WO2012176105A1 - Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes - Google Patents

Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes Download PDF

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Publication number
WO2012176105A1
WO2012176105A1 PCT/IB2012/053049 IB2012053049W WO2012176105A1 WO 2012176105 A1 WO2012176105 A1 WO 2012176105A1 IB 2012053049 W IB2012053049 W IB 2012053049W WO 2012176105 A1 WO2012176105 A1 WO 2012176105A1
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pharmaceutical composition
antagonist
subject
composition according
compound
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PCT/IB2012/053049
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English (en)
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Neelima Khairatkar-Joshi
Abhay Kulkarni
Vikram Mansingh BHOSALE
Dinesh Pradeep WALE
Anil Hari KADAM
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Glenmark Pharmaceuticals Sa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic 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
    • A61K31/403—Heterocyclic 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 carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic 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
    • A61K31/407—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present patent application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a transient receptor potential ankyrin-1 receptor (“TRPAl”) antagonist and a leukotriene receptor antagonist.
  • TRPAl transient receptor potential ankyrin-1 receptor
  • the application provides a pharmaceutical composition comprising a TRPAl antagonist having an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar with respect to TRPAl activity and a leukotriene receptor antagonist; 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 such as 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.
  • TRPAl 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.
  • TRP transient receptor potential
  • Leukotriene receptor antagonists are believed to act at the leukotriene receptors in tissues such as the bronchial smooth muscles and block the actions of leukotrienes at the receptor site.
  • Leukotriene receptor antagonists (such as montelukast and zafirlukast) are used to treat certain respiratory disorders.
  • Montelukast sodium is chemically [R - (E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-lmethylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid, monosodium salt.
  • Montelukast sodium is commercially available as SINGULAIR ® as lOmg tablets, 4mg and 5mg chewable tablets and as 4mg oral granules (marketed by Merck and Co., Inc.) in the United States.
  • Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma, for the prevention of exercise-induced bronchoconstriction and for the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis and perennial allergic rhinitis).
  • Zafirlukast is chemically, 4-(5-cyclopentyloxy-carbonylamino-l-methyl- indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide.
  • Zafirlukast is commercially available as ACCOLATE ® as lOmg and 20mg oral tablets (marketed by AstraZeneca Pharmaceuticals LP) in the United States.
  • Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a TRPAl antagonist and a leukotriene receptor antagonist.
  • TRPAl antagonist and a leukotriene receptor antagonist 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 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 and a leukotriene receptor antagonist.
  • the TRPAl antagonist of the present invention has an IC 50 for inhibiting human TRPAl 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 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 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
  • the leukotriene receptor antagonist includes montelukast, zafirlukast, pranlukast, tipelukast, masilukast, iralukast, cinalukast, tomelukast, verlukast, pobilukast, sulukast, SKF-106203, L-648051, DS-4574, CGP-57698, YM-158, AS-35, KP-496, MEN-91507, KP-496, MK-571 and CR- 3465 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 leukotriene receptor antagonist includes montelukast, zafirlukast 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 and a leukotriene receptor antagonist in a weight ratio ranging from about 1:0.005 to about 1:10, and preferably from about 1:0.05 to about 1:5 respectively.
  • 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 a leukotriene receptor antagonist.
  • the TRPA1 antagonist has an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar having structure of formul
  • 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 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 TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and montelukast or its salt.
  • 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 formul
  • 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 a leukotriene receptor antagonist for the treatment of respiratory disorders in a subject.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • TRPAl antagonist and the leukotriene receptor antagonist are preferably administered orally.
  • the TRPAl antagonist and the leukotriene receptor antagonist are incorporated into a single pharmaceutical composition (e.g., an oral dosage form).
  • a kit containing a unit dose formulation comprising the TRPAl antagonist and another unit dose formulation comprising the leukotriene receptor antagonist are provided.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • composition is a fixed dose combination.
  • the present invention relates to a method of treating a respiratory disorder by reducing eosinophils count and/or increasing FEVl value 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 leukotriene receptor antagonist is montelukast sodium
  • the composition is a fixed dose
  • the respiratory disorder is asthma
  • the present invention relates to a method of reducing eosinophils count and/or increasing FEVl value in a subject having a respiratory disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • montelukast sodium present in a weight ratio from about 1 :0.005 to about 1:5, wherein the composition is a fixed dose combination.
  • the present invention relates to use of
  • TRPA1 antagonist having structure of formula:
  • montelukast sodium present in a weight ratio from about 1 :0.005 to about 1:5 in the preparation of a pharmaceutical composition for the treatment of a respiratory disorder in a subject, wherein the composition is a fixed dose combination.
  • the present invention relates to a pharmaceutical composition for oral administration comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the composition is a fixed dose combination.
  • the TRPA1 antagonist and montelukast sodium are present in a weight ratio from about 1:0.05 to about 1:5 in the composition.
  • Figure 1 is a bar graph showing the effect of Compound 52 and
  • 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 effective amount of a TRPA1 antagonist as described herein ranges from about 10 ⁇ g/kg to about 20mg/kg, and preferably from about 50 ⁇ g/kg to about 15mg/kg.
  • the therapeutically effective amount of montelukast or its salt to be administered per day ranges from about 0.1 mg to about 50 mg, and preferably from about 1 mg to about 30 mg.
  • the therapeutically effective amount of zafirlukast or its salt to be administered per day ranges from about 1 mg to about 100 mg, and preferably from about 5 mg to about 50 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 this paragraph.
  • 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.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes a TRPA1 antagonist, a leukotriene receptor antagonist or a pharmaceutically acceptable salt thereof.
  • the active ingredient includes a TRPA1 antagonist having a human IC 50 value of less than ⁇ , montelukast or its salt, and zafirlukast or its salt.
  • 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.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the TRPAl receptor, or the leukotriene receptor, or by a combination of the two in a mammal.
  • 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, COPD or rhinitis.
  • 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.
  • the term “synergistic” or “synergy” with regard to the combination of a TRPA1 antagonist with a leukotriene receptor antagonist 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.
  • 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.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: a TRPA1 antagonist, and a leukotriene receptor antagonist.
  • 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 a leukotriene receptor antagonist.
  • 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.
  • 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 (C 1 -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.
  • 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 (I):
  • R 6 represents hydrogen, substituted or unsubstituted alkyl, 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;
  • R independently represents hydrogen or alkyl.
  • 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 (I
  • R 1 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 n
  • 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 1 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 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
  • L is a linker selected from -(CR x R y ) n - , -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 (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 .
  • 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 (V)
  • 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 .
  • 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
  • heterocyclylalkyl .
  • 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 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 ,
  • 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.
  • TRPA1 antagonists useful in the context of the invention are mentioned below:
  • the TRPAl antagonist useful in the context of the invention is Compound 90:
  • TRPAl 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 TRPAl antagonist useful in the context of the invention is 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.
  • TRPAl antagonists useful in the context of the invention are selected from those compounds generically or specifically disclosed in WO2011114184. Accordingly, a TRPAl antagonist useful in the context of the invention has the formula (I
  • 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 .
  • TRPAl antagonist useful in the methods of the invention is mentioned below:
  • TRPAl antagonist useful in the context of the invention has the formula (X):
  • 'Het' is selected from groups consisting of
  • 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 ;
  • R b and R c independently selected from hydrogen, substituted or unsubstituted alkyl arylalkyl, amino acid and heterocyclic ring; R is selected from hydrogen, alkyl, arylalkyl and pharmaceutically acceptable cation.
  • 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 (XI)
  • R 1 , and R 2" are independently hydrogen or (Ci-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 halogen haloalkyl, dialkylamino, and haloalkoxy.
  • TRPAl antagonists useful in the context of the invention is selected from one of the followin formul
  • R 1 , R 2 and R a which may be the same or different, are each independently hydrogen or (Ci-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 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 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 (C 1 -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 heterocyclylalkyl and a leukotriene receptor antagonist.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the leukotriene receptor antagonist includes montelukast, zafirlukast, pranlukast, tipelukast, masilukast, iralukast, cinalukast, tomelukast, verlukast, pobilukast, sulukast, SKF-106203, L-648051, DS-4574, CGP-57698, YM-158, AS-35, KP-496, MEN-91507, KP-496, MK-571 and CR- 3465 or 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 leukotriene receptor antagonist includes montelukast, zafirlukast or its salt.
  • 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 a leukotriene receptor antagonist in a weight ratio ranging from about 1:0.005 to about 1:10, and preferably from about 1:0.05 to about 1:5 respectively.
  • 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 present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • composition is a fixed dose combination.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPAl antagonist having structure of formula:
  • composition is a fixed dose combination.
  • the invention relates to a pharmaceutical composition wherein the composition is in the form of kit comprising separate formulations of a TRPAl antagonist and a leukotriene receptor antagonist.
  • 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.
  • 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.
  • 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.
  • compositions of the invention include those for oral, parenteral, inhalation, transdermal, transmucosal and nasal administration, among others.
  • pharmaceutical composition of present invention is for oral or inhalation administration.
  • 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.
  • compositions for transdermal or transmucosal administration include but are not limited to patches, gels, creams, ointments and the like.
  • composition in the above embodiments may optionally comprise one or more pharmaceutically acceptable excipients.
  • 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 therapeutically effective amount of a TRPA1 antagonist to be administered per day ranges from about 10 ⁇ g/kg to about 20mg/kg, and preferably from about 50 ⁇ g/kg to about 15mg/kg.
  • the therapeutically effective amount of montelukast or its salt to be administered per day ranges from about 0.1 mg to about 50 mg and more preferably from about 1 mg to about 30 mg.
  • the discrete dosage strengths of montelukast or its salt to be administered per day are 2mg, 4mg, 5mg and lOmg.
  • 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 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 active ingredients 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.
  • compositions 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. Rhinitis as described herein is characterized by irritation and inflammation of some internal areas of nose. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or irritants. The
  • Rhinitis is categorized into three types: infective, non-allergic (vasomotor) and allergic rhinitis.
  • Allergic rhinitis is caused by allergens such as dust or pollen which, when inhaled by the sensitized individuals, trigger antibody production.
  • the antibodies bind to mast cells (containing histamine), which upon stimulation cause itching (urticaria), swelling and mucous production.
  • mast cells containing histamine
  • urticaria urticaria
  • it leads to inflammation of the mucous membranes of the nose, eyes, eustachian tubes, middle ear, sinuses, and pharynx.
  • the nose invariably is involved, and the other organs are also affected in certain individuals.
  • Inflammation of the mucous membranes is characterized by a complex interaction of inflammatory mediators but ultimately is triggered by an immunoglobulin E (IgE)-mediated response to an extrinsic protein.
  • IgE immunoglobulin E
  • 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.
  • Leukotrienes are a class of inflammatory mediators derived from arachidonic acid that are believed to act at the leukotriene receptors and bring about inflammatory and bronchoconstrictive events in the airway.
  • the major leukotrienes are the cysteinyl leukotrienes (Cys-LTs) - LTC4, LTD4 and LTE4. Of these, LTE4 and LTD4 are believed to be the more potent mediators of airway inflammation.
  • the receptors for these mediators have been identified as Cys-LT receptor Type-1 (Cys-LTl) and Cys-LT receptor Type-2 (Cys-LT2).
  • the Cys-LT receptors are also believed to induce airway eosinophilia in patients with asthma. Antagonists to these receptors are thus believed to alleviate the airway
  • Cys-LT receptor antagonists that are currently available commercially are montelukast and zafirlukast, both of which are antagonists to the Cys-LTl receptor. These antagonists find use in indications like early and late response to allergen and exercise-induced asthma.
  • 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.
  • the therapeutic effect of the combination of a TRPAl antagonist and a leukotriene receptor antagonist is highly unpredictable.
  • a pharmaceutical composition comprising a TRPAl antagonist and a leukotriene receptor antagonists 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, the method comprising administering the subject a pharmaceutical composition of the present invention.
  • 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 a leukotriene receptor antagonist.
  • the TRPAl antagonist has an IC 50 for inhibiting human TRPAl receptor activity of less than 1 micromolar having structure of formul
  • 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 montelukast or its salt.
  • 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 a TRPA1 receptor activity of less than 1 micromolar and a leukotriene receptor antagonist for the treatment of respiratory disorders in a subject.
  • the present invention relates to a method of treating a respiratory disorder by reducing eosinophils count and/or increasing FEVl value in a subject, method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the present invention relates to a method of reducing eosinophils count and/or increasing FEVl value in a subject, method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the present invention relates to use of synergistically effective amount of a TRPA1 antagonist having an IC 50 for inhibiting human TRPA1 receptor activity of less than 1 micromolar and a leukotriene receptor antagonist in the preparation of a pharmaceutical composition of the present invention for the treatment of a respiratory disorder in a subject.
  • 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 a leukotriene receptor antagonist for the treatment of respiratory disorders in a subject.
  • the present invention relates to a method of reducing eosinophils count and/or increasing FEVl value in a subject having a respiratory disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising synergistically effective amount of a TRPA1 antagonist having structure of formula:
  • montelukast sodium present in a weight ratio from about 1 :0.005 to about 1:5, wherein the composition is a fixed dose combination.
  • the present invention relates to use of
  • TRPA1 antagonist having structure of formula:
  • montelukast sodium present in a weight ratio from about 1 :0.005 to about 1:5 in the preparation of a pharmaceutical composition for the treatment of a respiratory disorder in a subject, wherein the composition is a fixed dose combination.
  • 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
  • EXAMPLE 1 Determination of IC 50 of TRP A 1 antagonists
  • the human IC 50 values were measured by the following method: the inhibition of TRPA1 receptor activation is measured as inhibition of
  • AITC allylisothiocyanate
  • TRPA1 antagonists having a human IC 50 for inhibiting human TRPA1 receptor activity of less than lmicromolar.
  • EXAMPLE 2 Effect of Compound 52 and montelukast on ovalbumin induced eosinophilia in ovalbumin sensitized female Balb/C mice.
  • mice Female BALB/c mice were sensitized on day 0 and 7 with 50 ⁇ g ovalbumin and 4 mg alum given i.p. Mice were challenged with 3% aerosolized ovalbumin from Day 11-13 following sensitization. Sensitized mice were randomly assigned to different treatment groups. Test compounds were triturated with 2 drops of Tween-80 and volume was made up with 0.5% methyl cellulose (MC) solution for oral administration. Animals were administered Compound 52 orally 24 hrs before 1st ovalbumin challenge and 2 hrs before ovalbumin challenge from Day-11 to 13. Animals were assigned to one of the following 6 groups during each experiment as per Table 2.
  • Broncho Alveolar Lavage was performed at 24 hours after challenge with ovalbumin. Animals were anesthetized with an overdose of urethane, trachea was exposed and BAL was performed 4 times using 0.3 mL PBS. All aspirates of BAL were pooled and total number of cells determined using a hemocytometer. The BAL was centrifuged, and the cell pellet was used for preparation of smears. Slides were stained with Giemsa stain and a differential cell count of 500 cells based on standard morphology was performed manually.
  • E (6) 1 mg/kg + 5 6.57+0.8 1.36+0.5 51.4 + 8.6 74.4 + 3.7 mg/kg p.o.
  • EXAMPLE 3 Animal study for the effect of combination of TRPA1 antagonist and montelukast in rhinitis model.

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Abstract

Cette demande de brevet concerne une composition pharmaceutique comprenant un antagoniste du récepteur d'ankyrine-1 à potentiel de récepteur transitoire ( » TRPA1") et un antagoniste du récepteur de leucotriènes.
PCT/IB2012/053049 2011-06-22 2012-06-18 Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes WO2012176105A1 (fr)

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US20140377358A1 (en) * 2013-06-20 2014-12-25 Glenmark Pharmaceuticals S.A. Nanoparticulate formulation comprising a trpa1 antagonist
WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2017064068A1 (fr) 2015-10-14 2017-04-20 Almirall, S.A. Nouveaux antagonistes de trpa1
CN114656473A (zh) * 2022-04-27 2022-06-24 成都施贝康生物医药科技有限公司 吡咯并嘧啶类化合物、异构体或盐及其制备方法和用途
CN114656472A (zh) * 2022-04-27 2022-06-24 成都施贝康生物医药科技有限公司 吡唑并嘧啶类化合物、异构体或盐及其制备方法和用途

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US20140377358A1 (en) * 2013-06-20 2014-12-25 Glenmark Pharmaceuticals S.A. Nanoparticulate formulation comprising a trpa1 antagonist
CN105307642A (zh) * 2013-06-20 2016-02-03 格兰马克药品股份有限公司 包含trpa1拮抗剂的纳米颗粒制剂
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WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2017064068A1 (fr) 2015-10-14 2017-04-20 Almirall, S.A. Nouveaux antagonistes de trpa1
CN114656473A (zh) * 2022-04-27 2022-06-24 成都施贝康生物医药科技有限公司 吡咯并嘧啶类化合物、异构体或盐及其制备方法和用途
CN114656472A (zh) * 2022-04-27 2022-06-24 成都施贝康生物医药科技有限公司 吡唑并嘧啶类化合物、异构体或盐及其制备方法和用途
CN114656473B (zh) * 2022-04-27 2023-09-29 成都施贝康生物医药科技有限公司 吡咯并嘧啶类化合物、异构体或盐及其制备方法和用途

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