WO2010126953A1 - Composés bêta-agonistes liés à des corticostéroïdes pour une utilisation en thérapie - Google Patents

Composés bêta-agonistes liés à des corticostéroïdes pour une utilisation en thérapie Download PDF

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WO2010126953A1
WO2010126953A1 PCT/US2010/032689 US2010032689W WO2010126953A1 WO 2010126953 A1 WO2010126953 A1 WO 2010126953A1 US 2010032689 W US2010032689 W US 2010032689W WO 2010126953 A1 WO2010126953 A1 WO 2010126953A1
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compound according
pharmaceutically acceptable
formula
acceptable salt
compound
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PCT/US2010/032689
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English (en)
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William R. Baker
Musong Kim
Gary Phillips
Alexander Rudolph
Marcin Stasiak
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Gilead Sciences, Inc.
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Publication of WO2010126953A1 publication Critical patent/WO2010126953A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • the instant invention relates to new chemical entities which comprise corticosteroids and phosphorylated ⁇ -agonists for use in therapy and compositions comprising and processes for preparing the same.
  • Asthma is a chronic inflammatory disease of the airways produced by the infiltration of pro-inflammatory cells, mostly eosinophils and activated T- lymphocytes (Poston, Am. Rev. Respir. Dis. t 145 (4 Pt 1), 918-921 , 1992; Walker, J. Allergy Clin. Immunol., 88 (6), 935-42, 1991) into the bronchial mucosa and submucosa.
  • the secretion of potent chemical mediators, including cytokines, by these proinflammatory cells alters mucosal permeability, mucus production, and causes smooth muscle contraction.
  • Glucocorticoids which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21 , 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy CHn. Immunol., 75 (1 Pt) 1 - 13, 1985).
  • oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Giiman, 10 th edition, 2001 ).
  • ICS Inhaled corticosteroids
  • Combinations of inhaled ⁇ 2 -adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation associated with asthma and COPD (Symbicort ® and Advair ® , respectively).
  • these combinations have the side effects of both the ICS's and the ⁇ 2-adrenoreceptor agonist because of systemic absorption (tachycardia, ventricular dysrhythmias, hypokalemia) primarily because neither agent is delivered exclusively to the optimal sites of action in the lungs.
  • Phenylphosphate based mutual prodrugs of corticosteroids and ⁇ 2 -agonists have been described by Baker (WO/2006/138212) wherein the component drugs are released at the site of action in the lungs.
  • the present invention provides compounds of Formula I:
  • R 15 is a side chain radical of a ⁇ -agonist
  • R 16 is H 1 methyl or ethyl
  • R 19 is H 1 F 1 OH or methyl
  • L is a bond Or -(CH 2 O)-
  • each W 1 is the same or different and is O or S; W 2 is O, S or N(R 1 );
  • Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, OH, C 1-4 alkoxy[, NH 2 , N(H)C 1-4 aikyl, and N(C 1-4 aikyl) 2 ; each R 1 is the same or different and is independently H or C-i -4 alkyl; a is 0-6; b is 0 and c is 1-4, or b is 1 and c is 2-4; each W 3 is the same or different and is independently -O- or -N(R 1 )-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6; Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci -4 alkyl, OH 1 C 1-4 alkoxyl, NH 2 , N(H)C M
  • R 8 is H 1 OH, 0(CO)R 9 , or 0(CO)OR 9 ; each R 9 is independently Ci -4 alkyl; each R 10 and R 11 is independently H or C 1-4 alkyl;
  • R 12 is H, OH, or C 1-4 alkyl
  • R 13 and R 14 is H, methyl or ethyl and the other is H, C 1-10 alkyi, C2-10 alkenyl, C 2- io alkynyl, optionally substituted C3-1G carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C-
  • the compounds of Formula I are defined wherein R 15 is: C 1-6 alkyl;
  • C 6- iocarbocyde optionally substituted 1 or 2 times with halo, C ⁇ alkyl, O-C 1-4 alkyl, O-(CH 2 ) 4 -NH 2 , O-(CH 2 ) 4 -N(H)C 1-4 alkyl, O-(CH 2 ) 4 -N(C 1-4 alkyl) 2 , O-C 1-4 afkyl-C(O)-NH 2 , O-C ⁇ alkyl-CtOJ-N ⁇ C ⁇ alkyl, O-C ⁇ alkyl-C ⁇ -NfC ⁇ alkyl ⁇ , or a group represented by formula i, ii, iii, iv, v, vi, vii, viii, or ix: i: C 6 alkylene-O-R 21 -Ph 4 ; ii: C 2-3 alkylene-Ph 1 -O-R 21 -Ph 4 ; iii: C 2-3 alkylene-Ph
  • R 21 is C2- ecilkylene wherein one carbon of said alkylene is optionally replaced by O; Ph 4 is phenyl optionally substituted 1 or 2 times by halo,
  • Ph 1 is pheny ⁇ ene
  • R 22 is a bond or C 1-2 alkylene optionally substituted once by OH or NH 2 ;
  • Ph 2 is phenyl optionally substituted 1 or 2 times by O-methyl, -OCH 2 CH(CHS) 2 CH 2 NH 2 , unsubstituted phenyl,
  • Het is 4-10 ring atom heterocyclene wherein 1 , 2 or 3 ring atoms is/are N, O or S optionally substituted once by methyl;
  • R 23 is a C 2-4 aikylene wherein one carbon of said alkylene is optionally replaced by O or -C 0 - 2 alky!ene-C(O)N(H)-C 2 -4alkylene; and
  • Ph 3 is phenyl optionally substituted 1 or 2 times by halo or O-methyi.
  • the invention provides compounds of Formula II:
  • the invention provides compounds of Formula SV:
  • the invention provides compounds of Formula V:
  • the invention provides compounds of Formula Vl:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier.
  • the composition further comprises a therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, ⁇ -agonists, antiinfective agents and antihistamines.
  • the invention provides a method comprising administering to a human, an effective amount of a compound of Formula i, or a pharmaceuticaliy acceptable sait thereof.
  • the invention provides a method for the treatment of pulmonary inflammation or bronchoconstriction in a human in need thereof, comprising administering to said human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis or emphysema in a human in need thereof, comprising administering to the human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for delivering an effective amount of a steroid and a ⁇ -agonist to the iung of a human.
  • the method comprises delivering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the lung of the human, wherein a phosphate group of the compound is cleaved by an endogenous enzyme and an ester group of the compound is cleaved by an endogenous esterase or chemically by hydrolysis to deliver the steroid and the ⁇ -agonist.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary inflammation or bronchoconstriction in a human.
  • the invention provides a compound of Formula i or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.
  • the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of131monary inflammation or bronchoconstriction in a human.
  • the invention provides the use of a compound of Formula i or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.
  • the invention provides a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of pulmonary inflammation or bronchoconstriction in a human.
  • the invention provides a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human.
  • the invention provides a pharmaceutical composition for treating pulmonary inflammation or bronchoconstriction in a human comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition for treating reversible airway obstruction, asthma, COPD, bronchiectasis, or emphysema in a human comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the invention provides processes and novel intermediates which are useful for preparing the compounds of Formula 1 and pharmaceutically acceptable salts thereof.
  • the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amorphous forms thereof.
  • a compound of the invention means a compound of Formula i, which includes compounds of formula II, III, IV, V, and Vl, or a salt, particularly a pharmaceutically acceptable salt thereof.
  • a compound of Formula I means a compound having the structural formula designated herein as Formula I 1 including compounds of Formulas II, IH 1 IV, V, and Vl.
  • Compounds of Formula I include solvates and hydrates as well as any amorphous and crystalline (polymorphic) forms thereof.
  • a compound of Formula I includes one or more chiral centers
  • the phrase is intended to encompass each individual stereoisomer including optical isomers (enantiomers and diastereomers) and geometric isomers (cis ⁇ /trans-isomerism) and mixtures of stereoisomers.
  • a compound of Formula (number) means a compound of that formula and solvates and hydrates as well as amorphous and crystalline (polymorphic) forms thereof, and stereoisomers (where compounds include a chira!
  • alkyl refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., Ci -8 alkyl), unless a different number of atoms is specified.
  • alkyl as used herein include but are not limited to methyl (Me), ethyl (Et), n-propyS (1-Pr 1 1-propyl), isopropyl (i-Pr, 2-propyl), n-butyl (n-Bu, 1 -butyl), isobutyi, (i-Bu, 2-methyl-1 -propyl), sec-butyl (s-Bu, 2-butyl), tert-butyl (t-butyl, t-Bu, 2- methyl-2-propyl), n-pentyl (1-pentyl), 2-pentyi, 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyI-2-butyl (-C
  • alkyls may be the same or different.
  • alkylene refers to a linear or branched divalent hydrocarbon chain having from 1 to 8 carbon atoms (i.e., Ci_ ⁇ alkylene), unless a different number of carbon atoms is specified.
  • alkylene examples include but are not limited to methylene, 1 ,1 -ethyl (-CH(CH 3 ))-, ethylene, propylene (1 ,3- propyl (-CH 2 CH 2 CH 2 -)); 1 ,1 -propyl (-CH(CH 2 CH 3 )-), or 1 ,2-propyl (-CH 2 CH(CH 3 )-)) and butyiene (1 ,4-butyl (-CH 2 CH 2 CH 2 CH 2 -)), and the like.
  • the alkylenes may be the same or different.
  • alkenyl refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C 2- e alkenyl), unless a different number of atoms is specified, and at least one carbon-carbon double bond.
  • the alkenyls may be the same or different.
  • alkynyl refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C 2 -s alkyny!), unless a different number of atoms is specified, and at least one carbon-carbon triple bond.
  • the alkynyls may be the same or different.
  • halo or “halogen” are synonymous and refer to fluoro, chloro, bromo, and iodo.
  • alkoxyi refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., Ci -8 afkyi), unless a different number of carbon atoms is specified, and an oxygen atom, i.e., -O-Ci_ 8alkyl or alkyl-O-alky ⁇ wherein the total number of carbon atoms is from 2 to 8.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic (i.e., aryl ring) hydrocarbon rings having 3 to 7 carbon atoms as a monocycle, or 7 to 12 carbon atoms as a bicycle, including spiro-fused rings, unless a different number of carbon atoms is specified.
  • Monocyclic carbocycles typically have 3 to 6 ring atoms ("C- 3 . 6 carbocycle"), and in one embodiment, 5 or 6 ring atoms ("C 5-6 carbocycle").
  • Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicycio [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent-1- enyl, i-cyclopent-2-enyl, 1-cyclopent-3-enyi, cyclohexyl, 1-cyclohex-1- enyl, 1-cyclohex-2-enyi, 1-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl.
  • aryi refers to a subset of carbocycies, namely those mono- and bi-cyclic aromatic hydrocarbon rings having 6 to 12 carbon atoms.
  • Typical aryl groups include, but are not limited to phenyl, naphthyi, biphenyl, and the like, in those embodiments wherein the compound of Formula I includes more than one aryl, the aryls may be the same or different.
  • aryl refers to phenyl or naphthyi.
  • aryl is phenyl.
  • heterocycle or “heterocyclyl” are synonymous and refer to monocyclic saturated, partially saturated or aromatic rings having 3 to 7 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N, O and S, and fused or bridged bicyclic saturated, partially saturated, aromatic, or aromatic and non-aromatic (i.e., mixed functionality) rings having 7 to 12 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N, O and S. in all embodiments therein the heterocycle includes 2 or more heteroatoms (N, O and S) the heteroatoms may be the same or different.
  • heterocycle or “heterocyciyl” refers to saturated, partially unsaturated or aromatic monocyclic ring having 4, 5 or 6 ring atoms wherein 1 , 2 or 3 of the ring atoms is/are a heteroatom independently selected from N, O and S, and saturated, partially unsaturated, aromatic or mixed functionality bicyclic ring system of 9 or 10 ring atoms wherein 1 , 2, 3 or 4 of the ring atoms is/are a heteroatom independently selected from N, O and S.
  • the heterocycles may be the same or different.
  • heterocycles include but are not limited to pyridyl, dihydropyridyl, piperidyl, thiazoiyi, tetrahydrothtophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazoiyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indoiyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyi, 2-pyrroiidonyl, pyrrolinyl, tetrahydrofuranyi, tetrahydroquinolinyl, tetrahydroisoquinolinyi, decahydroquinoiinyl, octahydroisoquinol,
  • heteroaryl refers to a subset of heterocycles, namely monocyclic and bicyclic fused aromatic rings having 5 to 7 ring atoms wherein 1 , 2 or 3 ring atoms is/are a heteroatom independently selected from N, O and S, and fused or bridged bicyclic aromatic, or mixed functionality) rings having 7 to 12 ring atoms wherein 1 , 2, 3 or 4 ring atoms is/are a heteroatom independently selected from N 1 O and S.
  • heteroaryls include all of aromatic heterocycles listed above, and particularly pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyi, pyrazolyl, isothiazoly!, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • the heteroaryls may be the same or different.
  • heterocyclene refers to a bivalent heterocycle as defined herein.
  • heterocyclenes include:
  • heterocyclenes may be the same or different.
  • the invention comprises a compound of Formula I:
  • R 15 is a side chain radical of a ⁇ -agonist
  • R 16 is H, methyl or ethyl
  • R 19 is H, F, OH or methyl
  • L is a bond or -(CH 2 O)-
  • Q is selected from
  • Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci -4 a!kyl,
  • R 8 is H 1 OH 1 O(CO)R 9 S or 0(CO)OR 9 ; each R 9 is independently C- 1 . 4 alkyl; each R 10 and R 11 is independently H or Ci -4 alkyl; R 12 is H, OH, or C 1-4 alkyl; or R 11 and R 12 taken together with the carbon to which they are attached form a
  • R 13 and R 14 is H, methyl or ethyl and the other is H, C 1-10 alkyl, C-2--I0 alkenyi, C 2- io alkynyi, optionally substituted C 3-10 carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C 1-4 alkyi, and O-C 1-4 alkyi.
  • ⁇ -agonists from which the side chain radical R 15 may be derived include but are not limited to the following compounds:
  • R 15a is t-butyl; isopropyl; -(CH 2 ) 6 O(CH 2 ) 4 -phenyl; or any subset thereof.
  • R 15 is Ci-ealkyl
  • C 5 -iocarbocycle optionally substituted 1 or 2 times with halo, C-i ⁇ alkyS, O-C 1 -4 a ⁇ kyI, O-(CH 2 ) 4 -NH 2 , O-(CH 2 ) 4 -N(H)C 1-4 alkyl, O-(CH 2 )4-N(C 1-4 alky!) 2 , O-C 1-4 aikyl-C(O)-NH 2 , O-C 1-4 alkyl-C(O)-N(H)C 1-4 alkyi, O-C 1-4 alky ⁇ -C(O)-N(C 1-4 alkyl) 2 , or a group represented by formula i, it, iii, iv, v, vi, vii, viii or ix: i: C 6 alkyiene-O-R 21 -Ph 4 ; ii: C 2 .
  • Ph 4 is phenyl optionally substituted 1 or 2 times by halo, N(H)C(O)NH 2 , SO 2 NH 2 Or S-cyclopentyl,
  • Ph 1 is phenyiene
  • R 22 is a bond or Ci -2 alkylene optionally substituted once by OH or NH 2 ; Ph 2 is phenyl optionally substituted 1 or 2 times by O-methyl, -OCH 2 CH(CH S ) 2 CH 2 NH 2 , unsubstituted phenyl,
  • Het is 4-10 ring atom heterocyclene wherein 1 , 2 or 3 ring atoms is/are N, O or S (e.g., indolene or benzodioxolene);
  • R 23 is a C 2 -C 4 alkylene wherein one carbon of said alkylene is optionally replaced by O or -C 0-2 alkylene-C(O)N(H)-C 2 - 4 alkylene; and Ph 3 is phenyl optionally substituted 1 or 2 times by halo or O-methyl.
  • R 15 is C h alky!. More particularly R 15 is C 3-4 alkyl. In one particular embodiment, R 15 is isopropyl or t-butyl.
  • R 15 is C 6- io carbocycle optionally substituted 1 or 2 times with C h alky!, or O-Ci -4 alkyl-C(O)-NH 2 , or any subset thereof. In one embodiment, R 15 is Cg-iocarbocycle optionally substituted 1 or 2 times with C 1-4 alkyl, O-Ci -4 alkyl, or O ⁇ Ci -4 alky!-C(O)-NH 2 , or any subset thereof. In one embodiment, R 15 is
  • R 15 is a group represented by formula i: C 6 alkylene-O-R 21 -Ph 4 .
  • R 15 is a group represented by formula i and R 21 is C 4 alkylene.
  • R 15 is a group represented by formula i and R 21 is C 4 alkylene and Ph 4 is phenyl, particularly unsubstituted phenyl.
  • R 15 is -(CH 2 ) ⁇ 0(CH 2 )4-phenyl, i.e.,
  • R 15 is a group represented by formula i and R 21 is C 4 alkyiene wherein one C is replaced by O; more particularly, R 21 is -(CH 2 J 2 -O- CH 2 -. In one particular embodiment R 21 is -(CH 2 J 2 -O-CH 2 - and Ph 4 is phenyl optionally substituted 1 or 2 times with halo, particularly Cl, or 1 time with - N(H)-C(O)-NH 2 .
  • R 15 is a group represented by formula ii: C 2-3 alkylene-Ph 1 -O-R 21 -Ph 4 .
  • R 15 is a group represented by formula ii and R 21 is C 4 a!kylene wherein one C is optionally replaced by O and Ph 4 is unsubstituted phenyl.
  • R 15 is a group represented by formula it and R 21 is -(CH 2 J 4 - or -(CH 2 ⁇ -O-CH 2 - and Ph 4 is unsubstituted phenyl.
  • R 15 is a group represented by formula iii:
  • R 15 is a group represented by formula iii and R 22 is a bond or C 2 alkylene substituted once by OH or NH.
  • R 15 is a group represented by formula iii, R 22 is a bond and Ph 2 is phenyl substituted by O-methyl and unsubstituted phenyl or Ph 2 is phenyl substituted by -OCH 2 CH(CH S ) 2 CH 2 NH 2 .
  • R 15 is a group represented by formula iii, R 22 is C 2 alkylene substituted once by OH or NH, and Ph 2 is unsubstituted phenyl.
  • R 15 is a group represented by formula iv: C 2 . 3 alkylene-Het-(R 23 )-Ph 3 .
  • R 15 is a group represented by formula iv and Het is a 9 or 10 ring atom heterocyclene wherein 1 or 2 ring atoms is N, O or S.
  • R 15 is a group represented by formula iv and Het is indolene or benzodioxolene.
  • R 15 is a group represented by formula iv and R 23 is -CH 2 -O-CH 2 - or -C(O)N(H)-CH 2 -.
  • R 15 is a group represented by formula iv and Ph 3 is unsubstituted phenyl, phenyl substituted twice by halo (particularly Cl) or O-methyl, or any subset thereof.
  • R 15 is a group represented by formula v: C 2-3 alkylene-Ph 1 -Co-C 2 alkylene-C(O)N(H)-C 1-4 alkylene-Ph 3 .
  • R 15 is a group represented by formula v and Ph 3 is phenyl substituted twice by halo (particularly Ci) or O-methyl.
  • R 15 is C 2-3 aikylene-Ph 1 -CH 2 -C(O)N(H)-CH 2 "Ph 3 .
  • R 15 is a group represented by formula vi: C 2 - 3 alkylene-Ph 3 . In one embodiment, R 15 is a group represented by formula vi and Ph 3 is phenyl substituted once by O-methyl.
  • R 15 is a group represented by formula vii: C 2 - 3 alkylene-S(O) 2 ⁇ C 2 ⁇ 4 alkylene-O-C 2- 4alkylene-Ph 3 . in one embodiment, R 15 is a group represented by formula vii and Ph 3 is unsubstituted phenyl.
  • R 15 is a group represented by formula viii: C 3-6 alkylene ⁇ Ph 1 -Co -2 a ⁇ kylene-C(O)N(H)-Cio-i 2 bicyclic carbocycle. In one embodiment, R 15 is a group represented by formula viii-a: (branched) C 3 aikylene-Ph 1 -CH 2 C(O)N(H)-adamantyl.
  • R 15 is a group represented by formula ix: C 3 - 6 alkylene-Het-Ph 4 .
  • R 15 is a group represented by formula ix wherein Het is a 5 or 6 ring atom heterocyclene wherein 1 , 2 or 3 atoms are N and the remaining atoms are C, wherein said heterocyciene is optionally substituted once by methyl and Ph 4 is halo-substituted, particularly Cl-su bstituted phenyl.
  • R 15 is selected from:
  • R 15 is selected from t-butyl, isopropyl,
  • R 15 is In one preferred embodiment, R 1 5 ⁇ is OCH 3
  • R 16 is H or methyl. In one preferred embodiment, R 16 is H.
  • R 19 is OH.
  • L is a bond.
  • L is a bond, it is intended that the aryl oxygen is directly attached to the P atom.
  • L is - -CH 2 O-.
  • the compounds of Formula I also include a corticosteroid moiety:
  • R 13 and R 14 are H, methyl or ethyl and the other is H, Ci-io alkyl, C2-10 alkenyl, C-2.10 afkyny!, optionally substituted C 3 .1 0 carbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocycle and said heterocycie are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci -4 alkyl, and O-Ci -4 alkyl.
  • each of R 2 , R 3 , R 4 , and R 5 are independently H, methyl, F or Cl, or any subset thereof.
  • R 2 , R 3 , R 4 , and R 5 are H.
  • R 4 and R 5 are H and R 2 and R 3 are H, F, Cl or methyl
  • R 4 and R 5 are H
  • R 2 is H, F or Ci and R 3 is H, F or methyl.
  • R 4 and R 5 are H and R 2 and R 3 are H or F.
  • R 4 and R 5 are H and R 2 and R 3 are F.
  • R 4 and R 5 are H and R 2 and R 3 are F.
  • R 4 and R 5 are H, R 2 is H and R 3 is F or R 2 is F and R 3 is H.
  • R 6 and R 7 taken together with the carbon to which they are attached form a >C ⁇ O group.
  • R 6 is H and R 7 is OH.
  • R 8 is H, OH, 0(CO)CH 2 CH 31 0(CO)OCH 3 , or 0(CO)OCH 2 CH 3 , or any subset thereof.
  • R 10 is H. In one particular embodiment R 10 and R 11 are H. In one embodiment R 10 is H and R 11 is methyl.
  • R 12 is H, OH, or methyl. In one particular embodiment R 12 is H or methyl, more particularly H.
  • R 12 and R 8 taken together with the carbons to which they are attached form a 1 ,3-dioxolane ring represented by formula B:
  • R 12 and R 8 form a ring represented by formula B
  • one of R 13 and R 14 is H, methyl or ethyl and the other is H, C- M O aikyl, C 2- io alkeny!, C 2- io alkynyl, optionally substituted C 3- io carbocycle or optionafly substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N 1 O and S, or any subset thereof, wherein the carbocycle and heterocycle are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci -4 alkyl, and
  • R 12 and R 8 form a ring represented by formula B
  • one of R 13 and R 14 is H, methyl or ethyl and the other is H, C 1- I 0 alkyl, C 2- Io alkenyl, C 2-10 alkynyl, or optionally substituted C 3- -I 0 carbocycle
  • R 13 and R 14 is H, methyl or ethyl and the other is H, C 1- 10 alkyl, or C 3-10 carbocycle, or any subset thereof. In one embodiment one of R 13 and R 14 is H, methyl or ethyl and the other is H, C 1-4 aikyl, or C 3-6 cycloalkyl, or any subset thereof, more particularly cyclohexyi. In one embodiment one of R 13 and R 14 is H or methyl, more particularly H, and the other is H, C 1-4 alkyl, or C 3-6 cycioalkyl, or any subset thereof, more particularly cyclohexyi. !n one embodiment R 13 and R 14 are each methyl. In one embodiment R 13 is H and R 14 is propyl. In one preferred embodiment R 13 is H and R 14 is cyciohexyl.
  • each W 1 is the same or different and is O or S;
  • W 2 is O 1 S or N(R 1 ); Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, Ci -4 alkyl, OH, Ci -4 aikoxyl, NH 2 , N(H)C 1-4 alkyl, and N(C 1-4 alkyl) 2 ; each R 1 is the same or different and is independently H or C h alky!; a is 0-6; b is 0 and c is 1-4 or b is 1 and c is 2-4; each W 3 is the same or different and is independently -O- or -N(R 1 )-; x and y are both 0 and z is 1 or x is 1 , y is 0 or 1 and z is 0-6; Ring A is phenyl, pyridyi or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, Ci -4 alkyl, OH 1 C 1-4 al
  • Q is . in one embodiment, W 1 is O. In one embodiment, W 2 is O or N(R 1 ). in one embodiment, W 2 is O. In another embodiment, W 2 is N(H).
  • Q is . In one particular embodiment
  • R 1 is H.
  • Q is , wherein each W 1 is the same or different and is O or S; a is 0-6; and Ph is phenyl optionally substituted on any available carbon with a substituent selected from halo, C 1-4 alkyl, OH, C 1-4 alkoxyl, NH 2 , N(H)C 1-4 alkyI, and N(Ci -4 alkyl) 2 .
  • each W 1 is O.
  • a is 1-4, particularly 1-2.
  • a is 1.
  • Ph is optionally substituted 1 ,2- or 1 ,4-phenyl.
  • Ph is optionally substituted 1 ,4-phenyl.
  • Ph is unsubstituted phenyl or phenyl substituted with halo or methyl.
  • Ph is unsubstituted 1 ,4-phenyl.
  • Q is wherein each R is independently halo, Chalky!, OH, Ci -4 alkoxyl, NH 2 , N(H)Ci -4 alkyl, and N(Ci -4 alkyl) 2 , and al! other variables are as defined above.
  • each R is H, halo or methyl, more particularly H.
  • Q is wherein each W 1 is the same or different and is O or S; b is 0 and c is 1-4 or b is 1 and c is 2-4; and W 3 is -O- or -N(R 1 )-.
  • each W 1 is O. In one embodiment, b is O and c is 1-3. In one embodiment b is 1 and W 3 is N(H) and c is 2-3.
  • Q is
  • Ring A is phenyl, pyridyl or pyrimidyl each optionally substituted on any available carbon with a substituent selected from halo, C h alky!, OH, C 1-4 alkoxyl, NH 2 , N(H)C 1-4 alkyl, and N(C 1-4 alkyl) 2 ; and d is O or l
  • Ring A is optionally substituted pyridyl. In another embodiment, Ring A is optionally substituted phenyl. In one embodiment, Ring A is unsubstituted phenyl or phenyl substituted once with a halo or methyl or twice with the same or different substituents selected from halo and methyl, in one particular embodiment, Ring A is unsubstituted 1 ,4-phenyl. In one embodiment, Ring A is unsubstituted pyridyl or pyridyl substituted once with halo or methyl or twice with the same or different substituents selected from halo and methyl. In one embodiment, Ring A is unsubstituted pyridyl.
  • x and y are both 0 and z is 1. In one embodiment, x is 1 , y is 0 and z is 0-6, particularly z is 0-3. in one embodiment, x is 1 , y is 1 and z is 0-6, particularly z is 0-3. In one embodiment, x is 1 , y is 0 and z is 1.
  • a is 0-4, particularly 0-2. in one particular embodiment, a is 0. In one embodiment, d is 0. In one embodiment, x and y are both 0, z is 1 , d is 1 and (W 3 ) d is -N(R 1 )-, more particularly, (W 3 ) d is -N(H)-. In one embodiment, , x is 1 , y is 1 , z is 0-6, d is 1 and (W 3 ) d is O or -N(R 1 )-, more particularly, (W 3 ) d is O or -N(H)-.
  • all W 1 are O.
  • the invention provides compounds of Formula II, III, IV, V, or Vi:
  • the compounds of Formula ! may be in the form of a salt, particularly a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of the compounds of the Formula I include salts derived from an appropriate base, such as an alkali metal or an aikaline earth (for example,
  • salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maletc acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, iactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzenes
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric
  • salts of active ingredients of the compounds of Formula I will be pharmaceutically acceptable, i.e. they will be salts derived from a pharmaceuticaliy acceptable acid or base.
  • salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention.
  • the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are supertmposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • an enantiomerically enriched mixture comprises at least about 75% of the specified enantiomer, and preferably at least about 85% of the specified enantiomer. in one embodiment, the enantiomericaily enriched mixture is substantially free of the other enantiomer.
  • diastereomerically enriched mixtures are mixtures of diastereomers wherein amount of the specified diastereomer is greater than the amount of each alternative diastereomer. More particularly, a diastereomerically enriched mixture comprises at least about 75% of the specified diastereomer, and preferably at least about 85% of the specified diastereomer. In one embodiment, the diastereomericaily enriched mixture is substantially free of all other diastereomers.
  • the present invention provides an enantiomerically enriched mixture comprising acceptable salt thereof, as the predominant isomer.
  • a compound of Formula 1 and pharmaceutically acceptable salts thereof may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures.
  • the crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism also includes the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopoiymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I and pharmaceutically acceptable salts thereof.
  • a compound of Formula I and pharmaceutically acceptable salts thereof may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I and pharmaceutically acceptable salts thereof.
  • the compounds of the invention are useful as a medicament and more particularly, are useful for the treatment of ciinical conditions for which a corticosteroid and/or selective ⁇ -agonists, and particularly ⁇ 2 -agonists, are indicated.
  • Such conditions may involve pulmonary inflammation and/or bronchoconstriction, and include diseases associated with reversible or irreversible airway obstruction. More particularly, such conditions include asthma, chronic obstructive pulmonary diseases (COPD), chronic bronchitis, bronchiectasis, emphysema, respiratory tract infection and upper respiratory tract diseases (e.g., rhinitis, including seasonal and allergic rhinitis).
  • COPD chronic obstructive pulmonary diseases
  • COPD chronic bronchitis
  • bronchiectasis bronchiectasis
  • emphysema respiratory tract infection
  • upper respiratory tract diseases e.g., rhinitis, including seasonal and allergic rhinitis.
  • the present invention provides a method for the treatment of a condition in a mammal, such as a human, for which a corticosteroid and/or ⁇ -agonist is indicated.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition or one or more symptoms of such disorder or condition.
  • All therapeutic methods described herein are carried out by administering an effective amount of a compound of the invention, i.e., a compound of Formula I or a pharmaceutically acceptable salt thereof, to a subject (typically mammal and preferably human) in need of treatment.
  • a subject typically mammal and preferably human
  • the invention provides a method for the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof.
  • the present invention provides a method for the treatment of a condition associated with reversible airway obstruction in a mammal, particularly a human in need thereof.
  • the invention provides a method for the treatment of asthma in a mammal, particularly a human, in need thereof.
  • the invention provides a method for the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof.
  • the invention provides a method for the treatment of bronchitis, including chronic bronchitis in a mammal, particularly a human, in need thereof.
  • the invention provides a method for the treatment of bronchiectasis in a mammal, particularly a human, in need thereof.
  • the invention provides a method for the treatment of emphysema in a mammal, particularly a human in need thereof, in one embodiment the invention provides a method for the treatment of a respiratory tract infection or upper respiratory tract disease in a mammal, particularly a human in need thereof.
  • a compound of the invention for use in medical therapy, particularly for use in the treatment of condition in a mammal, such as a human, for which a corticosteroid and/or ⁇ -agonist is indicated. All therapeutic uses described herein are carried out by administering an effective amount of a compound of the invention to the subject in need of treatment.
  • a compound of the invention for use in the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof.
  • a compound of the invention for use in the treatment of a condition associated with reversible airway obstruction in a mammal, particularly a human in need thereof.
  • a compound of the invention for use in the treatment of asthma in a mammal, particularly a human, in need thereof.
  • a compound of the invention for use in the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof in need thereof.
  • a compound for use in the treatment of bronchitis including chronic bronchitis in a mammal, particuiariy a human, in need thereof.
  • a compound for use in the treatment of emphysema in a mammal particularly a human in need thereof.
  • the present invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition in a mammal, such as a human, for which a corticosteroid and/or ⁇ -agonist is indicated.
  • a compound of the invention in the manufacture of a medicament for the treatment of pulmonary inflammation and bronchoconstriction in a mammal, particularly a human, in need thereof.
  • a compound of the invention in the manufacture of a medicament for the treatment of asthma in a mammal, particularly a human, in need thereof.
  • a compound of the invention in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease in a mammal, particularly a human, in need thereof.
  • a compound of the invention in the manufacture of a medicament for the treatment of bronchitis, including chronic bronchitis in a mammal, particularly a human, in need thereof.
  • a compound of the invention in the manufacture of a medicament for the treatment of bronchiectasis in a mammal, particularly a human, in need thereof.
  • a compound of the invention for the manufacture of a medicament for the treatment of emphysema in a mammal, particularly a human in need thereof.
  • a compound of the invention for the manufacture of a medicament for the treatment of a respiratory tract infection or upper respiratory tract disease in a mammal, particularly a human in need thereof.
  • the term "effective amount”, as used herein, is an amount of compound of the invention which is sufficient in the subject to which it is administered, to elicit the biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance by a researcher or clinician.
  • the term also includes within its scope, amounts effective to enhance normal physio!ogica! function.
  • the effective amount is the amount needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by inhalation.
  • an effective amount of a compound of the invention for the treatment of a condition for which a corticosteroid and/or ⁇ -agonist is indicated is sufficient in the subject to which it is administered to treat the particular condition.
  • an effective amount is an amount of a compound of the invention which is sufficient for the treatment of asthma, or COPD in a human.
  • the precise effective amount of the compounds of the invention will depend on a number of factors including but not limited to the species, age and weight of the subject being treated, the precise condition requiring treatment and its severity, the bioavailability, potency, and other properties of the specific compound being administered, the nature of the formulation, the route of administration, and the delivery device, and wil! ultimately be at the discretion of the attendant physician or veterinarian.
  • An estimated dose (for inhalation) of a compound of the invention for treatment of a 70 kg human may be in the range of from about 10 to about 5000 ⁇ g.
  • the selection of the specific dose for a patient will be determined by the attendant physician, clinician or veterinarian of ordinary skill in the art based upon a number of factors including those noted above.
  • the dose of a compound of the invention for the treatment of a 70 kg human will be in the range of from about 50 to about 2500 ⁇ g.
  • the dose of a compound of the invention for the treatment of a 70 kg human will be in the range of from about 100 to about 1000 ⁇ g.
  • Doses may be adjusted if the compound is administered via a different route. Determination of an appropriate dose for administration by other routes is within the skill of those in the art in light of the foregoing description and the general knowledge in the art.
  • Delivery of an effective amount of a compound of the invention may entail delivery of a single dosage form or multiple unit doses which may be delivered contemporaneously or separate in time over a designated period, such as 24 hours.
  • a compound of the invention (alone or in the form of a composition comprising the same) wilt be administered four, three, two, or most preferably once per day (24 hours).
  • compositions for treating asthma, bronchitis, or COPD.
  • active ingredient refers to any of a compound of Formula i or a pharmaceutically acceptable salt thereof.
  • the composition is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising the active ingredient.
  • the composition is preferably suitable for treating asthma, bronchitis, or COPD.
  • compositions according to the invention include those suitable for oral administration; parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous and intraarticular; and administration to the respiratory tract, including the nasal cavities and sinuses, oral and extrathoracic airways, and the lungs, including by use of aerosols which may be delivered by means of various types of dry powder inhalers, pressurized metered dose inhalers, softmist inhalers, nebulizers, or insufflators.
  • the most suitable route of administration may depend upon, several factors including the patient and the condition or disorder being treated.
  • the formulations may be presented in unit dosage form or in bulk form as for example in the case of formulations to be metered by an inhaler and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier, diluent or excipient and optionally one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with one or more liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product into the desired formulation.
  • the composition is an inhalable pharmaceutical composition which is suitable for inhalation and delivery to the endobronchial space.
  • such composition is in the form of an aerosol comprising particles for delivery using a nebulizer, pressurized metered dose inhaler (pMDI), softmist inhaler, or dry powder inhaler (DPI).
  • pMDI pressurized metered dose inhaler
  • DPI dry powder inhaler
  • Aerosols used to administer medicaments to the respiratory tract are typically polydisperse, that is they are comprised of particles of many different sizes.
  • the particle size distribution is typically described by the Mass Median
  • Aerodynamic Diameter IvIMAD
  • GSD Geometric Standard Deviation
  • Aerosols having a MMAD above 10 ⁇ m are generally too large when inhaled to reach the lungs. Aerosols with a GSD greater than about 3 are not preferred for lung delivery as they deliver a high percentage of the medicament to the oral cavity.
  • the particles of the active ingredient as produced may be size reduced using conventional techniques such as micronisation or spray drying. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.
  • Aerosol particle size distributions are determined using devices well known in the art. For example a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols emitted from metered-dose and dry powder inhalers.
  • Dry powder compositions for topical delivery to the lung by inhalation generally contain a mix of the active ingredient and a suitable powder base (carher/diluent/exciptent substance) such as mono-, di- or polysaccharides (e.g., lactose or starch). Lactose is typically preferred. When a solid excipient such as lactose is employed, generally the particle size of the excipient will be much greater than the active ingredient to aid the dispersion of the formulation in the inhaler.
  • a suitable powder base such as mono-, di- or polysaccharides (e.g., lactose or starch). Lactose is typically preferred.
  • lactose lactose
  • the particle size of the excipient will be much greater than the active ingredient to aid the dispersion of the formulation in the inhaler.
  • Non-limiting examples of dry powder inhalers include reservoir multi-dose inhalers and pre-metered multi-dose inhalers.
  • a reservoir inhaler contains a large number of doses (e.g. 60) in one container.
  • the patient actuates the inhaler which causes the inhaler to meter one dose of medicament from the reservoir and prepare it for inhalation.
  • a pre-metered multi-dose inhaler each individual dose has been manufactured in a separate container, and actuation of the inhaler prior to inhalation causes a new dose of drug to be released from its container and prepared for inhalation.
  • the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
  • a compound of the invention is delivered as a dry powder using a dry powder inhaler wherein the particles emitted from the inhaler have an MMAD in the range of about 1 ⁇ rn to about 5 ⁇ m and a GSD about less than 2.
  • dry powder inhalers and dry powder dispersion devices for use in the delivery of compounds and compositions according to the present invention include but are not limited to those disclosed in US7520278; US7322354; US7246617; US7231920; US7219665; US7207330; US6880555; US5,522,385; US6845772; US6637431 ; US6329034; US5,458,135; US4.805.811.
  • the pharmaceutical formulation according to the invention is a dry powder for inhalation which is formuiated for delivery by a Diskus®-type device.
  • the Diskus® device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a predetermined amount active ingredient either alone or in admixture with one or more carriers or excipeints (e.g., lactose) and/or other therapeutically active agents.
  • the strip is sufficiently flexible to be wound into a roll.
  • the iid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
  • the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the base sheet.
  • Spray compositions for topical delivery to the endobronchial space or iung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurized packs, such as metered dose inhalers, with the use of suitable liquefied propeilants, softmist inhalers, or nebulizers.
  • aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient together with a pharmaceutically acceptable carrier or diluent (e.g., water, saline, or ethanoi) and optionally one or more therapeutically active agents.
  • Aerosol compositions for delivery by pressurized metered dose inhalers typically further comprise a pharmaceutically acceptable propellant.
  • propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3,-heptafiuoro-n-propane or a mixture thereof.
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants e.g., oleic acid or lecithin and cosolvents e.g., ethanol.
  • additional formulation excipients well known in the art such as surfactants e.g., oleic acid or lecithin and cosolvents e.g., ethanol.
  • Pressurized formulations will generally be retained in a canister (e.g., an aiuminum canister) closed with a valve (e.g., a metering valve) and fitted into an actuator provided with a mouthpiece.
  • a canister e.g., an aiuminum canister
  • a valve e.g., a metering valve
  • a pharmaceutical composition according to the invention is delivered as a dry powder using a metered dose inhaler.
  • metered dose inhalers and devices include those disclosed in US5,261 ,538; US5,544,647; US5,622,163; US4.955.371 ; US3,565,070; US3.361306 and US6, 116,234.
  • a compound of the invention is delivered as a dry powder using a metered dose inhaler wherein the emitted particles have an MMAD that is in the range of about 1 ⁇ m to about 5 ⁇ m and a GSD that is less than about 2.
  • a pharmaceutical composition comprising an effective amount of a compound of the invention in a dosage form suitable for delivery via a nebulizer, metered dose inhaler, or dry powder inhaler.
  • a pharmaceutical composition comprising an effective amount of a compound of the invention in a dosage form suitable for aerosofization by metered-dose inhaler; or jet, ultrasonic, or vibrating porous plate nebulizer.
  • Such liquid inhalable solutions for nebulization may be generated by solubilizing or reconstituting a solid particle formulation or may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, and isotonicity adjusting agents. They may be sterilized by in process techniques such as filtration, or terminal processes such as heating in an autoclave or gamma irradiation. They may also be presented in non-sterile form.
  • Such formulations may be administered using commercialiy available nebulizers or other atomizer that can break the formulation into particles or droplets suitable for deposition in the nasal cavities or respiratory tract.
  • nebulizers which may be employed for the aerosol delivery of a composition of the invention include pneumatic jet nebulizers, vented or breath enhanced jet nebulizers, or ultrasonic nebulizers including static or vibrating porous plate nebulizers.
  • a jet nebulizer utilizes a high velocity stream of air blasting up through a column of water to generate droplets. Particles unsuitable for inhalation impact on walls or aerodynamic baffles.
  • a vented or breath enhanced nebulizer works the same as a jet nebulizer except that inhaled air passes through the primary droplet generation area to increase the output rate of the nebulizer while the patient inhales.
  • vibration of a piezoelectric crystal creates surface instabilities in the drug reservoir that cause droplets to be formed.
  • porous plate nebulizers pressure fields generated by sonic energy force liquid through the mesh pores where it breaks into droplets by Rayleigh breakup.
  • the sonic energy may be supplied by a vibrating horn or plate driven by a piezoelectric crystal, or by the mesh itself vibrating.
  • Non-limiting examples of atomizers include any single or twin fluid atomizer or nozzle that produces droplets of an appropriate size.
  • a single fluid atomizer works by forcing a liquid through one or more holes, where the jet of liquid breaks up into droplets.
  • Twin fluid atomizers work by either forcing both a gas and liquid through one or more holes, or by impinging a jet of liquid against another jet of either liquid or gas.
  • the nebulizer which aerosolizes the formulation of the active ingredient is important in the administration of the active ingredient.
  • Different nebulizers have differing efficiencies based their design and operation principle and are sensitive to the physical and chemical properties of the formulation. For example, two formulations with different surface tensions may have different particle size distributions.
  • formulation properties such as pH, osmolality, and perrneant ion content can affect tolerability of the medication, so preferred embodiments conform to certain ranges of these properties, in a preferred embodiment, the formulation for nebulization is delivered to the endobronchial space as an aerosol having an MMAD between about 1 ⁇ m and about 5 ⁇ r ⁇ and a GSD less than 2 using an appropriate nebulizer.
  • the aerosol should not have a MMAD greater than about 5 ⁇ m and should not have a GSD greater than about 2. Jf an aerosol has an MMAD larger than about 5 ⁇ m or a GSD greater than about 2 a large percentage of the dose may be deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ m then the particles may remain suspended in the inhaled air and may then be exhaled during expiration.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oii-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a sachet, bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binders, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for topical administration in the mouth include lozenges, comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or muiti-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (iyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for- injection, immediately prior to use.
  • the aerosolizable formulation of a compound of the invention delivers an effective amount of the compound ranging from about 1 to about 5000 ⁇ g to the lungs wherein the composition produces plasma concentrations of the ⁇ -agonist and/or corticosteroid of less than about 10 nanograms/mL one hour after administration of said composition, in a preferred embodiment of the invention, the plasma concentrations of the ⁇ - agonist and/or corticosteroid produced are less than about 5 nanograms /mL one hour after administration of the composition. In a particularly preferred embodiment of the invention, the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are less than about 2 nanograms /mL one hour after administration of the composition.
  • the invention provides a method of treating pulmonary inflammation and bronchoconstriction comprising treating a subject in need thereof with an effective amount of an inhalable pharmaceutical composition of a compound of the invention wherein the inhalable pharmaceutica! composition produces plasma concentrations of the ⁇ -agonist and/or corticosteroid comprising the compound of the invention of less than 10 nanograms/mL one hour after administration of said composition.
  • the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are less than about 5 nanograms /ml_ one hour after administration of said formulation.
  • the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are less than about 2 nanograms /ml one hour after administration of said formulation.
  • the invention provides a method of treating asthma, COPD, bronchitis, bronchiectasis, emphysema or rhinitis in a human subject comprising treating the subject with an effective amount of a inhaiable pharmaceutical composition of a compound of the invention wherein the inhaiable pharmaceutical composition produces plasma concentrations of the ⁇ -agonist and/or corticosteroid of less than 10 nanograms/mL one hour after administration of said composition.
  • the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are less than about 5 nanograms /mL one hour after administration of said formulation.
  • the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are less than about 2 nanograms /mL one hour after administration of said formulation.
  • Preferred unit dosage formulations for the compounds of the invention are those containing an effective amount of the active ingredient or an appropriate fraction thereof.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question for example those suitable for oral administration may include flavoring agents.
  • the compounds of the invention may be formulated and/or used in combination with other therapeutically active agents.
  • therapeutically active agents which may be formulated or used in combination with the compounds of the invention include but are not limited to antiinflammatory agents, anticholinergic agents, ⁇ -agonists (including selective ⁇ 2 - agonists), peroxisome proliferator-activated receptor (PPAR) gamma agonists, PPAR delta agonists, epithelial sodium channel blockers (ENaC receptor blockers), kinase inhibitors, antiinfective agents and antihistamines.
  • ⁇ -agonists including selective ⁇ 2 - agonists
  • PPAR peroxisome proliferator-activated receptor
  • EaC receptor blockers epithelial sodium channel blockers
  • kinase inhibitors antiinfective agents and antihistamines.
  • the present invention thus provides, as another aspect, a composition
  • a composition comprising an effective amount of compound of the invention and another therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, ⁇ - agonists (including selective ⁇ 2 -agonists), PPAR gamma agonists, PPAR delta agonists, ENaC receptor blockers, kinase inhibitors, antiinfective agents and antihistamines.
  • another therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, ⁇ - agonists (including selective ⁇ 2 -agonists), PPAR gamma agonists, PPAR delta agonists, ENaC receptor blockers, kinase inhibitors, antiinfective agents and antihistamines.
  • Suitable anti-inflammatory agents for use in combination with the compounds of the invention include corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), particularly phosphodiesterase (PDE) inhibitors.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • PDE phosphodiesterase
  • Examples of corticosteroids for use in the present invention include oral or inhaled corticosteroids or prodrugs thereof.
  • Preferred corticosteroids for formulation or use in combination with the compounds of the invention are selected from ciclesonide, desisobutyryl-ciciesonide, budesonide, mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subset thereof.
  • NSAIDs for use in the present invention include but are not limited to sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, mixed PDE3/PDE4 inhibitors or mixed PDE4/PDE7 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (e.g., 5 LO and FLAP inhibitors), nitric oxide synthase (iNOS) inhibitors, protease inhibitors (e.g., tryptase inhibitors, neutrophil elastase inhibitors, and metailoprotease inhibitors) ⁇ 2-integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a agonists), cytokine antagonists (e.g., chemokine antagonists) or inhibitors of cytokine synthesis (e.g., prostaglandin D2 (CR
  • the PDE4 inhibitor, mixed PDE3/PDE4 inhibitor or mixed PDE4/PDE7 inhibitor may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are selective PDE4 inhibitors (i.e., compounds which do not appreciably inhibit other members of the PDE famiiy).
  • Leukotriene antagonists and inhibitors of leukotriene synthesis include zafirlukast, montelukast sodium, zileuton, and pranlukast.
  • Anticholinergic agents for formulation or use in combination with the compounds of the invention include but are not limited to muscarinic receptor antagonists, particularly including pan antagonists and antagonists of the M 3 receptors.
  • Exemplary compounds include the alkaloids of the belladonna plants, such as atropine, scopolamine, homatropine, hyoscyamine, and the various forms including salts thereof (e.g., anhydrous atropine atropine sulfate, atropine oxide or HCI, methylatropine nitrate, homatropine hydrobromide, homatropine methyl bromide, hyoscyamine hydrobromide, hyoscyamine sulfate, scopolamine hydrobromide, scopolamine methyl bromide) tolterodine, revatropate, solifenacine, darifenacin, or any combination or subset thereof.
  • Preferred anticholinergics for formulation and use in combination with the compounds of the invention include ipratropium (bromide), oxitropium (bromide) and tiotropium (bromide), or any combination or subset thereof.
  • Examples of ⁇ -agonists for formulation and use in combination with the compounds of the invention include but are not limited to salmeterol, R- salmeterol, and xinafoate salts thereof, albuterol or R-albuterol (free base or sulfate), formoterol (fumarate), indacaterol, fenoteroi, terbutaline and salts thereof, and any combination or subset thereof.
  • Examples of PPAR gamma agonists for formulation and use in combination with the compounds of the invention include but are not limited to thiazolidinediones, rosiglitazone, piogiitazone, and troglitazone.
  • ENaC receptor blockers for formulation and use in combination with the compounds of the invention include but are not limited to amiloride and derivatives thereof such as those compounds described in US Patent Nos. 6858615 to Parion Sciences, Inc.
  • kinase inhibitors include inhibitors of NFkB, PI3K (phosphatidylinositol 3-kinase), p38-MAP kinase and Rho kinase.
  • Antiinfective agents for formulation and use in combination with the compounds of the invention include antivirais and antibiotics.
  • suitable antivirals include Tamiflu® and Relenza®.
  • suitable antibiotics include but are not limited to aztreonam (arginine or lysine), fosfomycin, and tobramycin, or any combination or subset thereof.
  • Antihistamines for formuiation and use in combination with the compounds of the invention include but are not limited to: ethanolamines, ethylenediamines, alkylamines, pyridines, piperazines, piperidines, tri- and tetracyclics and combinations thereof.
  • antihistamines for formulation and use in combination with the compounds of the invention include but are not limited to diphenhydramine HC!, carbinoxamine maleate, doxylamine, clemastine fumarate, diphenylhydramine HCI, dimenhydrinate, pyrilamine maieate (metpyramine), tripelennamine HCI, tripelennamine citrate, antazoiine pheniramine, chloropheniramine, bromopheniramine, dexchlorpheniramine, triproiidine, acrivastine methapyrilene, hydroxyzine HCI, hydroxyzine pamoate, cycliztne HCI, cyclizine lactate, meclizine HCI, cetirizine HCl astemisole, levocabastine HCI, loratadine, descarboethoxy loratadine, terfenadine, fexofenadine HCI, promethazine,
  • the present invention provides a composition comprising a compound of the invention and an anti-inflammatory agent.
  • the composition comprises a compound of the invention and a corticosteroid, in one particular embodiment, the composition comprises a compound of the invention and a corticosteroid selected from ciciesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate.
  • the composition comprises a compound of the invention and ciciesonide or desisobutyryl- ciclesonide.
  • the present invention provides a composition comprising a compound of the invention and a PDE4 inhibitor.
  • the PDE4 inhibitor is roflumilast or cilomilast.
  • the present invention provides a composition comprising a compound of the invention and a ⁇ 2-agontst.
  • the composition comprises a compound of the invention and salmeteroi, R- salmeterol, formoterol, or indacaterol.
  • the composition comprises a compound of the invention and salmeteroi or R- salmeteroi.
  • the present invention provides a composition comprising a compound of the invention and an anticholinergic agent.
  • the composition comprises a compound of the invention and tiotropium.
  • the present invention provides a composition comprising a compound of the invention and anti-histamine.
  • a compound of the invention may be employed alone, or in combination with one or more other therapeutically active agents.
  • any therapeutically active agent that has a therapeutic effect in the disease or condition being treated with the compound of the invention may be utilized in combination with the compounds of the invention, provided that the particular therapeutically active agent is compatible with therapy employing a compound of the invention.
  • Typical therapeutically active agents which are suitable for use in combination with the compounds of the invention include the anti-inflammatory agents, anticholinergic agents, ⁇ -agonists, antiinfective agents and antihistamines described above.
  • the invention provides methods for treatment and uses as described above, which comprise administering an effective amount of a compound of the invention and at least one other therapeutically active agent.
  • the compounds of the invention and at least one additional therapeutically active agent may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the administration of a compound of the invention with one or more other therapeutically active agents may be by administration concomitantly in 1 ) a unitary pharmaceutical composition, such as the compositions described above, or 2) separate pharmaceutical compositions each including one or more of the component active ingredients.
  • the components of the combination may be administered separately in a sequential manner wherein the compound of the invention is administered first and the other therapeutically active agent is administered second or vice versa.
  • each compound of the invention When a compound of the invention is used in combination with another therapeutically active agent, the dose of each compound may differ from that when the compound of the invention is used alone. Appropriate doses will be readily determined by one of ordinary skill in the art. The appropriate dose of the compound of the invention, the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant physician, clinician or veterinarian.
  • the present invention provides methods for treating any of the conditions enumerated above, comprising administering an effective amount of a compound of the invention and an anti-inflammatory agent.
  • the method comprises administering an effective amount of a compound of the invention and a corticosteroid.
  • the method comprises administering an effective amount of a compound of the invention and a corticosteroid selected from cidesonide, desisobutyryl- ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate.
  • the method comprises administering an effective amount of a compound of the invention and ciciesonide or desisobutyryl-ciclesonide.
  • the present invention provides a method for treating any of the conditions enumerated above comprising administering an effective amount of a compound of the invention and a PDE4 inhibitor, particularly roflumilast or cilomiiast.
  • the present invention provides a method for treating any of the conditions enumerated above comprising administering an effective amount of a compound of the invention and a ⁇ -agonist, particularly a selective ⁇ 2 - agonist.
  • the method comprises administering an effective amount of a compound of the invention and salmeterol, R-salmeterol, formoterol, or indacaterol.
  • the method comprises administering an effective amount of a compound of the invention and salmeteroi or R-salmeterol.
  • the present invention provides a method for treating any of the conditions enumerated above by administering an effective amount of a compound of the invention and an anticholinergic agent.
  • the method comprises administering an effective amount of a compound of the invention and tiotropium.
  • the present invention provides a method for treating any of the conditions enumerated above by administering an effective amount of a compound of the invention and anti-histamine.
  • the present invention provides a combination comprising a compound of the invention and an anti-inflammatory agent for the treatment of any condition enumerated above; and a!so the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.
  • the combination comprises a compound of the invention and a corticosteroid selected from ciclesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate.
  • the combination comprises a compound of the invention and cidesonide or desisobutyryl- ciclesonide.
  • the present invention provides a combination comprising a compound of the invention and a PDE4 inhibitor for the treatment of any condition enumerated above; and a!so the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.
  • the present invention provides a combination comprising a compound of the invention and a ⁇ -agonist for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.
  • the combination comprises a compound of the invention and salmeterol, R-salmeterol, formoterol, or indacaterol.
  • the combination comprises a compound of the invention and saimeterol or R-salmeterol.
  • the present invention provides a combination comprising a compound of the invention and an anticholinergic agent for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.
  • the combination comprises a compound of the invention and tiotropium.
  • the present invention provides a combination comprising a compound of the invention and an antihistamine for the treatment of any condition enumerated above; and also the use of such combination for the manufacture of a medicament for the treatment of any of the conditions enumerated above.
  • the present invention also provides processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.
  • X 1 is halo, particularly Cl
  • R 25 is OH or NH 2 ; each PG 1 is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyl; each PG 2 is H or Boc; and all other variables are as defined herein.
  • the process comprises the steps of a) coupling a compound of formula 11 with a compound of formula 12 to prepare a compound of formula 13 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 13 to prepare a compound of
  • a compound of formula 11 may be reacted with the compound of formula 12 in the presence of a base such as 1 ,2,2,6,6- pentamethyipiperidine, N,N-diisopropylethyiamine, triethylamine or other amine base.
  • a base such as 1 ,2,2,6,6- pentamethyipiperidine, N,N-diisopropylethyiamine, triethylamine or other amine base.
  • the reaction may be carried out at an appropriate temperature based the definition of R 25 .
  • Suitable solvents include acetonitrile and methylene chloride.
  • Deprotection of a compound of formula 13 may be carried out using conventional techniques, including acidic conditions, either by brief treatment with HCi in dioxane or by fow-temperature treatment with trifluoroacetic acid in dichloromethane at about 0 ° C.
  • the optimal method for removing the protecting groups may be based upon the definition of L. For example, in those embodiments wherein L is a bond, deprotection with HCI is preferred whereas in those embodiments wherein L is CH 2 O, deprotection via trifluoroacetic acid may be preferred.
  • protecting groups on the compound of formula 13 will be based at least in part on the steric bulk of the particular ⁇ -agonist side chain (R 15 ) selected.
  • deprotection may be accomplished using conventional techniques including reaction with TMS-Br or TMS-i in a solvent such as acetonitrile or methylene chloride at a temperature from room temperature to 7O 0 C.
  • the compound of formula 11 may be prepared by reacting the corresponding compound of formula 1 :
  • the compounds of formula 12 wherein R 25 is OH may be prepared by the processes described below for the preparation of intermediate compounds of formula 7 wherein R 35 is H.
  • each PG 1 is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyi;
  • LG is a suitable leaving group, such as mesylate, triflate or iodide; each PG 2 is H or Boc;
  • R 35 is H or an alcohol protecting group such as tert-butyldimethylsilyl; and all other variables are as defined herein, in one embodiment, the process comprises the steps of: a) oxidizing a compound of formula 4 to prepare a compound of formula 5; b) phosphoryiating the compound of formula 5 to prepare a compound of formula 6; c) reducing the compound of formula 6 to prepare a compound of formula 7; and d) installing a leaving group on the compound of formula 7 to prepare the compound of formula 2.
  • the starting material compounds of formula 4 are either commercially available or may be prepared using conventional techniques. See, PCT Publication No. 2006/138212 to Baker et al., published 28 Dec 2006.
  • the compounds of formula 4 may be oxidized using conventional oxidation techniques and oxidizing agents to prepare compounds of formula 5.
  • Suitable oxidation techniques include, for example, manganese(IV) oxide in chloroform.
  • Suitable protecting groups include carboaikoxy protecting groups such as Boc, Methods are well known in the art for installing and removing such protecting groups and such conventional techniques may be employed in the instant reaction as well.
  • the compound of formula 5 may be phosphorylated using conventional techniques and phosphoryiating agents.
  • suitable phosphorylation techniques include but are not limited to reacting with ds-t-butyl- phosphobromidate synthesized in situ in a one-pot procedure and alkylating at 5OO with di-tert-butyl chloromethyl phosphate (Krise et al., J Med Chem (1999) 42:3094-3100).
  • the aldehyde moiety of the thus produced compound of formula 6 may be reduced using conventional techniques and reagents such as sodium borohydride at O 0 C.
  • additional secondary hydroxyl protection can be introduced by reaction with excess di-t-butyi-dicarbonate.
  • the foregoing reduction may then be employed to prepare the primary alcohol analog of formula 7.
  • the installation of the leaving group on the compound of formula 7 may be accomplished using conventional techniques.
  • the foregoing protection strategy advantageously allows for quantitative sulfonylation carried out at room temperature, using methanesulfonyl chloride (MsCI) in the presence of 1 ,2,2,6, 6-pentamethylpiperidine (PMP) to give the compound of formula 2 wherein LG is mesylate.
  • MsCI methanesulfonyl chloride
  • PMP 1- ,2,2,6, 6-pentamethylpiperidine
  • the reaction may be carried out at -78 ° C in order to minimize the formation of byproducts.
  • the process comprises the steps of a) phosphoryiating and reducing 5-bromosalicyiaidehyde to prepare a compound of formula 8; b) reacting the compound of formula 8 under Suzuki reaction conditions to prepare a compound of formuia 9; c) reacting the compound of formula 9 with an epoxidation agent to prepare a compound of formula 10; d) reacting the compound of formula 10 with an amine of formula H 2 N-R 15 to prepare a compound of formula 7; and e) instaliing a leaving group on the compound of formula 7 to prepare the compound of formula 2.
  • R 15 is t-butyl
  • the syntheses starts with 5-bromosaiicylaldehyde, which is phosphorylated using the techniques and reagents described above and reduced to form the alcohol.
  • An alcohol protecting group is typically installed, such as by treatment with tert-butyidimethyls ⁇ yl chloride in the presence of imidazole, to prepare the compound of formuia 8.
  • Suzuki reaction conditions including the trivinylboroxine-pyridine complex in the presence of catalytic amounts of tricyclohexylphosphine and palladium (il) acetate may be used to introduce the vinyl substituent, thereby preparing the compound of formula 9.
  • the compound of formula 9 then undergoes epoxidation and the epoxide is then opened through nucleophtiic substitution by treatment with an appropriate amine of formula NH 2 -R 15 , in the presence of a Lewis acid such as lithium perchlorate.
  • the epoxidation reaction may be accomplished by conventional means, including treatment with 2,2-dimethyidioxirane (DMDO) which may be conveniently generated in situ in a mixture of oxone and acetone.
  • DMDO 2,2-dimethyidioxirane
  • the nucleophiiic substitution results in compounds of formula 7.
  • the compounds of formula 7 may be acylated with, for example, di-tert-butyf dicarbonate, to install the Boc protecting group.
  • the removal of R 35 ⁇ if not H) and installation of the leaving group LG 1 in the compounds of formula 7 results in the compounds of formula 2, as described above.
  • a compound of formula 7 is reacted with diphenyl azidophosphate to give the azide compound of formula 14, which may be reduced by reaction with a conventional reducing agent, such as triphenyl phosphine, using standard techniques, to yield the compound of formula 12, wherein R 25 is NH 2 .
  • a conventional reducing agent such as triphenyl phosphine
  • the foregoing process may be utilized to prepare the corresponding R-isomer of a compound of Formula I-B by substituting the R-enantiomer of the N-Boc- protected compound of formula 12 starting material for the racemate.
  • the corresponding S-isomer of a compound of Formula I-B may be made by using the S-enantiomer of the N-Boc-protected compound of formula 12.
  • This same approach may be utilized to prepare enantiomerically enriched mixtures of any of the compounds of Formula I which contain a chiral center, and pharmaceutically acceptable salts thereof via any of the processes which follow.
  • LG is a suitable leaving group, such as mesylate, triflate or iodide; each PG 2 is H or Boc; and all other variables are as defined herein.
  • the process comprises the steps of a) coupling a compound of formula 15 with a compound of formula 2 to prepare a compound of formula 16 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 16 to prepare a compound of
  • a compound of formula 15 may be reacted with the compound of formula 2 in an analogous manner to that described above for the coupling of a compound of formula 1 to a compound of formula 2.
  • Deprotection of a compound of formula 16 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13.
  • R 27 is halo, particularly Cl 1 or OH
  • PG 3 is a silyl, acetate, or benzyl protecting group optionally substituted by methoxy or nitro;
  • the compound of formula 15 may be prepared by reacting a compound of formula 1 with a compound of formula 18 with or without an activating agent such as HATU 1 and a general amine base such as triethyiamine, DIEA, or the like, in acetonitrile or dimethylformamide at appropriate temperature.
  • an activating agent such as HATU 1 and a general amine base such as triethyiamine, DIEA, or the like
  • Compounds of formula 18 are commercially available or may be prepared using commercially available reagents and conventional techniques.
  • Formula I-D may be prepared according to the process illustrated in Scheme 4.
  • each PG 1 is a phosphonic acid protecting group such as methyl, ethyl, benzyl or t-butyl; each PG 2 is H or Boc; and all other variables are as defined herein.
  • the reaction may be carried out as a one-pot reaction.
  • the process comprises the steps of a) reacting a compound of formuia T with a compound of formula 20 and a compound of formula 1, in the presence of an activator, followed by phosphite oxidation to prepare a compound of formuia 22 or a pharmaceutically acceptable salt thereof; and c) deprotecting the compound of formula 22 to prepare a compound of Formula I-D, or a pharmaceutically acceptable salt thereof.
  • the process comprises reacting a compound of formula T with a compound of formula 20 in solution in a suitable solvent such as tetrahydrofuran at an appropriate temperature, followed by addition of an activator that includes tetrazole or 5-(ethy!thio)tetrazole).
  • an activator that includes tetrazole or 5-(ethy!thio)tetrazole.
  • the reaction may be continued in the same vessel without isolation or purification of intermediates.
  • the compound of formula 1 is added and reacted, preferably in the presence of the activator, followed by phosphite oxidation.
  • Phosphite oxidation may be accomplished with conventional means including reaction with tert-butyl hydrogen peroxide, iodine, 3-chioroperoxybenzoic acid or oxone.
  • the compound of formula 22, thus produced may be deprotected using conventional techniques including those described above for the deprotection of a compound of formula 3 (Meier et al.,
  • the compounds of formula T may be prepared as described above.
  • the compounds of formula 20 are commercially available or may be prepared using commercially available reagents using conventional techniques.
  • X 1 is halo, particularly Cl; b is 1; each PG 1 is a phosphonic acid protecting group such as methyl, ethyi, benzyl or t-butyt; each PG 2 is H or Boc; PG 3 is benzyl or Boc; and al! other variables are as defined herein.
  • a compound of formula 24 may be obtained by reacting a compound of a formula 11 with a compound of formula 23 with triethyiamine at appropriate temperature in CH 2 CI 2 follow by deprotection using conventional methods including hydrogenation in acid such as acetic acid or acid hydrolysis with HCI or TFA.
  • a compound of formula 25 may be prepared by the same process as compound of formula 11 by substituting the compound of formula 1 with the compound of formula 7.
  • a compound of formula 24 is coupled with a compound of formula 25 in presence of base such as triethyiamine at appropriate temperature to prepare a compound of formula 26 in a manner analogous to the process described in H. W. Scheeren and et al. J. Org. Chem. 2001 , 8815.
  • the resulting compound of formula 26 may be deprotected using acid as previously described.
  • LG 1 is a leaving group such as halo, preferably chloro or an activated carboxylic acid using HATU; each PG 1 is the same or different and is an alcohol protecting group such as methyl, ethyl, benzy! or t-butyl; each PG 2 is H or Boc; and all other variables are as defined herein.
  • the process comprises the steps of a) coupling a compound of formula 1 with a compound of formula 12 in the presence of a compound of formula 27, to prepare a compound of formula 28 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 28 to prepare a compound of Formula l-F, or a pharmaceutically acceptable salt thereof.
  • a compound of formula 1 may be reacted with a compound of formula 2 in the presence of a compound of formula 27, in a manner analogous to the process described above for the reaction of a compound of formula 11 with a compound of formula 12.
  • Suitable solvents include acetonitrile and methylene chloride.
  • Deprotection of a compound of formula 28 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13.
  • LG 1 is a leaving group such as a halo, particularly chioro, or an activated carboxyltc acid using HATU;
  • Y 3 is -(CH 2 ) Z — Ring A— (CH 2 ) a — (W 3 ) d — and (W 3 ) d is N(R 1 )-, particularly
  • the process comprises the steps of a) coupling a compound of formula 30 with a compound of formula 12 to prepare a compound of formula 31 or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 31 to prepare a compound of Formula I-G, or a pharmaceutically acceptable salt thereof.
  • a compound of formula 30 may be reacted with a compound of formula 12 in the same manner as the reaction of a compound of formula 11 with a compound of formula 12.
  • Suitable solvents include acetonitrile and methylene chloride.
  • Deprotection of a compound of formula 31 may be carried out using conventional techniques including those described above for the deprotection of a compound of formula 13.
  • Compounds of formula 30 may be prepared by reaction of a compound of formula 1 with a compound of formula 32 to prepare a compound of formula 33 which is reacted with phosgene in a manner analogous to the methods described above for the preparation of compounds of formula 11 and 15.
  • LG is a leaving group such as halo (e.g., Ci); Y 3 is -(CH 2 )z— Ring A ⁇ (CH 2 ) a — (W 3 ) d — ;
  • PG 3 is a silyl, acetate or benzyl protecting group optionally substituted by methoxy or nitro;
  • LG 1 is a leaving group such as halo, particularly Cl or activated carboxyiic acid using HATU.
  • HATU (0.227 g, 0.598 mmol), DIEA (0.142 mL, 0.742 mmoi), pyridtne-3,5- dicarboxylic acid (0.045 g, 0 272 mmol), and des-isobutyryi-ciclesomde (0.128 g, 0 272 mmol) were added to a stirring solution of carbonic acid [2-[tert- butoxycarbonyl[6-(4-phenylbutoxy)hexyl]am ⁇ no]-1-[4-(d ⁇ -tert- butoxyphosphoryloxy)-3 ⁇ hydroxymethylphenyl]ethyl] ester tert-butyl ester (0 22 g, 0 272 mmol) in DMF (3 mL) at it The reaction mixture was stirred over night and quenched with H 2 O (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL).
  • Example 1 Carbonic acid rM 1 ⁇ .16 ⁇ H16,17-f(R)- cvdohexyimethylene)bis(oxy)l-11-hydroxypreqna-1 1 4-diene-3,20-dion-21-yl1 ester f5-[1fR) ⁇ hvdroxy-2-rr6-(4- ⁇ henylbutoxy)hexynamino1ethyll-2-f2- phosphonooxy)benzyll ester Neat TFA (2 mL) was added to a stirring solution of intermediate 2 (0.19 g,
  • Example 2 Carbonic acid rn i ⁇ ,16 ⁇ 1-M6.17-f(R)- cvclohexyimethylene)bis(oxy)1-11-hvdroxypregna-1 ,4-diene-3,20-dion-21-v ⁇ ester [5-[1-hvdroxy-24f6-(4-phenylbutoxy)hexyllamino1ethv ⁇ -2-(2- phosphonooxy)benzyi1 ester
  • Example 3 f5-[1 -Hvdroxy-2-r6-(4-phenylbutoxy)hexyiamino1ethyl
  • Example 4 Pyridine-3,5-dicarboxylic acid [ " 5-[ " 1(R)-hydroxy-2-lT6-(4- phenylbutoxy)hexynamino1ethyi]-2-(phosphonooxy)benzyl1 ester IT11 ⁇ ,16 ⁇ ]- ⁇ 6,17-((R)-cvciohexylmethylene)bis(oxy)l-11-hvdroxypregna-1 ,4-diene-3,20- dion-21- ⁇ l] ester
  • foilowing compounds may be made using the general techniques described herein and methods analogous to those employed for making Examples 1-4 and Intermediates therefore.
  • Example 10 Method for Evaiuating Stability of Compounds of the Invention in Rat Lung Homogenate Preparation of rat lung homogenate Lungs from Fischer 344 rats are obtainable fresh by overnight delivery at 4°C from BioReciamation Inc. (Hicksville, NY). Lungs are weighed and homogenized in a 1 :3 w/v ratio with sterile phosphate buffered saline (PBS, 1OmIvI, pH 7.4) in glass vials on ice. After centrifugation at 3,000 x g for 10 min at 4°C the supernatant is decanted into sterile conical tubes and placed on ice.
  • PBS sterile phosphate buffered saline
  • the total protein content of the supernatant is determined by the bicinchoninic acid (BCA) method (Pierce Biotechnology, Rockford, IL), using bovine serum albumin (BSA) as the standard. Lung homogenates are prepared to a final concentration of 1 mg total protein/mL in 1OmM PBS, pH 7.4.
  • BCA bicinchoninic acid
  • BSA bovine serum albumin
  • the metabolism reactions are initiated by the addition of stock solutions of 21-derivatized steroids ciclesonide and des-isobutyryl ciclesonide in 1 mM dimethyl sulfoxide (DMSO) to a final concentration of 900 nM.
  • DMSO dimethyl sulfoxide
  • DMSO 2.7 ⁇ L
  • 3 mL of temperature-equilibrated homogenate serves as a control.
  • the glybuhde serves as an internal LC/MS/MS standard.
  • each drug + homogenate solution is aliquoted into a 96-well tissue culture plates. After an additional 30min and 120 min incubation at 37°C, 100 ⁇ L aliquots are added to 400 ⁇ L quenching solution. Denatured proteins in the quenching solution are separated by centrifugation at 3000 x g for 2 min at 4°C, and 160 ⁇ L of the supernatants are transferred to new 96-wel! plate for analysis by LC/MS/MS. Collection plates are covered with plastic film and kept on ice. For storage, covered plates are kept stored at -80 0 C until further use.
  • LC/MS/MS Liquid chromatography and mass spectrometry analysis
  • a Multiplex LX-2 HPLC system (Cohesive Technologies, Franklin, MA) with two identical Agilent 1100 series binary pumps (P/N G1312A) are used for eiution and separation. Samples are maintained at 4°C in an HTS Pal autosampler (LEAP Technologies, Carrboro, NC) in order to reduce any potential spontaneous hydrolysis of the compounds before injection onto the HPLC.
  • the analytes are eluted using the following mobile phases: Mobile phase A contains 1 % acetonitrile in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% acetonitrile in 10 mM ammonium formate with 1 % formic acid.
  • the HPLC eiution program used to elute the analytes is as follows:
  • the samples are further analyzed by tandem mass spectrometry using a TSQ Quantum Ultra triple quadrupole mass spectrometer (Thermo Finnigan, San Jose, CA) using a selective reaction monitoring (SRM) scan type.
  • the mass spectrometry parameters used are as follows: ⁇ n source C!D Spray Sheath gas Aux gas Capiliary
  • Example 11 Pharmacokinetic Analysis of Drug Levels of Saimeterol, Des- isobutyryl Ciclesonide ("des-ciclesonide”) and Compounds of the Invention Conducted in Lung, Bronchoalveoiar Lavage Fluid and Plasma After IT Administration in the Rat Dosing
  • Compounds of the invention are formulated for intratracheal (!T) dosing in 10%EtOH, 90% Sterile Water, and are dosed in male Sprague-Dawley rats at 3 mg/kg or 1 mg/kg. Each dosing group consists of 3 male, na ⁇ ve purebred Sprague-Dawiey rats. At dosing, the animals are weighed. The animals are fasted overnight prior to dose administration and up to 2 hr after dosing. The compounds are administered IT using a Penn Century Microsprayer (Model 1A- 1B).
  • BALF The animals are anesthetized with an intramuscular (IM) injection of a ketamine/xylazine/acepromazine (80/10/2 mg/kg) cocktail at a dose volume of 1.1 mL/kg.
  • IM intramuscular
  • a cannula modified Bard® infant feeding tube
  • Warmed sterile saline is injected into the lungs.
  • the lungs are gently massaged by palpation of the chest for approximately 45 seconds.
  • the fluid (BALF) is recovered and placed on ice. The procedure is repeated two more times, and all three BALF samples are pooled.
  • the fluid is centrifuged under refrigerated conditions at 350 g for 10 min.
  • the supernatant and ceil pellet are collected and stored at approximately -70 0 C until shipped for analysis.
  • the lungs from each animal are removed, blotted dry, weighed, and stored frozen at -70°C until shipped for analysis.
  • An LC/MS/MS method is used to measure the concentration of compound in plasma.
  • IxPBS buffer 90:10-PBS:ACN
  • the sample is homogenized with Polytron (PT1200) and a 5OuL supernatant sample is injected to an LC/MSMS.
  • a HyPurity C18 HPLC column (30 X 2.1 mm, 5 ⁇ ) from ThermoHypersil (Part #: 22105-032130) is used.
  • Mobile phase A contains 1 % acetonitrile in 10 mM ammonium formate aqueous solution with 1 % formic acid.
  • Mobile phase B contains 80% acetonitrile in 10 mM ammonium formate with 1 % formic acid.
  • An Agilent 1100 series binary pump (P/N G1312A Bin Pump) is used for elution and separation, HTS Pal autosampler from LEAP Technologies, Carrboro, NC is used.
  • TSQ Quantum Ultra triple quadrupole mass spectrometer from Thermo Finnigan, San Jose, CA is used in selective reaction monitoring (SRM) operation mode, Tune fife: ESI_tune112807_BL.
  • SRM selective reaction monitoring
  • results will demonstrate whether the compounds of the invention are metabolized to salmeterol and des-isobutyryl ciciesonide in the lung following IT administration. Based upon the structure of the compounds of the invention, it is believed that the results will demonstrate that the compounds of the invention are metabolized to salmeterol and des-isobutyryf ciciesonide.
  • Example 12 Drug Metaboiism Studies Using Airway Epithelial Ceils Cultured at an Air-Liquid Interface
  • Cryopreserved passage 1 cells are cultured in bronchial epithelial growth medium (Fulcher, M. L., et a!., Well-differentiated human airway epithelial cell cultures. Methods MoI Med, 2005. 107: p. 183-206) on 100 mm Type I collagen-coated plastic dishes. At 70% confluence, passage 2 ceils are transferred to type IV collagen-coated Millicell membranes (Miliipore, Bedford, MA) in medium that supports growth at an air-liquid-interface (AL! (Fuicher et a/., 2005). Ceils are maintained at an ALl and allowed to differentiate fully for approximately 28 days.
  • bronchial epithelial growth medium Frulcher, M. L., et a!., Well-differentiated human airway epithelial cell cultures. Methods MoI Med, 2005. 107: p. 183-206
  • passage 2 ceils are transferred to type IV collagen-coated Millicell membranes
  • the apical surfaces of the cells are washed with sterile phosphate buffered saline (PBS 1 1OmM, pH 7.4) and the basolaterat media is replaced with fresh ALI media.
  • PBS 1 1OmM, pH 7.4 sterile phosphate buffered saline
  • the basolaterat media is replaced with fresh ALI media.
  • the apical surfaces of the cells are washed once again with PBS and the basolateral media replaced with fresh ALI media.
  • the test article is diluted from a 10 mM stock solution in DMSO to a 40 ⁇ M solution in ALI media/PBS/10% EtOH/water (v/v). 50 ⁇ ! of the resulting 40 ⁇ M solution is immediately added to the apical surface of the cells.
  • 200 ⁇ l of the dosing solution is also added to 800 ⁇ l of 100% ACN and frozen immediately on dry ice.
  • the remaining dosing solution is placed in the incubator with the cells.
  • the three washes from each millicell ceil culture insert are pooled.
  • cell culture insert is also collected as are the airway epithelial cells which are excised from each miliicell cell culture insert and added to 300 ⁇ l of 90% ACN/0.1 % formic acid/9.9% water and immediately frozen on dry ice. The cells are thawed and lysed for 2 mins with a sonicator (Misonix, Farmingdale, NY) set at 30 Amp. The DC vii suspension is then centrifuged at 18,000 g for 2 min and 50 ⁇ i of the supernatant is added to 200 ⁇ l of acetonitrile containing 100 ng ml "1 glyburide.
  • Untreated control cells dosed at the apical surface with 50 ⁇ l of test article vehicle (ALI media/PBS/10% EtOH/water (v/v) are also included to provide apical, basoiateral and cellular matrices for LC/MS/MS analytical standards.
  • the above samples are thawed prior to centrifugation for 10 minutes at 3000 rpm at 4 0 C.
  • An aliquot of 150 ⁇ L of the above solution is mixed with 150 ⁇ L of water.
  • 10 ⁇ L of the acetonitrile/water mix are injected into the Applied Biosystems/ Sciex API 5000 LC/MS/MS system.
  • the compounds are separated by HPLC using a Zorbax Extend C18 HPLC column (50 X 2.1 mm, 3.5 ⁇ ) from Agiient Technologies.
  • An Aria Transcend duplexed HPLC system (Thermo Fisher, Franklin, MA) with two identical Agilent 1100 series binary pumps ⁇ P/N G1312B) are used for elution and separation.
  • the samples are further analyzed by tandem mass spectrometry using an ABI/Sciex APi 5000 triple quadrupole mass spectrometer (Applied Biosystems, Foster City, CA) using a selective reaction monitoring (SRM) scan type.
  • SRM selective reaction monitoring
  • Eleven-point standard curves for each test compound are prepared and analyzed in heat-inactivated iung homogenate, the concentration ranged from 1 nM to 10 ⁇ M.
  • the calibration curves of the steroid linkers, ciclesonide (CIC) and des-isobutyryl ciclesonide (des-CIC) are prepared by quadratic regression analysis.
  • mice are immunized by intraperitoneal injection of ovalbumin (10 ⁇ g OVA suspended in 2 mg aluminum hydroxide) on day 0 and 7.
  • One group is sensitized and treated with vehicle (NSV).
  • One group is immunized with sterile water only and treated with vehicle, e.g. to serve as a nonsensitized (negative) control (Vehicie).
  • Ciclesonide positive control treatment; 1X per day (day 14 and 15; 3 mg/kg), Compound of the invention at 1 , 3, and 6 mg/kg
  • vehicle is delivered by intratracheal (IT) instillation 1X/day (day 14 and 15), 1 hour prior to OVA inhalation challenge.
  • mice On days 14 and 15, the animals are exposed to OVA by inhalation (3 h; 5 mg/m 3 ). Forty eight hours following the last OVA challenge (day 17) mice are sacrificed. Bronchoalveolar lavage (BAL) is taken from each animal to collect ceils and fluid. Cell numbers and differentials were calculated from BAL.
  • BAL Bronchoalveolar lavage
  • Compound of the invention is evaluated in an LPS-induced airway inflammation model in rats.
  • Example 15 Tobacco Smoke Model of Airway Inflammation in Mice
  • Mice are exposed to cigarette smoke for 6 hours per day, 5 days per week for 3 weeks, in H1000 or H2000 chambers.
  • Type 2R4F research cigarettes (Kentucky Tobacco Research and Development Center) are used in the study.
  • Total particulate material (TPM) exposure is kept at 100 TPM/m 3 for the first week to allow animals to reduce adverse effects during adaptation to smoke exposure.
  • TPM exposure is maintained between 100 and 250 mg TPM/m 3 during the remainder of the study.
  • animals are euthanized and bronchoalveolar lavage fluid is obtained for cell differentials and cytokine analysis by Luminex multiplex immunoassay.
  • Inhibition of neutrophil influx is not expected in other treatment groups, including ciclesonide, salmetero! xinafoate, and is not expected to be as high in the ciclesonide + salmeterol xinafoate combination.
  • a 20-plex Luminex assay for cytokines and growth factors it is expected that the compounds of the invention will exhibit inhibition of tobacco-smoke-induced IL-1 ⁇ and MiP-Ia production (p ⁇ 0.05 versus vehicle control at 1.0 and 0.6 mg/kg doses).
  • Example 16 Ragweed-Induced Bronchoconstriction in Dogs
  • the compound of the invention may be assesed for bronchodilator activity in a ragweed-induced bronchoconstriction model in beagle dogs. Dogs are mechanically ventilated during each experiment. Airflow and tidai volume are measured using a differential pressure transducer located in front of the endotracheal tube. An esophageal balloon catheter placed in the esophagus is used to determine transpulmonary pressure. Pulmonary resistance and dynamic lung compliance are calculated from the simultaneous measurement of transpulmonary pressure and respiratory flow.
  • the canine exposure system is designed to expose an anesthetized animal via an intubation tube.
  • ragweed antigen ragweed short, Ambrosia artemisifolia, Greer, Lenoir, NC
  • Example 17 Ascaris sui/m-induced Pulmonary Responses in Sheep
  • the compound of the invention is assessed for inhibition of early and late phase bronchoconstriction and development of airway hyperreactivity in sheep sensitized to Ascaris suum antigen as previously described (Abraham, W. M., A. Ahmed, I Serebrlakov, IT. Lauredo, J. Bassuk, J.A. Adams, and M.A. Sackner. Am. J. Respir. Crit. Care. Med. 2006; 174:743-752).
  • Early and late phase responses are measured as a function of increased pulmonary resistance during the 8 hour period following antigen.
  • Airway hyperreactivity is evaluated as a function of PC400, the number of carbachol breath units required to induce a four-fold increase in bronchoconstriction measured 24 hours after antigen challenge.
  • One breath unit is defined as one breath of a 1 % w/v carbachol solution.
  • Test compound is administered either by a pre-dosing or duration of action protocol. In the pre-dosing regimen, animals are dosed once daily for four days, with the last dose administered 1 hr before antigen. In the duration of action regimen, animais are dosed once daily for four days, with the last dose administered 24 hours before antigen. Test compound, Ascaris antigen, and carbachol are administered by nebulized aerosol to intubated sheep.
  • the compounds of the invention may be assessed for inhibition of carbachol- induced bronchoconstriction as previously described (Abraham, VJM., A. Ahmed, I Serebrtakov, A.N. Carmillo, J. Ferrant, A.R. de Fougerolles, E.A. Garber, P. J. Gowals, V.E. Koteilansky, F. Taylor, R. R. Lobb. Am, J. Respir. Crtt. Care. Med. 2004; 169:97-104). Bronchoconstriction is evaluated as a function of increased pulmonary resistance following carbachol challenge.
  • Measurements of R L are repeated immediately after inhalation of buffer and after each administration of 10 breaths of increasing concentrations of carbachol solution (0.25%, 0.5%, 1.0%, and 2.0% w/v).
  • Test compound is administered either by a pre-dosing or duration of action protocol.
  • animals are dosed once daily for four days, with the last dose administered 1 hr before carbachol challenge.
  • duration of action regimen animals are dosed once daily for four days, with the last dose administered 24 hours before carbachol challenge.
  • Test article and carbachoS are administered by nebulized aerosol to intubated sheep.
  • API 500 meg micronized compound of Formula I
  • a mill e.g. jet mill
  • MMAD mass median aerodynamic diameter
  • lactose may be milled or sieved. Suitable commercial sources of lactose include DMV-Fonterra Excipients (Lactohaie®) and Friesiandfoods Domo (Respotise®).
  • 500 mg of API is blended with 15 g of lactose using an appropriate mixer (e.g. Turbula® Powder Blender). Additional fine lactose particles of less than 10 ⁇ m may be added.
  • the blended product is filled into capsules or blister strips.
  • Target Unit 250 meg of micronized API
  • propeliant e.g., HFA 134a or 2257
  • Each canister is to contain 120 dose equivalents of API and propeliant + 10% overage.
  • Each canister is filled with 33 mg of AP! and sealed with a metering valve. The canister is then pressurized with 19.8 mL of propeliant.

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Abstract

L'invention porte sur des nouvelles entités chimiques qui comprennent des corticostéroïdes et des β-agonistes phosphorylés pour une utilisation en thérapie, ainsi que sur des compositions les comprenant et sur des procédés pour les préparer.
PCT/US2010/032689 2009-04-29 2010-04-28 Composés bêta-agonistes liés à des corticostéroïdes pour une utilisation en thérapie WO2010126953A1 (fr)

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WO2011081937A1 (fr) * 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
EP3492919A3 (fr) * 2014-02-24 2019-07-10 Ventana Medical Systems, Inc. Quinone methide analogue signal amplification
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10711032B2 (en) 2016-11-08 2020-07-14 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
IT201900014178A1 (it) * 2019-08-06 2021-02-06 Genetic S P A Esteri del montelukast e loro formulazioni farmaceutiche
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
WO2022171101A1 (fr) * 2021-02-10 2022-08-18 映恩生物制药（苏州）有限公司 Conjugué de stéroïdes
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
WO2023186072A1 (fr) * 2022-04-01 2023-10-05 江苏先声药业有限公司 Conjugué ligand-médicament et son utilisation

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011081937A1 (fr) * 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
EP3492919A3 (fr) * 2014-02-24 2019-07-10 Ventana Medical Systems, Inc. Quinone methide analogue signal amplification
US11780863B2 (en) 2014-02-24 2023-10-10 Ventana Medical Systems, Inc. Quinone methide analog signal amplification
US11365210B2 (en) 2014-02-24 2022-06-21 Ventana Medical Systems, Inc. Quinone methide analog signal amplification
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10711032B2 (en) 2016-11-08 2020-07-14 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
WO2021023751A1 (fr) * 2019-08-06 2021-02-11 Genetic S.P.A. Esters de montélukast et compositions pharmaceutiques les contenant
IT201900014178A1 (it) * 2019-08-06 2021-02-06 Genetic S P A Esteri del montelukast e loro formulazioni farmaceutiche
WO2022171101A1 (fr) * 2021-02-10 2022-08-18 映恩生物制药（苏州）有限公司 Conjugué de stéroïdes
WO2023186072A1 (fr) * 2022-04-01 2023-10-05 江苏先声药业有限公司 Conjugué ligand-médicament et son utilisation

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