WO2019116231A1 - Activateur de nrf2 pour le traitement d'une lésion pulmonaire aiguë, d'un syndrome de détresse respiratoire aiguë et d'un syndrome de dysfonction d'organes multiples - Google Patents

Activateur de nrf2 pour le traitement d'une lésion pulmonaire aiguë, d'un syndrome de détresse respiratoire aiguë et d'un syndrome de dysfonction d'organes multiples Download PDF

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WO2019116231A1
WO2019116231A1 PCT/IB2018/059885 IB2018059885W WO2019116231A1 WO 2019116231 A1 WO2019116231 A1 WO 2019116231A1 IB 2018059885 W IB2018059885 W IB 2018059885W WO 2019116231 A1 WO2019116231 A1 WO 2019116231A1
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alkyl
substituted
methyl
phenyl
hydrogen
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PCT/IB2018/059885
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William Rumsey
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Glaxosmithkline Intellectual Property Development Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to the use of an NRF2 activator to treat respiratory diseases.
  • the present invention relates to the treatment of respiratory diseases, in a mammal, in which related organ failure accompanied by accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation has occurred.
  • Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDs) results from a seemingly diverse array of etiologies such as bacterial infection, inhalation of toxic substances, direct injury to the lung, sepsis, burn, substantial levels of blood transfusion, eclampsia, etc.
  • ALI and ARDs occur in hospital settings where 5-10% of patients are within intensive care units (ICU) and up to 25% of ventilated individuals become afflicted by this syndrome (Cannon et al., Crit Care Clin 33: 259-275, 2017; Umbrello et al., Int J Mol Sci 18: 64-84, 2017). It is a heterogenous condition that results from a diverse ICU population.
  • ALI and ARDs contain a systemic component, in particular when coupled with infection of the lung.
  • MODS organ dysfunction syndrome
  • mtDAMPs fragments of mtDNA, so-called mtDAMPs, are released into the circulation following severe injury which can serve as mediators of inflammation in areas distal to the site of insult.
  • MtDNA is thought to be more susceptible to damage and mutation than nuclear DNA.
  • ROS reactive oxygen species
  • NRF2 Nfe212
  • the NRF2 (Nfe212) transcription factor is activated, primarily in alveolar type II cells, to promote mitochondrial biogenesis and counter inflammation (Athale et al., Free Radio Biol Med 53(8): 1584-1594, 2012).
  • the molecular deletion of this transcription factor suppresses mitogenesis and enhances inflammation, thereby exacerbating ALI.
  • Genetic variation of NRF2 provide susceptibility to ALI in both mice and in humans (Marzec et al., FASEB J 21 : 2237-2246, 2007, Cho et al., Antioxidants Redox Signaling 22:/4; 325338, 2015).
  • the treatment of animals with Bardoxolone, an NRF2 activator protected them from hyperoxia-induced ALI (Reddy et al., Am J Respir Crit Care Med 180: 867-874, 2009).
  • PQ paraquat
  • PQ is a redox cycler that associates with the mitochondrial respiratory chain, principally at Complex I where it converts molecular oxygen to the superoxide radical which damages mitochondrial lipids, proteins, and DNA (Cocheme and Murphy J Biol Chem. 283(4):1786-1798, 2008).
  • the principal cellular target of PQ’s destructive action is the alveolar epithelium, specifically Type I and II pneumocytes (Smith and Heath J Clin Pathol Suppl (R Coll Pathol). 9:81 -93,1975).
  • a single intraperitoneal administration of the agent to rats results in rapid swelling of Type I alveolar epithelium with additional degenerative changes in Type II cells (ibid).
  • Progressive damage, i.e. , sloughing of the epithelium, alveolar edema, congested capillaries and inflammation with mononuclear cells apparent in the alveolar spaces can be found within a few days.
  • Ozone is the most prevalent form of air pollution and the most dangerous causing premature death due to respiratory diseases (Jerrett et al., N Engl J Med. 360(1 1):1085-95, 2009). Even low levels of ozone exposure to humans is associated with ALI/ARDS in at risk critically-ill persons (Ware et al., Am J Respir Crit Care Med. 93(10):1 143-50, 2016).
  • Ozone and other environmental hazards like tobacco smoke, may serve as risks factors for the development of ALI/ARDs. Similar to PQ, ozone invokes oxidative stress within the cells that they contact and adversely affect mitochondrial function.
  • ALI and ARDS remains a global health problem for which there are few medical recourses or medications.
  • ALI/ARDs presents in afflicted persons as hypoxemia with bilateral pulmonary infiltrates.
  • the pulmonary edema is of non-cardiogenic origin and the compliance of the lung is adversely affected.
  • the small vessels of the pulmonary circulation become leaky permitting passage of fluid and proteins into the gas exchange units or alveoli thereby compromising the diffusion of oxygen and the removal of carbon dioxide to and from the blood stream.
  • Treatment is largely dependent upon mechanical maneuvers to improve the ventilatio perfusion ratio of the lung.
  • Pharmacological treatments are few with bronchodilators, neuromuscular blockade and corticosteroids demonstrating mixed results.
  • Compound I is an NRF2 activator 3-(3-(((R)-4-ethyl-1 ,1-dioxido- 3,4-dihydro-2H-pyrido[2,3-b][1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4- methyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)propanoic acid (Compound I) or a pharmaceutically acceptable salt thereof, described in PCT application WO 2015/092713A1 , published on June 25, 2015, incorporated herein by reference. The preparation of the specific NRF2 activator claimed herein is found in Example 146.
  • NRF2 activator is a compound of Formula (I) as disclosed in co-pending published patent application WO2015/092713, published 25 June 2015.
  • A is -C(0)0Ri or tetrazolyl
  • R1 is hydrogen, -CH 2 C(0)N(R 7 ) 2 , -CH 2 -(4-methyl-1 ,3-dioxol-2-one), -C2-3 alkyl-OH, Ci_ 3 alkyl, -C2-5 alkyl-N(R 7 )2, -(CH2)n-morpholinyl, -(CFhVfuryl, -CH 2 -0-C(0)-CI-5 alkyl, -(CH 2 ) n -imidazolyl, -(CF Vpyrrolidinyl, -(CH 2 ) n -piperidyl, or 2-oxotetrahydrofuran-3-yl;
  • morpholinyl and piperidyl may be substituted by one or two C 1-3 alkyl; and the pyrrolidinyl, imidazolyl, and furyl may be substituted by one or two groups independently selected from C 1-3 alkyl, halo, and -O-C 1-3 alkyl;
  • R 2 is: -(CH 2 ) n -phenyl, which may be substituted by one, two, or three groups independently selected from -CN, -F, -Cl, -C(0)N(R 7 ) 2 , -C(Q)OH, -C(0)CH 3 , -O-C 1-3 alkyl,
  • -S-C 1 -3 alkyl C 1 -3 alkyl, -C 1 -3 alkyl-N(R 7 ) 2 , -CF 3 , and -OCF 3 ; benzotriazolyl, which may be substituted by one, two, or three groups independently selected from -O-C 1-3 alkyl, -F, -Cl, -CF 3 , -OCF 3 , C 1-3 alkyl, and -C 2-3 alkyl- NH-C(0)-0-Ci- 4 alkyl, or may be substituted by R 13 and optionally by one or two additional groups independently selected from -O-C 1-3 alkyl, -F, -Cl, -CF 3 , -OCF 3 , and C 1-3 alkyl;
  • R 3 is R 4 -S0 2 -N(Re)-;
  • R 4 is phenyl, C cycloalkyl, thienyl, imidazolyl, pyrazolyl, pyridyl, piperidyl, tetrahydro-2H-pyranyl, Ci_ 3 alkyl, or each of which may be substituted by one or two groups independently selected from Ci_ 3 alkyl, -NH-C(0)-CH 3 , -0-Ci_ 3 alkyl,
  • X is CH 2 , NRg or O; each Y is independently N or CH; provided that not more than one Y is N; each Z is independently O, CH 2 , or NRi 0 ;
  • R 5 is hydrogen, -F, -Cl, Ci_ 3 alkyl, or -CF 3 ;
  • R 6 is hydrogen, Ci_ 3 alkyl, or -C2-3 alkyl-OH;
  • each R 7 is independently hydrogen or Ci_ 3 alkyl;
  • each R 8 is independently hydrogen, -NH 2 , or Ci_ 3 alkyl, provided that at least one R 8 is hydrogen or Ci_ 3 alkyl;
  • R11 is hydrogen, halo, -CF 3 , -CN, -C(0)N(R 7 ) 2 , -Ci_ 3 alkyl-N(R 7 ) 2 , or -Ci_ 3 alkyl-NH- C(0)-0-Ci- 4 alkyl;
  • RI 2 is hydrogen; or R 5 and RI 2 taken together represent -CH 2 CH 2 -; each RH is independently hydrogen, Ci_ 3 alkyl, or -CH 2 -phenyl; each n is independently 0, 1 , 2, or 3; and m is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Another NRF2 activator useful in treating the diseases disclosed herein is a compound of Formula (II) as disclosed in co-pending published patent application
  • B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH 2 )2 triazolyl, each of which is unsubstituted or substituted by 1 , 2, or 3 substituents independently selected from -C i_ 3 alkyl,
  • D is -C(0)0H, -C(0)NHS0 2 CH 3 , -S0 2 NHC(0)CH 3 , 5-(trifluoromethyl)-4H-1 ,2,4- triazol-2-yl, or tetrazolyl;
  • Ri is independently hydrogen, Ci_ 3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two Ri groups together with the carbon they are attached to form a cyclopropyl group;
  • R 2 is hydrogen, methyl, CF 3 , or halo
  • R 3 is CH 3 , -(CH 2 ) 2 -OH, or NH 2 ;
  • R 4 is hydrogen or Ci_ 3 alkyl
  • A is cyclopentyl, cyclohexyl, cycloheptyl, or phenyl each of which is unsubstituted or substituted by one or two moieties selected from -Ci_ 3 alkyl, CN, halo, -OH and -0-Ci- 3 alkyl groups; or A is C1-5 alkyl which is unsubstituted or substituted by -OCH 3 ; and phenyl which is unsubstituted or substituted by -0-CH(CH 3 )-C(0)-0H- or N0 2 ; or a pharmaceutically acceptable salt thereof.
  • NRF2 activator useful in treating the diseases disclosed herein is a compound of Formula (III) as disclosed in co-pending published patent application
  • B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1 , 2, or 3 substituents independently selected from -C i_ 3 alkyl, -O- C i- 3 alkyl, CN, -(CH 2 ) 2 -0-(CH 2 ) 2 -0R 4 and halo;
  • D is -C(0)0H, -C(0)NHS0 2 CH 3 , -S0 2 NHC(0)CH 3 , 5-(trifluoromethyl)-4H-1 ,2,4- triazol-2-yl, or tetrazolyl;
  • Ri is independently hydrogen, Ci_ 3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two Ri groups together with the carbon to which they are attached form a cyclopropyl group;
  • R 4 is hydrogen or Ci_ 3 alkyl
  • A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl, or tetrahydro-pyrido-oxazepinyl, all of which is unsubstituted or substituted by 1 , 2, or 3 substituents independently selected from -Ci_ 3 alkyl, halo, CN, -OC i- 3 alkyl, -CH 2 -0-CH 3 , C 3. 6 spirocycloalkyl, and OH; n is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Another NRF2 activator useful in treating the diseases disclosed herein is a compound of Formula (IV) as disclosed in co-pending published patent application
  • B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH 2 )2 triazolyl each of which is unsubstituted or substituted by 1 , 2, or 3 substituents independently selected from -C i_ 3 alkyl,
  • D is -C(0)0H, -C(0)NHS0 2 CH 3 , -S0 2 NHC(0)CH 3 , 5-(trifluoromethyl)-4H-1 ,2,4- triazol-2-yl, or tetrazolyl;
  • Ri is independently hydrogen, Ci_ 3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two Ri groups together with the carbon to which they are attached form a cyclopropyl group;
  • R 2 0 or hydrogen
  • R 4 is hydrogen or -Ci_ 3 alkyl
  • Linker is -CH 2 , -O-C(O)-, -CH 2 -C(0)-, -C(O)-, -CH(CH 3 )-C(0)-, or -N(CH 3 )-C(0)-;
  • A is cyclohexyl, cyclopentyl, phenyl or decahydronapthalenyl; each of which is unsubstituted or substituted by one or more substituents independently selected from Ci_ 3 alkyl, CN, and halo; or A is C4-5 alkyl which is substituted by -OCi_ 3 alkyl; n is 1 or 2;
  • X is CH 2 or O; or a pharmaceutically acceptable salt thereof.
  • Another NRF2 activator useful in treating the diseases disclosed herein is a compound of Formula (V) as disclosed in co-pending published patent application
  • B is benzotriazolyl, phenyl, triazolopyridinyl, or -(CH 2 ) 2 triazolyl each of which is unsubstituted or substituted by 1 , 2, or 3 substituents independently selected from -C 1- 3 alkyl,
  • D is -C(0)0H, -C(0)NHS0 2 CH 3 , -S0 2 NHC(0)CH 3 , 5-(trifluoromethyl)-4H-1 ,2,4- triazol-2-yl, or tetrazolyl;
  • R1 is independently hydrogen, Ci_ 3 alkyl, F, C 3-6 spirocycloalkyl, oxetane, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
  • R 2 is hydrogen, methyl, CF 3 , or halo
  • R 4 is hydrogen or -Ci_ 3 alkyl
  • Linker is -CH 2 -, -CH 2 -N(-cyclopropyl)-CH 2 -, -CH 2 -N(CH 3 )-CH 2 - or -N-(CH 3 )-CH 2 -;
  • A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl,
  • piperidinyl may additionally be independently substituted by pyrazolyl, - CH 2 pyrazolyl, or oxadiazolyl each of which may be further independently substituted by -Ci_ 3 alkyl, or, when A is piperidinyl, it may be substituted by -S0 2 R, wherein R is -Ci_ 3 alkyl, phenyl or C 3-7 cycloalkyl;
  • oxazepane may additionally be independently substituted by 1 or 2 of -Ci- 3 alkyl or -C 3-7 cycloalkyl;
  • morpholinyl may additionally be substituted by a phenyl which itself may be independently substituted by Ci_ 3 alkyl or -O- Ci_ 3 alkyl;
  • pyrrolidinyl may be additionally substituted by a triazolyl group which itself is may be substituted by -Ci- 3 alkyl;
  • imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may be additionally independently substituted by -CH 2 -C 4-7 cycloalkyl, -CH 2 -C 5-7 heterocycloalkyl, -CH 2 - azabicycloheptanyl, -CH 2 -oxepane, or -CH 2 -azabicyclohexanyl, all of which, including the - CH 2 -, may be further substituted independently by 1 or 2 of -Ci_ 3 alkyl or F; and
  • X is independently CH or N; or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to the novel use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for the treatment of acute lung injury.
  • the present invention is directed to the novel use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for the treatment of acute respiratory distress syndrome.
  • the present invention is directed to the novel use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for the treatment of multiple organ dysfunction syndrome.
  • the present invention is directed to a method of treating acute lung injury in a mammal in need thereof, comprising administering an effective amount of an NRF2 activator as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of treating acute respiratory distress syndrome in a mammal in need thereof, comprising administering an effective amount of an NRF2 activator as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of treating multiple organ dysfunction syndrome in a mammal in need thereof, comprising administering an effective amount of an NRF2 activator as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of treating the symptoms of acute lung injury in a mammal in need thereof, comprising administering an effective amount of an NRF2 activator as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), or a pharmaceutically acceptable salt thereof.
  • the symptoms include but are not limited to, an accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation.
  • these symptoms are exhibited by increased neutrophil and macrophage accumulation in the bronchoalveolar lavage fluid.
  • the present invention is directed to the use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), in the manufacture of a medicament for the treatment of acute lung injury.
  • the present invention is directed to the use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), in the manufacture of a medicament for the treatment of acute respiratory distress syndrome.
  • the present invention is directed to the use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula
  • the present invention is directed to the use of an NRF2 activator, or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), in the manufacture of a medicament for the treatment of the symptoms of acute lung injury including but not limited to, an accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation.
  • an accumulation of alveolar fluid including but not limited to, an accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation.
  • these symptoms are exhibited by increased neutrophil and macrophage accumulation in the bronchoalveolar lavage fluid.
  • the present invention is directed to an NRF2 activator or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula
  • the present invention is directed to an NRF2 activator or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for use in the treatment of acute respiratory distress syndrome.
  • the present invention is directed to an NRF2 activator or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for use in the treatment of multiple organ dysfunction syndrome.
  • the present invention is directed to an NRF2 activator or a pharmaceutically acceptable salt thereof, as defined by Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V), for use in the treatment of the symptoms of acute lung injury, including but not limited to, an accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation.
  • an accumulation of alveolar fluid, hypoxemia, cough, wheezing, dyspnea, hyperpnea and pulmonary inflammation Suitably, on a cellular level, these symptoms are exhibited by increased neutrophil and macrophage accumulation in the bronchoalveolar lavage fluid.
  • Figure 1A provides time-dependent changes in lung function, expressed as Penh.
  • Figure 1 B shows changes in lung wet:dry weight ratio in response to PQ and PQ plus Compound I.
  • Compound I was administered as a suspension by intra-tracheal delivery 24 hrs. prior to PQ (0.05 mg/kg i.t.) administration.
  • Figure 2 depicts the effect of NRF2 activator Compound I on measurements of pulmonary inflammation. These data show the reduction in inflammatory immune cells in bronchoalveolar lavage fluid obtained from paraquat-treated rats. All data represent means ⁇ S.E.M.
  • Figure 3 depicts the effect of NRF2 activator Compound I on relative mtDNA copy number, a measure of mtDNA damage (Figure 3A), NRF2-mediated gene expression (Figure 3B) and 8-OHdG levels (Figure 3C).
  • Other genes GCLC, HO-1 , etc., exception being TXNRD1 were also up-regulated relative to the PQ treated vehicle control animals.
  • Figure 4 depicts the effect of NRF2 activator Compound I on ozone-induced changes in lung wet to dry weight ratio (Figure 4A) and relative mtDNA copy number (Figure 4B).
  • Rats were administered the NRF2 activator (3 mhioI/kg i.t.) 24 hours prior to ozone exposure (1 ppm of ozone for 3 hours). Four hrs later the animals were sacrificed. All data represent means ⁇ S.E.M. (*, **, *** refer to p ⁇ 0.05, 0.01 and 0.001 , respectively).
  • Figure 5 depicts the protection offered by NRF2 activator Compound I against ozone- induced death (Figure 5A) and loss of glutathione (Figure 5B). Due to an unknown faulty ventilation system, ozone in the chamber built up to levels (unable to quantify) above those normally used in other studies. The intended exposure was 1 ppm. For those animals that survived, tissue values of NRF2-related parameters were examined 24 hrs. after ozone exposure. In addition, animals exposed to ozone within the control group were combined.
  • Figure 6 depicts the protective effect of administering NRF2 Compound I on the degradation or breakdown of the alveolar barrier in mice.
  • Mice were exposed to ozone (1 .5 ppm) for 3 hrs, twice per week for 3 weeks.
  • Compound 1 was administered for 5 days/week, with the first dose administered 1 hour prior to first ozone administration. Blood/serum was collected 2 hrs after the final ozone exposure.
  • Surfactant protein-D was measured using a commercially available ELISA kit. All data represent mean +/- S.E.M.
  • Methylpyrrolidin-3-yl 3-(1 ,4-dimethyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)-3-(4-methyl-3-((5- methyl-1 ,1-dioxido-4,5-dihydrobenzo[f][1 ,2,5]thiadiazepin-2(3H)- yl)methyl)phenyl)propanoate;
  • Specific compounds of Formula (II) useful in treating the diseases described herein are selected from: 3-[3-( ⁇ [(tert-butoxy)carbonyl](methyl)amino ⁇ methyl)-4-chlorophenyl]-3-(1 ,4-dimethyl-
  • “pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the methods of treatment of the invention comprise administering an effective amount of a Compound I or a pharmaceutically-acceptable salt thereof to a mammal in need thereof.
  • treat in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • effective amount or“an effective amount” in reference to a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • An effective amount of the compound will vary depending on factors such as the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • mammal refers to a human or other animal. It will be understood that the patient to be treated with a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, is a mammal, preferably a human.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof is administered via inhalation.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof is administered parenterally.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof is administered via inhalation.
  • the compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V) may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per day. Preferred dosages are 1 - 500 mg once daily, more preferred is 1 - 100 mg per person per day. IV dosages range from 0.1 -000mg/day, preferred is 0.1-500mg/day, and more preferred is 0.1-100mg/day. Inhaled daily dosages range from 10ug-10mg/day, with preferred 10ug-2mg/day, and more preferred 50ug-500ug/day.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be administered as a prodrug.
  • a prodrug of Compound I is a functional derivative of the compound which, upon administration to a patient, eventually liberates Compound I in vivo.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo (c) modify the transportation or distribution of the compound in vivo (d) modify the solubility of the compound in vivo and (e) overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • compositions comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically-acceptable excipients.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg of the active agent.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable, are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; and (3) inhalation such as dry powders, aerosols, suspensions, and solutions.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chel
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder.
  • Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the invention is directed to a dosage form adapted for administration to a patient parenterally including subcutaneous, intramuscular, intravenous or intradermal.
  • Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that 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 ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.
  • Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, as a finely divided powder together with one or more pharmaceutically acceptable excipients as finely divided powders.
  • Pharmaceutically acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
  • compositions for use in accordance with the present invention are administered via inhalation devices.
  • such devices can encompass capsules and cartridges of for example gelatin, or blisters of, for example, laminated aluminum foil.
  • each capsule, cartridge or blister may contain doses of composition according to the teachings presented herein.
  • inhalation devices can include those intended for unit dose or multi-dose delivery of composition, including all of the devices set forth herein.
  • the formulation can be pre-metered (e.g., as in Diskus ® , see GB2242134, U.S. Patent Nos.
  • the Diskus ® inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing the compound optionally with other excipients and additive taught herein.
  • the peelable seal is an engineered seal, and in one embodiment the engineered seal is a hermetic seal.
  • the strip is sufficiently flexible to be wound into a roll.
  • the lid 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 engineered 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.
  • a dry powder composition may also be presented in an inhalation device which permits separate containment of two different components of the composition.
  • these components are administrable simultaneously but are stored separately, e.g., in separate pharmaceutical compositions, for example as described in WO 03/061743 A1 WO 2007/012871 A1 and/or W02007/068896, as well as U.S. Patent Nos. 8,1 13,199, 8,161 ,968, 8,51 1 ,304, 8,534,281 , 8,746,242 and 9,333,310.
  • an inhalation device permitting separate containment of components is an inhaler device having two peelable blister strips, each strip containing premetered doses in blister pockets arranged along its length, e.g., multiple containers within each blister strip, e.g., as found in ELLIPTA®.
  • Said device has an internal indexing mechanism which, each time the device is actuated, peels open a pocket of each strip and positions the blisters so that each newly exposed dose of each strip is adjacent to the manifold which communicates with the mouthpiece of the device. When the patient inhales at the mouthpiece, each dose is simultaneously drawn out of its associated pocket into the manifold and entrained via the mouthpiece into the patient's respiratory tract.
  • a further device that permits separate containment of different components is DUOHALERTM of Innovata.
  • various structures of inhalation devices provide for the sequential or separate delivery of the pharmaceutical composition(s) from the device, in addition to simultaneous delivery.
  • Aerosols may be formed by suspending or dissolving Compound I in a liquefied propellant.
  • Suitable propellants include halocarbons, hydrocarbons, and other liquefied gases.
  • Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 ,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA- 227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising Compound I will typically be administered to a patient via a metered dose inhal
  • the aerosol may contain additional pharmaceutically acceptable excipients typically used with multiple dose inhalers such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • additional pharmaceutically acceptable excipients typically used with multiple dose inhalers such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • Suspensions and solutions comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, may also be administered to a patient via a nebulizer.
  • the solvent or suspension agent utilized for nebulization may be any pharmaceutically acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof.
  • Saline solutions utilize salts which display little or no pharmacological activity after administration.
  • organic salts such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
  • alkali metal or ammonium halogen salts e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid.
  • an inorganic acid e.g., hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid
  • an organic acid e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc.
  • a complexing agent such as EDTA or citric acid and salts thereof
  • an antioxidant such as antioxidant such as vitamin E or ascorbic acid.
  • benzalkonium chloride or benzoic acid and salts thereof Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.
  • One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimize the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will readily be appreciated by those skilled in the art.
  • the invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, together with another therapeutically active agent.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, or pharmaceutical formulations of the invention may be administered together with an anti-inflammatory agent such as, for example, a corticosteroid, or a pharmaceutical formulation thereof.
  • an anti-inflammatory agent such as, for example, a corticosteroid, or a pharmaceutical formulation thereof.
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be formulated together with an anti-inflammatory agent, such as a corticosteroid, in a single formulation, such as a dry powder formulation for inhalation.
  • a pharmaceutical formulation comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, may be administered in conjunction with a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, either simultaneously or sequentially.
  • an anti-inflammatory agent such as a corticosteroid
  • Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, may each be held in device suitable for the simultaneous administration of both formulations via inhalation.
  • Suitable corticosteroids for administration together with a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof include, but are not limited to, fluticasone furoate, fluticasone propionate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide and prednisolone.
  • compounds or pharmaceutical formulations of the invention may be administered together with one or more bronchodilators, or pharmaceutical formulations thereof.
  • Compound a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be formulated together with one or more bronchodilators in a single formulation, such as a dry powder formulation for inhalation.
  • a pharmaceutical formulation comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be administered in conjunction with a pharmaceutical formulation comprising one or more bronchodilators, either simultaneously or sequentially.
  • a formulation comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and a bronchodilator may be administered in conjunction with a pharmaceutical formulation comprising a further bronchodilator.
  • a pharmaceutical formulation comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutical formulation comprising one or more bronchodilators may each be held in device suitable for the simultaneous administration of both formulations via inhalation.
  • a pharmaceutical formulation comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof, together with a bronchodilator and a pharmaceutical formulation comprising a further bronchodilator may each be held in device suitable for the simultaneous administration of both formulations via inhalation.
  • Suitable bronchodilators for administration together with a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof include, but are not limited to, p 2 -adrenoreceptor agonists and anticholinergic agents.
  • Examples of p 2 -adrenoreceptor agonists include, for example, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.
  • Suitable anticholinergic agents include umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide).
  • a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), or a pharmaceutically acceptable salt thereof may be administered together with a p 2 -adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as, umeclidinium.
  • Age-matched male Lewis rats 250-400 g, Charles River Breeding Laboratories, Wilmington, MA were allowed free access to food and water. Animals were administered NRF2 compound via tracheal instillation 24 hours prior to oxidative insult.
  • the trachea was illuminated and either PQ or vehicle (300 pi, doses identified in figure legends) was directly instilled into the trachea, anterior to the primary bifurcation at the carina, using a blunt-tipped needle. The animal was returned to a recovery cage, where the righting reflex was regained in 2-3 minutes.
  • bronchoalveolar lavage was performed to identify the immune cells infiltrating the lung in response to the toxicant.
  • the trachea was surgically exposed and a blunt-tipped needle was inserted into the trachea for administration of lavage fluid (5 X 5 ml Dulbecco’s phosphate buffered saline, PBS).
  • lavage fluid 5 X 5 ml Dulbecco’s phosphate buffered saline, PBS.
  • the lavage fluid was collected, placed on ice and centrifuged (3000 rpm X 10 min, Beckman-Coulter, Danvers, MA,). Supernatant was aspirated and frozen whereas the pellet was resuspended in 5 ml of PBS.
  • ozone In another study, rats were exposed to ozone (2.0 ppm) for a 3 hr period twice a week with a resting period of 2 days between treatments. In some cases, ozone (1 ppm) was applied twice per week for three consecutive weeks. Ozone was generated (Oxycycler ozonator (model# A84ZV, Biospherix Inc., Lacona, NY) by passing room air through the ozonator at a rate of 50 -75 cm 3 /min, mixing it with filtered room air at a rate of 10 L/min, and flowing this sample into a Plexiglass chamber containing the rodents.
  • Ozone was generated (Oxycycler ozonator (model# A84ZV, Biospherix Inc., Lacona, NY) by passing room air through the ozonator at a rate of 50 -75 cm 3 /min, mixing it with filtered room air at a rate of 10 L/min, and flowing this sample into a Plexiglass
  • Ozone, carbon dioxide and humidity levels in the chamber were constantly monitored (Ozone Monitor Model 450, Teledyne Advanced Pollution Instrumentation, Inc., Thousand Oaks, CA). The animals were euthanized as described above 24 hrs after the last exposure to ozone. See Figure 4- 5.
  • Total DNA was extracted from samples of the frozen right inferior pulmonary lobe excised from animals exposed to toxicant or from respective sham animals.
  • tissue was added to lysis buffer (Kingfisher DNA or RNA extraction kit, Thermo Fisher Scientific, Waltham, MA) and the samples were processed according to the manufacturer’s instructions.
  • the nucleotide quantities were determined with respective Qubit kits (Thermo Fisher, Waltham, MA).
  • Qubit kits For measurement of mtDNA copy number by quantitative real time PCR, nuclear and mitochondrial primer sets (1 pmol/pl), and 2x SYBR green master mix (Life Technologies, Waltham, MA) were added to 50 ng of DNA combined with water (total 20 ul).
  • the reaction was run according to the following protocol: 95°C X 20 sec, then 40 cycles of 95°C X 1 sec and 60°C X 20 sec followed by a melt curve of one cycle of 95°C X 15 sec, 60°C X 60 sec, and 95°C X 15 sec (Viia 7, Life Technologies, Waltham, MA, and Viia 7 software version 1.2.2).
  • the primer sequences were:
  • MAPK1 sense G CTTAT GAT AAT CT C AAC AAAGTTCG , and
  • MAPK1 antisense ATGTTCTCATGTCTGAAGCG for the mitochondrial and nuclear primer sets respectively.
  • Relative copy number was calculated using the modified delta CT method as previously described (20) and expressed as a relative fold-change based upon control values with confidence intervals.
  • thermocycler reaction conditions for long PCR were: 2 min incubation at 94°C followed by 20 cycles at 94°C X 15 sec, 65°C X 30 sec, and 68°C X 8 min, and then finished at 72°C X 7min and 94°C X 2 min.
  • the short reaction was carried out as for the mouse.
  • the long and short primer sequences for rat were:
  • the long and short PCR products were then diluted 1 :10 with Tris EDTA buffer containing 5 pl/ml of Pico Green (Molecular Probes, Invitrogen, Carlsbad CA) and fluorescence was monitored (485 nm excitation/528 nm emission, Envision PerkinElmer, Waltham, MA). The replicates for each sample were averaged, the long primer was subtracted from the short primer, and transformed into percent of control using normalization functions (GraphPad Prism v6.0, La Jolla, CA). The data were calculated to reflect an increase in damage by subtracting the long primer from the short primer, rather than the opposite which would show the reduction of signal. See Figure 3.
  • SP-D Surfactant protein-D
  • MSFPD0 Surfactant protein-D
  • Gen5 software version 2.03. Ink
  • Blood was collected via cardiac puncture from mice anesthetized with 3-5% isoflurane, allowed to congeal at room temperature for 30 min, and centrifuged (3000 rpm X 10 min). The serum was removed and placed into 96 well microplates (Nunc Maxisorp microplates, #12-565-135,

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Abstract

La présente invention concerne l'utilisation d'un activateur de NRF2 pour traiter des maladies respiratoires. En particulier, la présente invention concerne le traitement de maladies respiratoires, chez un mammifère, dans lequel une défaillance d'organe associée s'accompagne d'une accumulation de fluide alvéolaire, de toux, de sibilance (sifflement respiratoire), de dyspnée, d'hyperpnée, d'hypoxémie et d'inflammation pulmonaire s'est produite.
PCT/IB2018/059885 2017-12-11 2018-12-11 Activateur de nrf2 pour le traitement d'une lésion pulmonaire aiguë, d'un syndrome de détresse respiratoire aiguë et d'un syndrome de dysfonction d'organes multiples WO2019116231A1 (fr)

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