WO2010132743A1 - Composés de β-agonistes et de corticostéroïdes destinés à être utilisés en thérapie - Google Patents

Composés de β-agonistes et de corticostéroïdes destinés à être utilisés en thérapie Download PDF

Info

Publication number
WO2010132743A1
WO2010132743A1 PCT/US2010/034861 US2010034861W WO2010132743A1 WO 2010132743 A1 WO2010132743 A1 WO 2010132743A1 US 2010034861 W US2010034861 W US 2010034861W WO 2010132743 A1 WO2010132743 A1 WO 2010132743A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
pharmaceutically acceptable
acceptable salt
alkylene
human
Prior art date
Application number
PCT/US2010/034861
Other languages
English (en)
Inventor
William R. Baker
Alexander Rudolph
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Publication of WO2010132743A1 publication Critical patent/WO2010132743A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

Definitions

  • the 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. , 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. All of these factors lead to an increased reactivity of the airways to a wide variety of irritant stimuli (Kaliner, "Bronchial asthma, Immunologic diseases" E. M. Samter, Boston, Little, Brown and Company: 117-1 18. 1988).
  • 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 fuliy 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 Gilman, 10 th edition, 2001).
  • ICS Inhaled corticosteroids
  • Combinations of inhaled ⁇ 2 -adrenoreceptor agonist bronchodilators such as formoterol, indacaterol, or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation associated with asthma and COPD (Symbtcort ® 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 et a!. (WO/2006/138212) wherein the component drugs are released at the site of action in the iungs.
  • the present invention provides a compound of Formula I:
  • R 6 is H, and R 1 is CH 2 -OH, CH 2 -CI,
  • R 10 is H or C 1-4 alkyl
  • R 15 is a side chain radical of a ⁇ -agonist
  • R 16 is H, methyl or ethyl
  • R 19 is H 1 F, OH or methyl; each R 2 , R 3 , R 4 , and R 5 are independently H 1 C h alky! or halo; R 8 is H 1 OH 1 0(CO)R 9 , or 0(CO)OR 9 ; each R 9 is independently R 11 is H or C h alky!; R 12 is H 1 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-i.-ioalkyl, C 2- i ⁇ alkenyl, C 2- - IO a I kynyl, optionally substituted Ca.-iocarbocyclyl or optionally substituted 5-6 ring atom heterocycie wherein one or two ring atoms are selected from N, O and S, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci- 4 alkyl, and O-Ci -4 alkyl.
  • the compounds of Formula I is defined wherein R 1 is
  • R 6 is H, and R 1 is CH 2 -OH, CH 2 -CI, CH 2 -O-C(O)Ci -4 a!kyl, S-C ⁇ alkyl, S-haloC 1-4 alkyi, or CH 2 -O-PO 3 H 2 .
  • the compounds of Formula I are defined wherein R 15 is C 1-6 alkyl
  • Ci -4 alkyl O-C 1-4 alkyl, O-(CH 2 ) 4 -NH 2 , O ⁇ (CH 2 ) 4 -N(H)C 1-4 aIkyl,
  • O-(CH 2 )4-N(Ci -4 aikyl) 2 O-C 1-4 alkyl-C(O)-NH 2 , O-C 1-4 alkyl-C(O)-N(H)C 1-4 alkyl, O-C 1-4 alkyl-C(O)-N(C 1-4 alkyl) 2, or a group represented by formula i, ii, Ni, iv, v, vi, vii, viii, or ix: i: C 6 alkylene-O-R 21 -Ph 4 ; ii: C 2 , 3 aikylene-Ph 1 -O-R 21 -Ph 4 ; iii: C 2 .
  • R 21 is C 2 - ealkyiene 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 phenylene
  • 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 , -SO 2 -NH-(C 6 H 3 XCH 3 )(C 7 H 15 ) or
  • 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 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;
  • Ph 3 is phenyl optionally substituted 1 or 2 times by halo or O-methyi.
  • the present invention provides compounds of Formula M:
  • the present invention provides compounds of Formula III:
  • the present invention provides a composition
  • a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrier, in one embodiment, the composition is suitable for inhalation.
  • the present invention provides a method comprising administering to a human, an effective amount of a compound of Formula I or a pharmaceuticaily acceptable salt thereof.
  • the present invention provides a method for the treatment of pulmonary inflammation or bronchoconstriction in a human in need thereof. The method comprises administering to the human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of a disease associated with reversible airway obstruction in a human in need thereof.
  • the method comprises administering to the human an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of asthma in a human in need thereof.
  • the method comprises administering to the human an effective amount of a compound of Formula i or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of COPD in a human in need thereof.
  • the method comprises administering to the human an effective amount of a compound of Formula t or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of bronchiectasis in a human in need thereof.
  • the method comprises administering to the human an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of emphysema in a human in need thereof.
  • the method comprises administering to the human an effective amount of a compound of Formula ! or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present 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 present invention provides a compound of Formula ! 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 present 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 pulmonary inflammation or bronchoconstriction in a human,
  • the present 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 present 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 present invention provides a composition comprising a compound of Formula ! 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.
  • a compound of the invention means a compound of Formula I, which includes compounds of formula II, and III, 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, including compounds of Formulas II, and 111.
  • Compounds of Formula I include solvates and hydrates as well as any amorphous and crystalline (polymorphic) forms thereof. In those embodiments wherein a compound of Formula I includes one or more chira! 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 chiral center) thereof, "alky! as used herein refers to linear or branched hydrocarbon chains containing from 1 to 8 carbon atoms (i.e., C h alky!), unless a different number of atoms is specified. Examples of "alkyl as used herein include but are not limited to methy!
  • alkyiene refers to a linear or branched divalent hydrocarbon chain having from 1 to 8 carbon atoms (i.e., C- ⁇ -8 alkyiene), unless a different number of carbon atoms is specified.
  • alkyiene as used herein include but are not limited to methylene, 1 ,1 -ethyi (-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 butyfene (1 ,4-butyl (-CH 2 CH 2 CH 2 CH 2 -)), and the like.
  • alkylenes When the compound of Formula I includes more than one alkyiene, the alkylenes may be the same or different.
  • alkenyl "alkenyl” " as used herein refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C 2 . 8 aikenyl), unless a different number of atoms is specified, and at least one carbon-carbon double bond.
  • alkenyls When the compound of Formula I includes more than one alkenyl, the alkenyls may be the same or different, "alkynyl” as used herein refers to linear or branched hydrocarbon chains containing from 2 to 8 carbon atoms (i.e., C 2 - 8 a'kynyi), unless a different number of atoms is specified, and at least one carbon-carbon triple bond. Examples of aikynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like. When the compound of Formula I includes more than one alkynyl, the alkynyls may be the same or different.
  • halo or “halogen” are synonymous and refer to fluoro, chloro, bromo, and iodo.
  • haloalkyi refers to a linear or branched hydrocarbon chain containing from 1 to 8 carbon atoms, unless a different number of carbon atoms is specified, wherein at least one carbon atom is substituted by 1 , 2 or 3 halogen atoms which may be the same or different and are selected from fluoro, chloro, bromo and iodo. In those instances where the alkyl group does not contain from 1 to 8 carbon atoms, the number of carbon atoms in the haloalkyi is expressed as, for example "haloC 1-4 a!kyr.
  • carbbocycle or “carbocyclyl” refers to a saturated (i.e., cycioalkyl), partially unsaturated (e.g., cycioalkeny!, cycloalkadienyi, etc.) or aromatic (i.e., aryl ring) hydrocarbon rings having 3 to 7 carbon atoms as a monocycie, 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 (“Cs-gcarbocycle”).
  • 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 bicyclo [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyi, 1-cyclopent-1- enyl, i-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1- enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicycio carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl. In those embodiments wherein the compound of Formula I includes more than one carbocycle, the carbocycles may be the same or different.
  • aryl refers to a subset of carbocycles, 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, naphthyl, 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, in one embodiment, aryi refers to phenyl or naphthyl. In one particular embodiment, ary! is phenyl.
  • heterocyclycie or “heterocycly!” 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 1 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 heterocycie includes 2 or more heteroatoms (N, O and S) the heteroatoms may be the same or different.
  • heterocyclycie 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 heterocycies may be the same or different.
  • heterocycles include but are not limited to pyridyl, dihydropyridyl, piperidyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, im ⁇ dazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzim ⁇ dazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyi, octahydroisoquinolin
  • heteroaryl refers to a subset of heterocycles, namely monocyclic 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, O and S.
  • heteroaryls include all of aromatic heterocycles listed above, and particularly pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindoiyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, imidazoly!, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, py ⁇ midyl, pyrazyl, etc.
  • the heteroaryls may be the same or different, "heterocyclene" refers to a bivalent heterocycle as defined herein.
  • heterocyclenes include:
  • the heterocyclenes may be the same or different.
  • the invention comprises compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein:
  • R 7 is R 6 is H 1 and R 1 is CH 2 -OH, CH 2 -CI,
  • R 10 is H or C 1-4 alkyl
  • R 15 is a side chain radical of a ⁇ -agonist
  • R 19 is H, F, OH or methyl; each R 2 , R 3 , R 4 , and R 5 are independently H, Ci -4 alkyl or halo; R 8 is H, OH, 0(CO)R 9 , or 0(CO)OR 9 ; each R 9 is independently C ⁇ alkyl; R 11 is H or C 1-4 aikyl; R 12 is H, OH, or Ci_ 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- M oalkyl, C-2-ioalkenyl, C 2 -ioalkynyl, optionally substituted C 3- iocarbocyclyl or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, O and S, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted 1 , 2 or 3 times with a substituent selected from halo, Ci- 4 alkyl, and O-Ci -4 alkyl.
  • ⁇ -agonist moiety of the compound of Formula I may be bound at the 11- or 21-oxy of the corticosteroid moiety.
  • compounds of the invention include compounds of Formula I wherein
  • Such compounds may be referred to as compounds of Formula I-A, and are illustrated as follows:
  • the compounds of the invention also include compounds of Formula I wherein
  • R 7 is R 6 is H, and R 1 is CH 2 -OH, CH 2 -Ci,
  • R 1 is S-Ci -4 alkyl or S-haioC-Malkyl, or any subset thereof. In one particular embodiment, R 1 is S-haloCi -4 alkyl, more particularly S-f!uoroCi- 4 alkyI. In one preferred embodiment, R 1 is -S-CH 2 F.
  • 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, CI or methyl.
  • R 4 and R 5 are H, R 2 is H, F or Cl 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, R 2 is H and R 3 is F or R 2 is F and R 3 is H.
  • R 8 is H, OH 1 0(CO)CH 2 CH 3 , 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 methyi.
  • R j12 is H, OH, or methyl.
  • R 12 is H or methyl, more particularly H.
  • R 11 and R 12 taken together with the carbon to which they are attached form a group.
  • 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, d-ioalkyl, C 2- -soaikenyi, C ⁇ -ioaikynyl, optionally substituted C 3 ⁇ ocarbocycle or optionally substituted 5-6 ring atom heterocycle wherein one or two ring atoms are selected from N, 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 O-C 1 . 4 alk.yl.
  • R 12 and R 8 form a ring represented by formula B
  • one of R 13 and R 14 is H, methyl or ethy! and the other is H, Ci_i O a!kyl, C 2- ioaIkenyl, C 2 -ioaIkynyl, or optionally substituted C 3-10 carbocycle, wherein the carbocycle is optionally substituted 1 , 2 or 3 times with a substituent selected from halo, C h alky!, and
  • one of R 13 and R 14 is H, methyl or ethyl and the other is H, Ci- l oalkyt, or C 3- iocarbocycle, or any subset thereof.
  • one of R 13 and R 14 is H, methy! or ethyl and the other is H, C 1-4 alkyl, or C 3-6 cycloalkyl, or any subset thereof, more particularly cyclohexyl.
  • one of R 13 and R 14 is H or methyl, more particularly H, and the other is H, C ⁇ aikyi, or Cs-ecycloalkyl, or any subset thereof, more particularly cyclohexyl.
  • R 13 and R 14 are each methyl.
  • R 13 is H and R 14 is propyl.
  • R 13 is H and R 14 is cyclohexyl.
  • the corticosteroid moiety is or , or any subset thereof.
  • ⁇ -agonists from which the side chain radical R 15 may be derived include but are not limited to the following compounds:
  • R 15 is d-Cealkyl
  • C 6 ⁇ C t ocarbocycle optionally substituted 1 or 2 times with halo, C 1 - C 4 alkyl, O-CrC 4 alkyl, O-(CH 2 ) 4 -NH 2 , 0- ⁇ CH 2 ) 4 -N(H)C 1-4 alkyl ! O-(CH 2 )4-N(C 1 . 4 aikyl) 2 , O-C 1-4 afkyl-C(O)-NH 2 ,
  • alkylene-Ph 1 -O-R 21 -Ph 4 iii: C 2-3 alkylene-Ph 1 -N(H)-R 22 -Ph 2 ; iv: C 2-3 aikylene-Het-(R 23 )-Ph 3 ; v: C 2-3 alkylene-Ph 1 -Co- 2 a ⁇ kylene-C(O)N(H)-C 1-4 alkyiene-Ph 3 ; vi: C 2-3 alkylene-Ph 3 ; vii: C 2 - 3 alkylene-S(0) 2 -C 2 .
  • R 21 is C 2- 6 alkylene 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 phenylene
  • 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,
  • 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 aikyiene-C(O)N(H)-C 2-4 alkylene; and
  • Ph 3 is phenyl optionally substituted 1 or 2 times by halo or O- rnethyl.
  • R 15 is Ci -6 alkyl. More particularly R 15 is C ⁇ alkyl. In one preferred embodiment, R 15 is isopropyl or t-butyl.
  • R 15 is Cg--I ocarbocycle optionally substituted 1 or 2 times with C 1-4 alkyl, O-C 1-4 alkyl, or O-Ci -4 alkyl-C(O)-NH 2 , or any subset thereof.
  • R 15 is Cg.-i ⁇ carbocycle optionally substituted 1 or 2 times with C 1-4 alkyl, O-Ci» 4 alkyl, or O-Ci. 4 aikyl-C(O)-NH 2> or any subset thereof.
  • R 15 is
  • R 15 is a group represented by formula i:
  • 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 afkylene and Ph 4 is phenyl, particularly unsubstituted phenyl.
  • R 15 is - ⁇ CH 2 ) 6 ⁇ (CH 2 ) 4 -pheny!, i.e.,
  • R is a group represented by formula i and R is C 4 alkylene 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 alkylene wherein one C is optionally replaced by O and Ph 4 is unsubstituted phenyl.
  • R 15 is a group represented by formula ii 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: C 2-3 alkylene-Ph 1 -N(H)-R 22 -Ph 2 .
  • 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 3 ) 2 CH 2 NH 2.
  • R 15 is a group represented by formula iii, R 22 is C 2a ⁇ k ylene 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 16 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 CI) or O-methyl, or any subset thereof.
  • R 15 is a group represented by formula v: C 2-3 a!kylene-Ph 1 -C 0 -C 2 alky!ene-C(O)N(H)-C 1-4 alky!ene-Ph 3 .
  • R 15 is a group represented by formula v and Ph 3 is phenyl substituted twice by halo (particularly Cl) 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 formuia vii: C 2 - 3 alkylene-S(O) 2 -C 2 - 4 alkylene ⁇ O » C2- 4 alkylene-Ph 3 .
  • 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- 6alky!ene-Ph 1 -Co -2 a[kylene-C(0)N(H)-Cio-i2 bicyclic carbocycle. In one embodiment, R 15 is a group represented by formuia viii-a: (branched) C 3 alky!ene-Ph 1 -CH 2 C(O)N(H)-adamanty!.
  • 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 heterocyciene 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
  • R 15 is In one preferred embodiment, R 15 is
  • R in one preferred embodiment, R 15 is
  • R 15 is
  • R 15 is
  • R )16 is H or methyl. In one preferred embodiment, R 16 is H
  • R 19 is OH.
  • the invention provides compounds of Formula II:
  • the invention provides compounds of Formula III:
  • R 20 is ethyl or furanyl and all other variables are as defined above, including all embodiments of each variable as described hereinabove.
  • Specific embodiments, including particular and preferred embodiments of R 15 are as described above for compounds of Formula I. For the sake of brevity, the disclosure of those embodiments, including particular and preferred embodiments is not repeated. Any of the previously disclosed embodiments, particular embodiments and preferred embodiments of R 15 are contemplated for combination in any of the foregoing Formula.
  • the compounds of Formula I may be in the form of a sait, 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 alkaiine 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, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polygiutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benz
  • salts of active ingredients of the compounds of Formula I will be pharmaceutically acceptable, i.e. they will be salts derived from a pharmaceutically 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.
  • 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 superimposable 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.
  • optically active forms i.e., they have the ability to rotate the plane of plane-polarized light.
  • D and L or R and S are used to denote the absolute configuration of the molecule about its chira! center(s).
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species. It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopoiymorphs of compounds within the scope of Formula I and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers, including enantiomerically enriched mixtures and diastereomericaliy enriched mixtures are within the scope of the present invention. Enantionmerically enriched mixtures are mixtures of enantiomers wherein the ratio of the specified enantiomer to the alternative enantiomer is greater than 50:50.
  • 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 enantiomerically enriched mixture is substantially free of the other enantiomer.
  • diastereomericaliy enriched mixtures are mixtures of diastereomers wherein amount of the specified diastereomer is greater than the amount of each alternative diastereomer. More particularly, a diastereomericaliy 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 diastereomericaliy enriched mixture is substantially free of all other diastereomers.
  • the present invention provides an enantiomericaily enriched mixture comprising
  • the present invention provides an enantiomerically enriched mixture comprising
  • a compound of Formula I 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 pseudopolymorphs 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 clinical 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, in one embodiment the invention provides a method for the treatment of bronchiectasis in a mammal, particularly a human, in need thereof, in one embodiment the invention provides a method for the treatment of emphysema in a mammal, particularly a human in need thereof.
  • 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.
  • Ail 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, particularly a human, in need thereof.
  • a compound for use in the treatment of emphysema in a mammal, particularly a human in need thereof In one embodiment there is provided a compound of the invention for use in the treatment of a respiratory tract infection or upper respiratory tract disease 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 mamma!, 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 a condition associated with reversible airway obstruction in a mammal, particularly a human in need thereof, In one embodiment is provided 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. In one embodiment is provided the use of 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.
  • an effective amount 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 ceil 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 physiological 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 will 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.
  • 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) will be administered four, three, two, or most preferably once per day (24 hours).
  • the invention provides compositions, and particularly pharmaceutical compositions (such as an inhalable pharmaceutical composition) comprising a compound of the invention as an active ingredient and a pharmaceutically acceptable excipient, diluent or carrier.
  • active ingredient refers to any of a compound of Formula I, II, or II! or a pharmaceutically acceptable salt of any of the foregoing.
  • 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 (MMAD) and the Geometric Standard Deviation (GSD).
  • MMAD Mass Median Aerodynamic Diameter
  • 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.
  • processes or techniques that can be used to produce respirabie particles include spray drying, precipitation, supercritical fluid, and freeze drying.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • Aerosoi 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 contain a mix of the active ingredient and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (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.
  • carrier/diluent/excipient substance such as mono-, di- or poly-saccharides (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 inhaier 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 ⁇ r ⁇ 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 formulated for delivery by a Diskus®-type device.
  • the Diskus® device comprises an eiongate 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 excipients (e.g., lactose) and/or other therapeutically active agents.
  • the strip is sufficiently flexible to be wound into a roll.
  • the Nd 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.
  • the pharmaceutical formulation according to the invention is a dry powder for inhalation wherein the dry powder is formulated into microparticles as described in PCT Publication No. WO2009/015286 or WO2007/114881 , both to NexBio.
  • microparticles are generally formed by adding a counterion to a solution containing a compound of the invention in a solvent, adding an antisolvent to the solution; and gradually cooling the solution to a temperature below about 25 0 C, to form a composition containing microparticles comprising the compound.
  • the microparticles comprising the compound may then be separated from the solution by any suitable means such as sedimentation, filtration or lyophilization.
  • suitable counterions, solvents and antisolvents for preparing microparticles of the compounds of the invention are described in WO2009/015286.
  • Spray compositions for topical delivery to the endobronchial space or lung 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 propellants, 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 ethanol) 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 chforofluorocarbon or mixtures thereof, particularly hydroffuoroalkanes, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichJorotetrafluoroethane, especially 1 ,1 ,1 ,2-tetraf!uoroethane, 1 ,1 ,1 ,2,3,3,3,-heptafluoro-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 aluminum canister) closed with a valve (e.g., a metering valve) and fitted into an actuator provided with a mouthpiece.
  • 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 aerosolization 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 formuiated 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 commercially available nebulizers or other atomizer that can break the formulation into particles or droplets suitable for deposition in the nasal cavities or respiratory tract.
  • nebuiizers 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-iimiting 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. Additionally, formulation properties such as phi, osmolality, and permeant ion content can affect tolerability of the medication, so preferred embodiments conform to certain ranges of these properties.
  • the formulation for nebulization is delivered to the endobronchial space as an aerosol having an MMAD between about 1 ⁇ m and about 5 ⁇ m 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. If an aerosol has an MIvIAD 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 oil-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.
  • a suitable machine 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
  • 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 multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for- injection, immediateiy prior to use.
  • sterile liquid carrier for example saline or water-for- injection, immediateiy prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • 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.
  • the plasma concentrations of the ⁇ - agonist and/or corticosteroid produced are less than about 5 nanograms/mL one hour after administration of the composition.
  • the plasma concentrations of the ⁇ -agonist and/or corticosteroid produced are iess 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 inhaiable pharmaceutical composition of a compound of the invention wherein the inhaiable pharmaceutical 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 asthma, bronchitis or COPD comprising treating a 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 ⁇ -agontst 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 iess than about 5 nanograms/mL one hour after administration of said formulation, in a particularly preferred embodiment of the method, 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 formuiations for the compounds of the invention are those containing an effective amount of the active ingredient or an appropriate fraction thereof.
  • the formuiations 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 proiiferator-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 proiiferator-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.
  • ester 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-1 Ia- propionyloxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yi) ester, beclomethasone esters (e.g., the 17-propionate ester or the 17,21-dipropionate ester, fluoromethy! ester, triamcinolone acetonide, rofleponide, or any combination or subset thereof.
  • beclomethasone esters e.g., the 17-propionate ester or the 17,21-dipropionate ester, fluoromethy! ester, triamcinolone acetonide, rofleponide, or any combination or subset thereof.
  • Preferred corticosteroids for formulation or use in combination with the compounds of the invention are selected from ciciesonide, desisobutyryl-ciclesonide, budesonide, mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subset thereof.
  • NSAlDs 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 ( ⁇ NOS) inhibitors, protease inhibitors (e.g., tryptase inhibitors, neutrophil elastase inhibitors, and metalloprotease 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 family).
  • PDE4 inhibitors for formulation and use in combination with the compounds of the present invention include but are not limited to roflumilast, pumafentrine, arofylline, cilomilast, tofimilast, oglemiiast, tolafentrine, piclamilast, ibudiiast, apremilast, 2-[4-[6,7-diethoxy ⁇ 2,3 ⁇ bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridiny!-1(2H)- phthalazinone (T2585), N-(3,5-dichioro-4-py ⁇ dinyi)-1-[(4-fluorophenyl)methyl]-5- hydroxy- ⁇ -oxo-1 H-indo!e-3-acetamide (AWD- 12-281 , 4-[(2R)-2-[3- (cyclopentyloxy)-4-methoxyphenyl]-2-
  • Leukotriene antagonists and inhibitors of leukotriene synthesis include zafirlukast, montelukast sodium, ziieuton, 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 saits 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.
  • Additional anticholinergics for formulation and use in combination with the methantheline, propantheline bromide, anisotropine methyl bromide or Valpin 50, aclidinium bromide, glycopyrrolate (Robinul), isopropamide iodide, mepenzolate bromide, tridihexethyl chloride, hexocyclium methylsulfate, cyclopentolate HCf, tropicamide, trihexyphenidyl CCI, pirenzepine, telenzepine, and methoctramine, or any combination or subset thereof.
  • aclidinium bromide glycopyrrolate (Robinul)
  • isopropamide iodide mepenzolate bromide
  • mepenzolate bromide tridihexethyl chloride
  • hexocyclium methylsulfate cyclopentolate HCf
  • tropicamide trihexyphenidyl CCI
  • 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.
  • ⁇ -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), indacaterol, formoterol (fumarate), fenoterol, 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, pioglitazone, and troglitazone.
  • ENaC receptor blockers for formulation and use in combination with the compounds of the invention include but are not iimited 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 formulation and use in combination with the compounds of the invention include but are not limited to: Ethanolamines, ethylenediamines, alkyiamines, 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 HCI 1 carbinoxamine maleate, doxylamine, clemastine fumarate, diphenylhydramine HCI, dimenhydrinate, pyrilamine maleate (metpyramine), tripeiennamine HCI, tripelennamine citrate, antazoline pheniramine, chloropheniramine, bromopheniramine, dexchlorpheniramine, triprolidine, acrivastine methapyhlene, hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCl, cetirizine HCI astemisole, levocabastine HCI, loratadine, descarboethoxy loratadine, terfenadine, fexofenadine HCl, promethazine, chlorpromethazine, chlor
  • 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.
  • the composition comprises a compound of the invention and a corticosteroid selected from ciciesonide, desisobutyryl-ciciesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate.
  • the composition comprises a compound of the invention and cidesonide or desisobutyryl- ciciesonide.
  • the present invention provides a composition comprising a compound of the invention and a PDE4 inhibitor. In one aspect, the present invention provides a composition comprising a compound of the invention and a ⁇ 2-agonist. In one embodiment, the composition comprises a compound of the invention and salmeterol, R- salmeterol, indacaterol, or formoterol. In one particular embodiment, the composition comprises a compound of the invention and salmeterol or R- salmeterol.
  • the present invention provides a composition comprising a compound of the invention and an anticholinergic agent, in one embodiment, the composition comprises a compound of the invention and tiotropium. in one aspect, 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 skili 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, in one embodiment, the method comprises administering an effective amount of a compound of the invention and a corticosteroid. In one particular embodiment, the method comprises administering an effective amount of a compound of the invention and a corticosteroid selected from ciclesonide, desisobutyryl- ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate. In one particular embodiment, 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. In one embodiment 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 (J 2 - agonist. In one embodiment, the method comprises administering an effective amount of a compound of the invention and salmeteroi, R-salmeterol, indacaterol, or formoterol. In one particular embodiment, 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 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 a corticosteroid selected from ciciesonide, desisobutyryl-ciclesonide, budesonide mometasone, fluticasone propionate, and fluticasone furoate.
  • the combination comprises a compound of the invention and ciciesonide 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 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 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, indacaterof, or formoterol.
  • the combination comprises a compound of the invention and salmeterol 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, in one embodiment 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.
  • R 1a is selected from CHR 10 -OH,CH 2 -OH, CH 2 -Cl, CH 2 -O-C(O)C 1-4 alkyl,
  • S-Ci -4 alky!, S-haloC 1-4 alkyl, or CH 2 -O-PO 3 H 2 R 7a is H or OH, each PG is H or Boc, and all other variables are as defined herein.
  • the process comprises the steps of: a) reacting a compound of formula 1 with phosphorous trichloride followed by a base, adding to a compound of formula 2 and base and then oxidizing in a one-pot reaction to prepare a compound of formula 3-A or 3-B or a pharmaceutically acceptable salt thereof; and b) deprotecting the compound of formula 3-A or 3-B to prepare a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the first step is carried out in a manner analogous to that described in C. Meter et al., J. Med. Chem., 2007, 50(6), 1335-1346. More specifically, the process comprises reacting the alcohol of formula 1 with phosphorous trichloride then a base, such as triethylamine, or DIPEA in a suitable solvent. Suitable solvents include but are not limited to diethyl ether, tetrahydrofuran, and dichloromethane. The reaction is typically carried out at reduced temperature, from about -20 to about -80°C, particularly at about -78 0 C 1 then warmed to ambient temperature if required.
  • reaction is then added to a solution at, from about -20 to about -8O 0 C, particularly at about -78 0 C, of the compound of formula 2 and additional base and then the solution is allowed to warm to room temperature.
  • a suitable oxidizing agent such as terf-butyl hydroperoxide, iodine, MCPBA or oxone is then added to prepare a compound of formula 3-A or 3-B or a pharmaceutically acceptable salt thereof.
  • the substitution on the steroid occurs on the 11 or 21 position is dependent upon the steric hindrance around the 11 and 21 position.
  • the substitution may be driven toward one over the other through the use of protecting groups on the steroid.
  • the selection, installation and removal of protecting groups on the steroid is within the ordinary skill of those in the art.
  • the resulting compound of formula 3-A or 3-B may be deprotected using conventional processes, including acidic conditions, either by brief treatment with HCI in dioxane or by low-temperature treatment with trifluoroacetic acid in dichloromethane at about 0 ° C.
  • the choice of protecting groups on the compound of formula 3-A or 3-B will be based at least in part on the steric bulk of the particular ⁇ -agonist side chain (R 15 ) selected.
  • the foregoing process may be utilized to prepare the corresponding R-isomer of a compound of Formula I-A by substituting the R-enantiomer of the N-Boc- protected compound of formuia 2 starting material for the racemate.
  • the corresponding S-isomer of a compound of Formuia I-A may be made by using the S-enantiomer of the N-Boc-protected compound of formula 2.
  • This same approach may be utilized to prepare enantiomericaify enriched mixtures of any of the compounds of Formula I which contain a chiral center, and pharmaceuticaliy acceptable salts thereof.
  • Example 2 (6 ⁇ ,113,16 ⁇ ,17 ⁇ ) 6 1 9-difluoro-16-methyi-11-rr2-oxido-7-r2-[f6-(4- phenylbutyoxy)hexynamino1-1 (R)-hydroxyethv ⁇ -4H-1 ,3,2- benzodioxaphosphorin-2-yl1oxy1-3-oxo-17-(1-oxopropoxy)androsta-1 ,4-diene- 17-carbothioic acid, S-(fluoromethyi) ester
  • Example 7 Method for Evaluating Stability of Compounds of the Invention and Metabolites thereof 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. (Hicksvilie, NY). Lungs are weighed and homogenized in a 1 :3 w/v ratio with sterile phosphate buffered saline (PBS, 1OmM, 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. 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
  • DMSO 2.7 ⁇ L added to 3 mL of temperature-equilibrated homogenate serves as a control.
  • the glyburide serves as an internal LC/MS/MS standard.
  • the remainder of each drug + homogenate solution is aliquoted into a 96-well tissue culture plates. After an additional 30 min and 120 min incubation at 37 0 C, 100 ⁇ L aliquots are added to 400 ⁇ L quenching solution.
  • Denatured proteins in the quenching solution are separated by centrifugation at 3000 x gravity for 2 min at 4°C, and 160 ⁇ L of the supematants are transferred to new 96-weil piate 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
  • An aliquot (50 ⁇ l_) of each sample is diluted with 50 ⁇ l_ of water containing internal standard at 4 0 C.
  • the diluted samples are then centrifuged for 20 min at 3000 rpm at 4 0 C.
  • An aliquot of 20 ⁇ L of the solution is injected into the TSQ Ultra Quantum LC/MS/MS system.
  • the compounds are separated by HPLC using a HyPurity C18 HPLC column (30 X 2.1 mm, 5 ⁇ ) from ThermoHypersil.
  • a Multiplex LX-2 HPLC system (Cohesive Technologies, Franklin, MA) with two identical Agilent 1100 series binary pumps (P/N G1312A) are used for elution and separation. Samples are maintained at 4 0 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 eiuted 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% acetonitriie in 10 mM ammonium formate with 1 % formic acid.
  • the HPLC elution 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,
  • SRM selective reaction monitoring
  • Example 8 Pharmacokinetic Analysis of Drug Levels of Beta-agonist, Steroid and Compounds of the Invention Conducted in Lung, Bronchoalveolar Lavage
  • 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 cell pellet are collected and stored at approximately -70 0 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 ThermoHypersiS (Part #: 22105-032130) is used.
  • Mobile phase A contains 1 % ACN in 10 mM ammonium formate aqueous solution with 1 % formic acid.
  • Mobile phase B contains 80% ACN 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 Pa! autosampler from LEAP Technologies, Carrboro, NC is used.
  • passage 1 ceils are cultured in bronchial epithelial growth medium (Fulcher, M. L., et al., 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 (Millipore, Bedford, MA) in medium that supports growth at an air-liquid-interface (ALi) (Fulcher et al., 2005). Cells are maintained at an AL! and allowed to differentiate fully for approximately 28 days.
  • bronchial epithelial growth medium Fulcher, M. L., et al., 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 (Millipore, Bedford, MA) in medium
  • the apical surfaces of the cells are washed with sterile phosphate buffered saline (PBS, 1OmM, pH 7.4) and the basolatera! media is replaced with fresh ALI media.
  • PBS sterile phosphate buffered saline
  • 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).
  • the resulting 40 ⁇ M solution is immediately added to the apicai 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 cell culture insert are pooled.
  • the entire basolateral medium from each milliceli cell culture insert is also collected as are the airway epithelial cells which are excised from each millicell 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 cell suspension is then centrifuged at 18,000 g for 2 min and 50 ⁇ l 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, basolateral and cellular matrices for LC/MS/MS analytical standards.
  • 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 % ACN in 10 mM ammonium formate aqueous solution with 1 % formic acid. Mobile phase B contains 80% ACN in 10 mM ammonium formate with 1 % formic acid.
  • the HPLC elution program used to elute the analytes is as follows:
  • the samples are further analyzed by tandem mass spectrometry using an ABI/Sciex API 5000 triple quadrupoie 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 lung homogenate, the concentration ranged from 1 nM to 10 ⁇ M.
  • the calibration curves of the compounds of the invention and their metabolites are prepared by quadratic regression analysis.
  • the results indicate the amount of each of 1 ) the parent compound of the invention, 2) beta-agonist and 3) steroid in the apicai and cellular compartments and whether the amount in each compartment increases or decreases over time. It is expected that the amount of the compound of the invention will decrease over time in both the apical and cellular compartments while the amount of beta-agonist and steroid will increase in the cellular compartment.
  • Example 1 gives the expected breakdown
  • Example 10 In vivo Efficacy of Compound of the Invention in the Mouse Ovalbumin Model of Lung inflammation
  • 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 (Vehicle).
  • Steroid (positive contro! treatment; 1X per day (day 14 and 15; 3 mg/kg), Compound of the invention at 1 , 3, and 6 mg/kg) or 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. Bronchoalveoiar lavage (BAL) is taken from each animal to collect cells and fluid. Cell numbers and differentials were calculated from BAL.
  • BAL Bronchoalveoiar lavage
  • Compound of the invention is evaluated in an LPS-induced airway inflammation mode! in rats.
  • Lungs are lavaged for bronchoalveoiar lavage cell differentials and cytokine analysis by Luminex multiplex immunoassay, it is believed that compounds of the invention will inhibit LPS-induced airway inflammation measured as neutrophil influx and TNF ⁇ production at doses tested (p ⁇ -0.05 versus vehicle control).
  • Example 12 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 H 1000 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 bronchoalveoiar lavage fluid is obtained for cell differentials and cytokine analysis by Luminex multiplex immunoassay.
  • Luminex multiplex immunoassay In 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 IVlIP-I ⁇ production (p ⁇ 0.05 versus vehicle controi at 1.0 and 0.6 mg/kg doses).
  • Example 13 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 tidal volume are measured using a differential pressure transducer located in front of the endotracheal tube. An esophageal bailoon catheter placed in the esophagus is used to determine transpulmonary pressure. Pulmonary resistance and dynamic Sung compliance are calculated from the simultaneous measurement of transpuimonary 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
  • an inhibition of ragweed-induced increases in pulmonary resistance is expected.
  • An inhibition of increased pulmonary resistance change following antigen challenge may also be observed at 10 mg/kg of salmeterol xinafoate (10 mg/kg).
  • Example 14 Ascaris suum-m ⁇ uce ⁇ 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 Serebriakov, 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 h 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 h 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 h before antigen. In the duration of action regimen, animals are dosed once daily for four days, with the last dose administered 24 h before antigen. Test compound, Ascaris antigen, and carbachol are administered by nebulized aerosol to intubated sheep.
  • Example 15 Carbachol-induced bronchoconstriction in sheep
  • the compounds of the invention may be assessed for inhibition of carbachol- induced bronchoconstriction as previously described (Abraham, W. M., A. Ahmed, I Serebrlakov, A.N. Carmillo, J. Ferrant, A.R. de Fougerolies, E.A. Garber, P. J. Gowals, V.E. Koteliansky, F. Taylor, R. R. Lobb. Am. J. Respir. Crit. 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 carbachoi are administered by nebulized aerosol to intubated sheep.
  • API 500 ⁇ g micronized compound of Formula I
  • Micronize the API using a mill e.g. jet mill
  • a mass median aerodynamic diameter from about 1 to about 10 ⁇ m, and preferably a MMAD from about 1 to about 5 ⁇ m.
  • lactose may be milled or sieved. Suitable commercial sources of lactose include DMV-Fonterra Excipients (Lactohaie®) and Frieslandfoods 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.
  • 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.
  • Each canister is to contain 120 dose equivalents of API and propellant + 10% overage.
  • Each canister is filled with 33 mg of API and sealed with a metering valve. The canister is then pressurized with 19.8 mi_ of propellant.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles entités chimiques comprenant des corticostéroïdes et des β-agonistes phosphorylés, destinées à être utilisées en thérapie, et des compositions les comprenant ainsi que des procédés de préparation de celles-ci.
PCT/US2010/034861 2009-05-15 2010-05-14 Composés de β-agonistes et de corticostéroïdes destinés à être utilisés en thérapie WO2010132743A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17879009P 2009-05-15 2009-05-15
US61/178,790 2009-05-15

Publications (1)

Publication Number Publication Date
WO2010132743A1 true WO2010132743A1 (fr) 2010-11-18

Family

ID=42617448

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/034861 WO2010132743A1 (fr) 2009-05-15 2010-05-14 Composés de β-agonistes et de corticostéroïdes destinés à être utilisés en thérapie

Country Status (1)

Country Link
WO (1) WO2010132743A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019136487A3 (fr) * 2018-01-08 2019-09-12 Regeneron Pharmaceuticals, Inc. Stéroïdes et leurs conjugués-anticorps
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
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063777A1 (fr) * 2003-12-23 2005-07-14 Corus Pharma Promedicaments de benzylphosphate et de benzylphosphate substitue utilises dans le traitement d'une inflammation pulmonaire
WO2006138212A1 (fr) * 2005-06-14 2006-12-28 Gilead Sciences, Inc. Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de ? -agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
WO2009152171A1 (fr) * 2008-06-10 2009-12-17 Gilead Sciences, Inc. Composés bêta agonistes liés à des corticostéroïdes en vue d'une utilisation en thérapie

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063777A1 (fr) * 2003-12-23 2005-07-14 Corus Pharma Promedicaments de benzylphosphate et de benzylphosphate substitue utilises dans le traitement d'une inflammation pulmonaire
WO2006138212A1 (fr) * 2005-06-14 2006-12-28 Gilead Sciences, Inc. Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de ? -agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
WO2009152171A1 (fr) * 2008-06-10 2009-12-17 Gilead Sciences, Inc. Composés bêta agonistes liés à des corticostéroïdes en vue d'une utilisation en thérapie

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ABRAHAM, W.M.; A. AHMED; I SEREBRLAKOV; A.N. CARMILLO; J. FERRANT; A.R. DE FOUGEROLLES; E.A. GARBER; P. J. GOWALS; V.E. KOTELLANSK, AM. J. RESPIR. CRIT. CARE. MED., vol. 169, 2004, pages 97 - 104
ABRAHAM, W.M.; A. AHMED; I SEREBRLAKOV; I.T. LAUREDO; J. BASSUK; J.A. ADAMS; M.A. SACKNER, AM. J. RESPIR. CRIT. CARE. MED., vol. 174, 2006, pages 743 - 752
C. MEIER ET AL., J. MED. CHEM., vol. 50, no. 6, 2007, pages 1335 - 1346
CARRYER, JOURNAL OF ALLERGY, vol. 21, 1950, pages 282 - 287
FULCHER, M.L. ET AL.: "Well-differentiated human airway epithelial cell cultures", METHODS MOL MED, vol. 107, 2005, pages 183 - 206
MORRIS, J. ALLERGY CLIN. IMMUNOL., vol. 75, 1985, pages 1 - 13
POSTON, AM. REV. RESPIR. DIS., vol. 145, 1992, pages 918 - 921
WALKER, J. ALLERGY CLIN. IMMUNOL., vol. 88, no. 6, 1991, pages 935 - 42

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2019136487A3 (fr) * 2018-01-08 2019-09-12 Regeneron Pharmaceuticals, Inc. Stéroïdes et leurs conjugués-anticorps
CN112004557A (zh) * 2018-01-08 2020-11-27 里珍纳龙药品有限公司 类固醇类化合物及其抗体偶联物
JP2021509908A (ja) * 2018-01-08 2021-04-08 レゲネロン ファーマシューティカルス，インコーポレーテッド ステロイド及びその抗体コンジュゲート
JP7366028B2 (ja) 2018-01-08 2023-10-20 レゲネロン ファーマシューティカルス，インコーポレーテッド ステロイド及びその抗体コンジュゲート
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
IT201900014178A1 (it) * 2019-08-06 2021-02-06 Genetic S P A Esteri del montelukast e loro formulazioni farmaceutiche
WO2021023751A1 (fr) * 2019-08-06 2021-02-11 Genetic S.P.A. Esters de montélukast et compositions pharmaceutiques les contenant

Similar Documents

Publication Publication Date Title
US20090318396A1 (en) Corticosteroid linked beta-agonist compounds for use in therapy
WO2010126953A1 (fr) Composés bêta-agonistes liés à des corticostéroïdes pour une utilisation en thérapie
US10174038B2 (en) Compounds and methods for antiviral treatment
US8946238B2 (en) Pyrazolo[1,5-A]pyrimidines as antiviral agents
EP1893220A1 (fr) Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de beta-agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
WO2010132743A1 (fr) Composés de β-agonistes et de corticostéroïdes destinés à être utilisés en thérapie
JP4446661B2 (ja) 抗炎症性の、１７α位に環状エステル基を有するアンドロスタンの１７β−カルボチオ酸エステル誘導体
WO2011081937A1 (fr) Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
US8524697B2 (en) C20-C21 substituted glucocorticoid receptor agonists
ES2699507T3 (es) Composición farmacéutica que comprende una suspensión acuosa de un derivado de androstano para el tratamiento de afecciones inflamatorias y alérgicas
WO2011098746A1 (fr) Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
US8450490B2 (en) Bi-functional pyrazolopyridine compounds
EP3877383A1 (fr) Composés et compositions pour le traitement de maladies respiratoires
SG188575A1 (en) Novel combinations
MX2007016094A (en) Substituted phenylphosphates as mutual prodrugs of steroids andî²-agonists for the treatment of pulmonary inflammation and bronchoconstriction

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10720098

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10720098

Country of ref document: EP

Kind code of ref document: A1