WO2010135470A1 - Dérivés de pirfénidone pour le traitement de l'asthme - Google Patents

Dérivés de pirfénidone pour le traitement de l'asthme Download PDF

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WO2010135470A1
WO2010135470A1 PCT/US2010/035476 US2010035476W WO2010135470A1 WO 2010135470 A1 WO2010135470 A1 WO 2010135470A1 US 2010035476 W US2010035476 W US 2010035476W WO 2010135470 A1 WO2010135470 A1 WO 2010135470A1
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pirfenidone analog
patient
pharmaceutically acceptable
substituted
ester
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PCT/US2010/035476
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English (en)
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Karl Kossen
Erwin W. Gelfand
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Intermune, Inc.
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Publication of WO2010135470A1 publication Critical patent/WO2010135470A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention relates to methods of treating patients with bronchial asthma with a pirfenidone analog described herein.
  • Bronchial asthma is a heterogeneous respiratory disease characterized by airway inflammation, airway hyperresponsiveness (AHR), and reversible obstruction. It is also associated with allergen-induced chronic airway inflammation. The pathophysiology of AHR is complex, and many factors contribute to its development.
  • Airway mucosal inflammation is characterized by an influx of activated eosinophils and T lymphocytes [Azzawi et al., 1990, Am Rev Respir Dis 142:1407-1413], and numerous investigations have shown that Th2 cytokines (particularly IL-4, IL-5, and IL-13) play critical roles in orchestrating the allergic inflammatory response leading to AHR [Ying et al., 1997, J Immunol 158:3539-3544; Kotsimbos et al., 1996, Proc Assoc Am Physicians 108: 368-373; Minty et al., 1997, Eur Cytokine Netw 8:203-213; Hogan et al., 1998, J Immunol 161:1501-1509; Hansen et al., 1999, J Clin Invest 103:175-183].
  • Airway structural changes occur in response to persistent inflammation and include subepithelial fibrosis, hyperplasia of mucus glands, myofibroblast and smooth muscle proliferation, and vascular changes [Elias et al., 1999, J Clin Invest 104:1001-1006]. Collectively, these responses are termed airway remodeling, which is thought to occur as a result of an imbalance in the mechanism of regeneration and repair. Transforming growth factor (TGF)- ⁇ l, which accelerates fibrotic changes through the accumulation of extracellular matrix, may play a key role in this airway remodeling process.
  • TGF Transforming growth factor
  • TGF- ⁇ l expression correlates with basement membrane thickness and fibroblast number [Elias et al., 1999, J Clin Invest 104:1001-1006; Vignola et al., 1997, Am J Respir Crit Care Med 156:591-599]. Furthermore, although TGF- ⁇ l is reported to be an important factor in the regulation of acute pulmonary inflammation, as in pneumonia [Buhling et al., 1999, J Interferon Cytokine Res 19:271-278], its role in asthma remains to be defined. [0004] The pathophysiology of asthma involves allergens triggering a cascade of cellular interactions and the release of cytokines and mediators in sensitized individuals, resulting in acute and late or delayed symptoms.
  • Th2 cells through the release of cytokines and chemokines, regulate inflammatory cell recruitment to the lung, leading to AHR.
  • Airway inflammation is a fundamental characteristic of asthma and over time may lead to airway remodeling.
  • the structural alterations induced during remodeling may play an important role in eliciting the airway functional changes.
  • Subepithelial fibrosis, goblet cell hyperplasia, mucus hypersecretion, and myofibroblast hypertrophy are components of the remodeling response [Elias et al., 1999, J Clin Invest 104:1001-1006].
  • a compound that inhibits fibrosis and possesses antiinflammatory properties has beneficial effects on the effects of bronchial asthma including allergen-induced chronic airway inflammation, AHR, and airway remodeling.
  • Provided herein are means to prevent the development or increase in AHR, prevent allergen-induced chronic airway inflammation, reduce goblet cell hyperplasia, and reduce airway basement membrane collagen deposition.
  • the reduction in goblet cell hyperplasia is at least 15%.
  • the reduction of airway basement membrane collagen deposition is at least 20%.
  • a method for treating bronchial asthma comprising administering a therapeutically effective amount of a pirfenidone analog to a patient in need thereof. It will be understood that the use of pirfenidone is expressly excluded from the methods and practice of the invention.
  • administration of the pirfenidone analog prevents an increase in airway hyperresponsiveness (AHR) relative to a patient not administered the pirfenidone analog.
  • AHR airway hyperresponsiveness
  • administration of the pirfenidone analog prevents development of airway hyperresponsiveness (AHR).
  • AHR airway hyperresponsiveness
  • administration of the pirfenidone analog prevents or reduces airway inflammation.
  • the airway inflammation is allergen-induced.
  • administration of the pirfenidone analog results in an increase in IL- 12 production in the patient administered a pirfenidone analog relative to the patient not administered the pirfenidone analog. In one aspect, the increase is at least 15%.
  • administration of the pirfenidone analog results in a decrease in cytokine and/or growth factor production in the patient administered a pirfenidone analog relative to the patient not administered the pirfenidone analog.
  • the cytokine is selected from the group consisting of IL-13, IL-5, or both IL-13 and IL-5.
  • the growth factor is selected from the group consisting of PDGF and TGF- ⁇ l. In one aspect, the decrease is at least 15%.
  • administration of the pirfenidone analog results in a reduction in long term airway remodeling relative to a patient not administered the pirfenidone analog.
  • administration of the pirfenidone analog reduces goblet cell hyperplasia relative to a patient not administered the pirfenidone analog.
  • administration of the pirfenidone analog reduces airway basement membrane collagen deposition relative to a patient not administered the pirfenidone analog.
  • the pirfenidone analog can be administered in combination with an asthma therapeutic agent.
  • the asthma therapeutic agent can be selected from the group consisting of an inhaled corticosteroid, oral corticosteroid, leukotriene modifier (e.g., leukotriene receptor antagonist or 5-lypoxygenase inhibitor), beta agonist (both long and short acting), mast cell stabilizer, anti-IgE (Xolair ® ), PDE4 inhibitors, PDE5 inhibitors, muscarinic receptor antagonists, Theophyline, cromolyn, and an IL- 13 inhibitor.
  • leukotriene modifier e.g., leukotriene receptor antagonist or 5-lypoxygenase inhibitor
  • beta agonist both long and short acting
  • mast cell stabilizer anti-IgE (Xolair ® )
  • PDE4 inhibitors PDE5 inhibitors
  • muscarinic receptor antagonists muscarinic receptor antagonists
  • Theophyline cromolyn
  • cromolyn IL- 13 inhibitor
  • the pirfenidone analog can be administered in the form of a formulated pharmaceutical product, e.g. as combined with a pharmaceutically acceptable carrier.
  • the administering can be oral.
  • the therapeutically effective amount is a total daily dose of about about lmg to about 4800mg, or about 50 mg to about 2400 mg of the pirfenidone analog (including a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof).
  • the therapeutically effective amount can be administered in divided doses, for example three times a day or two times a day, or can be administered in a single dose once a day.
  • the pirfenidone analog preferably is a compound of formula (I), (II), (III), (IV), or (V), a pharmaceutically acceptable salt, ester, solvate (including hydrates), or prodrug of any of the foregoing, or combinations of any of the foregoing:
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from the group consisting of H, deuterium, C 1 -C 1O alkyl, C 1 -C 1O deuterated alkyl, substituted C 1 -C 1O alkyl, Ci-Cio alkenyl, substituted C 1 -C 1 O alkenyl, C 1 -C 1 O thioalkyl, C 1 -C 1 O alkoxy, substituted C 1 -C 1 O alkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxyl, C 1 -C 1O
  • X 6 and X 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X 6 and X 7 together form an optionally substituted 5 or 6 membered heterocyclic ring; and
  • Ar is pyridinyl or phenyl; and Z is O or S.
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from the group consisting of H, deuterium, optionally substituted C 1 -C 1O alkyl, optionally substituted C 1 - Cio deuterated alkyl, optionally substituted C 1 -C 1 O alkenyl, optionally substituted C 1 -C 1 O thioalkyl, optionally substituted C 1 -C 1O alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amido, optionally substituted sulfonyl, optionally substituted amino, optionally substituted sulfonamido, optionally substituted sulfoxyl, cyan
  • X 6 and X 7 are independently selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylenylaryl, optionally substituted alkylenylheteroaryl, optionally substituted alkylenylheterocycloalkyl, optionally substituted alkylenylcycloalkyl, or X 6 and X 7 together form an optionally substituted 5 or 6 membered heterocyclic ring; and
  • Ar is optionally substituted pyridinyl or optionally substituted phenyl; and Z is O or S, with the proviso that pirfenidone is specifically omitted.
  • the pirfenidone analog administered to said patient can comprise a compound of formula (II)
  • Ar is pyridinyl or phenyl
  • X 3 is H, OH, or Ci_ioalkoxy
  • Z is O
  • R 4 is H or hydroxyl, or a salt, ester, solvate, or prodrug thereof.
  • the pirfenidone analog administered to said patient can comprise a compound of formula (II)
  • Ar is pyridinyl or phenyl; Z is O or S; X 3 is H, F, Cl, OH, CH 3; or OCH 3 ; R 2 is fluoromethyl, difluoromethyl, or trifluoromethyl,; and R 4 is H or hydroxyl, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and wherein pirfenidone is specifically omitted.
  • the pirfenidone analog is selected from the group consisting of a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.
  • the pirfenidone analog administered to said patient can be selected from the group consisting of
  • the patient can be human.
  • Figure 1 depicts the sensitization and challenge protocol used in the examples presented herein.
  • Figure 2 depicts the effect of a pirfenidone analog (PA) administration on airway responsiveness (2A and 2B) and cellular infiltration (2C and 2D).
  • Administration of a pirfenidone analog (PA) prevents the development of airway eosinophilia and hyperresponsiveness in a dose-dependent manner.
  • Figure 3 shows that treatment with a pirfenidone analog (PA) prevents allergen- induced airway inflammation.
  • PA pirfenidone analog
  • Figure 4 shows that treatment with a pirfenidone analog (PA) prevents goblet cell hyperplasia and collagen deposition.
  • PA pirfenidone analog
  • Figure 5 shows an additional study protocol featuring a 10-day exposure to OVA.
  • Figure 6 shows results from a mast cell-dependent EFS model in tracheal smooth muscle.
  • the term "pharmaceutically acceptable carrier” includes any suitable liquid pharmaceutical carrier, including, for example, a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents, and solid carriers, such as lactose.
  • suitable liquid pharmaceutical carrier including, for example, a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents, and solid carriers, such as lactose.
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
  • the salts, e.g., pharmaceutically acceptable salts, of the disclosed therapeutics may be prepared by reacting an appropriate base or acid with a stoichiometric equivalent of the therapeutic.
  • pharmaceutically acceptable derivatives e.g., esters
  • metabolites, hydrates, solvates and prodrugs of the therapeutic may be prepared by any suitable method.
  • another embodiment provides compounds that are prodrugs of an active compound.
  • a prodrug is a compound which is metabolized in vivo (e.g., by a metabolic transformation such as deamination, dealkylation, de-esterification, and the like) to provide an active compound.
  • a “pharmaceutically acceptable prodrug” means a compound which is, within the scope of sound medical judgment, suitable for pharmaceutical use in a patient without undue toxicity, irritation, allergic response, and the like, and effective for the intended use, including a pharmaceutically acceptable ester as well as a zwitterionic form, where possible, of the therapeutic.
  • pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • Examples of pharmaceutically-acceptable prodrug types are described in Higuchi and Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • the compounds and compositions described herein may also include metabolites.
  • the term "metabolite” means a product of metabolism of a pirfenidone analog disclosed herein that exhibits a similar activity in vitro or in vivo to the base analog.
  • the pirfenidone analog compounds and compositions described herein may also include hydrates and solvates.
  • the term "solvate” refers to a complex formed by a solute (herein, the therapeutic) and a solvent. Such solvents for the purpose of the embodiments preferably should not negatively interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.
  • an "effective" amount or a "therapeutically effective amount” of a pirfenidone analog refers to a nontoxic but sufficient amount of the agent(s) to provide the desired effect.
  • one desired effect would be to prevent the development or increase in AHR in a patient.
  • An alternative desired effect for the pirfenidone analog would be to prevent allergen-induced chronic airway inflammation in a patient.
  • a further desired effect for the pirfenidone analog would be to reduce goblet cell hyperplasia in a patient.
  • Yet another desired effect of the pirfenidone analog would be to reduce airway basement membrane collagen deposition in a patient.
  • the amount that is "effective” may vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify a universal "effective amount.” However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation, in view of the present disclosure.
  • in combination with refers to a protocol in which more than one therapeutic agent described herein is administered. Administration of the more than one therapeutic agents therefore occurs concurrently. Concurrent administration can be completely or partially overlapping in nature. Thus, “in combination with” is understood to mean any protocol for administering more than one therapeutic agent in which at least one therapeutic agent is administered, for at least one administration event, concurrently with at least one other (i.e., different) therapeutic agent, during a course of treatment.
  • asthma therapeutic agents include an inhaled corticosteroid (including but not limited to flunisolide and salbutamol), oral corticosteroid, leukotriene modifier (e.g., leukotriene receptor antagonist or 5-lypoxygenase inhibitor), beta agonist (both long and short acting), mast cell stabilizer, anti-IgE (Xolair®), PDE4 inhibitors, PDE5 inhibitors, muscarinic receptor antagonists, Theophyline, cromolyn, an IL- 13 inhibitor, acidic mammalian chitinase (AMCase) inhibitors and/or inhibitory antibodies. Dosing amounts and regimens for these agents can be determined by the clinician of skill in the art.
  • leukotriene modifier e.g., leukotriene receptor antagonist or 5-lypoxygenase inhibitor
  • beta agonist both long and short acting
  • mast cell stabilizer anti-IgE (Xolair®)
  • PDE4 inhibitors PDE5 inhibitor
  • pirfenidone analogs contemplated include compounds of formula (I), (II), (III), (IV), and (V)
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from the group consisting of H, deuterium, C 1 -C 1O alkyl, C 1 -C 1O deuterated alkyl, substituted C 1 -C 1O alkyl, Ci-Cio alkenyl, substituted C 1 -C 1O alkenyl, C 1 -C 1O thioalkyl, C 1 -C 1O alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxyl, C 1 -C 1O alkoxyalkyl,
  • X 6 and X 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X 6 and X 7 together form an optionally substituted 5 or 6 membered heterocyclic ring; and
  • Ar is pyridinyl or phenyl; and Z is O or S; or a pharmaceutically acceptable salt, ester, solvate, or prodrug of pirfenidone or the compound of formula (I), (II), (III), (IV), or (V).
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , and Y 4 are independently optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrrolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted isothiazolyl, optionally substituted napthyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, optionally substituted benzothiazolyl, optionally substituted benzothiophenyl, optionally substituted benzofuranyl, optional
  • the pirfenidone analog therapeutic can be a compound of formula (II), wherein X 3 is H, OH, or Ci-ioalkoxy, Z is O, and R 2 is fluoromethyl, difluoromethyl, or trifluoromethyl,; and R 4 is H or hydroxyl.
  • X 3 is H, OH, or Ci-ioalkoxy
  • Z is O
  • R 2 is fluoromethyl, difluoromethyl, or trifluoromethyl
  • R 4 is H or hydroxyl.
  • alkyl refers to a saturated or unsaturated straight or branched chain hydrocarbon group of one to ten carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like. Alkyls of one to six carbon atoms are also contemplated.
  • alkyl includes "bridged alkyl,” i.e., a bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl.
  • Alkyl groups optionally can be substituted, for example, with hydroxy (OH), halo, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and amino.
  • the alkyl group consists of 1-40 carbon atoms, preferably 1-25 carbon atoms, preferably 1-15 carbon atoms, preferably 1-12 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms, and preferably 1-6 carbon atoms.
  • “Heteroalkyl” is defined similarly as alkyl, except the heteroalkyl contains at least one heteroatom independently selected from the group consisting of oxygen, nitrogen, and sulfur.
  • cycloalkyl refers to a cyclic hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl.
  • Heterocycloalkyl is defined similarly as cycloalkyl, except the ring contains one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Nonlimiting examples of heterocycloalkyl groups include piperdine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, thiophene, and the like.
  • Heterocycloalkyl groups optionally can be further N- substituted with alkyl, hydroxyalkyl, alkylenearyl, or alkyleneheteroaryl.
  • alkenyl used herein refers to a straight or branched chain hydrocarbon group of two to ten carbon atoms containing at least one carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • alkylene used herein refers to an alkyl group having a substituent.
  • alkylene aryl refers to an alkyl group substituted with an aryl group.
  • the alkylene group is optionally substituted with one or more substituent previously listed as an optional alkyl substituent.
  • an alkylene group can be -CH 2 CH 2 -.
  • alkenylene is defined identical as “alkylene,” except the group contains at least one carbon-carbon double bond.
  • aryl refers to a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.
  • heteroaryl refers to a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents selected from, for example, halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms (D).
  • thioalkyl used herein refers to one or more thio groups appended to an alkyl group.
  • hydroxyalkyl used herein refers to one or more hydroxy groups appended to an alkyl group.
  • alkoxy refers to straight or branched chain alkyl group covalently bonded to the parent molecule through an — O— linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec- butoxy, t-butoxy and the like.
  • alkoxyalkyl refers to one or more alkoxy groups appended to an alkyl group.
  • arylalkoxy refers to a group having an aryl appended to an alkoxy group.
  • a non-limiting example of an arylalkoxy group is a benzyloxy (Ph-CH 2 -O-).
  • amino refers to -NR 2 , where R is independently hydrogen or alkyl.
  • Non-limiting examples of amino groups include NH 2 and N(CHs) 2 .
  • amido refers to -NHC(O)alkyl or -NHC(O)H.
  • a non- limiting example of an amido group is -NHC(O)CH 3 .
  • carboxy refers to — COOH or its deprotonated form -COO " .
  • Ci-iocarboxy refers to optionally substituted alkyl or alkenyl groups having a carboxy moiety. Examples include, but are not limited to, -CH 2 COOH, -CH 2 CH(COOH)CH 3 , and -CH 2 CH 2 CH 2 COOH.
  • alkoxycarbonyl refers to — (CO) — O-alkyl, wherein the alkyl group can optionally be substituted.
  • alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, and the like.
  • alkylcarbonyl refers to — (CO)-alkyl, wherein the alkyl group can optionally be substituted.
  • alkylcarbonyl groups include, but are not limited to, methylcarbonyl group, ethylcarbonyl group, propylcarbonyl group, and the like.
  • sulfonamido refers to -SO 2 NR 2 where R is independently hydrogen or an optionally substituted alkyl group.
  • R is independently hydrogen or an optionally substituted alkyl group.
  • examples of a sulfonamido group include, but are not limited to, -SO 2 N(CH 3 ) 2 and -SO 2 NH 2 .
  • sulfonyl refers to -SO2alkyl, wherein the alkyl group can optionally be substituted.
  • a sulfonyl group is methylsulfonyl (e.g., -SO2CH3).
  • Carbohydrates are polyhydroxy aldehydes or ketones, or substances that yield such compounds upon hydrolysis. Carbohydrates comprise the elements carbon (C), hydrogen (H) and oxygen (O) with a ratio of hydrogen twice that of carbon and oxygen. In their basic form, carbohydrates are simple sugars or monosaccharides. These simple sugars can combine with each other to form more complex carbohydrates. The combination of two simple sugars is a disaccharide. Carbohydrates consisting of two to ten simple sugars are called oligosaccharides, and those with a larger number are called polysaccharides.
  • uronide refers to a monosaccharide having a carboxyl group on the carbon that is not part of the ring.
  • the uronide name retains the root of the monosaccharide, but the -ose sugar suffix is changed to -uronide.
  • the structure of glucuronide corresponds to glucose.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term "radical” can be used interchangeably with the term "group.”
  • substituted group is derived from the unsubstituted parent structure in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • a "substituent group,” as used herein, means a group selected from the following moieties:
  • the substituent group is a "size-limited substituent” or “size-limited substituent group,” which refers to a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 2O alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -Cg cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
  • the substituent group is a "lower substituent” or “lower substituent group,” which refers to a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • the substituent group(s) is (are) one or more group(s) individually and independently selected from alkyl, cycloalkyl, aryl, fused aryl, heterocyclyl, heteroaryl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, alkoxycarbonyl, nitro, silyl, trihalomethanesulfonyl, trifluoromethyl, and amino, including mono and di substituted amino groups, and the protected derivatives thereof.
  • Asymmetric carbon atoms can be present. All such isomers, including diastereomers and enantiomers, as well as the mixtures thereof, are intended to be included in the scope of the disclosure herein. In certain cases, compounds can exist in tautomeric forms. All tautomeric forms are intended to be included in the scope of the disclosure herein. Likewise, when compounds contain an alkenyl or alkenylene group, there exists the possibility of cis- and trans- isomeric forms of the compounds. Both cis- and trans- isomers, as well as the mixtures of cis- and trans- isomers, are contemplated.
  • One class of pirfenidone analog compounds contemplated for use in the disclosed methods is a deuterated (D) form of any of the compounds disclosed herein.
  • One specific such compound is a compound having a CD 3 moiety and/or a D to replace any or all of the methyl or hydrogens of the compound, such as pirfenidone. Examples include
  • pirfenidone analog compounds contemplated for use in the disclosed methods include compounds of Genus I, II, III, and IV, below. Synthesis of compounds of Genus I, II, III, and IV are described in detail in International Patent Publication No. WO 07/062167, incorporated by reference in its entirety herein.
  • each of R, R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, halo, cyano, nitro, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 3 - 7 cycloalkyl, optionally substituted C 4-1 O alkylcycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6 or 10 aryl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted phenoxy, optionally substituted thiophenoxy, optionally substituted sulphonamido, optionally substituted urea, optionally substituted thiourea, optionally substituted amido, optionally substituted keto, optionally substituted keto
  • the salts, e.g., pharmaceutically acceptable salts, of the disclosed therapeutics may be prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the therapeutic.
  • pharmaceutically acceptable derivatives e.g., esters
  • metabolites, hydrates, solvates and prodrugs of the therapeutic may be prepared by any suitable methods, including those generally known to those skilled in the art.
  • another embodiment provides compounds that are prodrugs of an active compound.
  • a prodrug is a compound which is metabolized in vivo (e.g., by a metabolic transformation such as deamination, dealkylation, de- esterification, and the like) to provide an active compound.
  • a “pharmaceutically acceptable prodrug” means a compound which is, within the scope of sound medical judgment, suitable for pharmaceutical use in a patient without undue toxicity, irritation, allergic response, and the like, and effective for the intended use, including a pharmaceutically acceptable ester as well as a zwitterionic form, where possible, of the therapeutic.
  • pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. Examples of pharmaceutically-acceptable prodrug types are described in Higuchi and Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
  • the compounds and compositions described herein may also include metabolites.
  • the term "metabolite” means a product of metabolism of a compound of the embodiments or a pharmaceutically acceptable salt, analog, or derivative thereof, that exhibits a similar activity in vitro or in vivo to a disclosed therapeutic.
  • the compounds and compositions described herein may also include hydrates and solvates.
  • the term "solvate” refers to a complex formed by a solute (herein, the therapeutic) and a solvent.
  • Solvents for the purpose of the embodiments preferably should not negatively interfere with the biological activity of the solute.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • reference herein to a particular compound or genus of compounds will be understood to include the various forms described above, including pharmaceutically acceptable salts, esters, prodrugs, metabolites and solvates thereof.
  • the pirfenidone analogs disclosed herein can be dosed at any suitable amount, for example a total amount of about 1 mg to about 4800 mg, or about 50 mg to about 2400 mg or 2403 mg per day.
  • the dosage can be divided, e.g. into two or three doses over the day, or can be given in a single daily dose.
  • Specific amounts of the total daily amount of the therapeutic contemplated for the disclosed methods include about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,
  • Dosages of the pirfenidone analog can alternately be administered as a dose measured in mg active agent per kg body weight.
  • Such doses of the disclosed therapeutics can include, for example, about 0.1 mg/kg to about 40 mg/kg.
  • Other specific ranges of doses in mg/kg include about 0.1 mg/kg to about 1 mg/kg, about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 20 mg/kg, about 10 mg/kg to about 20 mg/kg, about 25 mg/kg to about 40 mg/kg, and about 30 mg/kg to about 40 mg/kg.
  • doses and dosing thresholds for the disclosed therapeutics in mg/kg include but are not limited to about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg or more.
  • Airway responsiveness can be assessed in animal models as a change in airway function after challenge with aerosolized methacholine (MCh) using invasive plethysmography (Flexivent) as described [Takeda et al., 1997, J. Exp. Med. 186(3):449-454].
  • MCh aerosolized methacholine
  • Flexivent invasive plethysmography
  • mice can be mechanically ventilated and lung function can be assessed using methods similar to those described by Martin et al. [Martin et al., 1988, J. Appl. Physiol. 64:2318-2323].
  • a four-way connector can be attached to the tracheostomy tube, with two ports connected to the inspiratory and expiratory sides of a ventilator (e.g. model 683; Harvard Apparatus, South Natick, MA). Ventilation can be achieved at 160 breaths/min. [Takeda et al., 1997, J Exp Med 186:449-454].
  • PC20 for human study, one can characterize the PC20 (rather than PC200 as in animals) using pulmonary function testing and MCh or histamine challenge. These methods are known and can be carried out by those of skill in the art, but any suitable methods may be used. Measurement of Bronchoalveolar Lavage Fluid Cytokines and In Vitro Cytokine Production
  • lungs can be lavaged via a tracheal tube with saline (2 X 1 ml, 37°C).
  • the volume of the collected bronchoalveolar lavage fluid (BALF) will be measured in each sample, and the number of cells in the BALF will be counted.
  • Cytospin slides will be stained and differentiated in a blinded fashion by counting at least 300 cells under light microscopy. It is contemplated that treatment with a pirfenidone analog disclosed herein will reduce the number of eosinophils in BALF at least about 10% relative to a patient not administered a pirfenidone analog disclosed herein.
  • the reduction in the number of eosinophils in a patient administered the pirfenidone analog is at least about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 60%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 2-fold, or about 3-fold, or about 4-fold, or about 5-fold, or about 10-fold or more relative to a patient that is not administered a pirfenidone analog disclosed herein.
  • Cytokine concentrations in the BALF and cytokine levels in the presence or absence of a pirfenidone analog will be measured by ELISA according to the manufacturer's instructions. The limits of detection are 4 pg/ml for IL-4, IL-5, IL-12, IL-13, IFN- ⁇ , and plateletderived growth factor (PDGF) (R&D Systems, Minneapolis, MN).
  • TGF- ⁇ l levels in the BALF will be assayed using a TGF- ⁇ l ELISA kit (TGF- ⁇ l E max ImmunoAssay System; Promega, Madison, WI). The assay detects only the active form of TGF- ⁇ l.
  • each sample will be directly measured for the detection of the active form or is activated before measuring, according to the manufacturer's recommendations, for the detection of total amount of TGF- ⁇ l. It is contemplated that the increase in IL-12 and/or IFN- ⁇ production in a patient administered a pirfenidone analog disclosed herein is at least about 20% relative to a patient that is not administered the pirfenidone analog.
  • the increase in IL-12 and/or IFN- ⁇ production in a patient administered a pirfenidone analog is at least about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 60%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 2-fold, or about 3-fold, or about 4-fold, or about 5-fold, or about 10-fold or more relative to a patient that is not administered the pirfenidone analog.
  • a decrease in IL-4, IL-13, PDGF, IL-5 and/or TGF- ⁇ l production in a patient administered a pirfenidone analog disclosed herein is at least about 20% relative to a patient that is not administered the pirfenidone analog.
  • the decrease in IL-4, IL-13, PDGF, IL-5 and/or TGF- ⁇ l production in a patient administered the pirfenidone analog is at least about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 60%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 99% or more relative to a patient that is not administered the pirfenidone analog.
  • Airway remodeling can be assessed by determining both the level of goblet cell hyperplasia as well as collagen deposition on airway basement membrane. These levels can be determined by any suitable methods, including those known to those of ordinary skill in the art.
  • a lung biopsy specimen can be obtained from a patient with, e.g., a bronchoscope and stained with Masson's Trichrome or Sirius Red (for quantitation of collagen deposition/fibrosis) or PAS (Periodic Acid Schiff) (for quantitation of mucus-containing cells). Any other suitable techniques and methods can be used for quantitation of the level of goblet cell hyperplasia and collagen deposition.
  • a decrease in goblet cell hyperplasia and/or collagen deposition on airway basement membrane in a patient administered a pirfenidone analog disclosed herein will be at least about 20% relative to a patient that is not administered the pirfenidone analog.
  • the decrease in goblet cell hyperplasia and/or collagen deposition on airway basement membrane in a patient administered the pirfenidone analog will be at least about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 60%, or about 70%, or about 75%, or about 80%, or about 2-fold, or about 3-fold, or about 4-fold, or about 5-fold, or about 10-fold or more relative to a patient that is not administered the pirfenidone analog.
  • the compounds described herein may be formulated in pharmaceutical compositions with a pharmaceutically acceptable excipient, carrier, or diluent.
  • the compound or composition comprising the compound can be administered by any route that permits treatment of the disease or condition.
  • a preferred route of administration is oral administration.
  • the compound or composition comprising the compound may be delivered to a patient using any suitable route of administration, including parenterally, such as intravenously, intraperitoneally, intrapulmonary, subcutaneously or intramuscularly, intrathecally, transdermally, rectally, orally, nasally or by inhalation.
  • Slow release formulations may also be prepared from the agents described herein in order to achieve a controlled release of one or more active agents in contact with the body fluids, for example in the gastro intestinal tract, and to provide a substantially constant and effective level of one or more active agents in the blood plasma.
  • a crystal form may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water-soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers. Controlled release formulations are also obtained through encapsulation of dispersed micro-particles or emulsified micro-droplets via any suitable dispersion or emulsion coating technologies.
  • Administration may take the form of single dose administration, or the pirfenidone analog and optional asthma therapeutic can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump).
  • a continuous-release formulation or administration method e.g., a pump
  • the compounds are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.
  • the pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form.
  • the pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11, preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8. More particularly, the pharmaceutical compositions may comprise a therapeutically or prophylactically effective amount of at least one compound as described herein, together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions may comprise a combination of the compounds described herein, or may include a second active ingredient useful in the treatment or prevention of bacterial infection (e.g., antibacterial or anti-microbial agents for use as a preservative).
  • a second active ingredient useful in the treatment or prevention of bacterial infection e.g., antibacterial or anti-microbial agents for use as a preservative.
  • Formulations for parenteral or oral administration can include, but are not limited to, solids, liquid solutions, emulsions or suspensions.
  • Inhalable formulations for pulmonary administration can include, but are not limited to, liquids or powders, with powder formulations being generally preferred.
  • a preferred pharmaceutical composition may also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration.
  • Alternative pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, and the like.
  • compositions of the invention can be formulated for administration by inhalation.
  • Suitable pharmaceutical compositions for administration by inhalation can be in the form of an aerosol or a powder, for example.
  • Such compositions can be administered using suitable delivery devices, including but not limited to a metered-dose inhaler, a dry powder inhaler, a nebulizer or a similar delivery device.
  • the pharmaceutical compositions of the invention can comprise the active ingredient and a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • pharmaceutically acceptable excipient refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein.
  • the term refers to any pharmaceutical excipient that may be administered without undue toxicity.
  • compositions are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions (see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • excipients include antioxidants (e.g., ascorbic acid), chelating agents (e.g., EDTA), carbohydrates (e.g., dextrin, hydroxyalkylcellulose, and/or hydroxyalkylmethylcellulose), stearic acid, liquids (e.g., oils, water, saline, glycerol and/or ethanol) wetting or emulsifying agents, pH buffering substances, binders (e.g., povidone, microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose), disintegrants (e.g., agar-agar, algins, calcium carbonate, carboxmethylcellulose, cellulose, clays, colloid silicon dioxide, croscarmellose sodium, crospovidone, gums, magnesium aluminium silicate, methylcellulose, polacrilin potassium, sodium alginate, low substituted hydroxypropylcellulose, and cross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium
  • compositions described herein may be formulated in any form suitable for an intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any suitable method for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • compositions particularly suitable for use in conjunction with tablets and capsules include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • disintegrating agents such as cross-linked povidone, maize starch, or alginic acid
  • binding agents such as povidone, microcrystalline cellulose, starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by suitable techniques including but not limited to microencapsulation to modify release properties such as by providing delayed release and/or sustained release properties.
  • a coating can be used to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules wherein one or more active ingredients are mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, a binder, such as povidone and/or microcrystalline cellulose, and a disintegrant, or as soft gelatin capsules wherein one or more active ingredients are mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin, a binder, such as povidone and/or microcrystalline cellulose, and a disintegrant
  • non-aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • compositions may be formulated as suspensions comprising a compound of the embodiments in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
  • compositions may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
  • Excipients suitable for use in connection with suspensions include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia); dispersing or wetting agents (e.g., a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate)); and thickening agents (e.g., carbomer, beeswax, hard paraffin or cetyl alcohol).
  • suspending agents
  • the suspensions may also contain one or more preservatives (e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate); one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • preservatives e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate
  • coloring agents e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate
  • flavoring agents e.g., methyl or n-propyl p-hydroxy-benzoate
  • sweetening agents such as sucrose or saccharin.
  • the pharmaceutical compositions may also be in the form of oil-in water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. This emulsion or suspension may be formulated by a person of ordinary skill in the art using those suitable dispersing or wetting agents and suspending agents, including those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol.
  • the sterile injectable preparation may also be prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids e.g., oleic acid
  • a pharmaceutically acceptable salt of a compound described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid, or more preferably, citric acid. If a soluble salt form is not available, the compound may be dissolved in a suitable co- solvent or combination of co- solvents. Examples of suitable co- solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from about 0 to about 60% of the total volume. In one embodiment, one ore more active compounds are dissolved in DMSO and diluted with water.
  • the pharmaceutical composition may also be in the form of a solution of a salt form of an active ingredient in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solution.
  • an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.
  • esterification glycosylation, PEGylation, etc.
  • the compounds described herein may be formulated for oral administration in a lipid-based formulation suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds.
  • a preferred pharmaceutical composition comprises a therapeutically or prophylactically effective amount of a compound described herein, together with at least one pharmaceutically acceptable excipient selected from the group consisting of medium chain fatty acids and propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids, such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.
  • cyclodextrins may be added as aqueous solubility enhancers.
  • Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin.
  • a particularly preferred cyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above-described compositions to further improve the aqueous solubility characteristics of the compounds of the embodiments.
  • BPBC hydroxypropyl-o-cyclodextrin
  • the composition comprises about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15% hydroxypropyl-o-cyclodextrin, and even more preferably from about 2.5% to about 10% hydroxypropyl-o-cyclodextrin.
  • solubility enhancer employed will depend on the amount of the compound of the invention in the composition.
  • mice were then challenged on days 28-30 via the airways with 1% OVA by aerosol for 20 minutes, using an ultrasonic nebulizer.
  • Control (challenge only; C) animals received PBS in the sensitization phase.
  • mice were assessed for AHR to inhaled methacholine and cell composition in bronchoalveolar lavage (BAL).
  • AHR was assessed as changes in airway function after challenge with aerosolized methacholine (MCh; Sigma Chemical, St Louis MO).
  • mice were anesthetized, tracheostomized and mechanically ventilated with lung function assessed [Takeda et al., 1997, J Exp Med. 186: 449-454].
  • Ventilation was achieved at 160 breaths/minute at a tidal volume of 0.16 mL with a positive end-expiratory pressure of 2 to 4 cm H 2 O.
  • Lung resistance (RL) was continuously computed (Lab View, National Instruments, TX) by fitting flow, volume, and pressure to an equation of motion using a recessive least squares algorithm.
  • Aerosolized methacholine (MCh) was administered through bypass tubing via an ultrasonic nebulizer placed between the expiratory port of the ventilator and a 4 way connector. Aerosolized MCh was administered for 8 seconds with a tidal volume of 0.45 mL and a frequency of 60 breaths per minute using another ventilator (model 683; Harvard Apparatus, South Natick MA). The data of RL was continuously collected for up to 3 minutes and shown as the percent change from baseline levels. The initial dose of MCh given was 2 mg/ml, and lung resistance was recorded. Additional increasing doses of MCh were administered up to 12 mg/mL.
  • the pirfenidone analog (PA) was administered on days 27 to 31, at doses of 0.3-100 mg/kg by oral gavage.
  • the PA dosing solutions were prepared daily by weighing the PA into a porcelain mortar, approximately 0.5 mL of 0.1% solution by weight methylcellulose (prepared from methylcellulose (Methocel 65 HG (Fluka 64670) and distilled water) was added to the compound and this was triturated in a unidirectional fashion to form a paste. Additional 0.1% methylcellulose solution was then added to a volume of 2 mL distilled water and mixed with a pestle to form a uniform suspension.
  • methylcellulose prepared from methylcellulose (Methocel 65 HG (Fluka 64670) and distilled water
  • the suspension was transferred to a 50 mL conical tube, and the mortar and pestle was washed with 3 aliquots of methylcellulose to ensure complete transfer of the drug to the mixture, bringing to the desired final volume.
  • the suspension of prepared test article was constantly mixed during the per os (PO) administration to ensure a uniform administration of the article suspension.
  • Mice were dosed orally once daily on days 27- 30 with either 0.1% methylcellulose vehicle, 100 mg/kg PA, 30 mg/kg PA, 3 mg/kg PA, 1 mg/kgPA, or 0.3 mg/kg PA.
  • Dexamethasone (DEX; 3 mg/kg) or vehicle alone were administered in the same manner as positive and negative controls, respectively.
  • mice treated with vehicle control developed AHR and airway eosinophilia, and these responses were ameliorated following DEX treatment.
  • the pirfenidone analog (PA) at doses of 3, 30, and 100 mg/kg prevented the development of AHR and eosinophilia in BAL fluid ( Figures 2A-B).
  • the 1 mg/kg dose showed a moderate suppressive effect on AHR but no effect on eosinophil numbers in BAL; 0.3 mg/kg of the pirfenidone analog (PA) was without effect ( Figures 2C-D). Therefore, administration of a pirfenidone analog prevents the development of airway eosinophilia and hyperresponsiveness in a dose-dependent manner.
  • Cytokine analysis in BAL fluid revealed that 5-difluoromethyl-l-phenyl-2-(lH)- pyridone, a pirfenidone analog (PA) increased IL-12 and IFN- ⁇ and decreased IL-4, IL-5, IL-13, TGF- ⁇ l, and PDGF-AA in the airways ( Figure 3 and data not shown) relative to vehicle-treated mice.
  • PA pirfenidone analog
  • Example 1 Treatment with the pirfenidone analog (PA) 5-difluoromethyl-l-phenyl-2-(lH)- pyridone as outlined in Example 1 was shown to prevent goblet cell hyperplasia and collagen deposition (Figure 4), two components of airway remodeling observed in asthmatic patients.
  • PA pirfenidone analog
  • Second Asthma-related airway inflammation model model of active airway sensitization (10 day exposure to OVA) in the absence of adjuvant. The protocol is shown in Figure 5.

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Abstract

Cette invention concerne des méthodes de traitement des patients souffrant d'asthme à l'aide d'un analogue de la pirfénidone.
PCT/US2010/035476 2009-05-19 2010-05-19 Dérivés de pirfénidone pour le traitement de l'asthme WO2010135470A1 (fr)

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USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8377932B2 (en) 2009-05-25 2013-02-19 Central South University Preparation of 1-(substituted benzyl)-5-trifluoromethyl-2(1H)pyridone compounds and salts thereof and their applications
US8426407B2 (en) 2009-05-25 2013-04-23 Central South University Preparation of 1-(substituted aryl)-5-trifluoromethyl-2-(1H)pyridone compounds and salts thereof and their applications
US10092552B2 (en) 2011-01-31 2018-10-09 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10105356B2 (en) 2011-01-31 2018-10-23 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10479771B2 (en) 2011-03-08 2019-11-19 Biotie Therapies Corporation Pyridazinone and pyridone compounds
WO2012120195A1 (fr) 2011-03-08 2012-09-13 Biotie Therapies Corporation Nouveaux composés de pyridazinone et pyridone
US9815795B2 (en) 2011-03-08 2017-11-14 Biotie Therapies Corporation Pyridazinone and pyridone compounds
US9371290B2 (en) 2011-03-08 2016-06-21 Biotie Therapies Corporation Pyridazinone compounds
US20150050240A1 (en) * 2012-03-27 2015-02-19 Novartis Ag Treatment of fibrosis
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US9770443B2 (en) 2014-01-10 2017-09-26 Genoa Pharmaceuticals, Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10028966B2 (en) 2014-01-10 2018-07-24 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

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