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WO2011131749A1 - Nouveaux macrolides à 14 et 15 chaînons pour le traitement de maladies inflammatoires à dominance en neutrophiles - Google Patents

Nouveaux macrolides à 14 et 15 chaînons pour le traitement de maladies inflammatoires à dominance en neutrophiles Download PDF

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Publication number
WO2011131749A1
WO2011131749A1 PCT/EP2011/056401 EP2011056401W WO2011131749A1 WO 2011131749 A1 WO2011131749 A1 WO 2011131749A1 EP 2011056401 W EP2011056401 W EP 2011056401W WO 2011131749 A1 WO2011131749 A1 WO 2011131749A1
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Prior art keywords
methyl
aza
dideoxy
didehydro
homoerythromycin
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English (en)
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Sulejman Alihodzic
Ivaylo Jivkov Elenkov
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POLJAK TANJA
Glaxo Group Ltd
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POLJAK TANJA
Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • 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.
  • inflammatory diseases are characterized by enhanced accumulation of differing proportions of inflammatory cells, including monocytes/macrophages, granulocytes, plasma cells, lymphocytes and platelets.
  • monocytes/macrophages including monocytes/macrophages, granulocytes, plasma cells, lymphocytes and platelets.
  • granulocytes including monocytes/macrophages, granulocytes, plasma cells, lymphocytes and platelets.
  • lymphocytes including lymphocytes and platelets.
  • 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.
  • neutrophilic inflammation is characterized by infiltration of the inflamed tissue by neutrophilic polymorphonuclear leukocytes (PMN, i.e. neutrophils), which are a major component of host defence.
  • PMN neutrophilic polymorphonuclear leukocytes
  • 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.
  • various non-infectious diseases are characterized by extravascular recruitment of neutrophils.
  • 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.
  • intermittent resurgence e.g. flare in autoimmune diseases such as rheumatoid arthritis
  • continuous generation e.g. chronic obstructive pulmonary disease (COPD)
  • 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.
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • DBP diffuse panbronchiolitis
  • BOS bronchiolitis obliterans
  • bronchitis bronchiectasis
  • emphysema emphysema
  • ARDS adult respiratory distress syndrome
  • RDS respiratory distress syndrome
  • 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.
  • 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):
  • R 1 is hydrogen or CH 3 ;
  • R 2 is a ⁇ -D-desosaminyl group of Formula (a);
  • R is:
  • 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:
  • R is hydroxyl or hydroxyl protecting group
  • R 10 is independently selected from:
  • 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.
  • 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.
  • the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medical therapy.
  • 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.
  • 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.
  • Figure 1 shows correlation of inhibition of IL-6 production in vitro and inhibition of cell infiltration into BALF in vivo.
  • alkyl 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.
  • 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.
  • C h alky examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, hexyl and the like.
  • alkoxy 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.
  • -C ⁇ alkyl substituted by phenyl 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.
  • ary 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.
  • cycloaikyi 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.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • heteroaryl ring refers to a 5-6 membered monocyclic aromatic ring containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • 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.
  • 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.
  • 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, tetrahydrothi
  • 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.
  • hydroxyl protecting group include: ester and ether hydroxy! protecting group.
  • ester hydroxyl protecting group examples 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!
  • ether hydroxyl protecting group examples include: alky! silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl, triethylsilyl, triisopropylsi!yi and the like.
  • 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).
  • hydroxyl protecting group is: acetyl (Ac or -C(0)CH 3 ), benzoyl (Bz) or benzyloxycarbonyl (Cbz).
  • hydroxyl protecting group is: acetyl (Ac or -C(0)CH 3 ).
  • inert solvent 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, ⁇ , ⁇ -dimethy!acetamide, dimethyl sulfoxide, pyridine, and polar protic solvents such as lower alcohol, acetic acid, formic acid and water.
  • 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, ⁇ , ⁇ -dimethy!ace
  • lower alcohol refers to a C 1-4 alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, t-butano!, and the like.
  • the present invention relates to a compound of Formula (I) or a salt thereof wherein the salt is a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt 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
  • isethionate eg hydrochloride or acetate salt.
  • compounds of the present invention may be in the form of pharmaceutically acceptable salts, solvates or solvates of salts.
  • 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.
  • the compounds of Formula (I) have more than one asymmetric carbon atom.
  • 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.
  • the substituents on the macro!ide may also have one or more asymmetric carbon atoms.
  • 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.
  • 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.
  • A is a bivalent radical -N(R 5 )CH 2 - wherein R 5 is -C 1-4 alkyl and R 1 is hydrogen.
  • A is a bivalent radical -N(R 5 )CH 2 - wherein R 5 is methyi and R is hydrogen.
  • A is a bivalent radical -NHC(O)- and R 1 is CH 3 .
  • 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 .
  • R 1 is hydrogen
  • R 1 is CH 3 .
  • R 3 is a-L-cladinosyl group of Formula (b). In one aspect of the invention R 3 is hydroxy!.
  • 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
  • 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)-.
  • R is a-L- cladinosyi group of Formula (b) and A is a bivalent radical -N(R 5 )CH 2 - or -NHC(O)-.
  • R 5 is methyl.
  • R 7 is hydroxyl
  • R 7 is a hydroxyl protecting group.
  • the hydroxyl protecting group is -OC(0)C 1- a!kyl.
  • the hydroxyl protecting group is -OC(0)CH 3 (acetyl).
  • 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.
  • 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!.
  • 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].
  • R 10 is methyl, ethy! or n-propy! substituted at the terminal carbon atom by methoxy.
  • R 10 is methyl substituted by methoxy.
  • R 10 is methyl, ethyl or n-propyl substituted at the terminal carbon atom by -C(0)OCH 3 .
  • R 10 is ethyl substituted at the terminal carbon atom by -C(0)OCH 3 .
  • R 10 is methyl, ethyl or n-propyl substituted at the terminal carbon atom by -N(CH 3 ) 2 .
  • R 10 is methyl substituted by -N(CH 3 ) 2 .
  • R 10 is methyl, ethyl or n-propyl substituted at the terminal carbon atom by a six membered unsubstituted heteroaromatic ring.
  • R 10 is methyl and R 12 is pyridyl.
  • R 12 is 4-pyridyl.
  • R 10 is six membered monocyclic unsubstituted heteroaromatic ring containing two heteroatoms.
  • R 10 is pyrazinyl.
  • R 0 is 2-pyrazinyl,
  • 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).
  • R 11 is methyl, ethyl or n-propyl. In a further aspect of the invention R 1 is methyl.
  • R 2 is 5-6 membered unsubstituted heteroaromatic ring.
  • R 12 is six membered unsubstituted heteroaromatic ring containing one heteroatom.
  • R 12 is pyridyl.
  • R 12 is 4-pyridyl.
  • 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 ⁇ -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:
  • 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
  • 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,
  • 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)
  • R 1 is hydrogen or CH 3 ;
  • R 2 is a ⁇ -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-
  • 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.
  • R q and R l independently are -C -4 alkyl or -C h alky! substituted by phenyl, or a salt thereof.
  • R 2 is a ⁇ -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.
  • R q and R 1 independently are methyl.
  • 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 .
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • DPB diffuse panbronchiolitis
  • BOS bronchiolitis obliterans
  • ARDS adult respiratory distress syndrome
  • RDS severe or steroid-resistant asthma
  • 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.
  • vasculitis systemic lupus erythematodes (SLE), systemic inflammatory response syndrome (SIRS), sepsis, ischemia-reperfusion injury, rosacea, periodontitis, gingival hyperplasia and prostatitis syndrome.
  • SLE systemic lupus erythematodes
  • SIRS systemic inflammatory response syndrome
  • sepsis sepsis
  • ischemia-reperfusion injury ischemia-reperfusion injury
  • rosacea rosacea
  • gingival hyperplasia gingival hyperplasia
  • prostatitis syndrome systemic inflammatory response syndrome
  • Treating" or “treatment” of neutrophil dominated inflammatory diseases 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, period
  • 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 prostatiti
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • 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, ros
  • 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).
  • 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.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of bronchiolitis obliterans.
  • 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).
  • 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 (SIR)
  • COPD
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • pharmaceutically acceptable 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).
  • 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 hyperplasi
  • 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
  • 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.
  • 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.
  • the pharmaceutical composition is formulated for oral administration.
  • 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.
  • a delayed release can be achieved by a coating that is simply slow to disintegrate.
  • 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 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethyScellulose
  • gelatin glucose, dextrose, xylitol, polymethacryiates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth,
  • 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.
  • 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.
  • 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.).
  • 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.
  • EDTA ethylenediaminetetraacetic acid
  • thiourea thiourea
  • tocopherol thiourea
  • butyl hydroxyanisoie ethylenediaminetetraacetic acid
  • 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.
  • 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.
  • 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.
  • compositions may also contain other pharmaceutically acceptable excipients, such as polymers, oils, iiquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and flavourings.
  • 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.
  • 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.
  • 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.
  • the dosage unit may be determined by providing a valve to
  • 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.
  • a lubricant e.g., sorbitan trioleate.
  • Capsules and cartridges 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.
  • a suitable powder base such as lactose or starch.
  • the compound according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.
  • 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.
  • 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.
  • the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • compositions of the invention may contain from 0,01 to 99% weight per volume of the active material.
  • 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.
  • 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.
  • 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.
  • compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers thereof represent a further aspect of the invention.
  • 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.
  • acyl groups such as alkanoy!, alkoxycarbonyl and aryloyl groups
  • 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.
  • DMADMA N,N- dimethylacetamide
  • DMFDMA dimethyl acetal of ⁇ , ⁇ -dimethylformamide
  • 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.
  • 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.
  • compounds of Formula (I) may be purified by differential partition between aqueous and organic solvents and/or crystallisation.
  • 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.
  • a suitable base such as K 2 C0 3
  • a suitable solvent such as methanol or a mixture of methanol and water at room temperature.
  • 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 ⁇ , ⁇ -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.
  • a tertiary organic base such as triethylamine or dimethySaminopyridine
  • an inorganic base eg. sodium hydroxide
  • 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.
  • organic base suitably N,N- diisopropylethylamine
  • inert organic solvent such as lower alcohol (suitably methanol) or acetonitrile.
  • 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 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, ⁇ , ⁇ -dimethylformamide or a mixture thereof, in the presence of asuitabie reducing agent, for example sodium t iacetoxyborohydride or sodium cyanoborohydride,
  • a suitableabie reducing agent for example sodium t iacetoxyborohydride or sodium cyanoborohydride
  • compounds of Formula (I) wherein R 3 is an ⁇ -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.
  • compounds of Formula (I) wherein R 3 is an ⁇ -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.
  • tertiary organic base such as diisopropylethylamine (DSPEA), triethylamine (TEA), or mixture thereof.
  • DSPEA diisopropylethylamine
  • TAA triethylamine
  • 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).
  • a lower alcohol solvent such as methanol
  • DIPEA diisopropylethylamine
  • 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.
  • PS CDI polymer-supported carbodiimide
  • EDC 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide
  • DCC dicyclohexylcarbodiimide
  • DBU 1 ,8- diazabicyclo[5.4.0.]undec-7-ene
  • HOBt hydroxybenzotriazole monohydrate
  • suitable inert organic solvent such as a halohydrocarbon
  • 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 ⁇ -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.
  • 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 ⁇ -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.
  • reaction may be carried out for example using methanol at a temperature in the range from room temeperature to 60 °C.
  • 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.
  • tertiary organic base such as triethylamine (TEA), diisopropyiethylamine (DIPEA) or mixture thereof
  • DMAP dimethylaminopyridine
  • 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!
  • 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
  • tertiary organic base such as triethylamine (TEA), diisopropy!ethy!amine (DIPEA) or mixture thereof
  • DMAP dimethylaminopyridine
  • 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.
  • 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.
  • 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), ⁇ /,/V-dimethy!formamide (DMF) or toluene at a temperature in the range from room to reflux.
  • a suitable inert organic solvent such as halohydrocarbon (e.g. chloroform or DCM), ⁇ /,/V-dimethy!formamide (DMF) or toluene
  • reaction may be carried out for example using excess of ⁇ /,/V-substituted formamide acetal (suitably ⁇ /,/V-dimethySformamide dimethylacetal (DMF-DMA)) suitably 2 to 6 equivalents, in a halohydrocarbon (e.g. chloroform) or in DMF at 60-70 °C.
  • ⁇ /,/V-substituted formamide acetal suitably ⁇ /,/V-dimethySformamide dimethylacetal (DMF-DMA)
  • a halohydrocarbon e.g. chloroform
  • DMF-DMA halohydrocarbon
  • 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.
  • 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,
  • compositions 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
  • 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.
  • 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
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffered saline
  • DME Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • LPS bacterial lipopolysaccharide
  • BALF bronchoa!veolar lavage fluid
  • 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 ⁇ , 25 ⁇ , 12.5 ⁇ , 6.3 ⁇ and 3.1 ⁇ 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
  • DMSO dimethyl sulfoxide
  • FBS heat inactivated fetal bovine serum
  • 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.
  • PBS sterile phosphate buffered saline
  • % 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
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • methyl-cellulose methyl-cellulose
  • the obtained solution is applied in a dose volume of 0.1 mL per 10g of animal. Therefore, the compound dose is 10Qmg/kg.
  • 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).
  • MPO myeloperoxidase
  • 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 ⁇ /,/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.
  • DMF-DMA for ⁇ /,/V-dimethyl
  • the compounds of Formula (I) and derivatives thereof may be purified by conventional methods known in the art.
  • 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.
  • 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, 5 ⁇ ) 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.
  • Example 2 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 ⁇ 50 mL).
  • Example 2 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).
  • Example 2 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.
  • Example 4 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).
  • PS-CDI Dry PS-Carbodiimide resin
  • loading 1 .25 mmo!/g, 1 equivalent
  • 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.
  • 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 12 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).
  • Example 12 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.
  • Example 12 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).
  • 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.
  • PS-CDI Dry PS-Carbodiimide resin
  • loading 1.25 mmoi/g, 1 equivalent
  • 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.
  • PS-CD! 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.
  • 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.
  • Example 12 (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).
  • 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 50 ⁇ or/and 25 ⁇ concentration.
  • compounds of Formula (I) exhibit 50% or more inhibition of interleukin-6 (IL-6) production in LPS-stimulated spienocytes treated by the compound at 50 ⁇ or/and 25 ⁇ 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 50 ⁇ or/and 25 ⁇ concentration.
  • IL-6 interfeukin-6
  • 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 50 ⁇ 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 25 ⁇ concentration.
  • IL-6 interieukin-6
  • 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.

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Abstract

L'invention concerne des (E)-11,12-didehydro-11,12-didéoxy macrolides à 14 chaînons et des macrolides de type azalide à 15 chaînons représentés par la Formule (I) : utiles dans le traitement de maladies inflammatoires à dominance en neutrophiles, particulièrement dans le traitement de maladies inflammatoires à dominance en neutrophiles résultant de l'infiltration de neutrophiles et/ou de maladies associées à une fonctionnalité cellulaire modifiée des neutrophiles. L'invention concerne également des intermédiaires pour leur préparation, des procédés pour leur préparation, leur utilisation comme agents thérapeutiques et des sels de ceux-ci.
PCT/EP2011/056401 2010-04-23 2011-04-21 Nouveaux macrolides à 14 et 15 chaînons pour le traitement de maladies inflammatoires à dominance en neutrophiles Ceased WO2011131749A1 (fr)

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WO2016057798A1 (fr) * 2014-10-08 2016-04-14 President And Fellows Of Harvard College Kétolides à 14 chaînons et leurs procédés de préparation et d'utilisation
US9982005B2 (en) 2013-04-04 2018-05-29 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US10508154B2 (en) 2012-06-25 2019-12-17 Zymeworks Inc. Process and methods for efficient manufacturing of highly pure asymmetric antibodies in mammalian cells
US10640528B2 (en) 2015-03-25 2020-05-05 President And Fellows Of Havard College Macrolides with modified desosamine sugars and uses thereof
US20210363238A1 (en) * 2018-01-31 2021-11-25 Motokazu Kato Therapeutic agent for asthma containing il-6 inhibitor
EP4118091A1 (fr) * 2020-03-12 2023-01-18 Zoetis Services LLC Azalides d'urée immunomodulateurs
US12060436B2 (en) 2012-11-28 2024-08-13 Zymeworks Bc Inc. Engineered immunoglobulin heavy chain-light chain pairs and uses thereof
US12528874B2 (en) 2021-11-16 2026-01-20 Genentech, Inc. Methods and compositions for treating systemic lupus erythematosus (SLE) with mosunetuzumab

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