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US20120234316A1 - Isoxazolidine derivatives - Google Patents

Isoxazolidine derivatives Download PDF

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Publication number
US20120234316A1
US20120234316A1 US13/421,150 US201213421150A US2012234316A1 US 20120234316 A1 US20120234316 A1 US 20120234316A1 US 201213421150 A US201213421150 A US 201213421150A US 2012234316 A1 US2012234316 A1 US 2012234316A1
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US
United States
Prior art keywords
hydroxy
dimethyl
aza
pentaleno
tetradecahydro
Prior art date
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US13/421,150
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English (en)
Inventor
Eleonora Ghidini
Andrea Rizzi
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Application filed by Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GHIDINI, ELEONORA, RIZZI, ANDREA
Publication of US20120234316A1 publication Critical patent/US20120234316A1/en
Priority to US14/537,184 priority Critical patent/US9845337B2/en
Priority to US15/807,066 priority patent/US10280193B2/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0057—Nitrogen and oxygen
    • C07J71/0068—Nitrogen and oxygen at position 16(17)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

Definitions

  • the present invention relates to novel anti-inflammatory and antiallergic compounds of the glucocorticosteroid series, methods of preparing such a compound, pharmaceutical compositions which contain such a compound them, combinations which contain such a compound, and therapeutic uses of such a compound.
  • the present invention also relates to methods of treating and/or preventing certain diseases and conditions by administering such a compound. More particularly, the invention relates to glucocorticosteroids that are isoxazolidine derivatives.
  • Corticosteroids are potent anti-inflammatory agents, able to decrease the number, activity and movement of inflammatory cells. They are commonly used to treat a wide range of chronic and acute inflammatory conditions including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases. Corticosteroids mediate their effects through the glucocorticoid receptor (GR). The binding of corticosteroids to GR induces its nuclear translocation which, in turn, affects a number of downstream pathways via DNA-binding-dependent (e.g. transactivation) and -independent (e.g. transespression) mechanisms.
  • Corticosteroids for treating chronic inflammatory conditions in the lung are currently administered through inhalation.
  • One of the advantages of employing inhaled corticosteroids (ICS) is the possibility of delivering the drug directly at site of action, limiting systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
  • ICS treatment can afford important benefits, expecially in asthma it is important to minimise ICS systemic exposure which leads to the occurrence and severity of unwanted side effects that may be associated with chronic administration. Moreover, the limited duration of action of ICS currently available in the clinical practice contributes to suboptimal management of the disease. While the inhaler technology is the key point to target the lung, the modulation of the substituents on the corticosteroids molecular scaffold is important for the optimization of pharmacokinetic and pharmacodynamic properties in order to decrease oral bioavailability, confine pharmacological activity only in the lung (prodrugs and soft drugs) and increase systemic clearance.
  • Glucocorticoids isoxazolidine derivatives are for instance described in WO 2006/005611, GB 1578446 and in “Synthesis and topical anti-inflammatory activity of some steroidal [16 ⁇ ,17 ⁇ -d] isoxazolidines” ( J. Med. Chem., 25, 1492-1495, 1982), all of which are incorporated herein by reference in their entireties. Some glucocorticoid isoxazolidine derivatives are also described in the co-pending patent application WO 2011/029547, which is incorporated herein by reference in its entirety.
  • the present invention provides anti-inflammatory and antiallergic compounds of the glucocorticosteroid series of formula (I).
  • the present invention provides to processes for preparing a compound of formula (I).
  • the present invention provides pharmaceutical compositions which contain a compound of formula (I).
  • the present invention provides combinations of a compound of formula (I) with other pharmaceutical active ingredients for the treatment of respiratory disorders, among which beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs) and mucus regulators.
  • beta2-agonists P38 MAP kinase
  • IKK2 nuclear factor kappa-B kinase subunit beta
  • HNE human neutrophil elastase
  • PDE4 phosphodiesterase 4
  • leukotriene modulators non-steroidal anti-inflammatory agents
  • NSAIDs non-steroidal anti-inflammatory agents
  • the present invention provides methods of treating and/or preventing certain diseases by administering a compound of formula (I).
  • the compounds of the present invention show improved developability, pharmacokinetic or pharmacodynamic characteristics, such as low systemic exposure, great selectivity, potency or duration of action.
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n and n′ are each independently 0, 1 or 2; Z is a single bond or is selected from —S—, —O— and —OC(R 4 R 5 )—; R 3 is selected from the group consisting of:
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • (C 1 -C 6 )alkyl refers to straight or branched chain alkyl groups wherein the number of carbon atoms is from 1 to 6, 1 to 8 or 1 to 15 respectively.
  • Examples of said groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, eptyl, octyl, ethyl-butyl, propyl-butyl, methyl-butyl, ethyl-methyl-propyl, hexadecyl and the like.
  • (C 2 -C 6 )alkenyl refers to straight or branched carbon chains with one or more double bonds, wherein the number of carbon atoms is from 2 to 6. Examples of said groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • (C 2 -C 6 )alkynyl refers to straight or branched carbon chains with one or more triple bonds, wherein the number of carbon atoms is from 1 to 6. Examples of said groups comprise ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • (C 1 -C 6 )alkylcarboxyl refers to alkyl-COO groups.
  • (C 1 -C 6 )alkoxy refers to alkyl-oxy (e.g. alkoxy) groups, being the alkyl portion as above defined. Examples of said groups may thus comprise methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • (C 1 -C 6 )alkoxycarbonyl and “(C 1 -C 6 ) hydroxyalkoxy” refer respectively to alkoxy-CO— and (OH)alkoxy-groups.
  • (C 1 -C 6 )haloalkyl and “(C 1 -C 6 )haloalkoxy” refer to the above “(C 1 -C 6 )alkyl” and “(C 1 -C 6 )alkoxy” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other.
  • Examples of said (C 1 -C 6 )haloalkyl and (C 1 -C 6 )haloalkoxy groups may thus include halogenated, poly-halogenated and fully halogenated alkyl and alkoxy groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or trifluoromethoxyl groups.
  • (C 3 -C 8 )cycloalkyl refers to mono or bi-cycloaliphatic hydrocarbon groups with from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl and the like.
  • (C 3 -C 8 )heterocycloalkyl refers to (C 3 -C 8 )cycloalkyl groups, in which at least one ring carbon atom is replaced by a heteroatom or heteroaromatic group (e.g. N, NH, S or O).
  • aryl refers to mono or bi- or tri-cyclic ring systems which have 6 to 20 ring atoms, preferably from 6 to 15 and wherein at least one ring is aromatic.
  • (C 1 -C 6 )arylalkyl refers to (C 1 -C 6 )alkyl groups further substituted by aryl.
  • aryloxy and arylthio refer respectively to aryl-oxy- and aryl-S— groups, with the aryl portion as above defined.
  • (C 1 -C 6 )alkylsulfanyl and “(C 1 -C 6 )alkylsulfonyl” refer respectively to alkyl-S— and alkyl-SO 2 — groups.
  • (C 1 -C 6 )haloalkylsulfonyloxy refers to haloalkyl-SO 2 (O)— groups.
  • aminosulfonyl refers to NH 2 S(O 2 )—.
  • heteroaryl refers to mono, bi- or tri-cyclic ring systems with 5 to 20 ring atoms, preferably from 5 to 15, in which at least one ring is aromatic and in which at least one carbon ring atom is a heteroatom or heteroaromatic group (e.g. N, NH, S or O).
  • Suitable aryl or heteroaryl monocyclic systems include, for instance, thiophene (thiophenyl), benzene (phenyl), pyrrole (pyrrolyl), pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoazolyl), oxazole (ozazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl), pyridine (pyidinyl), imidazolidine (imidazolidinyl), furan (furanyl) radicals and the like.
  • Suitable aryl or heteroaryl bicyclic systems include naphthalene (naphthyl), biphenylene (biphenylenyl), purine (purinyl), pteridine (pteridinyl), benzotriazole (benzotriazolyl), quinoline (quinolinyl), isoquinoline (isoqinolinyl), indole (indolyl), isoindole (isoindolyl), benzothiophene (benzothiophenyl), dihydrolbenzo dioxin, dihydrobenzo dioxepine, thiazole, benzo oxazine radicals and the like.
  • Suitable aryl or heteroaryl tricyclic systems include fluorene radicals as well as benzocondensed derivatives of the aforementioned heteroaryl bicyclic systems.
  • Preferred compounds are those of general formula (I) wherein the stereochemistry of stereogenic carbon atoms is as reported in formula (I′) below, absolute configuration is assigned on the basis of Cahn-Ingold-Prelog nomenclature based on groups' priorities
  • absolute configuration at asymmetric center 4a is (S), at 4b is (R), at 5 is (S), at 6a is (S), at 6b is (R), at 9a is (S), at 10a is (S), at 10b is (S) and at 12 is (S).
  • Compounds of general formula (I) may form acid addition salts, particularly with pharmaceutically acceptable acids.
  • Pharmaceutically acceptable acid addition salts of the compounds of formula (I), thus encompassing also those of formula (I′), include those of inorganic acids, for example hydrohalogen acids such as hydrofluoric, hydrochloric, hydrobromic or hydroiodic; nitric, sulfuric, phosphoric; and organic acids, for example aliphatic monocarboxylic acids such as formic, acetic, trifluoroacetic and propionic; aliphatic hydroxyl acids such as lactic, citric, tartaric or malic; dicarboxylic acids such as maleic, fumaric, oxalic or succinic; aromatic carboxylic acids such as benzoic; aromatic hydroxyl acids and sulfonic acids.
  • These salts may be prepared from compounds of formula (I) or (I′) by known salt-forming procedures.
  • X and Y is a halogen atom
  • m is zero and R 6 is optionally substituted aryl, (C 3 -C 8 )cycloalkyl or heteroaryl.
  • both X and Y are independently halogen atoms and m is zero and R 6 is optionally substituted aryl, (C 3 -C 8 )cycloalkyl or heteroaryl.
  • both X and Y are fluorine and m is zero and R 6 is optionally substituted aryl, (C 3 -C 8 )cycloalkyl or heteroaryl.
  • R 6 is optionally substituted aryl, (C 3 -C 8 )cycloalkyl or heteroaryl
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 , wherein n is 1, Z is a single bond, n′ is 0 and R 3 is —OH
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 , wherein n is 0, Z is —S—, n′ is 1, and R 3 is an halogen atom
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n —R 3 , wherein n is 0, Z is a bond, n′ is 1, and R 3 is selected from the group consisting of an halogen atom, CN, CONH 2 , (C 1 -C 6 )haloalkyl, and (C
  • R 1 is —(CH 2 ) n —(CH 2 ) n′ —R 3 , wherein n is 0, Z is —S—, n′ is 1, and R 3 is an halogen atom, or R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 , wherein n is 0, Z is a bond, n′ is 1 and R 3 is an halogen atom.
  • R 1 is selected from the group consisting of methyl, hydroxy, hydroxymethyl, N-methoxy-N-methylamino, N-methyl-N-cyanomethyl, chloromethyl, fluoromethyl, fluoromethoxy, fluoroethoxy, chloromethoxy, cyanomethyl, methylsulfanyl, methylsulfanylmethyl, cyclopropylmethoxy, fluoroethylsulfanyl, trifluoroethylsulfanyl, cyclobutylsulfanyl, cyanomethoxy and a group of formula (h), (h′), (h′′′), (i), (i′), (l), (l′), (l′′) or (l′′′) below
  • R 2 is selected from the group consisting of cyclohexyl, ethyl-butyl, phenyl-propyl, phenoxy-ethyl, amino-carbonyl-phenyl, amino-sulfonyl-phenyl, bromo-phenyl, cyano-phenyl, cyclopropyl-phenyl, methoxy-benzyl, propyl-butyl, methyl-butyl, tert-butyl-benzyl, methyl-benzyl, dichloro-phenyl, chloro-furan-2-yl-methyl, chloro-thiophen-2-yl-methyl, phenylsulfanyl-ethyl, cyclohexyl, cyclopentylmethyl, ethyl-2-methyl-propyl, 4-chloro-3-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 4-chloro-3-tri
  • Preferred compounds of general formula (I) or (I′) have the formula OA), wherein X and Y are fluorine, n is 0 or 1, n′ is 0 or 1; Z is a single bond, or is selected from —S—, —O— and —OC(R 4 R 5 ); R 3 is selected from the groups consisting of H, halogen, —OH, —CN, —CONH 2 , —NR 4 R 5 , (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylcarbonyl, an optionally substituted monocyclic (C 3 -C 8 )heterocycloalkyl, (C 1 -C6)alkyl, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl; and the groups R 2 , R 4 , R 5 are as above defined for compounds of formula (I).
  • Preferred compounds of general formula (I) or (I′) have formula (IC), wherein X and Y are fluorine, m is zero and R 6 is an optionally substituted aryl or heteroaryl, such that R 2 represents an optionally substituted aryl or heteroaryl; and R 1 is as above defined for compounds of formula (I).
  • R 2 is optionally substituted phenyl.
  • R 2 is an optionally substituted heteroaryl.
  • the invention is directed to compounds of general formula (ID)
  • R 1 is—(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n and n′ are each independently 0, 1 or 2; Z is a single bond or is selected from —S— and —O—; R 3 is selected from the group consisting of:
  • Examples of compounds of formula (ID) include:
  • the invention is directed to compounds of general formula (IE)
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n and n′ are each independently 0, 1 or 2; Z is a single bond or is selected from —S— and —O—; R 3 is selected from the group consisting of:
  • Examples of compounds of formula (IE) include
  • the invention is directed to compounds of general formula (IF)
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is 1 and n′ is zero;
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is 1 and n′ is zero;
  • R 2 is (C 1 -C 8 )alkyl or —(CH 2 ) m R 6 , where m is 1 and R 6 is optionally substituted heteroaryl.
  • the invention is directed to compounds of general formula (IH)
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is zero and n′ is 1;
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is zero and n′ is 1;
  • R 2 is (CH 2 ) m R 6 , m is 1 and R 6 is optionally substituted aryl or heteroaryl.
  • the invention is directed to compounds of general formula (IM)
  • R 1 is —(CH 2 ) N Z—(CH 2 ) n′ —R 3 wherein n is zero and n′ is 1; Z is a single bond;
  • R 3 is —OH
  • R 2 is selected from the group consisting of:
  • the invention is directed to compounds of general formula (IN)
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is zero and n′ is 1; Z is a single bond;
  • R 3 is —OH
  • R 2 is —(CH 2 ) m R 6 , wherein R 6 is aryl optionally substituted by one or more substituents selected from the group consisting of halogen, CN, CONH 2 , NHC(O)H, linear or branched (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, linear or branched (C 1 -C 6 )haloalkyl, linear or branched (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxysulfonyl, (C 1 -C 6 )haloalkylsulfonyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, aminosulfonyl, and heteroaryl and m is 0 and pharmaceutically acceptable salts thereof.
  • Methanesulfonic acid 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4-b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4-a,6a-dimethyl-2-oxo-2,4-a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-phenyl ester;
  • the invention is directed to compounds of general formula (IN′)
  • R 1 is —(CH 2 ) n —Z—(CH 2 ) n′ —R 3 wherein n is zero and n′ is 1; Z is a single bond;
  • R 3 is —OH
  • R 2 is —(CH 2 ) m R 6 , wherein R 6 is heteroaryl and m is 0 and pharmaceutically acceptable salts thereof.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, either as such or as pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs) and mucus regulators.
  • beta2-agonists e.g. beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors, phosphodie
  • the present invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a ⁇ 2-agonist selected from the group consisting of carmoterol, GSK-642444, indacaterol, milveterol, arformoterol, formoterol, salbutamol, levalbuterol, terbutaline, AZD-3199, BI-1744-CL, LAS-100977, bambuterol, isoproterenol, procaterol, clenbuterol, reproterol, fenoterol, and ASF-1020 and salts thereof.
  • a ⁇ 2-agonist selected from the group consisting of carmoterol, GSK-642444, indacaterol, milveterol, arformoterol, formoterol, salbutamol, levalbuterol, terbutaline, AZD-3199, BI-1744-CL, LAS-100977, bambuterol, isoproteren
  • the present invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with an antimuscarinic agent selected from the group consisting of aclidinium, tiotropium, ipratropium, trospium, glycopyrronium, and oxitropium salts.
  • an antimuscarinic agent selected from the group consisting of aclidinium, tiotropium, ipratropium, trospium, glycopyrronium, and oxitropium salts.
  • the present invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a PDE4 inhibitor selected from the group consisting of AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, cipamfylline, cilomilast, roflumilast, BAY19-8004 and SCH-351591, AN-6415, indus-82010, TP1-PD3, ELB-353, CC-11050, GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414, and RPL-554.
  • a PDE4 inhibitor selected from the group consisting of AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779
  • the present invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a P38 MAP kinase inhibitor selected from the group consisting of semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minokine, and losmapimod and salts thereof.
  • a P38 MAP kinase inhibitor selected from the group consisting of semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minokine, and losmapimod and salts thereof.
  • the present invention provides combinations of a compound of the invention with an IKK2 inhibitor.
  • the invention also provides combinations of a compound of the invention with a HNE inhibitor selected from the group consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C and prolastin inhaled.
  • a HNE inhibitor selected from the group consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C and prolastin inhaled.
  • the invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a leukotriene modulator selected from the group consisting of montelukast, zafirlukast, and pranlukast.
  • the invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a NSAID selected from the group consisting of ibuprofen, and ketoprofen.
  • the invention also provides combinations of a compound of the invention, either as such or as pharmaceutically acceptable salt, with a mucus regulator selected from the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, and gefitinib.
  • a mucus regulator selected from the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, and gefitinib.
  • the present invention also provides a compound of the invention for use as a medicament.
  • the invention also relates to the use of a compound of the invention to decrease the number, activity and movement of the inflammatory cells in vitro and/or in vivo.
  • the present invention is also directed to compounds of the invention for use in the prevention or treatment of any disease wherein the decrease in the number, activity, and movement of inflammatory cells is involved.
  • the present invention provides the use of compounds of the invention for the prevention and/or treatment of any disease wherein the decrease in the number, activity, and movement of inflammatory cells is involved.
  • compounds of the invention may be administered for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction such as asthma and COPD.
  • the present invention provides the use of compounds of the invention for the preparation of a medicament for the prevention and/or treatment of any disease wherein the decrease in the number, activity, and movement of inflammatory cells is involved.
  • the present invention provides a method for prevention and/or treatment of any disease wherein the decrease in the number, activity, and movement of inflammatory cells is involved, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the present invention also provides pharmaceutical preparations of compounds of the invention suitable for administration by inhalation, by injection, orally or intra-nasally.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the invention is also directed to a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer, in particular a soft mist nebulizer comprising a compound of the invention.
  • the invention is also directed to a kit comprising the pharmaceutical compositions of compounds of the invention alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.
  • the compounds of the present invention may be prepared according to a variety of synthetic steps which are carried out according to conventional methods and techniques or which are hereinbelow described.
  • the present invention provides processes for the preparation of compounds of the invention and intermediates thereof.
  • LG may be displaced by a nucleophile or wherein, after introduction of the LG on the C21 hydroxy moiety, an oxidoreduction reaction can be performed, to afford the corresponding methyl ketone.
  • the present invention is also directed to a process for the preparation of compounds of general formula (VI)
  • the present invention is also directed to a process for the preparation of a compound of general formula (VI), which comprises:
  • the present invention is also directed to a process for the preparation of a compound of general formula (VI), which comprises:
  • the compounds of the invention may be prepared according to different routes described in scheme 1, depending on the nature of the substituents R 1 and R 2 .
  • Route A1 the reaction of compounds of general formula (IV) with N-tetrahydropyranyl hydroxylamine (HO—NH-THP), to prepare a compound of formula (V), can be conveniently conducted in a protic solvent such as EtOH at a temperature ranging from 80 to 100° C.
  • a protic solvent such as EtOH
  • the reaction with aryl halides may be performed under the known copper catalyzed N-arylation of isoxazolidine ( Bioorg. Med. Chem. Lett., 2834, 2005, which is incorporated herein by reference in its entirety).
  • the acetyl ester may be easily hydrolyzed using standard conditions for the deacetylation of alcohols, treating for example the compound with a base such as sodium or potassium hydroxide or potassium carbonate in a suitable solvent (e.g. methanol or ethanol).
  • a suitable solvent e.g. methanol or ethanol
  • Compounds of general formula (IV) may be conveniently prepared according to standard procedures reported in the literature. For instance they may be prepared by treatment of compounds of general formula (III) with a base such as potassium acetate. This reaction is usually performed in a suitable polar solvent such as dimethylformamide (DMF) and typically proceeds at a temperature range from 80 to 110° C., over a period of 0.5 to 4 hours.
  • a base such as potassium acetate.
  • DMF dimethylformamide
  • the compounds of general formula (VI) may be prepared starting from the reaction of a compound of formula (VII) with a compound of formula (X) in the presence of paraformaldehyde, using known procedures for the isoxazolidine formation, by cycloaddition of nitrones ( J. Med. Chem., 25, 1492-1495, 1982, which is incorporated herein by reference in its entirety).
  • the reaction is conveniently carried out in a protogenic solvent, such as ethanol, at temperatures ranging from 80 to 100° C.
  • Hydroxylamine of formula (X) are either commercially available or may be easily prepared using procedures well known for those skilled in the art, for example by reducing an oxime with a reducing agent, such as borane pyridine complex ( J. Med. Chem., 40, 1955-1968, 1997, which is incorporated herein by reference in its entirety) or by reaction of O-tetrahydropyranyl hydroxylamine with a suitable alkylating agent such as alkyl halides ( Chem. Pharm. Bull., 46, 966-972, 1998, which is incorporated herein by reference in its entirety).
  • a reducing agent such as borane pyridine complex
  • a suitable alkylating agent such as alkyl halides
  • the compounds of formula (VII) may be prepared hydrolyzing the compounds of formula (IV). This reaction is preferably carried out by subjecting compounds (IV) to the action of an enzyme, such as immobilized Lipase from Candida Antarctica (Sigma Aldrich) ( Tetrahedron, 50, 13165-13172, 1994, which is incorporated herein by reference in its entirety).
  • an enzyme such as immobilized Lipase from Candida Antarctica (Sigma Aldrich) ( Tetrahedron, 50, 13165-13172, 1994, which is incorporated herein by reference in its entirety).
  • Route A3 compounds of general formula (VIII) may be prepared stalling from the reaction of a compound of formula (VII) with HO—NH-THP.
  • This reaction may be conveniently conducted in dioxane or in a protic solvent such as EtOH at a temperature ranging from 80 to 100° C.
  • the THP protecting group is directly cleaved in the reaction conditions.
  • the obtained (VIII) can be conveniently and selectively protected by treatment with dihydropyran in a suitable solvent such as DCM or THF, at temperature from 0° C. to RT, to obtain compound of formula (IX).
  • the reaction is complete in time ranging from 0.5 to 3 hours.
  • Compounds of formula (IX) may be further functionalized with alkyl halides, acyl halides, isocyanates, carbamoyl chlorides or sulphonyl chlorides as described in Route A1.
  • the THP protecting group can be easily removed by treating the protected intermediate with HCl in a suitable solvent, such as THF or dioxane. This reaction usually proceeds at RT over a period of 1 to 15 hours leading to compounds of general formula (VI).
  • Route A—conversion of the hydroxyl group of 2-hydroxy acetyl moiety at position 6b of compounds of general formula (VI) into a leaving group (LG) of compounds of general formula (XI) can be carried out by treating compounds of formula (VI) with methanesulfonyl chloride or p-toluenesulphonyl chloride (March's, “Advanced Organic Chemistry”, Wiley-Interscience, which is incorporated herein by reference in its entirety), in a suitable solvent, such as pyridine. This reaction is usually performed at RT over a period of 1 to 5 hours.
  • nucleophiles such as halide anions, alcohols, thiols, thioacids, amines, amides and carbanions
  • the reaction is usually performed in a suitable solvent, such as DCM, THF or DMF, in a range of temperature from 0 to 80° C. over a period of 1 to 5 hours and may be promoted by a base such as sodium or potassium carbonate or sodium hydride.
  • a suitable solvent such as DCM, THF or DMF
  • a base such as sodium or potassium carbonate or sodium hydride.
  • an oxidoreduction reaction can be performed, for example by means of an excess of sodium iodide, to afford the corresponding methyl ketone.
  • the obtained product may be further functionalized modifying the moiety introduced by the described nucleophilic substitution reaction.
  • Route B reaction of compounds of formula (VI) under well known oxidation conditions to obtain the intermediates of general formula (XII). This reaction is usually performed in open air at RT over a period of 12 to 48 hours, in a suitable solvent such as THF in the presence of aqueous solution of an inorganic base, such as sodium or potassium hydroxide.
  • a suitable solvent such as THF
  • an inorganic base such as sodium or potassium hydroxide.
  • Z and R 3 are as defined above, by treating the acid (XII) with one or more equivalents of an acid activating agent such as carbonyldiimidazole or HATU.
  • the reaction is usually performed in a suitable polar solvent such as DMF, in a range of temperature from 0 to 80° C. over a period of 1 to 2 hours.
  • the activated acid may be reacted with a nucleophile, such as alcohols, thiols, thioacids and amines.
  • a nucleophile such as alcohols, thiols, thioacids and amines.
  • the reaction may be promoted by a base such as sodium or potassium carbonate, sodium hydride and proceeds at a temperature ranging from 0 to 20° C. over a period of 1 to 24 hours.
  • the intermediates of formula (XII) may be converted into the corresponding acyl chloride under well known conditions, using oxalyl chloride in a suitable solvent such as DCM.
  • the activated intermediate may be reacted with a nucleophile such as alcohols, thiols, thioacids, amines and carbanions such as alkyl, aryl and heteroaryl cuprates or other metallorganic compounds reported in the literature, to be suitable for the conversion of acyl chlorides into the corresponding ketones.
  • a base such as potassium sodium or cesium carbonate and triethylamine
  • a suitable solvent such as DMF or acetonitrile
  • Route B2 conversion of intermediates of formula (XII) into compounds of general formula (XIII), derived from reaction of acid (XII) with carbonyldiimidazole or HATU, followed by reaction with the sodium salt of thioacetic acid and/or anhydrous hydrogen sulphide.
  • the reaction is usually performed adding the solution of the preformed salt in the reaction solvent to the solution of the activated acid at a temperature ranging from 0 to 20° C. or directly adding the solid sodium hydrogen sulphide anhydrous.
  • alkylating reagent such as bromoalkanes
  • bromoalkane such as bromo-chloromethane
  • R 3 chloromethyl
  • R 3 fluoromethyl
  • Route C reaction of the intermediates of general formula (IV) with hydroxylamines of formula (X) in the presence of paraformaldehyde using known procedures for the isoxazolidine formation by cycloaddition of nitrones.
  • the reaction is conveniently performed in a protogenic solvent, such as ethanol.
  • dichloro-5,5-dimethylhydantoin and is promoted by an acid such as perchloric acid.
  • the reaction is usually carried out in a polar solvent such as THF, in a range of temperature from 0 to 20° C. over a period of 1 to 4 hours.
  • the acetyl ester of compounds of formula (XIV) may be easily hydrolyzed using standard conditions for the deacetylation of alcohols, treating for example the compound with a base such as sodium or potassium carbonate in a solvent such as methanol or ethanol. This reaction usually proceeds at low temperature, ranging from 0 to 20° C., over a period of 0.5 to 2 hours.
  • Route D reaction of the intermediates of general formula (VI) with acyl chlorides, using procedures well known for those skilled in the art.
  • the reaction is conveniently performed in DCM as solvent in the presence of a base such as triethylamine, at room temperatures over a period of 20 to 50 hours.
  • Route E reaction of compound (VII) with mesyl chloride and N,N-diisopropylethylamine (DIPEA) in dry acetonitrile. Then, the introduction of fluorine atom can be conveniently performed by in situ addition of tetra-n-butylammonium fluoride (TBAF) and KI and heating over a period of 8 to 20 hours.
  • DIPEA N,N-diisopropylethylamine
  • Hydroxylamines of formula (X) are either commercially available or may be prepared according to different synthetic routes, some of which are well known to those skilled in the art.
  • Route F reaction of compounds of general formula (XVI) with hydroxylamine hydrochloride (NH 2 OH HCl) in presence of triethyl amine, to prepare an oxime of formula (XVII) can be conveniently conducted in DCM as solvent at a temperature ranging from RT to 50° C.
  • oximes of general formula (XVII) may be reduced to hydroxylamines of general formula (Xa), wherein Rx and Ry may assume different meanings within the scope of the instant invention, with a reducing agent such as, for example, borane pyridine complex and HCl in polar protic solvents such as ethanol at RT ( Tetrahedron, 1992, Vol. 47, No 17, 3557-3570 ; J. Med. Chem., 1997, 40, 1955-1968, both of which are incorporated herein by reference in their entireties).
  • a reducing agent such as, for example, borane pyridine complex and HCl in polar protic solvents such as ethanol at RT ( Tetrahedron, 1992, Vol. 47, No 17, 3557-3570 ; J. Med. Chem., 1997, 40, 1955-1968, both of which are incorporated herein by reference in their entireties).
  • the compounds of general formula (Xa) may be prepared by the reaction of an activated compound of general formula (XIX), where LG is a suitable leaving group, such as for example an halide (Cl, Br or I), a mesylate, a tosylate or another leaving group, with O-tetrahydropyranyl hydroxylamine (NH 2 OTHP) to generate an intermediate of formula (XX), using well known procedures ( J.A.C.S., 2000, 122, 18, 4522; Tetrahedron, 1999, 55, 41, 12069, both of which are incorporated herein by reference in their entireties), and subsequent deprotection of the THP protective group.
  • LG is a suitable leaving group, such as for example an halide (Cl, Br or I)
  • NH 2 OTHP O-tetrahydropyranyl hydroxylamine
  • substitution reaction is conveniently carried out in DMF, ethanol or acetonitrile as solvents, in the presence of different kind of bases such as K 2 CO 3 or DIPEA and at temperatures ranging from RT to 80° C.
  • Compounds of general formula (XIX) may be commercially available or may be prepared starting from an alcohol of general formula (XVIII) and converting the hydroxyl group into the suitable leaving group by procedures well known to those skilled in the art.
  • mesylates can be conveniently obtained from alcohols (XVIII) with mesylchloride and TEA in DCM ( Organic Letters, 2002, vol. 4, No 15, 2485, which is incorporated herein by reference in its entirety).
  • Route H Hydrophillamines of general formula (Xb), wherein R2 is optionally substituted aryl or heteroaryl, may be prepared starting from the corresponding nitro-aryl or nitro-heteroaryl compounds.
  • nitro compounds (XXI) can be conveniently reduced to hydroxylamines ( Synthetic Communications, 1997, Vol. 27, No 20, 3497-3504, which is incorporated herein by reference in its entirety) with BiCl 3 and KBH 4 in polar protic solvents, such as ethanol at RT.
  • aryl or heteroaryl hydroxylamines may be conveniently obtained by reduction of nitro compounds (XXI) with hydrazine in the presence of Raney nickel in an appropriate mixture of solvents, such as ethanol and dichloromethane ( Synthesis, 1984, 11, 938-941, which is incorporated herein by reference in its entirety). It is necessary, in this procedure, to control the temperature between 0 and 10° C.
  • Another convenient reductive method to afford compounds of general formula (Xb) entails the reduction of compounds (XXI) with Zn and NH 4 Cl ( Tetrahedron Letters, 2005, Vol. 46, No 35, 5913-5918; J. Org. Chem., 1982, 47, 7, 1171, both of which are incorporated herein by reference in their entireies), in different polar solvents such as acetone or ethanol.
  • aryl or heteroaryl hydroxylamines of general formula (Xb) as above defined may be prepared by nucleophilic aromatic substitution from aryl or heteroaryl electron-poor chlorides or fluorides with hydroxylamine, using methods readily apparent for those skilled in the art.
  • reaction of a compound of general formula (XXII), wherein Y is a suitable leaving group such as chlorine or fluorine with aqueous hydroxylamine in ethanol ( J. Med. Chem., 2009, 52, 19, 5974, which is incorporated herein by reference in its entirety) may give hydroxylamines of general formula (Xb).
  • the reaction is conducted at reflux in time ranging from 6 to 10 hours.
  • the compounds of the invention may be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.
  • the dosage of the compounds of the invention is advantageously comprised between 0.01 and 20 mg/day, preferably between 0.1 and 10 mg/day.
  • the exact dosage will depend on the identity of the compound or salt being administered, the route of administration, the condition being treated, and the age, weight, and condition of the patient, and may be easily determined by a doctor treating the patient.
  • the compounds of the invention alone or combined with other active ingredients may be administered for the prevention and/or treatment of any obstructive respiratory disease such as asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD).
  • any obstructive respiratory disease such as asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention may be administered for the prevention and/or treatment of any disease wherein the decrease in the number, activity and movement of inflammatory cells is involved.
  • diseases include: diseases involving inflammation such as asthma and other allergic disorders, COPD, acute rhinitis; reverse acute transplant rejection and acute exacerbations of selected autoimmune disorders, graft-versus-host disease in bone-marrow transplantation; autoimmune disorders such as rheumatoid and other arthritis; skin conditions such as systemic lupus erythematosus, systemic dermatomyositis, psoriasis; inflammatory bowel disease, inflammatory ophthalmic diseases, autoimmune hematologic disorders, and acute exacerbations of multiple sclerosis; kidney, liver, heart, and other organ transplantation; Behçet's acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease, and nephrotic syndrome; Hodgkin's disease and non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia (CLL); autoimmune hemolytic anemia and
  • the compounds of the invention may be administered for the prevention and/or treatment of respiratory diseases such as from mild to acute severe conditions of asthma and COPD.
  • TEA triethylamine
  • DCM diichloromethane
  • RT room temperature
  • AcOEt ethyl acetate
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.
  • N,O-dimethyl hydroxylamine hydrochloride 164 mg, 1.685 mmol
  • TEA 0.313 ml, 2.247 mmol
  • Conversion is complete.
  • the mixture is diluted with AcOEt (60 ml) and washed with brine (60 ml).
  • Aqueous layer is extracted with AcOEt (2 ⁇ 60 ml), and then organic extracts are washed with 1N HCl solution, dried over Na 2 SO 4 and evaporated.
  • Crude (700 mg) is purified via preparative HPLC (neutral mobile phase), obtaining 96 mg of pure solid (30% yield).
  • the reaction mixture was diluted with AcOEt (130 ml), and the organic phase was washed with water and brine, dried (Na 2 SO 4 ) and concentrated.
  • reaction mixture was diluted with AcOEt, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated.
  • the residue was purified by flash chromatography on silica gel, in gradient elution from DCM to DCM/AcOEt 7:3 affording 256 mg, (92% yield).
  • Methanesulfonyl chloride (79 ⁇ L, 1.011 mmol) was added at 0° C. under nitrogen atmosphere to a solution of 123 (450 mg, 0.843 mmol) and DIPEA (221 ⁇ L, 1.264 mmol) in DCM (dried over CaCl 2 , 20 ml). The mixture was stirred at RT for 2 hours. The mixture was diluted with DCM, and washed with 2.5% aqueous NaHCO 3 . The aqueous phase was extracted with DCM, and the combined organics were washed with brine, dried over Na 2 SO 4 and filtered. The solvent was evaporated.
  • the compounds in Table 12 were prepared as previously described for compound 184, starting from acid 159, the suitable alkylating agent and a base such as Na 2 CO 3 , K 2 CO 3 or triethylamine with the suitable solvent:
  • the reaction mixture was diluted with AcOEt, and the organic layer was washed with water and brine, dried (Na 2 SO 4 ) and concentrated.
  • the crude was purified by silica gel flash chromatography (eluent DCM/AcOEt 95/5 to 9/1) affording a solid that was further triturated with Et2O, to yield the desired compound (22% yield).
  • Methanesulfonic acid 181 (653 mg, 1.067 mmol) was dissolved in acetonitrile (20 ml), tetrabutylammonium bromide (344 mg, 1.067 mmol) was added, and the mixture was heated at 80° C. for 6 hours, then at room temperature overnight. Further tetrabutylammonium bromide (344 mg, 1.067 mmol) was added, and the mixture was heated at 80° C. for further 2 hours. The reaction mixture was partitioned between water and AcOEt. The organic layer was separated, dried over Na 2 SO 4 and concentrated. The crude was purified by silica gel flash chromatography (eluent DCM/AcOEt from 8/2 to 7/3) to yield the title compound (630 mg, 1.055 mmol, 99% yield).
  • a mixture of 190 (373 mg, 0.625 mmol) and sodium iodide (937 mg, 6.25 mmol) in acetone (17 ml) was heated under microwave irradiation at 110° C. for 3 hours. More sodium iodide (468 mg, 3.12 mmol) was added, and the mixture was heated under microwave irradiation for further 3 hours.
  • the reaction mixture was partitioned between AcOEt and a saturated solution of NaS 2 O 3 . The organic layer was washed with water, dried over Na 2 SO 4 and concentrated.
  • LPS Lipopolysaccharide
  • Intratracheal instillation of LPS resulted in a statistically significant increase in neutrophil concentration in BALF, a hallmark of acute ongoing pulmonary inflammation.
  • compounds (0.01-1 ⁇ moles/Kg of body weight) were administered intratracheally as suspension (0.2% Tween 80 in NaCl 0.9%) 1 hour before LPS challenge.
  • a dose-response curve of the inhibitory effect of the test compounds on LPS-induced lung neutrophilia was performed, and the ED50 dose of glucocorticoid was taken as a measure of potency in this bioassay.
  • the ED50 dose values for some representative compounds of the present invention were comprised between 0.05 and 0.16 ⁇ moles/Kg of body weight.
  • the compounds were administered as suspension intratracheally, at the ED75 dose, administered 24 hours before LPS challenge.
  • the most interesting compounds were active (percent of inhibition higher than 50%) when administered 24 hours before LPS challenge.
  • GR nuclear translocation of the compounds of the present invention was performed according to ASSAY Drug Devel. Technol., 4(3), 263-272, 2006 (which is incorporated herein by reference in its entirety), through a novel cell-based GR-translocation assay in Enzyme Fragment Complementation (EFC) format developed by DiscoveRx (Fremont, Calif.).
  • EFC Enzyme Fragment Complementation
  • DiscoveRx DiscoveRx
  • glucocorticoid When a glucocorticoid diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR), it results in release of the heat shock proteins and the translocation into the nucleus where it modulates gene transcription.
  • GR glucocorticoid receptor
  • the DiscoveRx assay uses EFC of b-galactosidase (b-gal) as an indicator of GR-translocation in engineered CHO-K1 biosensor cells.
  • the enzyme acceptor (EA) fragment of b-gal resides in the nucleus, as designed through the use of a proprietary set of sequence additions and modifications.
  • the small peptide enzyme donor (ED) fragment of b-gal was fused directly to the C-terminus of GR, and was localized in the cytoplasm in the absence of receptor signaling. Upon binding to a GR ligand, the complex translocates to the nucleus, where intact enzyme activity was restored by complementation and b-gal activity was detected.
  • CHO-K1 cells stably expressing NLS-enzyme acceptor fragment (EA) of b-gal and GR-enzyme donor (ED) fragment of b-gal were maintained in F12 medium (Invitrogen, Carlsbad, Calif.) at 37° C. under a humidified atmosphere containing 5% CO 2 and 95% air.
  • the medium contained 10% FBS, 2 mM L-glutamine, 50 U/ml penicillin 50 ⁇ g/ml streptomycin, and 250 ⁇ g/ml hygromycin and 500 ⁇ g/ml G418 (Invitrogen).
  • GR-translocation was measured using the PathHunter Detection Kit containing cell membrane permeabilizing reagent and beta-gal substrate (DiscoveRx, Fremont, Calif.). All compounds were screened using varying concentrations ranging from 10 ⁇ 11 to 10 ⁇ 6 M. The assay was performed in 48-wells (105 cells/well). Incubation with screened compounds was performed at 37° C. for two hours. Detection was made by adding the detection buffer from the kit supplied by DiscoveRx and incubating at room temperature for one hour. Luminescence was detected by using a CENTRO LB 960 microplate reader (Berthold Technologies).
  • An in vitro model based on macrophagic murine cell line RAW 264.7 was used for testing the anti-inflammatory effects of the corticosteroids of the present invention.
  • large amounts of nitric oxide (NO) were generated by the inducible isoforms of NO synthase (iNOS).
  • Bacterial lipopolysaccharide (LPS) was commonly used in experimental settings to stimulate inflammatory responses in macrophages.
  • Cells were grown in a culture medium (RPMI supplemented with heat-inactivated 10% fetal calf serum, 2 mM glutamine, 100 U/ml penicillin and 0.1 mg/ml streptomycin) without phenol red. Cell stimulation was elicited by incubating cells for 24 hours with LPS to final concentrations ranging from 100 ng/ml. Treatments with the compounds of the invention were carried out by adding such compounds vehicled in DMSO (0.1% final concentration) to the final desired concentrations 15 minutes before LPS exposure. As an index of nitric oxide production, the concentration of nitrite was measured in the conditioned media by using the Griess colorimetric reaction ( J. Neuroimmunol., 150, 29-36, 2004, which is incorporated herein by reference in its entirety).
  • IC50 values tested on some representative compounds of the invention were comprised between 0.06 and 5.3 nM.

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