WO2013084153A1 - Pharmaceutical composition comprising a trpa1 antagonist and an anticholinergic agent - Google Patents

Pharmaceutical composition comprising a trpa1 antagonist and an anticholinergic agent Download PDF

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Publication number
WO2013084153A1
WO2013084153A1 PCT/IB2012/056966 IB2012056966W WO2013084153A1 WO 2013084153 A1 WO2013084153 A1 WO 2013084153A1 IB 2012056966 W IB2012056966 W IB 2012056966W WO 2013084153 A1 WO2013084153 A1 WO 2013084153A1
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Prior art keywords
subject
pharmaceutical composition
composition according
anticholinergic agent
compound
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PCT/IB2012/056966
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French (fr)
Inventor
Neelima Khairatkar-Joshi
Raghuram ANUPINDI
Selvan VAIYAPURI THAMIL
Abhay Kulkarni
Amol Waghchoure
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Glenmark Pharmaceuticals S.A.
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Priority to JP2014545421A priority Critical patent/JP2015500278A/en
Priority to CA2857109A priority patent/CA2857109A1/en
Priority to US14/362,003 priority patent/US20140364445A1/en
Priority to EP12813986.2A priority patent/EP2787991A1/en
Publication of WO2013084153A1 publication Critical patent/WO2013084153A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/439Heterocyclic 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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/468-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/02Drugs for disorders of the nervous system for peripheral neuropathies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present patent application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a transient receptor potential ankyrin-1 receptor (“TRPA1”) antagonist and an anticholinergic agent.
  • TRPA1 transient receptor potential ankyrin-1 receptor
  • composition comprising a TRPA1 antagonist having IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent; a process for preparing such composition; and its use in treating a respiratory disorder in a subject.
  • Respiratory disorders related to airway inflammation include a number of severe lung diseases including asthma and chronic obstructive pulmonary disease ("COPD").
  • COPD chronic obstructive pulmonary disease
  • the airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is believed to be the most prominent component.
  • Inflammatory sensitization of airway neurons is believed to increase nasal and cough sensitivity, heighten the sense of irritation, and promote fluid secretion, airway narrowing, and bronchoconstriction.
  • TRPA1 receptor activation in the airways by exogenous noxious stimuli including cold temperatures (generally, less than about 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic), tobacco smoke, tear gas and environmental irritants as well as by endogenous biochemical mediators released during inflammation, is supposed to be one of the mechanisms for neurogenic inflammation in the airways.
  • Neurogenic inflammation is an important component of chronic airway diseases like COPD and asthma.
  • Anticholinergic agents are believed to inhibit vagally-mediated reflexes by blocking acetylcholine at the cholinergic receptor. Anticholinergic agents are also believed to inhibit secretions of the serous and sero-mucous glands of the nasal mucosa. Anticholinergic agents for treatment or control of respiratory disorders include tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salt thereof.
  • Tiotropium bromide is available commercially as SPIRIVA ® capsules containing 18 meg tiotropium (equivalent to 22.5 meg tiotropium bromide monohydrate) marketed by Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. Tiotropium bromide is indicated for the maintenance treatment of bronchospasm associated with COPD, and for reducing COPD exacerbations.
  • Ipratropium bromide is chemically, 8- azoniabicyclo (3.2.1) octane, 3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8- (1-methylethyl)-, bromide monohydrate.
  • Ipratropium bromide is commercially available as ATROVENT® 0.06% nasal spray (42 meg per spray) marketed by Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. It is administered as a pressurized metered-dose aerosol unit for oral inhalation. Each actuation of the inhaler delivers 21 meg of ipratropium bromide.
  • Ipratropium bromide is indicated for the symptomatic relief of rhinorrhea associated with the common cold or seasonal allergic rhinitis.
  • ATROVENT HFA ® is another product of ipratropium bromide is approved as a bronchodilator for maintenance treatment of
  • COPD chronic obstructive pulmonary disease
  • Aclidinium bromide chemically known as [(8R)-l-(3-phenoxypropyl)-l- azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide is a novel long acting inhaled muscarinic antagonist. It is approved as TUDORZA® PRESSAIR ® 0.375mg/INH in the United States. It is approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
  • COPD chronic obstructive pulmonary disease
  • glycopyrrolate is chemically 3 -(2
  • Glycopyrrolate is being developed for the treatment of asthma and COPD.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a
  • TRPA1 antagonist and an anticholinergic agent.
  • TRPAl antagonists and an anticholinergic agent act synergistically in the treatment of respiratory disorders and are more effective and provide better therapeutic value than treatment with either active ingredient alone.
  • the anticholinergic agent including tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or their salt may be present in the form of their stereoisomers, polymorphs, and solvates, including hydrates, all of which are included in the scope of the invention.
  • the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: XII) or (D)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
  • the TRPA1 antagonist as contemplated herein and the anticholinergic agent are present in a weight ratio ranging from about 1 :0.0001 to about 1 : 10000.
  • the present invention relates to a
  • TRPA1 antagonist having structure of formula:
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent.
  • the respiratory disorder in the context of present invention, includes but is not limited to airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • airway inflammation asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering the subject a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the present invention relates to use of
  • a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent for the treatment of a respiratory disorder in a subject.
  • the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the pharmaceutical composition is a fixed dose combination.
  • the composition is for inhalation administration.
  • the composition is for inhalation administration, wherein the TRPAl antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.001 to about 1 :300.
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to a method of treating COPD by reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the respiratory disorder is asthma.
  • the composition is for inhalation administration.
  • the present invention relates to a method of reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to a method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the respiratory disorder is asthma.
  • the composition is for inhalation administration.
  • the present invention relates to a method of inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinerg agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to use of
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the composition is for inhalation administration.
  • Figure 1 is a bar graph showing the effect of Compound 52, tiotropium bromide, and their combination on methacholine-induced bronchoconstriction in male Dunkin Hartley guinea pigs.
  • Figure 2 is a bar graph showing the effect of Compound 52, aclidinium bromide, and their combination on LPS induced neutrophilia in male SD rats.
  • Figure 3 is a bar graph showing the effect of Compound 52, tiotropium and their combination on LPS induced neutrophilia in female SD rats.
  • Figure 4 is a bar graph showing the effect of Compound 52, ipratropium bromide and their combination on LPS induced neutrophilia in male SD rats.
  • an effective amount or "therapeutically effective amount” denotes an amount of an active ingredient that, when administered to a subject for treating a respiratory disorder, produces an intended therapeutic benefit in a subject.
  • the therapeutically effective amount of TRPA1 antagonist as described herein ranges from about O. lmcg/kg to about 20mg/kg, and preferably from about lmcg/kg to about 15mg/kg.
  • the therapeutically effective amount tiotropium to be administered per day ranges from about 5 ⁇ g to about 50 ⁇ g and preferably from about 10 ⁇ g to about 36 ⁇ g.
  • the discrete dosage strength of tiotropium or its salt is 18 ⁇ g.
  • the therapeutically effective amount of ipratropium to be administered per day ranges from about 0.05 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg.
  • the discrete dosage strengths of ipratropium or its salt are 168 ⁇ g or 336 ⁇ g or 504 ⁇ g or 672 ⁇ g.
  • the therapeutically effective amount of aclidinium to be administered per day ranges from about 0.05 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg.
  • the discrete dosage strengths of aclidinium or its salt are 200 ⁇ g or 400 ⁇ g or 800 ⁇ .
  • the therapeutically effective amount of glycopyrrolate to be administered per day ranges from about 0.01 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes a TRPA1 antagonist, an
  • the active ingredient includes TRPA1 antagonist having a human IC 50 value of less than 1 micromolar, tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or its salt.
  • the IC 50 value is believed to be measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure generally indicates molar concentration of a particular compound (or substance) is needed to inhibit a given biological process by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of the compound.
  • the IC 50 of a drug compound (or active substance) can be determined by constructing a concentration-response curve so as to examine the effect of different
  • IC 50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC 50 values can be used to compare the potency of two antagonists.
  • salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the TRPA1 receptor, or the anticholinergic agent, or by a
  • the respiratory disorder includes but is not limited to airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • the respiratory disorder is asthma or COPD.
  • subject includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife
  • the subject is a human.
  • pharmaceutically acceptable excipients any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • concentration or “synergy”, as used herein, refers to a combination exhibiting an effect greater than would be expected from the sum of the effects of the individual components of the combination alone.
  • synergistic or “synergy” with regard to the combination of a TRPA1 antagonist with an anticholinergic agent which is used in the treatment of a respiratory disorder refers to an efficacy for the treatment of the respiratory disorder that is greater than would be expected from the sum of their individuals effects.
  • advantages for the synergistic combinations of the present invention include, but are not limited to, lowering the required dose of one or more of the active compounds of the combination, reducing the side effects of one or more of the active compounds of the combination and/or rendering one or more of the active compounds more tolerable to the subject in need of treatment of the respiratory disorder.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a TRPA1 antagonist and an anticholinergic agent.
  • TRPA1 antagonists and an anticholinergic agent act synergistically in the treatment of respiratory disorders, and are more effective and provide better therapeutic value than treatment with either active ingredient alone.
  • TRPA1 antagonists useful in the context of the invention are selected from one of the following formulae: (A) or (B) or (C) or (D)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R b and R c independently selected from hydrogen, substituted or unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
  • R 10 is selected from hydrogen, alkyl, arylalkyl and pharmaceutically acceptable cation.
  • TRPA1 antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
  • TRPA1 antagonist useful in the context of the invention has the formula (I):
  • unsubstituted cycloalkyl substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl;
  • R 7 independently represents hydrogen or alkyl.
  • TRPAl antagonists useful in the methods of the invention are mentioned below:
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO2010004390. Accordingly, TRPAl antagonist useful in the context of the invention has the formula (II):
  • R and R 2 is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, (CR x R y ) n OR x , COR x , COOR x , CONR x R y , S0 2 NR x R y , NR x R y , NR x (CR x R y ) n OR x , NR x (CR x R y ) n CN (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , (CR x R y )NR x R y , NR x (CR x R y ) n CON
  • R x and R y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted
  • R x and R y may be joined together to form an optionally substituted 3 to 7 membered saturated, unsaturated or partially saturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR a or S;
  • ring A is selected from phenyl, pyridinyl, pyrazolyl, thiazolyl and thiadiazolyl;
  • each occurrence of R 6 is independently hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • R x and R y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
  • 'n' is independently selected from 1 to 5.
  • R J and R 2 are as defined above for the compound of formula (II);
  • R 6a and R 6b are independently selected from hydrogen, cyano, nitro, - NR x R y , halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • heterocyclylalkyl -C(0)OR x , -OR x , -C(0)NR x R y , -C(0)R x , -S0 2 R x , -S0 2 -NR x R y .
  • TRPA1 antagonists useful in the context of the invention are mentioned below:
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
  • TRPAl antagonist useful in the context of the invention has the formula (III):
  • Zi is NR a or CR a ;
  • Z 2 is NR b or CR b ;
  • Z 3 is N or C
  • R a and R b which may be same or different, are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, -(CR x R y ) n OR x , -COR x , -COOR x , -CONR x R y , -S(0) m NR x R y , -NR x R y ,
  • R 1 and R 2 which may be same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) n OR x , COR x , COOR x , CONR x R y , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , (CH 2 )NR x R y and (CH 2 ) n NHCOR x ;
  • R 3 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
  • L is a linker selected from -(CR x R y ) compassion- -0-(CR x R y ) n -, -C(O)-, -NR X -, - S(0) m NR x -, -NR x (CR x R y ) n - and -S(0) m NR x (CR x R y ) n ;
  • U is selected from substituted or unsubstituted aryl, substituted or unsubstituted five membered heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyroles, 1,2,3-triazoles and 1,2,4-triazole; and substituted or unsubstituted six membered heterocycles selected from the group consisting of pyrimidine, pyridine and pyridazine;
  • V is selected from hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)OR x , - OR x , -C(0)NR x R y , -C(0)R x and -S0 2 NR x R y ; or U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, that may optionally include one or more heteroatoms selected from O, S and N;
  • R x and R y are independently selected from the group consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and
  • 'm' and 'n' are independently selected from 0 to 2, both inclusive.
  • TRPA1 antagonists useful in the context of the invention are mentioned below:
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO 2010109334. Accordingly, TRPAl antagonists useful in the context of the invention has the formula (IV)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (d-C 4 )alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
  • TRPAl antagonists useful in the context of the invention has the formula (V)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C 1 -C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
  • TRPA1 antagonists useful in the context of the invention are mentioned below:
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
  • TRPAl antagonists useful in the context of the invention has the formula (VI)
  • R 1 and R 2 which may be the same or different, are each independently hydrogen or (Ci-C4)alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
  • TRPAl antagonists useful in the context of the invention have the formulas (Vila, Vllb and VIIc):
  • R a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and cycloalkylalkyl;
  • U is substituted or unsubstituted five membered heterocycle, for example selected from the group consisting of
  • R b is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
  • R z is independently selected from halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, COOR x , CONR x R y , S(0) m NR x R y , NR x (CR x R y ) n OR x , (CH 2 ) n NR x R y , NR x (CR x R y ) n CONR x R y , (CH 2 ) n NHCOR x , (CH 2 ) n NH(CH 2 ) n S0
  • R x andR y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
  • 'm' and 'n' are independently selected from 0 to 2, both inclusive; and 'p' is independently selected from 0 to 5, both inclusive.
  • the TRPAl antagonist useful in the context of the invention is Compound 89:
  • the TRPAl antagonist useful in the context of the invention is Compound 90:
  • TRPA1 antagonists useful in the context of the invention has the formula
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (Ci-C4)alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
  • a representative TRPA1 antagonist useful in the context of the invention is
  • the Compound 91 may be prepared, for example, by following the process provided for the preparation of similar compounds in PCT publication No.
  • TRPA1 antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO201 1 1 14184. Accordingly, a TRPA1 antagonist useful in the context of the invention has the formula (IX):
  • R 1 and R 2 are independently selected from hydrogen or substituted or unsubstituted alkyl
  • R 5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl
  • R 6 is selected from hydrogen, cyano, nitro, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
  • TRPA1 antagonist useful in the methods of the invention is mentioned below:
  • TRPA1 antagonist useful in the context of the invention has the formula (X):
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
  • R b and R c independently selected from hydrogen, substituted or unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
  • R 10 is selected from hydrogen, alkyl, arylalkyl and pharmaceutically acceptable cation.
  • TRPA1 antagonists useful in the context of the invention are mentioned below:
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO201 1 1 14184. Accordingly, TRPAl antagonist useful in the context of the invention has the formula (XI):
  • R 1 , and R 2 are independently hydrogen or (Ci-C4)alkyl; and R 4 , R 5 , R 6 , R 7 , R 8 and R 9 , which may be same or different, are each independently selected from halogen haloalkyl, dialkylamino, and haloalkoxy.
  • TRPA1 antagonists useful in the context of the invention is selected from one of the following formulae: (XII) or (D)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
  • TRPA1 antagonists of the formula (XII) useful in the context of the invention are compound 52, compound 73 and compound 84 as described above.
  • the anticholinergic agent includes tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the salt may be present in the form of their isomers, polymorphs, and solvates, including hydrates, all of which are included in the scope of the invention.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: (XII) or (D)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
  • the TRPA1 antagonist of the present invention has an IC 50 for inhibiting human TRPA1 receptor activity of less than 500 nanomolar, or more preferably less than 250 nanomolar, as measured by a method described herein.
  • the present invention relates to a
  • composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • composition comprising synergistically effective amount of a TRPA1 antagonist as
  • an anticholinergic agent in a weight ratio ranging from about 1 :0.0001 to about 1 : 10000.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the anticholinergic agent is tiotropium.
  • the anticholinergic agent is ipratropium.
  • the anticholinergic agent is aclidinium.
  • the pharmaceutical composition is a fixed dose combination.
  • the pharmaceutical composition of the present invention may be administered orally, nasally, intra-tracheally, parenterally, transdermally, transmucosal, inhalation or by any other route that a physician or a health-care provider may determine to be appropriate.
  • the route of administration is oral or by inhalation.
  • the composition is for inhalation administration and the TRPA1 antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.001 to about 1 :300.
  • the active ingredients may be administered together in a single dosage form or they may be administered in different dosage forms. They may be administered at the same time or they may be administered either close in time or remotely, such as, where one drug is administered in the morning and the second drug is administered in the evening. The combination may be used prophylactically or after the onset of symptoms has occurred.
  • both the active ingredients i.e., TRPA1 antagonist and the anticholinergic agent are formulated as a pharmaceutical composition suitable for administration by the same route (e.g., both the actives by oral or inhalation route), or by different routes (e.g., one active by oral and the other active by inhalation route).
  • the pharmaceutical compositions for oral administration may be in conventional forms, for example, tablets, capsules, granules (synonymously, "beads” or “particles” or “pellets”), suspensions, emulsions, powders, dry syrups, and the like.
  • the capsules may contain granule/pellet/particle/mini-tablets/mini- capsules containing the active ingredients.
  • the amount of the active agent that may be incorporated in the pharmaceutical composition may range from about 1% w/w to about 98% w/w or from about 5% w/w to about 90% w/w.
  • compositions for parenteral administration include but are not limited to solutions/suspension/emulsion for intravenous, subcutaneous or intramuscular injection/infusion, and implants.
  • pharmaceutical compositions for transdermal or transmucosal administration include but are not limited to patches, gels, creams, ointments and the like.
  • the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents/viscosifying agents, surfactants, solvents and the like.
  • the present invention provides a process for the preparing a pharmaceutical composition comprising TRPAl antagonist and an anticholinergic agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation.
  • the process comprises admixing TRPAl antagonist with the anticholinergic agent.
  • the process comprises formulating TRPAl antagonist and the anticholinergic agent in such a way that they are not in intimate contact with each other.
  • the invention in another embodiment, relates to a process for preparing a pharmaceutical composition comprising TRPAl antagonist, an anticholinergic agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of kit comprising separate formulations of TRPAl antagonist and the anticholinergic agent.
  • the process for making the pharmaceutical composition may for example include, (1) granulating either or both the active ingredients, combined or separately, along with pharmaceutically acceptable carriers so as to obtain granulate, and (2) converting the granulate into suitable dosage forms for oral administration.
  • the typical processes involved in the preparation of the pharmaceutical combinations include various unit operations such as mixing, sifting, solubilizing, dispersing, granulating, lubricating, compressing, coating, and the like.
  • Asthma is believed to be a chronic inflammatory disease wherein the airflow limitation is more or less reversible while it is more or less irreversible in case of COPD. Asthma among other things is believed to be triggered by inhalation of sensitizing agents (like allergens) unlike noxious agents (like particles and certain gases) in case of COPD. Though both are believed to have an inflammatory component, the inflammation in asthma is believed to be mostly eosinophilic and CD-4 driven, while it is believed to be mostly neutrophilic and CD-8 driven in COPD.
  • Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEVi), peak expiratory flow rate and severity (e.g., acute, intermittent, mild persistent, moderate persistent, and severe persistent) Asthma may also be classified as allergic (extrinsic) or non-allergic (intrinsic), based on whether symptoms are precipitated by allergens or not.
  • FEVi forced expiratory volume in 1 second
  • severity e.g., acute, intermittent, mild persistent, moderate persistent, and severe persistent
  • Asthma may also be classified as allergic (extrinsic) or non-allergic (intrinsic), based on whether symptoms are precipitated by allergens or not.
  • Asthma can also be categorized according to following types viz., nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, and cough variant asthma.
  • COPD chronic obstructive lung disease
  • COAD chronic obstructive airway disease
  • CORD chronic obstructive respiratory disease
  • COPD chronic obstructive pulmonary disease
  • ⁇ drugs are currently being used for the treatment and/or prophylaxis of respiratory disorders like asthma and COPD.
  • Some of the classes of such drugs are leukotriene receptor antagonists, antihistamines, beta-2 agonists, anticholinergic agents and corticosteroids.
  • Anticholinergic agents are believed to reverse the action of vagally derived acetylcholine on airway smooth muscle contraction.
  • Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle.
  • Vagally derived acetylcholine also regulates mucus production in the airways.
  • Anticholinergic drugs can effectively inhibit accelerated decline of lung function. Further, anticholinergic agents can achieve reductions in airway remodeling and lung function decline in addition to its effects as a bronchodilator (Reinoud et. al. "Review: Muscarinic receptor signaling in the pathophysiology of asthma and COPD", Respiratory Research 2006, 7:73).
  • a pharmaceutical composition comprising TRPAl antagonist and an anticholinergic agent are more effective in the treatment of respiratory disorders, and provide better therapeutic value when compared to both the actives alone (when administered individually) for the treatment of respiratory disorders.
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar and an anticholinergic agent.
  • the TRPAl antagonist has an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar having structure of formulae:
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering the subject a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the present invention relates to use of
  • the TRPA1 antagonist has an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: (XII) or (D)
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent for the treatment of a respiratory disorder in a subject.
  • the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the anticholinergic agent is selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the present invention relates to a method of treating
  • COPD by reducing neutrophil count in a subject
  • said method comprising administering to the subject the pharmaceutical composition comprising
  • TRPA1 antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the respiratory disorder is asthma.
  • the composition is for inhalation administration.
  • the present invention relates to a method of reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to a method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the respiratory disorder is asthma. In another aspect of the
  • the composition is for inhalation administration.
  • the present invention relates to a method of inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • the anticholinerg agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the composition is for inhalation administration.
  • the present invention relates to use of
  • the anticholinergic agent is selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • an anticholinergic agent for the treatment of a respiratory disorder in a subject.
  • the therapeutically effective amount of TRPA1 antagonist to be administered per day ranges from about lOmcg/kg to about 20mg/kg, and preferably from about 50mcg/kg to about 15mg/kg.
  • the therapeutically effective amount of tiotropium to be administered per day ranges from about 5mcg to about 50mcg and preferably from about 10 meg to about 36 meg.
  • the discrete dosage strengths of tiotropium or its salt are 15 meg or 18 meg or 20 meg or 22 meg or 22.5 meg or 25 meg or 36 meg.
  • the therapeutically effective amount of ipratropium to be administered per day ranges from about 10 meg to about 200 meg and preferably from about 20 meg to about 150 meg.
  • the discrete dosage strengths of ipratropium or its salt are 34 meg or 42 meg or 68 meg or 84 meg or 102 meg or 126 meg or 146 meg or 168 meg.
  • the therapeutically effective amount of aclidinium bromide to be administered per day ranges from 150 meg to about 800 meg, and preferably from about 200 meg to about 600 meg.
  • the discrete dosage strengths of aclidinium or its salt are 200 meg or 400 meg or 600 meg or 800 meg.
  • the optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of
  • composition type administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.
  • the active ingredient may be in the form of a single dosage form (i.e., fixed-dose formulation in which both the active ingredients are present together) or they may be divided doses, formulated separately, each in its individual dosage forms but as part of the same therapeutic treatment, program or regimen, either once daily or
  • the invention relates to a pharmaceutical composition wherein the composition is in the form of kit comprising separate formulations of TRPA1 antagonist and the anticholinergic agent.
  • the separate formulations are to be administered by same or different routes, either separately, simultaneously, or sequentially, where the sequential administration is close in time or remote in time.
  • the period of time may be in the range from 10 min to 12 hours.
  • a commonly used model for evaluation of drug candidates in COPD involves the chronic exposure of the animal to S0 2 or tobacco/cigarette smoke.
  • the model is believed to generate sloughing of epithelial cells, increase in the mucus secretions, increase in the polymorphonuclear cells and pulmonary resistance, and increase in the airway hyper-responsiveness (in rats).
  • LPS lipopolysaccharide
  • the human IC 50 values were measured by the following method:
  • TRPAl receptor activation was measured as inhibition of allylisothiocyanate (AITC) induced cellular uptake of radioactive calcium.
  • Test compound solution was prepared in a suitable solvent.
  • Human TRPAl expressing CHO cells were grown in suitable medium.
  • concentration response curves for compounds were plotted as a % of maximal response obtained in the absence of test antagonist, and the IC 50 values were calculated from such concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
  • Table 1 TRPAl antagonists having a human IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar.
  • EXAMPLE 2 Animal studies for the combination of Compound 52 and tiotropium bromide.
  • EXAMPLE 3 Animal studies for the combination of Compound 52 and aclidinium bromide.
  • LPS was nebulized at concentration of 100 meg ml "1 for 40 min at 0.4 ml/min and a pressure of 1.7 psig in a Perspex exposure chamber (1.5 x 1 x 1 ft) fitted with nebulizer (RCI Hudson). Control animals were given saline exposure under similar conditions. All the animals were treated with compounds as mentioned in Table 4. Compound 52 (3mg/kg/5ml) was administered orally 2 h prior to LPS and aclidinium (50mcg/ml) was nebulized at the rate of 0.05 ml/min and exposed to the animals for 3 min prior LPS exposure.
  • Bronchoalveolar lavage was done after 4h of LPS exposure.
  • EXAMPLE 4 Animal studies for the combination of Compound 52 and tiotropium.
  • BAL Bronchoalveolar lavage
  • Combination of Compound 52 with tiotropium showed significant inhibition in LPS induced neutrophilia compared to the individual treatments (Table 7 and Figure 3).
  • Compound 52 in combination with tiotropium showed synergy in inhibition of neutrophilia in LPS model in SD rats.
  • BAL Bronchoalveolar lavage
  • Remaining BAL fluid was centrifuged at 4000 rpm for 20 min. The pellet formed in the bottom of the tube was used for the smear preparation for differential leukocyte count estimation. The differential leukocyte count was done using Leishman's stain.
  • the total number of neutrophils in each BAL sample was calculated using the formula:
  • % inhibition of neutrophils was calculated using the following formula:

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Abstract

The present invention relates to a pharmaceutical composition comprising a transient receptor potential ankyrin-1 receptor ("TRPA1") antagonist and an anticholinergic agent. Particularly, the present invention provides a pharmaceutical composition comprising a TRPA1 antagonist having IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent; a process for preparing such composition; and its use in treating a respiratory disorder in a subject.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A TRPA1 ANTAGONIST AND AN ANTICHOLINERGIC AGENT
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent
Application number 3418/MUM/2011 (filed on Dec. 5, 2011), the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present patent application relates to a pharmaceutical composition comprising a transient receptor potential ankyrin-1 receptor ("TRPA1") antagonist and an anticholinergic agent. Particularly, the application provides a
pharmaceutical composition comprising a TRPA1 antagonist having IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent; a process for preparing such composition; and its use in treating a respiratory disorder in a subject.
BACKGROUND OF THE INVENTION
Respiratory disorders related to airway inflammation include a number of severe lung diseases including asthma and chronic obstructive pulmonary disease ("COPD"). The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is believed to be the most prominent component. Inflammatory sensitization of airway neurons is believed to increase nasal and cough sensitivity, heighten the sense of irritation, and promote fluid secretion, airway narrowing, and bronchoconstriction.
TRPA1 receptor activation in the airways by exogenous noxious stimuli, including cold temperatures (generally, less than about 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic), tobacco smoke, tear gas and environmental irritants as well as by endogenous biochemical mediators released during inflammation, is supposed to be one of the mechanisms for neurogenic inflammation in the airways. Neurogenic inflammation is an important component of chronic airway diseases like COPD and asthma.
International Publication Nos. viz., WO 2004/055054, WO 2005/089206, WO 2007/073505, WO 2008/0949099, WO 2009/089082, WO 2009/002933 WO 2009/158719, WO 2009/144548, WO 2010/004390, WO 2010/109287, WO 2010/109334, WO 2010/109329, WO 2010/109328, WO 2010/125469 and WO 2010/004390 describe various transient receptor potential ("TRP") receptor modulators.
Anticholinergic agents are believed to inhibit vagally-mediated reflexes by blocking acetylcholine at the cholinergic receptor. Anticholinergic agents are also believed to inhibit secretions of the serous and sero-mucous glands of the nasal mucosa. Anticholinergic agents for treatment or control of respiratory disorders include tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salt thereof.
One known anticholinergic agent is tiotropium bromide, the chemical name of which is, (la, 2B, 4B, 5a, 7B)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl- 3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. Tiotropium bromide is available commercially as SPIRIVA® capsules containing 18 meg tiotropium (equivalent to 22.5 meg tiotropium bromide monohydrate) marketed by Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. Tiotropium bromide is indicated for the maintenance treatment of bronchospasm associated with COPD, and for reducing COPD exacerbations.
Another anticholinergic agent, ipratropium bromide is chemically, 8- azoniabicyclo (3.2.1) octane, 3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl-8- (1-methylethyl)-, bromide monohydrate. Ipratropium bromide is commercially available as ATROVENT® 0.06% nasal spray (42 meg per spray) marketed by Boehringer Ingelheim Pharmaceuticals, Inc. in the United States. It is administered as a pressurized metered-dose aerosol unit for oral inhalation. Each actuation of the inhaler delivers 21 meg of ipratropium bromide. Ipratropium bromide is indicated for the symptomatic relief of rhinorrhea associated with the common cold or seasonal allergic rhinitis. ATROVENT HFA® is another product of ipratropium bromide is approved as a bronchodilator for maintenance treatment of
bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
Aclidinium bromide, chemically known as [(8R)-l-(3-phenoxypropyl)-l- azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide is a novel long acting inhaled muscarinic antagonist. It is approved as TUDORZA® PRESSAIR® 0.375mg/INH in the United States. It is approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
Another anticholinergic agent, glycopyrrolate is chemically 3 -(2
cyclopentyl-2-hydroxy-2-phen lacetoxy)- 1 , 1 -dimethylpyrrolidinium
Figure imgf000004_0001
(Glycopyrrolate)
Glycopyrrolate is being developed for the treatment of asthma and COPD.
There still exists a need for an effective therapeutic treatment for respiratory disorders like asthma, COPD and rhinorrhea.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising a
TRPA1 antagonist and an anticholinergic agent.
The inventors have surprisingly found that a TRPAl antagonist and an anticholinergic agent act synergistically in the treatment of respiratory disorders and are more effective and provide better therapeutic value than treatment with either active ingredient alone.
The anticholinergic agent, as contemplated herein, including tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or their salt may be present in the form of their stereoisomers, polymorphs, and solvates, including hydrates, all of which are included in the scope of the invention. In another embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: XII) or (D)
Figure imgf000005_0001
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000005_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
and an anticholinergic agent.
In an aspect of the embodiment, the TRPA1 antagonist as contemplated herein and the anticholinergic agent are present in a weight ratio ranging from about 1 :0.0001 to about 1 : 10000.
In yet another embodiment, the present invention relates to a
pharmaceutical composition comprising synergistically effective amount of a
TRPA1 antagonist having structure of formula:
Figure imgf000005_0003
and an anticholinergic agent. In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent.
The respiratory disorder, in the context of present invention, includes but is not limited to airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
In a further embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering the subject a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
In a further embodiment, the present invention relates to use of
synergistically effective amount of a TRPAl antagonist having an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject.
In a further embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar as contemplated herein and an anticholinergic agent for the treatment of a respiratory disorder in a subject. In an embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000007_0001
and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In an aspect of this embodiment, the pharmaceutical composition is a fixed dose combination. In another aspect of the embodiment, the composition is for inhalation administration.
In yet another aspect of this embodiment, the composition is for inhalation administration, wherein the TRPAl antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.001 to about 1 :300.
In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000007_0002
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating COPD by reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000008_0001
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of this embodiment, the respiratory disorder is asthma. In another aspect of the embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000008_0002
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000008_0003
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of this embodiment, the respiratory disorder is asthma. In another aspect of the embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000009_0001
and an anticholinergic agent. In an aspect of this embodiment, the anticholinerg agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the
embodiment, the composition is for inhalation administration.
In another embodiment, the present invention relates to use of
synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000009_0002
and an anticholinergic agent in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the embodiment, the composition is for inhalation administration.
In a further embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000010_0001
and an anticholinergic agent for the treatment of a respiratory disorder in a subject. In an aspect of the embodiment, the composition is for inhalation administration. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar graph showing the effect of Compound 52, tiotropium bromide, and their combination on methacholine-induced bronchoconstriction in male Dunkin Hartley guinea pigs.
Figure 2 is a bar graph showing the effect of Compound 52, aclidinium bromide, and their combination on LPS induced neutrophilia in male SD rats.
Figure 3 is a bar graph showing the effect of Compound 52, tiotropium and their combination on LPS induced neutrophilia in female SD rats.
Figure 4 is a bar graph showing the effect of Compound 52, ipratropium bromide and their combination on LPS induced neutrophilia in male SD rats.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth earlier in a provisional application from which priority is claimed are in conflict, the definition in the present application shall control the meaning of the terms.
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating a respiratory disorder, produces an intended therapeutic benefit in a subject.
The therapeutically effective amount of TRPA1 antagonist as described herein ranges from about O. lmcg/kg to about 20mg/kg, and preferably from about lmcg/kg to about 15mg/kg. The therapeutically effective amount tiotropium to be administered per day ranges from about 5 μg to about 50 μg and preferably from about 10 μg to about 36 μg. Preferably, the discrete dosage strength of tiotropium or its salt is 18 μg.
The therapeutically effective amount of ipratropium to be administered per day ranges from about 0.05 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg. Preferably, the discrete dosage strengths of ipratropium or its salt are 168 μg or 336 μg or 504 μg or 672 μg.
The therapeutically effective amount of aclidinium to be administered per day ranges from about 0.05 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg. Preferably, the discrete dosage strengths of aclidinium or its salt are 200 μg or 400 μg or 800 μ§.
The therapeutically effective amount of glycopyrrolate to be administered per day ranges from about 0.01 mg to about 10 mg, and preferably from about 0.1 mg to about 1 mg.
The therapeutically effective ranges of actives are given as above, although larger or smaller amount are not excluded if they fall within the scope of the definition of the above paragraphs.
The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes a TRPA1 antagonist, an
anticholinergic agent or a pharmaceutically acceptable salt thereof. Preferably, the active ingredient includes TRPA1 antagonist having a human IC50 value of less than 1 micromolar, tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or its salt.
The IC50 value is believed to be measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure generally indicates molar concentration of a particular compound (or substance) is needed to inhibit a given biological process by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of the compound. The IC50 of a drug compound (or active substance) can be determined by constructing a concentration-response curve so as to examine the effect of different
concentrations of antagonist on reversing agonist activity. IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC50 values can be used to compare the potency of two antagonists.
By "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
The term "treating" or "treatment" as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the TRPA1 receptor, or the anticholinergic agent, or by a
combination of the two in a subject.
The respiratory disorder includes but is not limited to airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy. Preferably, the respiratory disorder is asthma or COPD.
The term "subject" includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife). Preferably, the subject is a human.
By "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use. The term "synergistic" or "synergy", as used herein, refers to a combination exhibiting an effect greater than would be expected from the sum of the effects of the individual components of the combination alone. The term "synergistic" or "synergy" with regard to the combination of a TRPA1 antagonist with an anticholinergic agent which is used in the treatment of a respiratory disorder (for example, in the form of a pharmaceutical composition, a combination product or a kit according to the invention) refers to an efficacy for the treatment of the respiratory disorder that is greater than would be expected from the sum of their individuals effects. The advantages for the synergistic combinations of the present invention include, but are not limited to, lowering the required dose of one or more of the active compounds of the combination, reducing the side effects of one or more of the active compounds of the combination and/or rendering one or more of the active compounds more tolerable to the subject in need of treatment of the respiratory disorder.
Combinations
The present invention relates to a pharmaceutical composition comprising a TRPA1 antagonist and an anticholinergic agent.
The inventors have surprisingly found that a TRPA1 antagonist and an anticholinergic agent act synergistically in the treatment of respiratory disorders, and are more effective and provide better therapeutic value than treatment with either active ingredient alone.
In an aspect, TRPA1 antagonists useful in the context of the invention, are selected from one of the following formulae: (A) or (B) or (C) or (D)
Figure imgf000013_0001
(A) ( B) (C) ( D) or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000014_0001
P is selected from
Figure imgf000014_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
Rb and Rc independently selected from hydrogen, substituted or unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl;
R10 is selected from hydrogen, alkyl, arylalkyl and pharmaceutically acceptable cation.
In one aspect, TRPA1 antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
WO2009144548. Accordingly, a TRPA1 antagonist useful in the context of the invention has the formula (I):
Figure imgf000015_0001
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heterocyclylalkyl;
R7 independently represents hydrogen or alkyl.
Few representative TRPAl antagonists useful in the methods of the invention are mentioned below:
Figure imgf000015_0002
Compound 1 Compound 2
The preparation of above said compounds is described in WO2009144548. In another aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO2010004390. Accordingly, TRPAl antagonist useful in the context of the invention has the formula (II):
Figure imgf000015_0003
(II) or pharmaceutically acceptable salts thereof,
wherein,
at each occurrence R and R2 is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, (CRxRy)nORx, CORx, COORx, CONRxRy, S02NRxRy, NRxRy, NRx(CRxRy)nORx, NRx(CRxRy)nCN (CH2)nNRxRy, (CH2)nCHRxRy, (CRxRy)NRxRy, NRx(CRxRy)nCONRxRy, (CH2)nNHCORx and (CH2)nNH(CH2)nS02Rx, (CH2)nNHS02Rx;
Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl;
Rx and Rymay be joined together to form an optionally substituted 3 to 7 membered saturated, unsaturated or partially saturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRaor S;
ring A is selected from phenyl, pyridinyl, pyrazolyl, thiazolyl and thiadiazolyl;
each occurrence of R6 is independently hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl,
Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
at each occurrence of 'n' is independently selected from 1 to 5.
According to one aspect, specifically provided are compounds of the formula (Ila)
Figure imgf000017_0001
or pharmaceutically acceptable salts thereof,
wherein,
RJ and R2 are as defined above for the compound of formula (II);
R6a and R6b are independently selected from hydrogen, cyano, nitro, - NRxRy, halogen, hydroxyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted
heterocyclylalkyl, -C(0)ORx, -ORx, -C(0)NRxRy, -C(0)Rx, -S02Rx, -S02-NRxRy.
Few representative TRPA1 antagonists useful in the context of the invention are mentioned below:
Figure imgf000018_0001
Compound 3 Compound 4
Figure imgf000018_0002
Compound 5 Compound 6
Figure imgf000018_0003
Compound 11 Compound 12
Figure imgf000018_0004
Compound 13 Compound 14
Figure imgf000019_0001
Compound 15 Compound 16
Figure imgf000019_0002
Compound 17 Compound 18
Figure imgf000019_0003
Compound 19 Compound 20
Figure imgf000019_0004
Compound 21 Compound 22
Figure imgf000019_0005
Compound 23 Compound 24
Figure imgf000019_0006
Compound 25 Compound 26
Figure imgf000020_0001
Compound 29 Compound 30
Figure imgf000020_0002
Compound mpound 32
Figure imgf000020_0003
Compound 33
The preparation of above said compounds is described in WO2010004390.
In one aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
WO2010109287. Accordingly, TRPAl antagonist useful in the context of the invention has the formula (III):
Figure imgf000020_0004
(III)
or a pharmaceutically acceptable salt thereof, wherein,
Zi is NRa or CRa;
Z2 is NRb or CRb;
Z3 is N or C;
with the proviso that when Z2 is CRb then both Zi and Z3 are not nitrogen at the same time;
at each occurrence, Ra and Rb which may be same or different, are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, -(CRxRy)nORx, -CORx, -COORx, -CONRxRy, -S(0)mNRxRy, -NRxRy,
-NRx(CRxRy)nORx, -(CH2)nNRxRy, -(CH2)nCHRxRy, -(CH2)NRxRy,
-NRx(CRxRy)nCONRxRy, -(CH2)nNHCORx, -(CH2)nNH(CH2)nS02Rx and
(CH2)nNHS02Rx;
alternatively either of Ra or Rb is absent;
R1 and R2, which may be same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CRxRy)nORx, CORx, COORx, CONRxRy, (CH2)nNRxRy, (CH2)nCHRxRy, (CH2)NRxRy and (CH2)nNHCORx;
R3 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
L is a linker selected from -(CRxRy)„- -0-(CRxRy)n-, -C(O)-, -NRX-, - S(0)mNRx-, -NRx(CRxRy)n- and -S(0)mNRx(CRxRy)n;
U is selected from substituted or unsubstituted aryl, substituted or unsubstituted five membered heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyroles, 1,2,3-triazoles and 1,2,4-triazole; and substituted or unsubstituted six membered heterocycles selected from the group consisting of pyrimidine, pyridine and pyridazine;
V is selected from hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)ORx, - ORx, -C(0)NRxRy, -C(0)Rx and -S02NRxRy; or U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, that may optionally include one or more heteroatoms selected from O, S and N;
at each occurrence, Rx and Ry are independently selected from the group consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and
at each occurrence 'm' and 'n' are independently selected from 0 to 2, both inclusive.
Few representative TRPA1 antagonists useful in the context of the invention are mentioned below:
Figure imgf000022_0001
Compound 34 Compound 35
Figure imgf000022_0002
Compound 36 Compound 37
Figure imgf000022_0003
Compound 38 Compound 39
Figure imgf000023_0001
Compound 40 Compound 41
Figure imgf000023_0002
Compound 42 Compound 43
Figure imgf000023_0003
Compound 44 Compound 45
The preparation of above said compounds is described in WO2010109287. In one aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO 2010109334. Accordingly, TRPAl antagonists useful in the context of the invention has the formula (IV)
Figure imgf000023_0004
(IV)
or a pharmaceutically-acceptable salt thereof
wherein, R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (d-C4)alkyl; R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPAl antagonists useful in the context of the invention are mentioned below:
Figure imgf000024_0001
Compound 46 Compound 47
Figure imgf000024_0002
Compound 48 Compound 49
Figure imgf000024_0003
Compound ompound 51
Figure imgf000024_0004
Compound 52
The preparation of above said compounds is described in WO2010109334.
In one aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
WO2010109329. Accordingly, TRPAl antagonists useful in the context of the invention has the formula (V)
Figure imgf000025_0001
(V)
or a pharmaceutically acceptable salt thereof,
wherein, R1, R2 and Ra which may be the same or different, are each independently hydrogen or (C1-C4) alkyl; and
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPA1 antagonists useful in the context of the invention are mentioned below:
Figure imgf000025_0002
Compound 54
Figure imgf000025_0003
Compound 56
Figure imgf000025_0004
Compound 57 Compound 58
Figure imgf000026_0001
Compound 59 Compound 60
Figure imgf000026_0002
Compound 62
Figure imgf000026_0003
Compound 63 Compound 64
Figure imgf000026_0004
Compound 65 Compound 66
Figure imgf000026_0005
Compound 68
Figure imgf000026_0006
Compound 69 Compound 70
Figure imgf000027_0001
Compound 71 Compound 72
Figure imgf000027_0002
Compound 73 Compound 74
Figure imgf000027_0003
Compound 75 Compound 76
The preparation of above said compounds is described in WO2010109329. In one aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
WO2010109328. Accordingly, TRPAl antagonists useful in the context of the invention has the formula (VI)
Figure imgf000027_0004
(VI),
or a pharmaceutically-acceptable salt thereof.
wherein, R1 and R2, which may be the same or different, are each independently hydrogen or (Ci-C4)alkyl; and
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl.
Few representative TRPAl antagonists useful in the context of the invention are mentioned below:
Figure imgf000028_0001
Compound 77 Compound 78
Figure imgf000028_0002
Compound 79 Compound 80
Figure imgf000028_0003
Compound 81 Compound 82
Figure imgf000028_0004
Compound 83 Compound 84
The preparation of above said compounds is described in WO2010109328. In one aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in
WO2010125469. Accordingly, TRPAl antagonists useful in the context of the invention have the formulas (Vila, Vllb and VIIc):
Figure imgf000029_0001
Figure imgf000029_0002
(VIIc)
or pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, Ra is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and cycloalkylalkyl;
U is substituted or unsubstituted five membered heterocycle, for example selected from the group consisting of
Figure imgf000029_0003
at each occurrence, Rb is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and
heterocyclylalkyl;
at each occurrence, Rz is independently selected from halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, COORx, CONRxRy, S(0)mNRxRy, NRx(CRxRy)nORx, (CH2)nNRxRy, NRx(CRxRy)nCONRxRy, (CH2)nNHCORx, (CH2)nNH(CH2)nS02Rx and
(CH2)nNHS02Rx;
at each occurrence, Rx andRyare independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
at each occurrence, 'm' and 'n' are independently selected from 0 to 2, both inclusive; and 'p' is independently selected from 0 to 5, both inclusive.
Few representative TRPAl antagonists useful in the context of the invention are mentioned below:
Figure imgf000030_0001
Compound 85 Compound 86
Figure imgf000030_0002
Compound 87 Compound 88
The preparation of above said compounds is described in WO2010125469.
In one aspect, the TRPAl antagonist useful in the context of the invention is Compound 89:
H
Figure imgf000030_0003
Compound 89
In one embodiment, the TRPAl antagonist useful in the context of the invention is Compound 90:
Figure imgf000030_0004
Compound 90
embodiment, TRPA1 antagonists useful in the context of the invention has the formula
Figure imgf000031_0001
(VII I)
or a pharmaceutically-acceptable salt thereof
wherein,
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (Ci-C4)alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
A representative TRPA1 antagonist useful in the context of the invention is
Compound 91 :
Figure imgf000031_0002
Compound 91
The Compound 91 may be prepared, for example, by following the process provided for the preparation of similar compounds in PCT publication No.
WO2007073505.
In another aspect, TRPA1 antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO201 1 1 14184. Accordingly, a TRPA1 antagonist useful in the context of the invention has the formula (IX):
Figure imgf000032_0001
(IX)
or a pharmaceutically-acceptable salt thereof
wherein at each occurrence, R1 and R2 are independently selected from hydrogen or substituted or unsubstituted alkyl;
at each occurrence, R5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
at each occurrence, R6 is selected from hydrogen, cyano, nitro, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
A representative TRPA1 antagonist useful in the methods of the invention is mentioned below:
Figure imgf000032_0002
Compound 92
The preparation of above said compounds is described in WO2011114184. In another aspect, TRPA1 antagonist useful in the context of the invention has the formula (X):
Figure imgf000032_0003
(X)
wherein, 'Het' is selected from groups consisting of
Figure imgf000033_0001
P is selected from
Figure imgf000033_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
Rb and Rc independently selected from hydrogen, substituted or unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring;
R10 is selected from hydrogen, alkyl, arylalkyl and pharmaceutically acceptable cation.
Few representative TRPA1 antagonists useful in the context of the invention are mentioned below:
Figure imgf000034_0001
Compound 96
Figure imgf000034_0002
Compound 97 Compound 98
In another aspect, TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO201 1 1 14184. Accordingly, TRPAl antagonist useful in the context of the invention has the formula (XI):
Figure imgf000034_0003
(XI)
or a pharmaceutically acceptable salt thereof,
wherein, R1, and R2 are independently hydrogen or (Ci-C4)alkyl; and R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from halogen haloalkyl, dialkylamino, and haloalkoxy.
Few representative TRPAl antagonists useful in the context of the invention are mentioned below:
Figure imgf000034_0004
Compound 99 Compound 100
Figure imgf000035_0001
Compound 101 Compound 102
Figure imgf000035_0002
Compound 103 Compound 104
The preparation of above said compounds is described in WO2011114184. In an aspect, TRPA1 antagonists useful in the context of the invention, is selected from one of the following formulae: (XII) or (D)
Figure imgf000035_0003
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000035_0004
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl. Few representative TRPA1 antagonists of the formula (XII) useful in the context of the invention are compound 52, compound 73 and compound 84 as described above.
The anticholinergic agent, as contemplated herein, includes tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. The salt may be present in the form of their isomers, polymorphs, and solvates, including hydrates, all of which are included in the scope of the invention.
In another embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: (XII) or (D)
Figure imgf000036_0001
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000036_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
and an anticholinergic agent. Preferably, the TRPA1 antagonist of the present invention has an IC50 for inhibiting human TRPA1 receptor activity of less than 500 nanomolar, or more preferably less than 250 nanomolar, as measured by a method described herein.
In yet another embodiment, the present invention relates to a
pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
Figure imgf000037_0001
and an anticholinergic agent.
In another embodiment, there is provided a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist as
contemplated herein and an anticholinergic agent in a weight ratio ranging from about 1 :0.0001 to about 1 : 10000.
In an embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
Figure imgf000037_0002
and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In first aspect of this embodiment, the anticholinergic agent is tiotropium. In second aspect of this embodiment, the anticholinergic agent is ipratropium. In third aspect of this embodiment, the anticholinergic agent is aclidinium. In another aspect of this embodiment, the pharmaceutical composition is a fixed dose combination.
The pharmaceutical composition of the present invention may be administered orally, nasally, intra-tracheally, parenterally, transdermally, transmucosal, inhalation or by any other route that a physician or a health-care provider may determine to be appropriate. Preferably, the route of administration is oral or by inhalation. In yet another aspect of this embodiment, the composition is for inhalation administration and the TRPA1 antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.001 to about 1 :300.
As contemplated herein, the active ingredients may be administered together in a single dosage form or they may be administered in different dosage forms. They may be administered at the same time or they may be administered either close in time or remotely, such as, where one drug is administered in the morning and the second drug is administered in the evening. The combination may be used prophylactically or after the onset of symptoms has occurred.
In a preferred embodiment, both the active ingredients i.e., TRPA1 antagonist and the anticholinergic agent are formulated as a pharmaceutical composition suitable for administration by the same route (e.g., both the actives by oral or inhalation route), or by different routes (e.g., one active by oral and the other active by inhalation route).
The pharmaceutical compositions for oral administration may be in conventional forms, for example, tablets, capsules, granules (synonymously, "beads" or "particles" or "pellets"), suspensions, emulsions, powders, dry syrups, and the like. The capsules may contain granule/pellet/particle/mini-tablets/mini- capsules containing the active ingredients. The amount of the active agent that may be incorporated in the pharmaceutical composition may range from about 1% w/w to about 98% w/w or from about 5% w/w to about 90% w/w.
The pharmaceutical compositions for parenteral administration include but are not limited to solutions/suspension/emulsion for intravenous, subcutaneous or intramuscular injection/infusion, and implants. The pharmaceutical compositions for transdermal or transmucosal administration include but are not limited to patches, gels, creams, ointments and the like.
As set forth above, the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents/viscosifying agents, surfactants, solvents and the like. In an embodiment, the present invention provides a process for the preparing a pharmaceutical composition comprising TRPAl antagonist and an anticholinergic agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation. The process comprises admixing TRPAl antagonist with the anticholinergic agent. Alternately, the process comprises formulating TRPAl antagonist and the anticholinergic agent in such a way that they are not in intimate contact with each other.
In another embodiment, the invention relates to a process for preparing a pharmaceutical composition comprising TRPAl antagonist, an anticholinergic agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of kit comprising separate formulations of TRPAl antagonist and the anticholinergic agent.
The process for making the pharmaceutical composition may for example include, (1) granulating either or both the active ingredients, combined or separately, along with pharmaceutically acceptable carriers so as to obtain granulate, and (2) converting the granulate into suitable dosage forms for oral administration. The typical processes involved in the preparation of the pharmaceutical combinations include various unit operations such as mixing, sifting, solubilizing, dispersing, granulating, lubricating, compressing, coating, and the like. These processes, as contemplated by a person skilled in the formulation art, have been incorporated herein for preparing the pharmaceutical composition of the present invention.
Methods of treatment
Asthma and COPD are major chronic diseases related to airway
obstruction. The Global Initiative for Chronic Obstructive Lung Disease provides guidelines for the distinction between asthma and COPD. Asthma is believed to be a chronic inflammatory disease wherein the airflow limitation is more or less reversible while it is more or less irreversible in case of COPD. Asthma among other things is believed to be triggered by inhalation of sensitizing agents (like allergens) unlike noxious agents (like particles and certain gases) in case of COPD. Though both are believed to have an inflammatory component, the inflammation in asthma is believed to be mostly eosinophilic and CD-4 driven, while it is believed to be mostly neutrophilic and CD-8 driven in COPD.
Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEVi), peak expiratory flow rate and severity (e.g., acute, intermittent, mild persistent, moderate persistent, and severe persistent) Asthma may also be classified as allergic (extrinsic) or non-allergic (intrinsic), based on whether symptoms are precipitated by allergens or not.
Asthma can also be categorized according to following types viz., nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, and cough variant asthma.
COPD, also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), or chronic obstructive respiratory disease (CORD), is believed to be the co-occurrence of chronic bronchitis (characterized by a long-term cough with mucus) and emphysema (characterized by destruction of the lungs over time), a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath. An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days and is believed to be triggered by an infection with bacteria or viruses or by environmental pollutants. Based on the FEVi values, COPD can be classified as mild, moderate, severe and very severe.
It is believed that reduction of eosinophil or neutrophil count and increase in FEVI are important components of the treatment of respiratory disorders such as asthma and COPD. It is also believed that there exits an inverse correlation between eosinophil or neutrophil count and FEVI value in human. For example, Ulrik CS, 1995 (Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma; Clinical and Experimental Allergy; 1995, Volume 25, pages 820- 827) discloses the relationship between eosinophil count and severity of asthmatic symptoms. It describes that in childhood and adulthood subjects, there exists an inverse correlation between number of eosinophils and FEV1% (r = -0.75, P < 0.001, and r = -0.80, P < 0.001, respectively).
Further, Peleman RA, 1999 (The cellular composition of induced sputum in chronic obstructive pulmonary disease; European Respiratory Journal; 1999, Volume 13, pages 839-843) discloses the relationship between percentage of neutrophils and FEV1 in patients with COPD. It describes that in patients with COPD, an inverse correlation was noted between percentage of neutrophils and FEV1 (r= -0.48, p < 0.05).
Various classes of drugs are currently being used for the treatment and/or prophylaxis of respiratory disorders like asthma and COPD. Some of the classes of such drugs are leukotriene receptor antagonists, antihistamines, beta-2 agonists, anticholinergic agents and corticosteroids.
Human airways are innervated by a generous supply of efferent, cholinergic, parasympathetic autonomic nerves. Motor nerves derived from the vagus form ganglia within and around the walls of the airways. Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands. Epithelial and inflammatory cells also generate ACh and express functional muscarinic receptors. Recent findings indicate that ACh, acting on muscarinic receptors, may contribute to the pathophysiology and pathogenesis of asthma and COPD.
Anticholinergic agents are believed to reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. Anticholinergic drugs can effectively inhibit accelerated decline of lung function. Further, anticholinergic agents can achieve reductions in airway remodeling and lung function decline in addition to its effects as a bronchodilator (Reinoud et. al. "Review: Muscarinic receptor signaling in the pathophysiology of asthma and COPD", Respiratory Research 2006, 7:73).
Thus, it is believed that though the therapeutic outcomes of these two classes of drugs, the TRPAl antagonists and the anticholinergic agent are similar to some extent, the mechanism of actions may vary to a good extent and thus the therapeutic effect of their combination in the treatment of respiratory disorders is highly unpredictable. Particularly, the therapeutic effect of the combination of TRPAl antagonist and an anticholinergic agent is highly unpredictable.
The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising TRPAl antagonist and an anticholinergic agent are more effective in the treatment of respiratory disorders, and provide better therapeutic value when compared to both the actives alone (when administered individually) for the treatment of respiratory disorders.
In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar and an anticholinergic agent. In an aspect of this embodiment, the TRPAl antagonist has an IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar having structure of formulae:
(XII) o
Figure imgf000042_0001
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000042_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
In a further embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering the subject a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
In a further embodiment, the present invention relates to use of
synergistically effective amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject. In an aspect of this embodiment, the TRPA1 antagonist has an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: (XII) or (D)
Figure imgf000043_0001
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein, 'Het' is selected from the group consisting of
Figure imgf000044_0001
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.
In a further embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and an anticholinergic agent for the treatment of a respiratory disorder in a subject.
In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
Figure imgf000044_0002
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent is selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
In an embodiment, the present invention relates to a method of treating
COPD by reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising
synergistically effective amount of a TRPA1 antagonist having structure of formula:
Figure imgf000045_0001
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of this embodiment, the respiratory disorder is asthma. In another aspect of the embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000045_0002
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000045_0003
and an anticholinergic agent. In an aspect of this embodiment, the anticholinergic agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of this embodiment, the respiratory disorder is asthma. In another aspect of the
embodiment, the composition is for inhalation administration.
In an embodiment, the present invention relates to a method of inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000046_0001
and an anticholinergic agent. In an aspect of this embodiment, the anticholinerg agent selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof. In another aspect of the
embodiment, the composition is for inhalation administration.
In another embodiment, the present invention relates to use of
synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000046_0002
and an anticholinergic agent in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject. In an aspect of this embodiment, the anticholinergic agent is selected from a group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000046_0003
and an anticholinergic agent for the treatment of a respiratory disorder in a subject.
The therapeutically effective amount of TRPA1 antagonist to be administered per day ranges from about lOmcg/kg to about 20mg/kg, and preferably from about 50mcg/kg to about 15mg/kg.
In one embodiment of the present invention the therapeutically effective amount of tiotropium to be administered per day ranges from about 5mcg to about 50mcg and preferably from about 10 meg to about 36 meg. Preferably, the discrete dosage strengths of tiotropium or its salt are 15 meg or 18 meg or 20 meg or 22 meg or 22.5 meg or 25 meg or 36 meg.
In one embodiment of the present invention the therapeutically effective amount of ipratropium to be administered per day ranges from about 10 meg to about 200 meg and preferably from about 20 meg to about 150 meg. Preferably the discrete dosage strengths of ipratropium or its salt are 34 meg or 42 meg or 68 meg or 84 meg or 102 meg or 126 meg or 146 meg or 168 meg.
In one embodiment of the present invention the therapeutically effective amount of aclidinium bromide to be administered per day ranges from 150 meg to about 800 meg, and preferably from about 200 meg to about 600 meg. Preferably the discrete dosage strengths of aclidinium or its salt are 200 meg or 400 meg or 600 meg or 800 meg.
The optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of
administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.
In the pharmaceutical composition as described herein, the active ingredient may be in the form of a single dosage form (i.e., fixed-dose formulation in which both the active ingredients are present together) or they may be divided doses, formulated separately, each in its individual dosage forms but as part of the same therapeutic treatment, program or regimen, either once daily or
two/three/four times a day. Alternately, the invention relates to a pharmaceutical composition wherein the composition is in the form of kit comprising separate formulations of TRPA1 antagonist and the anticholinergic agent. The separate formulations are to be administered by same or different routes, either separately, simultaneously, or sequentially, where the sequential administration is close in time or remote in time. For sequential administration, the period of time may be in the range from 10 min to 12 hours.
Various animal models have been used for the evaluation of the therapeutic efficacy of drug candidates for respiratory disorders like asthma and COPD. For example, commonly used strategy for evaluation of drug candidates in asthma is the allergen sensitization and challenge method. The commonly used such model is the ovalbumin (OVA) sensitization and challenge in laboratory animals. Another model that can be used is the methacholine challenge test by using invasive whole body plethysmograph.
A commonly used model for evaluation of drug candidates in COPD involves the chronic exposure of the animal to S02 or tobacco/cigarette smoke. The model is believed to generate sloughing of epithelial cells, increase in the mucus secretions, increase in the polymorphonuclear cells and pulmonary resistance, and increase in the airway hyper-responsiveness (in rats).
Another model that can be used for evaluation of drug candidates in COPD involves the exposure of animals (e.g., rats) to lipopolysaccharide (LPS). The exposure to LPS is believed to result in the influx of neutrophils in the lungs, a condition that is believed to be one of the characteristics of COPD.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention. EXAMPLES
EXAMPLE 1 : Determination of IC50 value of TRPAl antagonists
The human IC50 values were measured by the following method:
The inhibition of TRPAl receptor activation was measured as inhibition of allylisothiocyanate (AITC) induced cellular uptake of radioactive calcium.
Test compound solution was prepared in a suitable solvent.
Human TRPAl expressing CHO cells were grown in suitable medium.
Cells were treated with test compounds followed by addition of AITC.
Cells were washed, lysed and the radioactivity in the lysate was measured in Packard Top count after addition of liquid scintillant.
The concentration response curves for compounds were plotted as a % of maximal response obtained in the absence of test antagonist, and the IC50 values were calculated from such concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
Table 1 : TRPAl antagonists having a human IC50 for inhibiting human TRPAl receptor activity of less than 1 micromolar.
Compound No hTRPAl IC50 values Compound No hTRPAl IC50 values
1 920.9 nM 52 2.49 nM
2 381.8 nM 53 18.20 nM
3 73.35 nM 54 17.74 nM
4 98.32 nM 55 2.15 nM
5 66.28 nM 56 3.38 nM
6 97.42 nM 57 1.45 nM
7 47.37 nM 58 11.88 nM
8 55.02 nM 59 2.21 nM
9 102.5 nM 60 3.54 nM
10 46.74 nM 61 2.93 nM
11 46.27 nM 62 1.68 nM
12 51.68 nM 63 9.04 nM Compound No hTRPAl ICso values Compound No hTRPAl ICso values
13 48.21 nM 64 4.52 nM
14 60.42 nM 65 6.65 nM
15 53.57 nM 66 3.63 nM
16 58.94 nM 67 13.59 nM
17 56.02 nM 68 4.84 nM
18 13.38 nM 69 7.10 nM
19 26.13 nM 70 12.57 nM
20 20.09 nM 71 3.18 nM
21 48.18 nM 72 4.16 nM
22 79.77 nM 73 8.54 nM
23 43.93 nM 74 5.29 nM
24 138.1 nM 75 3.34 nM
25 58.55 nM 76 4.02 nM
26 47.91 nM 77 5.60 nM
27 65.45 nM 78 10.57 nM
28 6.49 nM 79 5.29 nM
29 11.38 nM 80 6.28 nM
30 34.03 nM 81 6.74 nM
31 17.3 nM 82 8.04 nM
32 5.96 nM 83 4.40 nM
33 5.37 nM 84 5.35 nM
34 38.46 nM 85 8.92 nM
35 18.05 nM 86 6.91 nM
36 49.92 nM 87 19.32 nM
37 12.26 nM 88 11.45 nM
38 15.92 nM 89 98.44 nM
39 26.56 nM 90 5.61 nM
40 22.82 nM 91 451.4 nM
41 11.04 nM 92 17.08 nM Compound No hTRPAl ICso values Compound No hTRPAl ICso values
42 11.38 nM 95 88.50 nM
43 18.37 nM 96 559.3 nM
44 8.36 nM 97 21.91 nM
45 26.39 nM 98 54.29 nM
46 41.31 nM 99 5.06 nM
47 33.61 nM 100 5.15 nM
48 18.12 nM 101 10.10 nM
49 3.98 nM 102 7.67 nM
50 16.73 nM 103 27.41 nM
51 4.84 nM 104 7.58 nM
EXAMPLE 2: Animal studies for the combination of Compound 52 and tiotropium bromide.
The effect of Compound 52, tiotropium bromide and their combination methacholine challenge test in male Dunkin Hartley guinea pig was evaluated using invasive whole body plethysmograph (ElanTM RC, Buxco apparatus). Animals and grouped as described in Table 2.
Table 2
Figure imgf000051_0001
intravenous; ** intraperitonial Animals were anesthetized by intraperitonial injection of urethane (lg/kg). The surgical process carried out in the aseptic area. Right jugular vein of anesthetized animal was exposed and cannulated with fine bore polythene tube. Trachea was also cannulated for artificial respiration and to measure airway resistance. The prepared animal was fixed in the invasive whole body
plethysmograph with artificial respiration (tidal volume -7 ml). Methacholine challenge test was performed and the recordings were taken by the following schedule.
First log period: Baseline -5 min
Second log period: Normal saline -3 min
Third log period: Methacholine -3 min
This protocol was performed for all groups. Compound 52 (lOmg/kg, i.p.) was injected 4 hour prior to methacholine challenge. Tiotropium (0.5mcg/kg, i.v) was given at second log period. In third log period, the animal was injected with methacholine (60mcg/kg/2ml, i.v). The methacholine induced bronchoconstriction (expressed as airway resistance (RI value in cmH20*sec/ml)) was recorded by Buxco apparatus.
Table 3
Figure imgf000052_0001
*p<0.05-treated groups vs Group 1; #p<0.01 vs Group 2
Combination of Compound 52 and tiotropium bromide was found to produce significantly superior inhibition (synergistic effect) in airway resistance compared to the individual and sum of the activity of both in methacholine challenge as shown in Table 3 and Figure 1.
EXAMPLE 3 : Animal studies for the combination of Compound 52 and aclidinium bromide.
The effect of combination of Compound 52 and aclidinium bromide on LPS induced neutrophilia in male SD rats was evaluated. Animals were grouped mentioned in Table 4.
Table 4
Figure imgf000053_0001
All groups were exposed to LPS (0111 :B4) (1 OOmcg/ml) for 40min except vehicle control group
LPS was nebulized at concentration of 100 meg ml"1 for 40 min at 0.4 ml/min and a pressure of 1.7 psig in a Perspex exposure chamber (1.5 x 1 x 1 ft) fitted with nebulizer (RCI Hudson). Control animals were given saline exposure under similar conditions. All the animals were treated with compounds as mentioned in Table 4. Compound 52 (3mg/kg/5ml) was administered orally 2 h prior to LPS and aclidinium (50mcg/ml) was nebulized at the rate of 0.05 ml/min and exposed to the animals for 3 min prior LPS exposure.
Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure.
Animals were anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal saline) and BAL was done with PBS (3ml). This procedure was repeated three times and the BAL fluid was pooled for the measurement of total leukocyte. Remaining BAL fluid was centrifuged immediately at 4000 rpm for 20 min. The pellet formed in the bottom of the tube was used for the smear preparation for differential leukocyte count estimation. The smeared slides were fixed by alcohol and stained using Leishman's stain further carried for differential leukocyte count.
Table 5
Figure imgf000054_0001
p<0.001, saline vs LPS vehicle; p< 0.001, LPS vehicle vs Combination; p< 0.001, Aclidinium vs Combination; $$p< 0.01, Compound 52 vs Combination; one-way ANOVA, Bonferroni test.
Combination of compound 52 with aclidinium showed significant inhibition in LPS induced neutrophilia compared to the individual treatments (Table 5 and Figure 2). Compound 52 in combination with aclidinium showed significant synergy in inhibition of neutrophilia in LPS model in SD rats.
EXAMPLE 4: Animal studies for the combination of Compound 52 and tiotropium.
The effect of combination of Compound 52 and tiotropium on LPS induced neutrophilia in female SD rats was evaluated. Female SD rats were grouped as mentioned in Table 6. Compound 52 (3mg/kg/5ml) and tiotropium (1 mcg/ml as inhalation for 3 min at the rate of 0.05 ml/min) were administered 2 and 1 hour prior to LPS exposure respectively. LPS was nebulized at concentration of lOOmcg ml"1 for 40min at 0.4 ml min-1 and a pressure of 1.7 psig in a perspex exposure chamber (1.5 x 1 x 1 ft) fitted with nebulizer (RCI Hudson). Control animals were given saline exposure under similar conditions. Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure. Animal was anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal saline) and BAL was done with PBS (3ml). This procedure was repeated three times and the BAL fluid was pooled for the measurement of total leukocyte. BAL fluid was centrifuged immediately at 4000 rpm for 20 min and the pellet formed in the bottom of the tube was used for the smear preparation for differential leukocyte count estimation.
Table 6
Figure imgf000055_0001
Combination of Compound 52 with tiotropium showed significant inhibition in LPS induced neutrophilia compared to the individual treatments (Table 7 and Figure 3). Compound 52 in combination with tiotropium showed synergy in inhibition of neutrophilia in LPS model in SD rats.
Table 7
Figure imgf000055_0002
p . , sa ne vs ve ce; p< . , ve ce vs om ; p< . , otropum vs om ; p<
0.01, Compound 52 vs Combi; one-way ANOVA, Bonferroni test. EXAMPLE 5 : Animal studies for the combination of TRPA1 antagonist and ipratropium bromide.
The effect of Compound 52 and ipratropium bromide on LPS induced neutrophilia in male SD rats was evaluated. Animals were grouped as mentioned in Table 8.
Table 8
Figure imgf000056_0001
LPS at a concentration of lOOmcg ml"1 was nebulized for 40 min at 0.4 ml/min and a pressure of 1.7 psig in a Perspex exposure chamber (1.5 x 1 x 1 ft) fitted with nebulizer (RCI Hudson). Control animals were given saline exposure under similar conditions.
All the animals were treated as mentioned in Table 8. Compound 52 (6mg/kg/5ml) and ipratropium bromide (1 mg/ml as inhalation for 10 min at the rate of 0.3 ml/min) were administered 2 and 0 hour prior to LPS exposure respectively.
Bronchoalveolar lavage (BAL) was done after 4h of LPS exposure. Animals were anesthetized with urethane (1.2 gm/kg/5 mL, i.p. in normal saline) and BAL was done with PBS (3ml). This procedure was repeated three times and the BAL fluid was pooled for the measurement of total leukocyte.
Remaining BAL fluid was centrifuged at 4000 rpm for 20 min. The pellet formed in the bottom of the tube was used for the smear preparation for differential leukocyte count estimation. The differential leukocyte count was done using Leishman's stain.
The total number of neutrophils in each BAL sample was calculated using the formula:
Total cell count X 105/mL X % neutrophils
Total No. of neutrophils (in BAL) =
100
% inhibition of neutrophils was calculated using the following formula:
Avg. neutrophils (LPS control) - neutrophils (treatment)
% Inhibition of neutrophils = X 100
Avg. neutrophils (LPS control) - Avg. neutrophils (Saline control)
Statistical analysis was performed using One Way ANOVA followed by Dunnett's multiple comparisons with the help of Graph Pad Prism software. Statistical significance was set at p<0.05.
Results:
Combination of compound 52 with ipratropium showed significant inhibition in LPS induced neutrophilia compared to the respective individual treatments (Table 9 and Fig. 4). Compound 52 in combination with ipratropium showed significant synergy in inhibition of neurophilia in LPS model in SD rats.
Table 9
Figure imgf000057_0001
#p<0.001, saline vs LPS vehicle; @p< 0.001, LPS vehicle vsCombi; *p< 0.05, Ipratropium vs Combi; $$$p< 0.001, Compound 52 vs Combi; one-way ANOVA, Dunnett's multiple comparison test. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS We claim:
1. A pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist that has an IC50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formulae: (XII) or (D)
Figure imgf000059_0001
(XII) (D)
or a pharmaceutically-acceptable salt thereof, wherein,
'Het' is selected from the group consisting of
Figure imgf000059_0002
R1, R2 and Ra, which may be the same or different, are each independently hydrogen or (C1-C4) alkyl;
R4, R5, R6, R7, R8 and R9, which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl,
and an anticholinergic agent.
2. The pharmaceutical composition according to claim 1, wherein the
anticholinergic agent comprises tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or a salt thereof.
The pharmaceutical composition according to any one of claims 1-2, wherein the TRPA1 antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.0001 to about 1 : 10000.
A method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 1-3.
Use of synergistically effective amount of a TRPA1 antagonist and an anticholinergic agent in the preparation of the pharmaceutical composition according to any one of claims 1-3 for the treatment of a respiratory disorder in a subject.
The pharmaceutical composition according to any one of claims 1-3, for the treatment of respiratory disorder in a subject.
A pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
Figure imgf000060_0001
and an anticholinergic agent.
The pharmaceutical composition according to claim 7, wherein the anticholinergic agent comprises tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or a salt thereof.
The pharmaceutical composition according to any one of claims 7-8, wherein the composition is a fixed dose combination.
10. The pharmaceutical composition according to claim 7, wherein the composition is for inhalation administration, and the TRPAl antagonist and the anticholinergic agent are present in a weight ratio from about 1 : 0.001 to about 1 :300.
11. A method of treating a respiratory disorder in a subject, said method
comprising administering to the subject the pharmaceutical composition according to any one of claims 7-10.
12. A method of treating COPD by reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 7-10.
13. A method of reducing neutrophil count in a subject, said method
comprising administering to the subject the pharmaceutical composition according to any one of claims 7-10.
14. A method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 7-10.
15. A method of inhibiting airway resistance in a subject, said method
comprising administering to the subject the pharmaceutical composition according to any one of claims 7-10.
16. Use of synergistically effective amount of a TRPAl antagonist having structure of formula:
and an anticholinergic agent in the preparation of a pharmaceutical composition according to any one of claims 7-10 for the treatment of a respiratory disorder in a subject.
17. The pharmaceutical composition according to any one of claims 7-10, for the treatment of respiratory disorder in a subject.
18. A pharmaceutical composition for inhalation administration comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000062_0001
and an anticholinergic agent selected from the group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or a salt thereof, wherein the composition is a fixed dose combination.
19. The pharmaceutical composition according to claim 18, wherein the
TRPAl antagonist and the anticholinergic agent are present in a weight ratio from about 1 :0.001 to about 1 :300.
20. A method of treating a respiratory disorder in a subject, said method
comprising administering to the subject the pharmaceutical composition according to any one of claims 18-19.
21. A method of treating COPD by reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 18-19.
22. A method of reducing neutrophil count in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 18-19.
23. A method of treating asthma by inhibiting airway resistance in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 18-19.
24. A method of inhibiting airway resistance in a subject, said method
comprising administering to the subject the pharmaceutical composition according to any one of claims 18-19.
25. Use of synergistically effective amount of a TRPAl antagonist having structure of formula:
Figure imgf000063_0001
and an anticholinergic agent selected from the group consisting of tiotropium, oxitropium, ipratropium, glycopyrrolate and aclidinium or salts thereof in the preparation of the pharmaceutical composition according to any one of claims 18-19 for the treatment of a respiratory disorder in a subject.
PCT/IB2012/056966 2011-12-05 2012-12-05 Pharmaceutical composition comprising a trpa1 antagonist and an anticholinergic agent WO2013084153A1 (en)

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US14/362,003 US20140364445A1 (en) 2011-12-05 2012-12-05 Pharmaceutical composition comprising a trpa1 antagonist and an anticholinergic agent
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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004055054A1 (en) 2002-12-18 2004-07-01 Novartis Ag Anktm1, a cold-activated trp-like channel expressed in nociceptive neurons
WO2005089206A2 (en) 2004-03-13 2005-09-29 Irm Llc Modulators of ion channel trpa1
WO2007073505A2 (en) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Trpa1 inhibitors for treating pain
WO2008094909A2 (en) 2007-01-29 2008-08-07 Xenon Pharmaceuticals Inc. Quinazolinone and fused pyrimidinone compounds and their use in treating sodium channel-mediated diseases or conditions
WO2009002933A1 (en) 2007-06-22 2008-12-31 Hydra Biosciences, Inc. Methods and compositions for treating disorders
WO2009089082A1 (en) 2008-01-04 2009-07-16 Abbott Laboratories Trpa1 antagonists
WO2009144548A1 (en) 2008-05-28 2009-12-03 Glenmark Pharmaceuticals S.A. Imidazo [2,1-b] purine derivatives as trpa1 modulators
WO2009158719A2 (en) 2008-06-27 2009-12-30 Hydra Biosciences, Inc. Methods and compositions for treating disorders
WO2010004390A1 (en) 2008-06-17 2010-01-14 Glenmark Pharmaceuticals, S.A. Quinazoline dione derivatives as trpa1 modulators
US20100055045A1 (en) * 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
WO2010109328A1 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Isothiazolo-pyrimidinedione derivatives as trpa1 modulators
WO2010109334A2 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Thienopyrimidinedione derivatives as trpa1 modulators
WO2010109287A1 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals S.A. Fused pyrimidine-dione derivatives as trpa1 modulators
WO2010125469A1 (en) 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Pyrimidinedione-fused heterocyclic compounds as trpa1 modulators
WO2011114184A1 (en) 2010-03-15 2011-09-22 Glenmark Pharmaceuticals S.A. Amides of heterocyclic compounds as trpa1 inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135575B2 (en) * 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004055054A1 (en) 2002-12-18 2004-07-01 Novartis Ag Anktm1, a cold-activated trp-like channel expressed in nociceptive neurons
WO2005089206A2 (en) 2004-03-13 2005-09-29 Irm Llc Modulators of ion channel trpa1
WO2007073505A2 (en) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Trpa1 inhibitors for treating pain
WO2008094909A2 (en) 2007-01-29 2008-08-07 Xenon Pharmaceuticals Inc. Quinazolinone and fused pyrimidinone compounds and their use in treating sodium channel-mediated diseases or conditions
WO2009002933A1 (en) 2007-06-22 2008-12-31 Hydra Biosciences, Inc. Methods and compositions for treating disorders
WO2009089082A1 (en) 2008-01-04 2009-07-16 Abbott Laboratories Trpa1 antagonists
US20100055045A1 (en) * 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
WO2009144548A1 (en) 2008-05-28 2009-12-03 Glenmark Pharmaceuticals S.A. Imidazo [2,1-b] purine derivatives as trpa1 modulators
WO2010004390A1 (en) 2008-06-17 2010-01-14 Glenmark Pharmaceuticals, S.A. Quinazoline dione derivatives as trpa1 modulators
WO2009158719A2 (en) 2008-06-27 2009-12-30 Hydra Biosciences, Inc. Methods and compositions for treating disorders
WO2010109328A1 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Isothiazolo-pyrimidinedione derivatives as trpa1 modulators
WO2010109334A2 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Thienopyrimidinedione derivatives as trpa1 modulators
WO2010109287A1 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals S.A. Fused pyrimidine-dione derivatives as trpa1 modulators
WO2010109329A1 (en) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Furopyrimidinedione derivatives as trpa1 modulators
WO2010125469A1 (en) 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Pyrimidinedione-fused heterocyclic compounds as trpa1 modulators
WO2011114184A1 (en) 2010-03-15 2011-09-22 Glenmark Pharmaceuticals S.A. Amides of heterocyclic compounds as trpa1 inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PELEMAN RA: "The cellular composition of induced sputum in chronic obstructive pulmonary disease", EUROPEAN RESPIRATORY JOURNAL, vol. 13, 1999, pages 839 - 843
ULRIK CS: "Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma", CLINICAL AND EXPERIMENTAL ALLERGY, vol. 25, 1995, pages 820 - 827

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