WO2011110859A1 - Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd - Google Patents
Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- C07B2200/07—Optical isomers
Definitions
- This invention relates to heterocyclic compounds, which are pyrimidine derivatives having human neutrophil elastase inhibitory properties, and their use in therapy.
- HNE Human neutrophil elastase
- HNE has long been considered to play an important role in homeostasis through repair and disposal of damaged tissues via degradation of the tissue structural proteins. It is also relevant in the defence against bacterial invasion by means of degradation of the bacterial body. In addition to its effects on matrix tissues, HNE has been implicated in the upregulation of IL-8 gene expression and also induces IL- 8 release from the epithelial cells of the lung. In animal models of Chronic
- HNE Obstructive Pulmonary Disease induced by tobacco smoke exposure both small molecule inhibitors and protein inhibitors of HNE inhibit the inflammatory response and the development of emphysema (Wright, J. L. et al. Am. J. Respir. Crit. Care Med. 2002, 166, 954-960; Churg, A. et al. Am. J. Respir. Crit. Care Med. 2003, 168, 199-207).
- HNE may play a role both in matrix destruction and in amplifying inflammatory responses in chronic respiratory diseases where neutrophil influx is a characteristic feature.
- HNE chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- CF cystic fibrosis
- ARDS acute respiratory distress syndrome
- pulmonary emphysema pulmonary emphysema
- pneumonia pulmonary emphysema
- lung fibrosis pulmonary emphysema
- cardiovascular diseases in which tissue remodelling is involved, for example, in heart failure and the generation of ischaemic tissue injury following acute myocardial infarction.
- COPD chronic bronchitis
- emphysema emphysema
- small- airway disease emphysema
- BAL bronchoalveolar leakage
- protease-anti-protease balance also known as the 'elastase:anti-elastase hypothesis'
- an imbalance of HNE and endogenous antiproteases such as a1 -antitrypsin (ai-AT), secretory leukocyte protease inhibitor (SLPI) and pre-elafin leads to the various inflammatory disorders of COPD.
- ai-AT a1 -antitrypsin
- SLPI secretory leukocyte protease inhibitor
- pre-elafin leads to the various inflammatory disorders of COPD.
- Individuals that have a genetic deficiency of the protease inhibitor oc1 - antitrypsin develop emphysema that increases in severity over time (Laurrell, C. B.; Erikkson, S Scand. J. Clin. Invest.
- This invention provides novel compounds which are inhibitors of HNE, and are useful in the treatment of diseases or conditions in which HNE activity plays a part.
- A is C-R 1 or N;
- R 3 and R 5 are independently selected from hydrogen, halogen and C r C 6 -alkyl which can be further substituted with halogen;
- R 6 is selected from hydrogen, nitrile (-CN), -COOH, -COOR A , -COR A , -S0 2 R A , - CONH 2 , -SO2NH2, -CONHR A , -S0 2 NHR A , -CONR A R B , -S0 2 NR A R B , and heteroaryl, wherein R A and R B are independently an optionally substituted (CrC 6 )alkyl, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R A and R B when attached to the same nitrogen atom form a cyclic amino ring;
- R 7 is selected from CrC 6 -alkyl, hydroxy-CrC 6 -alkyl, CrC 4 -alkoxy, amino, mono- or di-Ci-C 4 -alkylamino, hydroxycarbonyl, aminocarbonyl, C 3 -C 6 -cycloalkyl, phenyl or C 2 - C 6 -alkenyl; wherein C 3 -C 6 -cycloalkyl can be substituted with one or more of C1-C4- alkyl, hydroxyl and CrC 4 -alkoxy and phenyl can be substituted with one or more of halogen, cyano, CrC 4 -alkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and CrC 4 -alkoxy; R 8 and R 9 are independently selected from hydrogen and CrC 6 -alkyl, and R 10 is C Ce-alkyl;
- R 15 and R 19 each independently represent a radical of formula -[Y] m -[Alk 1 ]p-[Q] t - [Alk 2 ] q -Z, wherein
- Alk 1 and Alk 2 each independently represent a Ci-C 6 alkylene radical
- Q represents a divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-9 ring members;
- Z is
- heteroatoms are nitrogen, said monocyclic ring or bridged ring system being linked to the rest of the molecule via a ring carbon, and wherein a ring nitrogen may be quaternised by substitution by Ci-C 3 alkyl or benzyl the latter being optionally substituted in the phenyl ring thereof; or
- R A and R B are independently hydrogen, or a CrC 6 - alkyl, C 3 -C 6 -cycloalkyl group, or a phenyl(CrC 6 )alkyl- group optionally substituted in the phenyl ring thereof; or, taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S; or
- R A , R B and R c are independently a CrC 6 -alkyl, C 3 -C 6 -cycloalkyl group, or a phenyl(CrC 6 )alkyl- group optionally substituted in the phenyl ring thereof; or
- R A is a CrC 6 -alkyl, C 3 -C 6 -cycloalkyl group, or a phenyl(CrC 6 )alkyl- group optionally substituted in the phenyl ring thereof and R B and R c taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S; or
- R A , R B and R c taken together with the nitrogen to which they are attached form a bridged heterocyclic ring system of 7 or 8 ring members;
- R A , R B , R c and R D are independently hydrogen or d-C 6 -alkyl; or any two of R A , R B , R c and R D are independently hydrogen or CrC 6 -alkyl, while the other two taken together represent a Ci-C 6 alkylene radical; or
- R A , R B and R c are independently hydrogen or CrC 6 -alkyl; or any one of R A , R B and R c is hydrogen or CrC 6 -alkyl, while the other two taken together represent a Ci-C 6 alkylene radical; provided that R is not (i) hydrogen or (ii) Ci-C 6 alkyl optionally substituted by hydroxy, CrC 6 alkoxy, C 3 -C 6 cycloalkyi or fluoro or (iii) CrC 6 alkoxy or CrC 6 alkoxycarbonyl, (iv) C 3 -C 6 cycloalkyi optionally substituted by C1-C4 alkyl or fluoro or (v) phenyl or 5- or 6-memberered heteroaryl optionally substituted by fluoro, chloro, cyano, C1-C4 alkyl, difluoromethyl, trifluoromethyl, C1-C4 alkoxy, difluoromethoxy or trifluoromethoxy or (vi
- Compounds of the invention may be used in the treatment or prevention of diseases in which HNE is implicated, for example chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, smoking-induced emphysema and cystic fibrosis.
- COPD chronic obstructive pulmonary disease
- ARDS acute respiratory distress syndrome
- pulmonary emphysema smoking-induced emphysema
- cystic fibrosis for example chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, smoking-induced emphysema and cystic fibrosis.
- COPD chronic obstructive pulmonary disease
- ARDS acute respiratory distress syndrome
- pulmonary emphysema smoking-induced emphy
- C a -C b -alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
- a 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
- C a -C b -alkenyl wherein a and b are integers refers to a straight or branched chain alkenyl moiety having from a to b carbon atoms having at least one double bond of either E or Z stereochemistry where applicable.
- a is 2 and b is 6, for example, the term includes, for example, vinyl, allyl, 1 - and 2- butenyl and 2-methyl-2-propenyl.
- C a -C b -alkynyl wherein a and b are integers refers to straight chain or branched chain hydrocarbon groups having from a to b carbon atoms and having in addition one triple bond.
- a is 1 and b is 6, for example, the term includes for example, ethynyl (-C ⁇ CH), 1 -propynyl, 1 - and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
- divalent C a -C b -alkylene radical wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.
- divalent C a -C b -alkenylene radical wherein a and b are integers refers to a divalent hydrocarbon chain having from a to b carbon atoms, and at least one double bond.
- carbocyclic refers to a mono-, bi- or tricyclic radical or bridged monocyclic or bicyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
- a bridged carbocyclic radical has a monocyclic or bicyclic ring with two ring atoms joined by an alkylene bridge, such as radicals of bicyclo[2.2.2]octane, bicyclo[3.1 .1]heptane and adamantane.
- cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
- aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond.
- Illustrative of such radicals are phenyl, biphenyl and napthyl.
- heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond.
- radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl,
- a heteroaryl ring contains an sp2 nitrogen such as in the case of pyridine or imidazole, that nitrogen may be a quaternary nitrogen as in pyridinium or imidazolium.
- heterocyclyl or “heterocyclic” or
- heterocycloalkyl includes “heteroaryl” as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic or bridged monocyclic or bicyclic non- aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
- a bridged heterocyclic radical has a monocyclic or bicyclic ring containing at least one S, N or O ring atom with two ring atoms, such as two ring carbons, or a ring nitrogen and a ring carbon, joined by an alkylene bridge, such as radicals of 1 -aza-bicyclo[2.2.2]octane. Where a ring nitrogen is bridged in this way, it may be further substituted as a quaternary nitrogen centre.
- radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido, succinimido and 1 -aza- bicyclo[2.2.2]octanyl or 1 methyl-1 -aza-bicyclo[2.2.2]octanyl groups.
- substituents each of which independently may be, for example, CrC 6 -alkyl, cycloalkyl, CrC 6 -alkoxy, hydroxy, hydroxyl-CrC 6 -alkyl, mercapto, mercapto-Ci-C 6 - alkyl, CrC 6 -alkylthio, phenyl, monocyclic heteroaryl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (- CN), oxo, -COOH, -COOR G , -COR G , -S0 2 R G , -CONH 2 , -S0 2 NH 2 , -CONHR G ,
- salts with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
- bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
- Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorgan
- hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
- organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
- Those compounds (I) which have a quaternary nitrogen can also form quaternary salts with a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate, methanesulfonate, xinafoate, and the like.
- a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate, methanesulfonate, xinafoate, and the like.
- the ring containing A is phenyl, R 1 is hydrogen, and R 2 is hydrogen or 2-methanesulphonyl.
- the ring containing A is 3-pyridyl and R 2 is hydrogen or 2-methanesulphonyl.
- R 3 and R 5 too may be selected from any of the substituent types for which they are defined in relation to formula (I), such as hydrogen, fluoro, chloro or bromo, and C r C 6 -alkyl such as methyl which can be further substituted with halogen as in the case of trifuoromethyl.
- R 5 is hydrogen and R 3 is 3-trifluoromethyl, 3-chloro or 3-bromo.
- R 6 is selected from hydrogen, nitrile (-CN), -COOH, -COOR A , -COR A , -S0 2 R A , - CONH 2 , -S0 2 NH 2 , -CONHR A , -S0 2 NHR A , -CONR A R B , -S0 2 NR A R B , and heteroaryl, wherein R A and R B are independently an optionally substituted (CrC 6 )alkyl, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R A and R B when attached to the same nitrogen atom form a cyclic amino ring.
- R 6 is -COOR A , wherein R A is C1-C4 alkyl such as methyl, ethyl or isopropyl.
- R E is hydrogen or CrC 6 alkyl such as methyl; m, p, q and t are independently 0 or 1 ;
- Alk 1 and Alk 2 each independently represent a Ci-C 6 alkylene radical such as — CH2-,— CH2CH2- or— CH2CH2CH2-;
- Q represents a divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-9 ring members, such as a 1 ,3-cyclopentylene, 1 ,4-cyclohexylene,
- a monocyclic nitrogen heterocyde of 5 or 6 ring members such as a pyridyl or imidazolyl ring or a bridged nitrogen heterocyclic system of 7 or 8 ring members such as a 1 -aza-bicyclo[2.2.2]octane ring, said monocyclic ring or bridged ring system being linked to the rest of the molecule via a ring carbon, and wherein a ring nitrogen may be quaternised by substitution by C1-C3 alkyl such as methyl, by phenyl or by benzyl the latter being optionally substituted in the phenyl ring thereof; or
- R A and R B are independently hydrogen, or a CrC 6 - alkyl group such as methyl, ethyl or n- or isopropyl, a C 3 -C 6 -cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl, or a phenyl(CrC 6 )alkyl- group such as benzyl, optionally substituted in the phenyl ring thereof; or, taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S, such as a piperidine, piperazine or morpholine ring; or
- R A , R B and R c are independently a CrC 6 -alkyl group such as methyl, ethyl or n- or isopropyl, a C 3 -C 6 -cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl, or a phenyl(CrC 6 )alkyl- group such as benzyl, optionally substituted in the phenyl ring thereof; or
- R A is a CrC 6 -alkyl group such as methyl, ethyl or n- or isopropyl, a C 3 - C 6 -cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl, or a phenyl(CrC 6 )alkyl- group such as benzyl, optionally substituted in the phenyl ring thereof and R B and R c taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S, such as a piperidine, piperazine or morpholine ring; or
- R A , R B and R c taken together with the nitrogen to which they are attached form a bridged heterocyclic ring system of 7 or 8 ring members;
- R A , R B , R c and R D are independently hydrogen or d-C 6 -alkyl such as methyl; or any two of R A , R B , R c and R D are independently hydrogen or CrC 6 -alkyl, while the other two taken together represent a Ci-C 6 alkylene radical such as -CH 2 -, -CH 2 CH 2 - or -CH2CH2CH2-; or
- R A , R B and R c are independently hydrogen or CrC 6 -alkyl such as methyl; or any one of R A , R B and R c is hydrogen or CrC 6 -alkyl such as methyl, while the other two taken together represent a Ci-C 6 alkylene radical such as -CH 2 -, -CH 2 CH 2 - or -CH2CH2CH2-; or
- R A , R B and R c are independently hydrogen or CrC 6 -alkyl such as methyl; or any one of R A , R B and R c is hydrogen or CrC 6 -alkyl such as methyl, while the other two taken together represent a Ci-C 6 alkylene radical such as -CH 2 -, -CH 2 CH 2 - or -CH2CH2CH2-.
- the -[Alk 1 ] p -[Q] t -[Alk 2 ] q - part may be selected from structures (IV) and (V) wherein V 1 and V 2 are each independently 0, 1 , 2, 3 or 4 and X is a divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-9 ring members such as 1 ,4-cyclohexylene, 1 ,3 cyclopentylene, 1 ,4 phenylene, or 2,4 pyridinylene, and the Z part may be selected from structures (VI)-(XVI) wherein R A , R B , R c , and R D are as defined in relation to formula (I), and V 1 , V 2 , and V 3 are each independently 0, 1 , 2, 3 or 4.
- Amine and pyridine nitrogen atoms, where present in groups (VI)-(XIV), may be quaternised with an optionally substituted CrC 6 -alkyl or benzyl group.
- the therapeutic utility of the present compounds is pertinent to any disease that is known to be at least partially mediated by the action of human neutrophil elastase.
- the present compounds may be beneficial in the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), pulmonary emphysema, pneumonia and lung fibrosis.
- COPD chronic obstructive pulmonary disease
- CF cystic fibrosis
- ARDS acute respiratory distress syndrome
- pulmonary emphysema pulmonary emphysema
- pneumonia and lung fibrosis lung fibrosis.
- the present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention.
- Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
- the present invention is also concerned with pharmaceutical compositions for preventing and treating inflammatory diseases of the lung comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
- Suitable therapeutic agents for a combination therapy with compounds of the invention include: (1 ) a corticosteroid, for example fluticasone or budesonide; (2) a 2-adrenoreceptor agonist, for example salmeterol or formeterol; (3) a leukotriene modulator, for example montelukast or pranlukast; (4) anticholinergic agents, for example selective muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, for example roflumilast or cilomilast; (6) an antitussive agent, such as codeine or dextramorphan; and (7) a non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen.
- a corticosteroid for example fluticasone or budesonide
- 2-adrenoreceptor agonist for example salmeterol or for
- the weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
- compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
- composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s)
- compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
- compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
- any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
- the active compound may be administered by any convenient, suitable or effective route.
- Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (by inhalation).
- compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions.
- composition may contain 0.01 -99% by weight of active compound.
- a unit dose comprises the active compound in an amount of ⁇ g to 10 mg.
- the most suitable dosage level may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
- the active compound is preferably in the form of microparticles.
- They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.
- a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
- Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI2F2) and HFA-152 (CH4F2 and isobutane).
- a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
- DPI dry powder inhaler
- Microparticles for delivery by administration may be formulated with excipients that aid delivery and release.
- microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ .
- a preferred composition is:
- Compounds of the invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which present compounds are useful.
- Such other drugs may be administered, by a route and in an amount commonly used therefore,
- a compound of the invention is used contemporaneously or sequentially with a compound of the invention.
- a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical
- compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the invention.
- Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.
- the active compounds may be dosed as described depending on the inhaler system used.
- the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
- a 3-amino-1 ,2,4-triazole and a ketone with a beta electron-withdrawing group E may be reacted to form an intermediate (1 ), which can then be arylated with a suitable arylboronic acid, such as 3- (trifluoromethyl)phenylboronic acid, under copper catalysis to give examples of type (2).
- the reaction may be performed in the presence of base e.g. pyridine or triethylamine, either in the presence or absence of a solvent such as
- the enantiomers of the racemic mixture (1 ) or (2) could be separated by chiral HPLC.
- a carboxylic acid can be incorporated into the structure of (1 ) or (2) for example, but not exclusively, by the cleavage of a corresponding ester, resolution could be carried out by crystallisation with a chiral base (Schemes 2 and 3).
- R' H or Ar Single enantiomer
- R" alkyl or aryl
- the three component reaction in Scheme 1 may also be carried out in a
- pentafluorophenylchloroformate produces (4). Ring closure can then be achieved using a substituted hydrazine to give (5).
- Arylation of (5) can be effected using an arylboronic acid, such as 3-(trifluoromethyl)phenylboronic acid, under copper catalysis and in the presence of a base e.g. pyridine or triethylamine.
- the reaction can be carried out with or without solvent.
- R' alkyl or aryl Single enantiomer
- R' H or Ar Single enantiomer
- R" e.g. allyl or benzyl
- R' alkyl or aryl Single enantiomer
- R' H or Ar Single enantiomer
- R" alkyl or aryl
- 'Isolute SPE Si cartridge' refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 ⁇ and nominal 60A porosity.
- Isolute® SCX-2 cartridge refers to a pre-packed polypropylene column containing a non end-capped propylsulphonic acid functionalised silica strong cation exchange sorbent.
- PE-AX cartridge' refers to a pre-packed polypropylene column containing a silica- based sorbent with a chemically bonded quaternary ammonium functional group. All solvents and commercial reagents were used as received.
- the solution was loaded onto an Isolute® SCX-2 cartridge (20 g) which had been conditioned with methanol.
- the cartridge was flushed with methanol and then the product was eluted with 2M ammonia in methanol. Evaporation gave a yellow foam.
- Aminoguanidine bicarbonate (2.0 g, 14.71 mmol) was suspended in water (5 ml) and 4-(dimethylamine)butyric acid hydrochloride was added portionwise. After foaming had subsided, the pH was adjusted to pH 4 by the addition of cone, nitric acid. The reaction was heated under reflux for 48 hours before being allowed to cool. The water was evaporated and the residue treated with methanol. A small amount of solid material was removed by filtration and the solution was then eluted through an
- the crude product was chromatographed on an Isolute® SPE Si II cartridge (10 g) eluting with 1 :1 ethyl acetate/pentane. 40 mg of this semi-purified material was further purified using HPLC system 2. The product was obtained as a white solid.
- Example 4 was prepared from Intermediate 8.
- Assays were performed in 96-well plates at a total assay volume of 10 ⁇ .
- the final concentration of the enzyme (human leukocyte elastase, Sigma E8140) was 0.00036 units/well.
- a peptide substrate (MeO-Suc-Ala-Ala-Pro-ValAMC, Calbiochem
- the potency of the compounds was determined from a concentration series of 10 concentrations in range from 1000 nM to 0.051 nM. The results are means of two independent experiments, each performed in duplicate.
- the compounds had activity in the range 1 -200nM.
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Abstract
Description
Claims
Priority Applications (14)
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BR112012022878A BR112012022878A2 (en) | 2010-03-12 | 2011-03-10 | compound, pharmaceutical composition, compound use and method of treatment |
JP2012556588A JP6044343B2 (en) | 2010-03-12 | 2011-03-10 | Compound or a pharmaceutically acceptable salt and pharmaceutical composition of the compound |
KR1020127022793A KR20130018672A (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
SG2012067310A SG184011A1 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
US13/640,004 US9120802B2 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as COPD |
MX2012010005A MX2012010005A (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd. |
RU2012138580/04A RU2604719C2 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and use thereof in treating respiratory diseases, such as copd |
CA2792726A CA2792726C (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
CN201180011534.9A CN102858773B (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as COPD |
AU2011225903A AU2011225903B2 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as COPD |
EP11709795.6A EP2545057B1 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
UAA201210669A UA109126C2 (en) | 2010-03-12 | 2011-10-03 | PYRIMIDINE DERIVATIVES HAVING INHIBITIVE PROPERTIES ON HUMAN NEUTROPHIL ELASTASES AND THEIR APPLICATIONS IN THERAPY |
IL221874A IL221874A (en) | 2010-03-12 | 2012-09-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
HK13107618.2A HK1180320A1 (en) | 2010-03-12 | 2013-06-28 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd copd |
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GB1004179.6 | 2010-03-12 | ||
GBGB1004179.6A GB201004179D0 (en) | 2010-03-12 | 2010-03-12 | Enzyme inhibitors |
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EP (1) | EP2545057B1 (en) |
JP (1) | JP6044343B2 (en) |
KR (1) | KR20130018672A (en) |
CN (1) | CN102858773B (en) |
AU (1) | AU2011225903B2 (en) |
BR (1) | BR112012022878A2 (en) |
CA (1) | CA2792726C (en) |
GB (1) | GB201004179D0 (en) |
HK (1) | HK1180320A1 (en) |
IL (1) | IL221874A (en) |
MX (1) | MX2012010005A (en) |
MY (1) | MY162555A (en) |
RU (1) | RU2604719C2 (en) |
SG (1) | SG184011A1 (en) |
UA (1) | UA109126C2 (en) |
WO (1) | WO2011110859A1 (en) |
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---|---|---|---|---|
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WO2014095700A1 (en) | 2012-12-18 | 2014-06-26 | Chiesi Farmaceutici S.P.A. | Novel compounds |
WO2014122160A1 (en) | 2013-02-06 | 2014-08-14 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2014135414A1 (en) | 2013-03-04 | 2014-09-12 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
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US9290457B2 (en) | 2014-07-31 | 2016-03-22 | Boehringer Ingelheim International Gmbh | Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9440930B2 (en) | 2014-07-31 | 2016-09-13 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9458113B2 (en) | 2014-07-31 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9475779B2 (en) | 2014-07-31 | 2016-10-25 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9657015B2 (en) | 2014-07-31 | 2017-05-23 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
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Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB201004179D0 (en) * | 2010-03-12 | 2010-04-28 | Pulmagen Therapeutics Inflamma | Enzyme inhibitors |
GB201004178D0 (en) * | 2010-03-12 | 2010-04-28 | Pulmagen Therapeutics Inflamma | Enzyme inhibitors |
AU2015362790A1 (en) | 2014-12-16 | 2017-07-20 | Axovant Sciences Gmbh | Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0505321A2 (en) | 1991-03-21 | 1992-09-23 | Ciba-Geigy Ag | Inhaler |
DE102006031314A1 (en) * | 2006-07-01 | 2008-01-03 | Bayer Healthcare Aktiengesellschaft | Use of 1,4-diaryl-dihydropyrimidin-2-one derivative for producing a medicament for the treatment and/or prophylaxis of e.g. pulmonary arterial hypertension, chronic-obstructive lung diseases and sleep apnea syndrome |
WO2008135537A1 (en) * | 2007-05-03 | 2008-11-13 | Argenta Discovery Limited | Tetrahydropyrrolopyrimidinediones and their use as human neutrophil elastase inhibitors |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2498052C (en) * | 2002-09-10 | 2011-05-17 | Bayer Healthcare Ag | Heterocyclic derivatives |
GB0520743D0 (en) * | 2005-10-12 | 2005-11-23 | Argenta Discovery Ltd | Compounds and their use |
PT2024367E (en) * | 2006-05-04 | 2010-12-03 | Pulmagen Therapeutics Inflammation Ltd | Tetrahydropyrrolopyrimidinediones and their use as human neutrophil elastase inhibitors |
GB0608844D0 (en) * | 2006-05-04 | 2006-06-14 | Argenta Discovery Ltd | Enzyme inhibitors |
NZ586263A (en) * | 2007-12-20 | 2012-06-29 | Bayer Schering Pharma Ag | 4-(4-cyano-2-thioaryl)dihydropyrimidinones and use thereof |
DE102008022521A1 (en) * | 2008-05-07 | 2009-11-12 | Bayer Schering Pharma Aktiengesellschaft | 1,4-Diaryl-pyrimidopyridazine-2,5-diones and their use |
DE102009004197A1 (en) | 2009-01-09 | 2010-07-15 | Bayer Schering Pharma Aktiengesellschaft | Heterocyclic fused diaryldihydropyrimidine derivatives and their use |
GB201004179D0 (en) * | 2010-03-12 | 2010-04-28 | Pulmagen Therapeutics Inflamma | Enzyme inhibitors |
-
2010
- 2010-03-12 GB GBGB1004179.6A patent/GB201004179D0/en not_active Ceased
-
2011
- 2011-03-10 EP EP11709795.6A patent/EP2545057B1/en active Active
- 2011-03-10 KR KR1020127022793A patent/KR20130018672A/en active IP Right Grant
- 2011-03-10 AU AU2011225903A patent/AU2011225903B2/en not_active Ceased
- 2011-03-10 SG SG2012067310A patent/SG184011A1/en unknown
- 2011-03-10 BR BR112012022878A patent/BR112012022878A2/en not_active IP Right Cessation
- 2011-03-10 WO PCT/GB2011/050478 patent/WO2011110859A1/en active Application Filing
- 2011-03-10 CA CA2792726A patent/CA2792726C/en not_active Expired - Fee Related
- 2011-03-10 US US13/640,004 patent/US9120802B2/en active Active
- 2011-03-10 MX MX2012010005A patent/MX2012010005A/en active IP Right Grant
- 2011-03-10 MY MYPI2012004035A patent/MY162555A/en unknown
- 2011-03-10 JP JP2012556588A patent/JP6044343B2/en not_active Expired - Fee Related
- 2011-03-10 CN CN201180011534.9A patent/CN102858773B/en not_active Expired - Fee Related
- 2011-03-10 RU RU2012138580/04A patent/RU2604719C2/en not_active IP Right Cessation
- 2011-10-03 UA UAA201210669A patent/UA109126C2/en unknown
-
2012
- 2012-09-10 IL IL221874A patent/IL221874A/en not_active IP Right Cessation
-
2013
- 2013-06-28 HK HK13107618.2A patent/HK1180320A1/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0505321A2 (en) | 1991-03-21 | 1992-09-23 | Ciba-Geigy Ag | Inhaler |
DE102006031314A1 (en) * | 2006-07-01 | 2008-01-03 | Bayer Healthcare Aktiengesellschaft | Use of 1,4-diaryl-dihydropyrimidin-2-one derivative for producing a medicament for the treatment and/or prophylaxis of e.g. pulmonary arterial hypertension, chronic-obstructive lung diseases and sleep apnea syndrome |
WO2008135537A1 (en) * | 2007-05-03 | 2008-11-13 | Argenta Discovery Limited | Tetrahydropyrrolopyrimidinediones and their use as human neutrophil elastase inhibitors |
Non-Patent Citations (12)
Title |
---|
ACTA PHARMACEUTICA, vol. 58, no. 1, 2008, pages 119 - 129 |
BIETH, G.: "Regulation of Matrix accumulation", 1986, ACADEMIC PRESS, pages: 217 - 306 |
CHURG, A. ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 168, 2003, pages 199 - 207 |
INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 42B, no. 4, 2003, pages 910 - 915 |
INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 14, no. 1, 2004, pages 43 - 46 |
INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 16, no. 4, 2007, pages 349 - 352 |
J. AM. CHEM. SOC., vol. 127, 2005, pages 16386 - 16387 |
JOURNAL OF THE INDIAN CHEMICAL SOCIETY, vol. 84, no. 12, 2007, pages 1234 - 1238 |
LAURRELL, C. B.; ERIKKSON, S, SCAND. J. CLIN. INVEST., vol. 15, 1963, pages 132 - 140 |
THOMPSON, A. B.; DAUGHTON, D. ET AL., AM. REV. RESPIR. DIS., vol. 140, 1989, pages 1527 - 1537 |
TRENDS IN APPLIED SCIENCES RESEARCH, vol. 3, no. 2, 2008, pages 203 - 208 |
WRIGHT, J. L. ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 166, 2002, pages 954 - 960 |
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WO2023118258A1 (en) | 2021-12-22 | 2023-06-29 | Chiesi Farmaceutici S.P.A. | Triazolone derivative salt as neutrophil elastase inhibitor |
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UA109126C2 (en) | 2015-07-27 |
SG184011A1 (en) | 2012-10-30 |
IL221874A (en) | 2016-09-29 |
RU2012138580A (en) | 2014-04-20 |
AU2011225903B2 (en) | 2016-08-11 |
CN102858773B (en) | 2015-05-06 |
CN102858773A (en) | 2013-01-02 |
CA2792726C (en) | 2018-01-02 |
BR112012022878A2 (en) | 2016-06-14 |
JP2013522183A (en) | 2013-06-13 |
AU2011225903A1 (en) | 2012-10-04 |
JP6044343B2 (en) | 2016-12-14 |
US20130123278A1 (en) | 2013-05-16 |
HK1180320A1 (en) | 2013-10-18 |
KR20130018672A (en) | 2013-02-25 |
MY162555A (en) | 2017-06-15 |
US9120802B2 (en) | 2015-09-01 |
MX2012010005A (en) | 2012-10-05 |
GB201004179D0 (en) | 2010-04-28 |
EP2545057B1 (en) | 2017-06-07 |
CA2792726A1 (en) | 2011-09-15 |
EP2545057A1 (en) | 2013-01-16 |
RU2604719C2 (en) | 2016-12-10 |
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