a dry reaction vessel. The corresponding acid (1 -1 .06 equivalent) and HOBt (0.7 equivalent), dissolved in a dry mixture of DCM (2 m!_) and DMF (0.3 mL), were added to the resin. The mixture was stirred at room temperature for 5 minutes upon which (£)-4"- 0-acetyl-3'-W-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-9a-aza-9a- homoerythromycin A, Example 4 dissolved in dry DCM (2 mL) was added. The reaction mixture was heated by microwave irradiation at 75 °C for 7 to 10 minutes.

HOBt was scavenged using PS-trisamine (loading: 4.1 1 mmol/g, 5 equivalent according to HOBt) for 3 hours at room temperature. The resin was removed from the reaction mixture by filtration and washed with DCM (2 x 5 mL). Evaporation of the solvent under reduced pressure afforded corresponding compound of examples 6 to 8 as crude product.

Table 1.:

a = molar quantity was calculated based on 91.5% purity of Example 4

Example 6

(E)-4"-0-Acetyl-3'-W-demethyl-11 ,12-didehydro-11 , 12-dideoxy-3'-N-(methoxy)acetyl- 6-O-methyl -9a-aza-9a-homoerythromycin A

Crude product (526 mg) obtained according the above general procedure was further purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/9/1 .5) to afford title product as two fractions: fraction A (45 mg, purity: 90 %) and fraction B (158 mg, purity: 95 %). Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1 .

Example 6, fraction A

MS (ES ⁺ , m/z): 829.53 [M] ⁺ .

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 9.75, 10.15, 10.76, 10.79, 16.04, 18.57, 18.62, 1 9.42, 19.43, 19.51 , 19.52, 20.85, 20.92, 21 .10, 21.64, 21 .70, 24.28, 26.63, 27.00, 33.34, 33.41 , 34.93, 34,97, 35.15, 35.62, 38.09, 40.00, 41 .36, 44.15, 44.22, 49.28, 49.35, 51 .28, 51 .37, 57.57, 58.50, 58.55, 62.96, 63.07, 66.49, 66.58, 69.92, 70.07, 71.05, 71 .61 , 72.59, 72.62, 78.19, 78.27, 78.99, 79.14, 79.19, 81.36, 96.1 1 , 96.21 , 101 .89, 134.35, 134.69, 134.84, 169.29, 169.35, 170.50, 170.65, 174.68, 174.74, 175.46.

Example 7

(E)-4 ^! '-0-Acetyl-3'-W-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-3'-W-(4- pyridinylthio)acetyl-9a-aza-9a-homoerythromycin A

Crude product (818.8 mg) obtained according the above genera! procedure was further purified by column chromatography (using solvent system: EtOAc/n-hexane/DEA = 1 /1 /0.2) to afford title product as two fractions: fraction A (75.9 mg, purity: 97 %) and fraction B (250 mg, purity: 80 %). Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 .5 : 1 .

Example 7, fraction A

MS (ES ⁺ , m/z): 908.37 [M] ⁺ .

¹³ C NMR (125 MHz, CDCI _r d) δ ppm: 9.80, 10.05, 10.09, 10.49, 16.46, 17.97, 18.01 , 18.39, 18.89, 19.01 , 20.80, 20.85, 20.97, 21 .29, 21.99, 22,43, 24.22, 29.87, 32.97, 34.18, 34.65, 35.12, 35.36, 36.55, 36.66, 40.00, 41 .30, 44,05, 44.10, 49.20, 49.26, 51 .39, 51 .43, 54.00, 58.01 , 63.22, 63.35, 66.53, 66.67, 71 .40, 71 .67, 72.42, 72.75, 78.27, 78.36, 78.62, 78.86, 79.01 , 79.49, 81.59, 81 .66, 96.39, 96.53, 100.83, 100.95, 120.60, 120.86, 134.64, 135.89, 148.00, 149.27, 167.85, 168.03, 170.09, 170.50, 174.02, 174.16, 175.82, 175.94,

Example 8

(£)-4"-0-Acetyi-3'-W-demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-3'-N-(2- pyrazinyl)carbonyl-9a-aza-9a-homoerythromycin A

Crude product (669 mg) obtained according the above general procedure was further purified by column chromatography (using solvent system: (DCM/MeOH/NH ₄ OH = 90/9/1.5)/DC = 7/5) to afford title product as two fractions: fraction A (56.9 mg, purity: 90 %) and fraction B (269 mg, purity: 85 %). Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1 .

Example 8, fraction A

MS (ES ⁺ , m/z): 863.44 [M] ⁺ .

¹³ C NMR (126 MHz, CDCI ₃ -d) δ ppm: 9.81 , 9.94, 10.10, 10.48, 10.51 , 16.44, 17.98, 18,92, 18.96, 20.74, 20.74, 20.88, 20.94, 20.94, 21 .02, 21 .02, 21 .35, 21 .99, 24.22, 27.32, 31 .29, 32.99, 35.00, 35.20, 35.28, 36.48, 36.60, 39.88, 39.95, 41.30, 44.04, 48.33, 49.24, 51 .32, 51 .42, 54.16, 58.66, 63.19, 63.26, 66.31 , 66.74, 71.26, 71.54, 72.40, 72.49, 78.20, 78.41 , 78.71 , 78.81 , 78.91 , 79.50, 79.55, 81 .59, 81 .64, 96.23, 96.54, 100.78, 100.97, 134.64, 134.68, 135.83, 135.92, 141 .90, 142.60, 144.69, 145.10, 145.25, 145.21 , 1 50.00, 150.29, 167.57, 167.72, 170.10, 170.53, 174.06, 174.19, 175.85, 175.95. EXAMPLES 9 AND 10

General procedure for Examples 9 and 10:

4"-0-Acetyl-compound was dissolved in methanol (15 mL), then K ₂ C0 ₃ (10 equivalents) dissolved in water (2 mL) was added. The mixture was stirred at room temperature for 24 hours and evaporated to dryness, The residue was portioned between DCM (60 mL) and water (60 mL), pH adjusted to 2, and the crude product isolated from the organic layer at pH 2, after drying over anhydrous K ₂ C0 ₃ , filtration and evaporation and then purified either by precipitation or by column chromatography to give desired product.

Table 2.:

a = molar quantity was calculated based on 95% purity of starting 4"-0-acetyl compound b = molar quantity was calculated based on 80% purity of starting 4"-0-acetyl compound

Example 9

(£)-3'-W-Demethyl-11 ,12-didehydro-11 ,12-dideoxy-3'-W-(methoxy)acetyl-6-0-methyi- 9a-aza-9a-homoerythromycin A

Crude product (128.1 mg) obtained according the above general procedure was isolated at pH 2 and further purified by precipitation from DCM/diisopropylether to afford title product (90.1 mg , purity: 92 %) as a white solid; MS (ES ⁺ , m/z) 809.40 [ +Na] ⁺ .

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1.

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 9.80, 10.15, 10.78, 16.12, 19.22, 19.36, 19.48, 21 .21 , 21 .25, 21.55, 21.61 , 21 .76, 24.28, 26.56, 28.10, 33.38, 35.22, 35.40, 36.52, 37.88, 38.01 , 40.00, 41 .35, 44.25, 49.14, 49.22, 51 .26, 51 .31 , 57.19, 58.49, 58.62, 65.58, 65.69, 66.57, 66.64, 69.98, 70,09, 70.98, 71 .09, 73.01 , 77.48, 78.20, 78.91 , 79.20, 79.27, 81 .25, 96.22, 96.34, 101.90, 134.33, 134.81 , 134.94, 169.18, 169.40, 174.68, 175.47.

Example 10

(£)-3'-W-Demethyl-11 ,12-didehydro-11 ,12-dideoxy-6-0-methyl-3'-W-(4- pyridinylthio)acetyl-9a-aza-9a-homoerythromycin A

Crude product (258.6 mg) obtained according the above general procedure was isolated at pH 2 and further purified by column chromatography (using system: n- hexane/EtOAc/DEA = 1 /1 /0.2), which after dying at 50 °C for 24 hours afforded title product (200.9 mg, purity: 92 %); MS (ES ⁺ , m/z): 866.41 [M] ⁺ .

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1 .

¹³ C NMR (125 MHz, CDCI ₃ - ) δ ppm: 9.80, 9.80, 10.52, 16.32, 17.96, 18.44, 18.52, 18.87, 18.93, 20.94, 20.99, 21 .28, 21 .44, 21 .99, 24.25, 27,45, 29,89, 33.02, 34.03, 34.59, 35.23,

35.33, 35.34, 36.27, 36.50, 36.59, 39.94, 40.01 , 41 .30, 44.09, 49.15, 49.23, 51.21 , 54.21 , 58.46, 66.91 , 67.07, 67.68, 67.93, 70.99, 71.41 , 72.86, 73.04, 77.10, 79.55, 80.01 , 80.12,

80.34, 80.42, 81.55, 81 .63, 96.54, 96.63, 102.25, 102.42, 120.64, 120.92, 134.53, 135.84, 135.91 , 147.90, 149.21 , 167.83, 167.95, 174.07, 174.17, 175.83, 175.92.

Example 11

(E^'^'-O-Diacetyi-11 ,12-didehydro-9-deoxo-1 1 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A

A solution of TEA (73.5 mL, 528 mmo!) and benzoyl chloride (55.7 mL, 480 mmol) in DCM (1500 mL) was stirred for 10 minutes. Then solution of Intermediate 4 (103.25 g, 96 mmol, calculated based on 82.5% purity of Intermediate 4) in DCM (500 mL) was added dropwise over 2 hours and stirring continued for 4 hours. Reaction mixture was quenched with saturated aqueous NaHC0 ₃ solution (1000 mL). Organic layer was washed with saturated aqueous NaHC0 ₃ solution (1000 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product. Crude product was dissolved in DCM (200 mL), water (500 mL) was added and pH adjusted to 3 (using 6 M HCI). Organic layer was discharged and to the aqueous one DCM (400 mL) was added and pH adjusted to 8.4 (using 20% NaOH), dried over anhydrous K ₂ C0 ₃ , filtered, evaporated and dried at 50 °C for 17 hours to attord title product (67.53 g, purity: 94 %). The water layer, pH 8.4 was re-extracted by DCM (2 x 200 mL), which after drying over over anhydrous K ₂ C0 ₃ , filtation, evaporation and drying at 50 °C for 17 hours afforded additional amount of title product (0.41 g, purity: 97 %), which was characterized as follows:

MS (ES\ m/z): 799.48 [M] ⁺

H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 0.78 (t, 3H), 0.83 (d, 3 H), 0.88 (d, 3H), 0.97 (d, 3H), 1.03 (m, 3H), 1.04 (s, 3H), 1.08 (d, 3H), 1.09 (s, 3H), 1.12 (m, 1H), 1.15 (d, 3H), 1.25 (m, 1H), 1.52 (5, 3H), 1.63 (m, 2H), 1.72 (m, 1H), 1.73 (m, 1H), 1.76 (m, 1H), 1.88 (m, 1H), 1.89 (m, 1H), 1.96 (s, 3H), 2.04 (m, 1H), 2.06 (s, 3H), 2.11 (s, 3H), 2.18 (s, 2x3H), 2.26 (m, 1H), 2.37 (d, 1H), 2.66 (m, 1H), 2.81 (m, 1H), 3.05 (m, 1H), 3.28 (s, 3H), 3.48 (d, 1H), 3.77 (m, 1H), 4.16 (dd, 1H), 4.29 (m, 1H), 4.55 (d, 1H), 4.61 (m, 1H), 4.67 (m, 1H), 4.68 (m, 1H), 4.99 (t, 1H), 5.17 (bs, 1 H), 5.40 (d, 1H).

Example 12

(£)-4"-0-Acetyl- 1 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A

Method A:

A solution of {^^'^"-O-diacetyl-l^^-didehydro-g-deoxo-l^^-dideoxy-ga-methy l- 9a-aza-9a-homoerythromycin A, Example 11 (1.5 g, 1.52 mmo!, calculated based on 81% purity of Example 11) in MeOH (20 mL) was shaken at 60 °C for 15 hours. Solvent was evaporated, the residue dissolved in DCM (100 mL), and washed with acidic water (pH 3, 100 mL). To the water layer DCM (100 mL) was added and pH adjusted to 9 (using 5 M NaOH). Organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to give crude product (1.8 g). Crude product was dissolved in DCM (60 mL), water added (70 mL) and pH adjusted to 2 (using 2 M HCI). Organic layer was discharged and to the water one DCM (60 mL) was added, and pH adjusted to 5.5 (using 2 M NaOH). Organic layer at pH 5.5 was dried over anhydrous Na ₂ S0 ₄ , filtered, and evaporated to afford title product (479.2 mg, purity: 98%); MS (ES ⁺ , m/z): 758.2 [MH] ⁺ .

¹³ C NMR (125 MHz, DMSO-C/ ₆ ) δ ppm: 8.99, 9.85, 13.12, 14.06, 17.96, 18.11, 20.98, 21.02, 21.72, 21.79, 24.63, 26.07, 27.28, 30.67, 34.80, 38.09, 40.80, 41.09, 43.01, 43.28, 49.35, 57.71, 62.84, 64.85, 65.03, 67.44, 70.58, 72.85, 73.49, 77.64, 77.71, 78.36, 83.13, 95.46, 102.03, 130.45, 130.48, 170.61, 174.83.

To the water layer at pH 5.5, DCM (60 mL) was added and pH adjusted to 9.5. Organic layer at pH 9.5 was dried over anhydrous Na ₂ S0 ₄ , filtered, and evaporated to afford additional amount of title product (985.0 mg, purity 87%). Method B:

To a solution of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (7,49 g, 10 mmol) in toluene (40 mL), Λ/,/V-dimethylformamide dimethylaceta! (5.36 m!_, 40.0 mmol) was added, reaction mixture heated to reflux temperature and stirred for 4 hours. Votati!es were removed under reduced pressure. The residue was dissolved in toluene (40 mL), then Ac ₂ 0 (5.66 mL, 60.0 mmo!) and TEA (8.36 mL, 60.0 mmol), followed by DMAP (0.122 g, 1.0 mmol) were added, and the reaction mixture was stirred at refiux temperature overnight. Reaction mixture was allowed to cool to ambient temperature, EtOAc (40 mL) and water (40 mL) were added and pH was adjusted to 3. Layers were separated and the organic one was washed with water (2 ^χ 40 mL). The combined aqueous layers were extracted with EtOAc (2 ^χ 20 mL). Aqueous layer was then submitted to the acid-base extraction at pH 4, 5, 6, 7 and 9, using at each pH level EtOAc for extraction (3 x 40 mL). Organic layers at pH 6 and 7 were combined, dried over anhydrous Na ₂ S0 , filtrated and evaporated to give crude product (7 g) as beige foam. Crude product was dissolved in MeOH (70 mL) and stirred at room temperature over the weekend, evaporated and the obtained residue purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/6/0.5) to afford title product as two fractions: fraction A (1.06 g, purity: 83 %) and fraction B (0.9 g, purity: 91 %), both of which, according to LC-MS profile, conform to the reference.

Example 13

(£)-11 , 12-Didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a-homoerythromycin A

To a solution of (£)-4"-0-acetyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl- 9a-aza-9a-homoerythromycin A, Example 12 (300.0 mg, 0.396 mmol) in MeOH (10 mL), potassium carbonate (548 mg, 3.96 mmol) was added, and the reaction mixture shaken at room temperature for 48 hours. Solvent was evaporated, the obtained residue dissolved in DCM (40 mL), water was added (40 mL) and pH adjusted to 3 (using 3M HCi). To the water layer DCM (40 mL) was added and pH adjusted to 9 (using 2N NaOH). Organic layer at pH 9 was dried over anhydrous Na ₂ S0 ₄ , filtrated and evaporated to give crude product (324.4 mg), which was first precipitated from DCM/diisopropylether (1 mL/50 mL) and than purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/9/0.5) to afford title product (229.5 mg), which was further purified by precipitation from DCM/diisopropylether to afford title product (57.3 mg, purity: 99%); MS (ES\ m/z): 715.25 [M] ⁺ .

H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 0.79 (t, 3H), 0.84 (d, 3H), 0.97 (d, 3H), 1 .02 (d, 3H), 1.06 (m, 3H), 1 ,08 (m, 3H), 1 .08 (m, 1 H), 1 .14 (s, 3H), 1.15 (m, 3H), 1.16 (s, 3H), 1.27 (m, 1 H), 1 .49 (m, 1 H), 1 .53 (s, 3H), 1 .61 (m, 1 H), 1 .64 (m, 2H), 1 .65 (m, 1 H), 1 .85 (m, 1 H), 1 .93 (m, 1 H), 1.98 (m, 1 H), 2.12 (s, 3H), 2.21 (m, 1 H), 2.26 (s, 2 * 3H), 2.28 (m, 1 H), 2.45 (m, 1 H), 2.75 (m, 1 H), 2.90 (dd, 1 H), 3.07 (m, 1 H), 3.08 (m, 1 H), 3.22 (s, 3H), 3.54 (d, 1 H), 3.69 (m, 1 H), 4.06 (m, 1 H), 4.17 (dd, 1 H), 4.27 (d, 1 H), 4.44 (d, 1 H), 4.61 (d, 1 H), 4.95 (t, 1 H), 5.16 (bs, 1 H), 5.44 (d, 1 H).

An additional amount of title product (149.9 mg) was obtained by evaporation of mother liquor.

Example 14

(E)-4"-0-Acetyl-3'-W-demethy 1 ,12-didehydro-9-deoxo-11 ,12-dideoxy~9a~methyl- 9a-aza-9a-homoerythromycin A

Method A

To a solution of (£E)-4"-0-acetyl-11 ,12-didehydro-9-deoxo-1 ,12-dideoxy-9a-methyl- 9a-aza-9a-homoerythromycin A, Example 12, (520 mg, 0.58 mmol, calculated based on 85% purity of Example 12) in DMF (25 mL), DEAD (0.14 mL, 0.88 mmol) was added and reaction mixture stirred at room temperature over night. Then additional amount of DEAD (30 ML, 0.19 mmol) was added and reaction mixture stirred over night. Solvent was evaporated, residue disolved in MeOH (15 mL), saturated aqueous NH ₄ CI (5 mL) was added and mixture refluxed for 2 hours. Reaction mixture was cooled to room temperature, solvent evaporated, residue dissolved in DCM (30 mL), water (30 mL) added and pH adjusted to 2.5 (using 2M HCI). Organic layer was discharged and to the water layer DCM (40 ml_) was added, pH adjusted to 7 (using 2M NaOH). Water layer was discharged and organic layer dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product (365 mg), which was purified by column chromatography (using solvent system (DCM/MeOH/NH OH = 90/9/1 .5) to afford title product in three fractions: fraction A (103.9 mg, purity: 96%), fraction B (67.4 mg, purity: 90%), and fraction C (67.6 mg, purity: 97%). Fraction A was characterized as follows:

MS (ES ⁺ , m/z): 744.10 [MHf

¹³ C NMR (75 MHz, DMSO- / ₆ ) δ ppm: 9.08, 9.97, 13,29, 14.07, 18.05, 18.33, 21.09, 21.13, 21 .76, 21.87, 24.77, 25.98, 27.44, 32.98, 34.89, 37.23, 38.31 , 41 .38, 43.19, 43.32, 49.42, 57.83, 60.58, 62.98, 64.97, 67.30, 72.96, 73.53, 73.59, 77.65, 77.77, 78.48, 83.24, 95.47, 101.64, 130.54, 130.66, 170.73, 175.00.

Method B

To a solution of (E)-4"-0-acetyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl- 9a-aza-9a-homoerythromycin A, Example 12, (7.7 g, 10.17 mmol, calculated based on 88% purity of Example 12) in DMF (250 mL), DEAD (2.416 mL, 15.26 mmol) was added and reaction mixture stirred at room temperature for 6 hours. Solvent was evaporated, residue disolved in MeOH (150 mL), saturated aqueous NH ₄ CI (70 mL) was added and mixture refluxed for 2 hours. Reaction mixture was cooled to room temperature, solvent evaporated, residue dissolved in DCM (70 mL), water (70 mL) added and pH adjusted to 2.5 (using 2M HCi). Organic layer was discharged and to the water layer DCM (80 mL) was added, pH adjusted to 7 (using 2M NaOH). Water layer was discharged and organic layer dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product ( 10.51 g), which was purified by silica gel column chromatography (using solvent system (DCM/MeOH/NH ₄ OH = 90/9/1.5) to afford title product in six fractions: fraction A (0.27 g, purity: 92%), fraction B (0.31 g, purity: 93%), fraction C (1 .15 g, purity: 96%), fraction D (0.96 g, purity 98.2%), fraction E (1.04 g, purity 98.5%) and fraction F (0.63 g, purity 89%).

Example 15

(£)-3'-W-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A

To a solution of (E)-4"-0-acetyl-3'-W-demethy!- 1 ,12-dide ydro-9-deoxo-11 ,12- dideoxy-9a-methyl-9a-aza-9a-homoerythromycin A, Example 14 (184.0 mg, 0.22 mmol, calculated based on 90% purity of Example 14) in MeOH (15 mL), potassium carbonate (308 mg, 2.23 mmol) was added, and the reaction mixture stirred at room temperature for 40 hours. Solvent was evaporated, the obtained residue dissolved in DCM (60 mL), water added (60 mL), pH adjusted to 2 (using 2M HC!), and organic layer discharged. To the water layer DCM (60 mL) was added, pH adjusted to 7 (using 2M NaOH), layers separated, the organic layer dried over anhydrous Na ₂ S0 _4l filtered, and evaporated to afford title product (76.4 mg, purity: 95 %); MS (ES ⁺ , m/z): 702.10 [MH] ⁺ . ¹³ C NMR (125 MHz, DMSO-c/ ₆ ) δ ppm: 9.08, 9.97, 12.97, 14.22, 17.94, 18.60, 21 .33, 21 .64, 21.67, 24.61 , 25.95, 27.24, 33.52, 35.18, 37.76, 37.90, 41.27, 43.13, 43.51 , 49.14, 57.63, 60.72, 64.97, 65.33, 67.38, 73.15, 73.59, 74.01 , 77.73, 77.95, 78.04, 83.36, 95.72, 101 .81 , 130.52, 30.91 , 174.96.

An additional amount of title product was obtained after adding fresh DCM (60 mL) to the water layer, re-adjusting pH to 7 (using 2M NaOH). The organic layer was dried over anhydrous Na ₂ S0 _> filtered, and evaporated to afford title product (20.5 mg, purity: 94 %).

EXAMPLES 16-18

General procedure for Examples 16-18:

Dry PS-Carbodiimide resin (PS-CDI, loading: 1.25 mmoi/g, 1 equivalent) was added to a dry reaction vessel. The corresponding acid (1 -1 .05 equivalent) and HOBt (0.7 equivalent), dissolved in a dry mixture of DCM (2 to 5 mL) and DMF (0.3 mL), were added to the resin. The mixture was stirred at room temperature for 5 minutes upon which (£)- 4"-0-acetyl-3'-W-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a- aza-9a-homoerythromycin A, Example 14, dissolved in dry DCM (2 to 3 mL) was added. The reaction mixture was heated by microwave irradiation at 75 °C for 7 minutes. HOBt was scavenged using PS-trisamine (loading: 4.1 1 mmol/g, 5 equivalent according to HOBt) for 3 hours at room temperature. The resin was removed from the reaction mixture by fiitration and washed with DCM (2 x 5 mL). Evaporation of the solvent under reduced pressure afforded corresponding compound of examples 16 to 18 as a crude product. Table 3.:

a = molar quantity was calculated based on 92.5% purity of starting Example 14 b = molar quantity was calculated based on 96% purity of starting Example 14 Example 16

(Ε)-4' '-O-Acetyl-S'-W-demethyM 1 , 12-didehydro-9-deoxo-11 ,12-dideoxy-3'-/V- (methoxy)acetyl-9a-methyl-9a-aza-9a-homoerythromycin A

Crude product (397.8 mg) obtained according the above general procedure was further purified by column chromatography (using solvent system: DCM/MeOH/NH OH = 90/9/1 .5) to afftod title product as two fractions: fraction A (92.2 mg, purity: 93 %) and fraction B (186.7 mg, purity: 80 %). Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1 . Fraction A was characterized as follows: MS (ES ⁺ , m/z): 815.72 [M] ⁺

3C NMR (125 MHz, DMSO-dg) δ ppm: 8.93, 8.96, 9.56, 10.00, 13.17, 1 3.95, 17.88, 17.97, 18, 19, 18.26, 20.93, 21 .07, 21 .48, 21 ,57, 21 .64, 24.63, 25,87, 26.67, 27.33, 29.02, 34.65, 35.61 , 36.57, 38.13, 38.24, 41 .22, 43.01 , 43.13, 43.14, 43.25, 49.30, 49.33, 57.65, 57.72, 58.53, 58.54, 62.93, 64.75, 64.86, 67.07, 67.15, 69.61 , 69.83, 71 .05, 71.54, 72.89, 73.44, 77.50, 77.62, 78.33, 78.40, 81 .41 , 83.68, 95.31 , 102.09, 130.39, 130.44, 169.39, 170.54, 170.68, 174.85, 174.91 . Example 17

(E)-4"-0-Acetyl-3'-W-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3'-W-(4- methoxy-4-oxobutanoyl)-9a-methyl-9a-aza-9a-homoerythromycin A

Crude product (646 mg) obtained according the above genera! procedure was further purified by precipitation using DC /n-hexane to afford title title product (300.4 mg, purity: 91 %), which was characterized as follows:

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1.

MS (ES ⁺ , m/z) 857.50 [ ] ⁺

1 ³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 8.93, 8.97, 9.92, 10.01 , 13.16, 13.96, 17.90, 17.99, 18.18, 18.25, 20.94, 20.99, 21 .08, 21 .50, 21.57, 21.64, 24.63, 25.72, 26.79, 27.31 , 28.16, 28.70, 29.12, 29.41 , 34.67, 34.82, 35.82, 36.50, 38.24, 41 .20, 42.98, 43.12, 43.24, 49.28,

49.33, 51.58, 54.50, 57.73, 57.98, 62.89, 64.86, 67.13, 69.89, 69.99, 72.88, 72.94, 73.47, 77.51 , 77.67, 78.40, 83.38, 83.59, 95.35, 102.15, 130.48, 131 .00, 170.60, 170.69, 171.23, 171 .46, 173.44, 174.85, 174.91 .

Evaporation of mother liqour gave additional amount of title product (131.9 mg, purity 75%).

Example 18

(£).4"-0-Acetyl-3'-W-demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3'-W-(W ₁ Af- dimethyig[ycyI)-9a-methyl-9a-aza-9a-homoerythromycin A

Crude product (61 1 .9 mg) obtained according the above general procedure was further purified by column chromatography (using solvent system: EtOAc/n-hexane/DEA = 1 /1 /0.1 ) to afford title product (338.8 mg, purity: 97 %); MS (ES ⁺ , m/z): 828.56 [M] ⁺ .

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 2 : 1.

¹³ C NMR (125 MHz, DMSO-d ^" ₆ ) δ ppm : 8.93, 8.96, 9.91 , 9.95, 13.17, 1 3.98, 17.85, 17.96, 18.20, 18.30, 20.81 , 20.84, 20.96, 21.08, 21 .47, 21 .59, 21.64, 24.63, 25.78, 26.79, 27.29,

27.34, 29.00, 34.58, 34.83, 35.68, 36.78, 38.1 1 , 38.26, 41.43, 43.12, 43.27, 45.31 , 45.48, 49.30, 49.33, 53.00, 57.62, 57.72, 58.45, 62.71 , 62.88, 62.98, 63.13, 64,70, 64.87, 67.09,

67.15, 69.76, 69.89, 72.86, 72.89, 73.44, 73.47, 77.53, 77.70, 78,30, 78,41 , 83.35, 83.80, 95.25, 95.35, 102.20, 102.26, 130.44, 130.58, 169.85, 170.26, 170.44, 170.68, 174.86, 174.92. EXAMPLES 19 AND 20

General procedure for Examples 19 and 20:

4"-0-Acetyl-compound was dissolved in methanol (15 mL), then K ₂ C0 ₃ (10 equivalents) dissolved in water (2 ml_) was added. The mixture was stirred at room temperature for 24 hours and evaporated to dryness. The residue was partitioned between DC (60 ml_) and water (60 ml_), and purified by acid-base extraction at pH 1.5 and 8. The crude product isolated from the organic layer at pH 8 was dried over anhydrous K ₂ C0 ₃ , filtrated, evaporated and purificated either by precipitation or by column chromatography to give desired product. Table 4.:

a = molar quantity was calculated based on 84% purity of starting 4"-0-acetyl compound b = molar quantity was calculated based on 97% purity of starting 4"-0-acetyl compound

Example 19

(E)-3'-W-Demethyl-11 , 12-didehydro-9-deoxo-11 ,12-dideoxy-3'-W-{methoxy)acetyl-9a- methyl-9a-aza-9a-homoerythromycin A

Crude product (108.5 mg) obtained according the above genera! procedure was isolated at pH 8 and further purified by column chromatography (using solvent system: DCM/MeOH/NH _f OH = 90/9/0.5), followed by reverse phase preparative HPLC (using mixture of e!uents 40 % 10mM NH ₄ HC0 ₃ /pH 10 and 60 % CH ₃ CN) to afford title product (39.8 mg, purity: 98 %); MS (ES ⁺ , m/z): 773.50 [M] ⁺ .

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 1 : 1.

¹³ C NMR (125 MHz, D SO-d ₆ ) δ ppm: 9.06, 9.99, 12.97, 14.26, 18.00, 18.62, 21.31 , 21.35, 21.38, 21.43, 21.65, 24.59, 25.87, 26.60, 27.22, 28.10, 35.10, 35.24, 35.61 , 37.88, 41.00, 43.02, 43.46, 49.15, 54.95, 57.34, 57.64, 58.50, 58.62, 64.76, 64.86, 65.34, 65.42, 67.11 , 67.23, 69.72, 69.88, 70.96, 71.10, 73.19, 73.60, 77.68, 77.73, 78.06, 83.00, 95.61 , 102.17, 102.31 , 130.40, 130.41 , 169,27, 169.46, 174.93. Example 20

{£)-3'-N-Demethyl-1 , 12-didehydro-9-deoxo- 1 ,12-dideoxy-3'-W-(W, W- dimethylglycyl)-9a-methyl-9a-aza-9a-homoerythromycin A

Crude product (271.8 mg) obtained according the above general procedure was isolated at pH 8 and further purified by column chromatography (using solvent system: EtOAc/n- hexane/DEA = 1 /1 /0, 1 ), followed by precipitation from DCM and n-hexane to afford title product (200.8 mg, purity: 99 %), MS (ES ⁺ , m/z): 786.59 [M] ⁺ .

Due to restrained rotation around amide bond, there are two rotamers present in ratio A : B = 2 : 1.

1 ³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 9.06, 9.96, 10.01 , 13.00, 14.26, 17.91 , 18.03, 18.64, 21 .22, 21.35, 21 .43, 21 .70, 24.60, 25.93, 26.06, 26.77, 27.22, 29.00, 35.07, 35.23, 35.40, 36.90, 37.87, 37.93, 41 .17, 43.03, 43.51 , 45.37, 45.48, 49.14, 49.28, 54.10, 57.61 , 58.14, 62.48, 62.73, 64.80, 64.86, 65.33, 65.38, 67.15, 67.24, 69.85, 69.99, 73.16, 73.20, 73.57, 77.61 , 77.72, 78.03, 83.52, 95.59, 102.34, 102.38, 130.55, 130.74, 169.75, 170.20, 174.90, 174.95.

Example 21

(£)-3'-W-demethyi-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-3 ^, -/V-(4-methoxy-4- oxobutanoyl)-9a-methyl-9a-aza-9a-homoerythromyci

Dry PS-Carbodiimide resin (PS-CD! , 401 mg, 0.50 mmol, loading: 1 .25 mmot/g, 1 equivalent) was added to a dry reaction vessel. The 4-(methyloxy)-4-oxobutanoic acid (50.9 mg, 0.39 mmol) and HOBt (41 .3 mg, 0.27 mmol, 0.7 equivalent) dissolved in a dry mixture of DCM (5 mL) and DMF (0.3 mL), were added to the resin. The mixture was stirred at room temperature for 5 minutes upon which (£)-3'-W-demethyl-11 ,12- didehydro-9-deoxo-11 ,12-dideoxy _" 9a-methyl-9a _" aza-9a-homoerythromycin A, Example 15 (300 mg, 0.385 mmol, calculated based on 90% purity of Example 1 5) dissolved in dry DCM (3 mL) was added. The reaction mixture was heated by microwave irradiation at 75 °C for 7 minutes.

HOBt was scavenged using PS-trisamine (328 mg, 1.35 mmol, loading: 4.1 1 mmol/g , 5 equivalent according to HOBt) for 3 hours at room temperature. The resin was removed from the reaction mixture by filtration and washed with DCM (2 x 5 mL). Evaporation of the solvent under reduced pressure afforded a crude product (508.8 mg), which was purified by column chromatography (using solvent system: DCM/MeOH/NH ₄ OH = 90/9/0.5), to afford title product (248.1 mg, purity: 94 %); MS (ES ⁺ , m/z): 815.58 [M] ⁺ .

Due to restrained rotation around amide bond , there are two rotamers present in ratio A : B = 1 .2 : 1 .

3C NMR (150 MHz, DMSO-c¼) 6 ppm: 8.58, 9.50, 9.63, 12.50, 12.55, 13.74, 17.43, 17.56, 18.16, 18.20, 20.88, 20.96, 21 .19, 24.13, 25.37, 26.30, 26.77, 27.71 , 28.29, 28.50, 28.72, 28.98, 34.61 , 34.77, 35.35, 36.09, 37.45, 40.72, 42.56, 42.98, 48.62, 48.72, 51 .09, 54.00, 57.15, 57.18, 57.37, 64.41 , 64.50, 64.88, 64.96, 66.68, 66.77, 69.51 , 69.58, 72.72, 73.06, 73.1 1 , 77.26, 77.41 , 77.53, 83.02, 83.33, 95.1 1 , 95.25, 101 .71 , 101 .83, 1 30.03, 130.07, 130.32, 130.40, 170.85, 170.88, 172.96, 174.45.

EXAMPLES 22-23

General procedure for Examples 22-23:

To a solution of (£)-3'-W-demethyl-11 ,12~didehydro-9~deoxo-11 ,12-dideoxy-9a-methyl- 9a-aza-9a-homoerythromycin A, Example 15 in MeOH (10 mL), D!PEA and corresponding R ⁸ -iodo reagent were added and the reaction mixture was stirred at the elevated temperature for 20 to 40 hours. Evaporation of the solvent under reduced pressure afforded corresponding compound of examples 22 to 23 as a crude product.

Table 5.:

a = molar quantity was calculated based on 92% purity of starting Example 15

Example 22

(£)-3'-W-Demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-3'-W-(2- hydroxyethyl)-9a-aza-9a-homoerythromycin A

Crude product (858.3 mg) obtained according the above general procedure was purified by column chromatography (using solvent system: DCM/MeOH/NH^OH = 90/9/1 .5) to afford titie product as two fractions: fraction A (133.5 mg, purity: 98 %) and fraction B (163.4 mg, purity: 94 %). Fraction A was characterized as follows:

MS (ES ⁺ , m/z): 745.00 [M] ⁺

¹³ C NMR (125 MHz, D SO-d ₆ ) δ ppm: 9.09, 9.93, 12.89, 14.29, 17.80, 18.57, 21 .35, 21 .64, 21.71 , 24.58, 25.95, 27.20, 30.96, 35.17, 37.20, 37.78, 41 .13, 43.05, 43.52, 49.12, 56 E _l xampe. 57.60, 59.13, 64.90, 64.95, 65.34, 67.78, 70.84, 73.17, 73.57, 77.73, 78.17, 78.17,

83.64, 95.80, 102.36, 130.52, 131.00, 174.88. Example 23

(£)-3'-W-Demethyl-11 ,12~didehydro-9-deoxo-11 , 12-dideoxy-9a-methyl-3'-W-(3- hydroxypropyl)-9a-aza-9a-homoerythromycin A

Crude product (909 mg) obtained according the above general procedure was purified by column chromatography (first using solvent system: DC /MeOH/NH ₄ OH = 90/9/1.5, then using solvent system: DC /MeOH/NH OH = 90/9/0.5), followed by reverse phase preparative HPLC (using mixture of eiuents 30 % 10mM NH ₄ HC0 ₃ /pH 10 and 70 % CH ₃ CN) to afford title product (95.0 mg, purity:99.6 %); MS (ES ⁺ , m/z): 759.53 [M] ⁺ . ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 9.10, 9.96, 12.89, 14.32, 17.79, 18.59, 21 .35,

21 .65, 21 .71 , 24.58, 25.99, 27.20, 31 .00, 31 .14, 35.17, 37.08, 37.77, 41.09, 43.03, 43.54, 49.12, 50.96, 57.62, 59.62, 64.50, 64.94, 65.33, 67.76, 70.72, 73.17, 73.57, 77.72, 78.12,

78.1 3, 83.58, 95.79, 102.38, 130.05, 130.10, 174.89.

EXAMPLES 24-25

General procedure for Examples 24-25:

To the solution of {E)-3'-W-demethyl- 1 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a- methyl-9a-aza-9a-homoerythromycin A, Example 15 in MeOH (10 ml_), DIPEA and corresponding R ³ -tosy!ate reagent were added and the reaction mixture was stirred at room or elevated temperature for 5 to 7 days. Evaporation of the solvent under reduced pressure afforded corresponding compound of examples 24 to 25 as a crude product.

Table 6.:

Reacti

Example temper

R osylate DIPEA on

R ⁸ 15 ature

{mg/mmol) (mL/mmol) time

(mg/mmol} <R)-(-)-dihydro-

5-(p- tolylsu!fonyloxy- room

1 50 mg/ 0.21 mL/

24 methy!)-2(3H)- temper 7 days

0.20 ^a mmol 1.18 mmol

furanone ature

(106 mg/

0.39 mmoi)

(S)-{+)-dihydro-

5-(p- to!ylsulfonyloxy-

150 mg/

25 methyl)-2(3H)- 0.21 mL/

50 °C 5 days 0.20 ^a mmol 1.18 mmol

furanone,

(106 mg/

0.39 mmol) a = molar quantity was calculated based on 98% purity of starting Example 15

Example 24

(E)-3'-W-Demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-3'-W-{t(2R)-5- oxotetrahydro-2-furanyl]methyi}-9a-aza-9a-homoerythromycin A

Crude product (280 mg) obtained according the above general procedure was purified by column chromatography (first using solvent system; DCM/MeOH/NH ₄ OH = 90/9/0.5 and then using solvent system; (DCM/MeOH/NH ₄ OH = 90/9/1 .5)/DCM = 7/3) to afford title product (52.0 mg, purity: 90 %); MS (ES ⁺ , m/z): 799.54 [M] ⁺ .

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 9.08, 10.01 , 12.92, 14.26, 17.85, 18.56, 21 .36, 21 .65, 21.66, 24.58, 25.71 , 25.95, 27.21 , 28.26, 32.75, 35.16, 37.81 , 38.24, 41.19, 43.09, 43.54, 49.13, 57.60, 58.40, 64.93, 65.35, 65.41 , 67.63, 71.00, 73.1 5, 73.58, 77.73, 78.1 1 , 78.12, 80.02, 83.64, 95.77, 102.43, 130.53, 130.97, 174.92, 177.65.

Example 25

(£)-3'-W-Demethyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-3'-W-{ [(2S)-5- oxotetrahydro-2-furanyl]methyl}-9a-aza-9a-homoerythromycin A

Crude product (230 mg) obtained according the above general procedure was purified by column chromatography (first using solvent system: (EtOAc/n-hexane/DEA = 1 /1 /0.2)/n- hexane = 7/3, and then using solvent system: DCM/MeOH/NH ₄ OH = 90/9/1 .5), followed by reverse phase preparative HPLC (using mixture of eluents 50 % 10mM NH4HCO3/PH 10 and 50 % CH ₃ CN) to afford title product (27.2 mg, purity:90 %); MS (ES\ m/z): 799.50 [Mf. ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm: 8.65, 9.52, 12.44, 13.89, 17.34, 18.1 1 , 20.90, 21 .19, 21.19, 24.00, 25.00, 25.04, 26.00, 27.96, 33.80, 35.00, 37.24, 37.74, 40.65, 42.00, 43.00, 48.69, 57.17, 57.80, 64.43, 64.85, 64.85, 67.23, 70.63, 72.69, 73.14, 77.27, 77.71 , 77.71 , 78.92, 83.19, 95.35, 101 .91 , 130.54, 130.98, 174.48, 177.23.

Example 26

(E)-4"-0-Acetyl-2'-0-(2-cyanoethyi)-11 , 12-didehydro-9-deoxo-11 ,12-dideoxy-9a- methyl-9a-az

A solution of TEA (4.26 mL, 30.6 mmol) and benzoyl chloride (3.23 mL, 27.8 mmo!) in DCM (120 mL) was stirred for 10 minutes. Then solution of 2*-O-(2-cyanoethy!-4"-0- acetyi-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 11 ,12-(N,N- dimethylformamide) acetal (5.0 g, 5.56 mmol, may be prepared by the procedure as described in WO2009/016142, Intermediate 1 , Procedure B, Step 4, compound 1 1 b) in DCM (80 mL) was added dropwise over 2 hours and stirring continued for 4 hours. Reaction mixture was washed with saturated aqueous NaHC0 ₃ solution (2 x 800 mL), dried over anhydrous Na ₂ S0 , filtered and evaporated to afford crude oily title product (8.4 g). Crude product was dissolved in DCM (100 mL), water (1 00 mL) was added and pH adjusted to 3 (using 6 M HCI). The organic layer was discharged and to the aqueous one DCM (100 mL) was added and pH adjusted to 9.0 (using 20% NaOH). Organic layer at pH 9.0 was separated, dried over anhydrous Na ₂ S0 , filtered and evaporated to attord crude product (1.7 g), which was purified by column chromatography (using solvent system: EtOAc/n-hexane/DEA ~ 10/10/2) to afford title product (0.71 g, purity: 94 %); MS (ES ⁺ , m/z): 810.82 [M] ⁺ .

1 ³ C NMR (125 MHz, DMSO-d ₆ ) δ ppm: 8.98, 9.54, 13.20, 1 3.65, 17.82, 18.32, 18.92, 20.99, 21 .02, 21 .48, 21.64, 24.68, 25.67, 27.35, 32.07, 34.71 , 38.28, 41 .32, 41.67, 43.22, 43.29, 49.31 , 57.69, 62.85, 64.32, 64.73, 66.84, 67.55, 72.90, 73.40, 77.19, 77.41 , 78.33, 80.10, 83.27, 95.22, 101.56, 1 19.47, 130.39, 130.65, 170.60, 175.03.

Example 27

(£)-3-0-Decladinosyl-11 , 2-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A

(E)-4"-0-Acetyl-11 ,12-didehydro-9-deoxo-11 ,12-dideoxy-9a-methyl-9a-aza-9a- homoerythromycin A, Example 12 (300 mg, 0.340 mmol, calculated based on 81 % purity of starting macrolide) was dissolved in hydrochloric acid (5 ml_, 15.00 mmol, 3 M) and stirred at room temperature for 2 hours. Then water (20 ml_) was added, and reaction mixture extracted with EtOAc (25 mL). EtOAc layer was discharged, to the water layer DCM (25 mL) was added, pH adjusted to 8.0 and water layer washed once more with DCM (25 mL). Combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated to afford crude product (192.3 mg), which was purified by column chromatography (using solvent system EtOAc/n-hexane/DEA = 1/1/0.2) to afford title product (1 15.2 mg, purity: 99 %); MS (ES ⁺ , m/z): 557.33 [M] ⁺ .

¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm: 8.61 , 9.23, 1 1.49, 15.22, 15.50, 21 .16, 21.77, 24.16, 26.58, 26.86, 30.56, 35.71 , 36.13, 40.43, 41 .16, 43.17, 57.16, 64.67, 64.92, 68.16, 70.42, 72.93, 76.42, 79.55, 87.02, 102.81 , 130.69, 131 .28, 173.76.

In Vitro Assay

The in vitro potency of the compounds of the invention was measured using the methodology described in the in vitro protocol for Inhibition of IL-6 production in LPS- stimulated murine spleenocytes in vitro.

Tested compounds of Formula (I) exhibited 40% or more inhibition of interleukin-6 (IL-6) production in LPS-stimulated spienocytes treated by the compound at 50μΜ or/and 25μΜ concentration. Suitably compounds of Formula (I) exhibit 50% or more inhibition of interleukin-6 (IL-6) production in LPS-stimulated spienocytes treated by the compound at 50μΜ or/and 25μΜ concentration.

Activity data is an average calculated from 1 , 2, 3, 4, 6 or 7 independent experiments in which each compound is tested in duplicate. Compounds of examples 1 -5, 7-15, 17-18, and 20-27 exhibited more than 40% inhibition of interfeukin-6 (IL-6) production in LPS-stimulated spienocytes treated by the compound at 50μΜ or/and 25μΜ concentration.

For example compound of example 3 showed 45.5% and compound of example 15 showed 94.6% inhibition of interieukin-6 (IL-6) production in LPS-stimulated spienocytes treated by the compound at 50μΜ concentration. Compound of example 3 showed 59.5% and compound of example 15 showed 86.6% inhibition of interleukin-6 (IL-6) production in LPS-stimu!ated splenocytes treated by the compound at 25μΜ concentration.

Compounds of examples 6, 16 and 19 exhibited less than 40% and more than 20% inhibition of interleukin-6 (IL-6) production in LPS-stimuiated splenocytes treated by the compound at 50μΜ concentration.

In Vivo Assay

The in vivo potency of representative compounds of the invention was measured using the methodoiogy described in the in vivo protocol for Lung neutrophilia induced by bacterial Hpopolysaccharide in mice.

The compound of example 20 showed more than 50% inhibition of total celi number and more than 15% decrease in myeloperoxidase concentration in BALF of treated animals which received intraperitoneally (i.p.) a single dose of 100 mg/kg of test compound tested in Lung neutrophilia induced by bacterial lipopoiysaccharide in mice.