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WO2008135537A1 - Tétrahydroxypyrrolopyrimidinédiones et leur utilisation comme inhibiteurs de l'élastase des neutrophiles humains - Google Patents

Tétrahydroxypyrrolopyrimidinédiones et leur utilisation comme inhibiteurs de l'élastase des neutrophiles humains Download PDF

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Publication number
WO2008135537A1
WO2008135537A1 PCT/EP2008/055439 EP2008055439W WO2008135537A1 WO 2008135537 A1 WO2008135537 A1 WO 2008135537A1 EP 2008055439 W EP2008055439 W EP 2008055439W WO 2008135537 A1 WO2008135537 A1 WO 2008135537A1
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Prior art keywords
alkyl
compound
hydrogen
independently
radical
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PCT/EP2008/055439
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English (en)
Inventor
Nicholas Charles Ray
Harry Finch
Christine Edwards
Elizabeth O'connor
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Argenta Discovery Limited
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Priority claimed from PCT/GB2007/001638 external-priority patent/WO2007129060A1/fr
Application filed by Argenta Discovery Limited filed Critical Argenta Discovery Limited
Publication of WO2008135537A1 publication Critical patent/WO2008135537A1/fr
Priority to US13/449,045 priority Critical patent/US8957082B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • 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

  • This invention relates to heterocyclic compounds which are substituted 3,4,6,7-tetrahydro-1 H-pyrrolo[3,4-d]pyrimidine-2,5-diones, and their use in therapy. Background to the invention
  • HNE Human neutrophil elastase
  • 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.
  • 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 is believed to play a role in several pulmonary diseases, including 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
  • BAL bronchoalveolar leakage
  • protease-anti-protease balance also known as the 'elastase:anti-elastase hypothesis'
  • an imbalance of HNE and endogenous antiproteases such as ⁇ 1 -antitrypsin ( ⁇ r AT), Secretory leukocyte protease inhibitor (SLPI) and pre-elafin leads to the various inflammatory disorders of COPD.
  • Individuals that have a genetic deficiency of the protease inhibitor u 1 -antitrypsin develop emphysema that increases in severity over time (Laurrell, C. B.; Erikkson, S Scand. J. Clin. Invest. 1963 15, 132-140).
  • Multimeric ligands consist of multiple binding domains which are tethered together through a suitable scaffold. Hence individual binding domains are linked together into a single molecule, increasing the probability that the multimer will bind sequentially in a step-wise manner with multiple active sites resulting in high-affinity interactions (Handl, H. L. et al. Expert OpIn. Ther. Targets2004, 8, 565-586; Han, Y. F. et al., Bioorg. Med. Chem. Letts. 1999, 7, 2569-2575). Also, multiple binding interactions (either sequential or parallel) with relatively high off-rates can combine to yield an overall low off-rate for the multimeric ligand.
  • a molecule consisting of a suitable linker and ligands may be expected to show advantage over the monomeric ligands alone in terms of potency and/or duration of action.
  • Multimeric compounds are unlikely to be orally bioavailable (as predicted by Lipinski's "Rule of 5") which may be advantageous where an inhaled route of administration to the lungs is targeted, since even after inhaled administration, a large proportion of drug is likely to enter the Gl tract.
  • Such compounds may be expected to show reduced systemic exposure after inhalation administration and hence an improved toxicity profile over orally administered therapies.
  • 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.
  • the compounds of the invention may be used as monomers or, particularly in the case of topical pulmonary application by inhalation, in the form of multimers, such as dinners, covalently linked via a linker framework.
  • the invention provides a compound of formula (I),:
  • A is aryl or heteroaryl; D is oxygen or sulphur;
  • R 1 and R 2 are independently each hydrogen, halogen, nitro, cyano, C r C 6 -alkyl,
  • R 3 and R 5 are independently each halogen, nitro, cyano, C r C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, hydroxy or d-C 6 -alkoxy or C 2 -C 6 -alkenyloxy, wherein Ci-C 6 - alkyl and CrC 6 -alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and CrC 4 - alkoxy;
  • R and R 4 each independently represent a radical of formula -[X] m -[Alk 1 ] p -[Q] n - [Alk 2 ] q -[X 1 ] k -Z wherein k, m, n, p and q are independently 0 or 1 ;
  • AIk 1 and AIk 2 each independently represent an optionally substituted CrC 6 alkylene, or C 2 -C 6 alkenylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NR A -) link wherein R A is hydrogen or d-C 3 alkyl;
  • R D and R E are independently hydrogen, CrC 6 alkyl, or C 3 -C 6 cycloalkyl, or R A and R B> or R D and R E taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S, or (ii) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members;
  • R A is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl
  • X 1 represents -O-, -S-, or -NH
  • Z is hydrogen or an optionally substituted mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members.
  • the invention also includes a multimeric compound comprising two, three or four molecules of a compound of formula (I) above, covalently linked through a linker framework.
  • Compounds of the invention may be useful 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.
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient; and (ii) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which HNE is implicated.
  • Terminology As used herein, the term "(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 is 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 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.
  • 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 2 to 6 carbon atoms, and at least one double bond.
  • the unqualified term “carbocyclic” refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
  • cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 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 tricyclic 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.
  • Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
  • heterocyclyl or “heterocyclic” or “heterocycloalkyl” includes “heteroaryl” as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic 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.
  • 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 and succinimido groups.
  • substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (CrC 6 )alkyl, cycloalkyl, (C r C 6 )alkoxy, hydroxy, hydroxy(Ci-C 6 )alkyl, mercapto, mercapto(Ci-C 6 )alkyl, (d-C 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 A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable 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-ethy
  • 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 basic nitrogen can also form quaternary ammonium salts with a pharmaceutically acceptable counter-ion such as chloride, bromide, acaetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate, methanesulfonate, xinafoate, and the like.
  • a pharmaceutically acceptable counter-ion such as chloride, bromide, acaetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate, methanesulfonate, xinafoate, and the like.
  • Compounds of the invention which contain one or more actual or potential chiral centres, because of the presence of asymmetric carbon atoms, can exist as a number of diastereoisomers with R or
  • the atom D may be O or S, but O is currently preferred.
  • the ring A is aryl or heteroaryl and may be any of those rings listed above as examples of aryl or heteroaryl, especially phenyl and monocyclic heteroaryl having 5 or 6 ring atoms. Specific examples include pyridyl, such as 2- and 3-pyridyl, or pyrimidinyl such as pyrimidin-2-yl, but presently it is preferred that A be phenyl.
  • R 1 and R 2 may be selected from any of the substituent types for which they are defined in relation to formula (I), including hydrogen, halogen, nitro, cyano, Ci-C 3 - alkyl, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, hydroxy or C r C 3 -alkoxy or C 2 -C 3 -alkenyloxy.
  • substitutuents include hydrogen, fluoro, chloro, bromo, cyano, methyl, methoxy and -C ⁇ CH.
  • -AR 1 R 2 may be 4-cyanophenyl or 4-ethynylphenyl.
  • 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), but in one currently preferred type of compound of the invention R 5 and R 3 are independently trifluoromethyl, fluoro, chloro or bromo. Preferred positions in the relevant phenyl ring for substitution by R 5 and R 3 are 3-, A-, and 5-.
  • R and R 4 may vary widely, and are defined in relation to formula (I) as a radical of formula -[X] m - [Alk 1 ] p -[Q] n -[Alk 2 ] q -[X 1 ] k -Z. According to that definition, k, m, n, p and q may all be 0, and Z may be hydrogen, so that R or R 4 itself may be hydrogen. However, many other classes of R or R 4 substituent are encompassed by selecting different combinations of values for the variables.
  • R or R 4 may be selected from d-C 6 -alkyl, formyl, aminocarbonyl, mono- or di-d-C- f -alkylaminocarbonyl, C 3 -C 8 -cycloalkylcarbonyl, CrC 6 -alkylcarbonyl, CrC ⁇ -alkoxycarbonyl, N-(C r C 4 -alkylsulfonyl)-aminocarbonyl, N-(C r C 4 -alkylsulfonyl)- N-(CrC 4 -alkyl)-aminocarbonyl, heteroaryl, heterocycloalkyl, heteroarylcarbonyl or heterocycloalkylcarbonyl; wherein CrC 6 -alkyl, mono- and di-C r C 4 - alkylaminocarbonyl, Ci-C 6 -alkylcarbonyl, d-C ⁇ -alkoxycarbonyl, heteroaryl and heterocycloal
  • R 4 and/or R is radical of formula -[X] m -[Alk 1 ] p -[Q] n -[Alk 2 ] q -[X 1 ] k -Z wherein m is 0, and k, p, n and q are each 1 , Q is -N(R A ) or -N + (R A )(R B )-, and R A , R B AIk 1 , AIk 2 , X 1 and Z are as defined in relation to formula (I).
  • X 1 may be, for example, -O-, and Z may be, for example optionally substituted phenyl or monocyclic hetroaryl, the latter having 5 or 6 ring atoms.
  • one of R and R 4 may be hydrogen, while the other is a substitutent other than hydrogen
  • R and R 4 groups have Formula (VINA), (VIIIB) or (VIIIC):
  • R 4B is hydrogen or C r C 6 -alkyl
  • R 4C , R 4D , R 4E are each CrC 6 -alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge; and additionally any two of R 4C , R 4D , R 4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or
  • R 4C , R 4D , R 4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary; and v1 and v2 are each independently 0-5.
  • Other types of R and R 4 groups are those selected from the following:
  • R 4B is hydrogen or d-C 6 -alkyl
  • R 4C , R 4D , R 4E are each CrC 6 -alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge
  • any two of R 4C , R 4D , R 4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or one of R 4C , R 4D , R 4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary;
  • R 4F and R 4 ' are independently hydrogen or d-C 6 -alkyl;
  • R 4G and R 4H are independently hydrogen or CrC 6 -alkyl, or R 4G and R 4H taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S;
  • v1 and v2 are each independently 0-5.
  • two, three or four molecules of a monomeric compound of the invention are covalently linked through a linker framework. Since the linker framework need not play an active role in interacting with the HNE enzyme, its role is simply to allow binding contact between one or more of the monomeric elements and the enzyme.
  • linker framework a vast range of chemistries may be envisaged for the linker framework.
  • point of attachment of the monomeric elements to the linker framework may be selected according to the particular linker chemistry to be employed.
  • linker chemistry it is preferred that two, three or four of the monomeric molecules are linked to the linker framework via their respective nitrogen atoms shown in formula (I) as linked to R or R 4 .
  • the said radical may be selected from, for example, the following:
  • the linker framework may have, for example, one of the following structures (A), (B) 1 (C), (D), (E), (G) and (E):
  • one preferred subset of the multimers of the invention has the formula M-L-M 1 wherein L is a divalent linker radical, for example of the kinds discussed above as linker frameworks, and M and M 1 are each independently a radical of formula (IA) wherein D, A and R 1 -R 5 are as defined and discussed above:
  • M and M 1 are the same.
  • M- L-M 1 Another preferred subset of the multimers of the invention has the formula M- L-M 1 wherein L is a divalent linker radical for example of the kinds discussed above as linker frameworks, and M and M 1 are each independently a radical of formula (IB) wherein D, A and R, R 1 , R 2 , R 3 and R 5 are as defined and discussed above:
  • M and M 1 are the same.
  • Specific examples of such dimeric compounds of formula (IA) and (IB) include those of the Examples herein.
  • 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
  • a ⁇ 2-adrenoreceptor agonist for example salmeter
  • 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.
  • prophylactic or therapeutic dose of a compound of the invention will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration, and will generally be detrmined by clinical trial as required in the pharmaceutical art. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical 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. Delivery by inhalation is preferred.
  • compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions.
  • the composition may contain 0.01 -99% by weight of active compound.
  • a unit dose comprises the active compound in an amount of 1 ⁇ 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).
  • PMDI pressurised metered dose inhaler
  • 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). Many types of DPI are known.
  • 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 ⁇ m.
  • a preferred composition is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister
  • 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, 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.
  • 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.
  • the agents of the invention may be administered in inhaled form.
  • 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.
  • the compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
  • the free acid or base form corresponding to isolated salts can be generated by neutralisation with a suitable base or acid such as sodium hydroxide, potassium carbonate, acetic acid and hydrochloric acid and extraction of the liberated free acid or base into an organic solvent followed by evaporation.
  • a suitable base or acid such as sodium hydroxide, potassium carbonate, acetic acid and hydrochloric acid
  • the free form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid or base and subsequent evaporation, precipitation, or crystallisation.
  • DIPEA N,N-Diisopropylethyamine
  • the crude product was purified on an Isolute® SPE Si Il cartridge (5 g) eluting with DCM, 10% MeOH in DCM and then 18% MeOH in DCM. Pure fractions were combined and the solvent removed under reduced pressure. The residue was dissolved in 1 :1 MeCN/H 2 O (10 ml) and then freeze-dried to give the desired product as a white solid. Yield: 0.122 g, 30%.
  • Example 2 was prepared from Intermediate 4 using a similar procedure to that used in the synthesis of Example 1. Yield: 0.151 g, 28%
  • Fluorescent peptide substrate Assays were performed in 96-well plates at a total assay volume of 10O ⁇ l. 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 #324745) was used, at the final concentration of 100 ⁇ M. The final concentration of DMSO was 1 % in the assay buffer (0.05M Tris.HCI, pH 7.5, 0.1 M NaCI; 0.1 M CaCI2; 0.0005% brij-35). The enzymatic reaction was started by adding the enzyme.
  • the enzymatic reaction was performed at RT and after 30mins stopped by adding 50 ⁇ l soybean trypsin inhibitor (Sigma T-9003) at a final concentration of 50 ⁇ g/well. Fluorescence was read on the FLEXstation (Molecular Devices) using 380 nm excitation and 460 nm emission filters. 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. Using Fluorescently labelled elastin
  • Assays were performed in 96-well plate at a total assay volume of 10O ⁇ l.
  • the final concentration of the enzyme human leukocyte elastase, Sigma E8140
  • Fluorescently labelled, solubilised elastin from bovine neck ligament (Molecular Probes, E-12056) was used at the final concentration of 15 ⁇ g/ml.
  • the final concentration of DMSO was 2.5% in the assay buffer (0.1 M Tris-HCL,pH8.0, containing 0.2mM sodium azide).
  • the enzymatic reaction was started by adding the enzyme.
  • the enzymatic reaction was performed at RT and read after 120 minutes.
  • the potency of the compounds was determined from a concentration series of 10 concentrations in range from 2500OnM to 1 nM. The results are means of two independent experiments, each performed in duplicate.
  • IC50s of the compounds of the Examples herein in the above assay were each less than 10OnM.

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Abstract

La présente invention concerne les composés de formule (I) et les multimères de ceux-ci qui sont des inhibiteurs de l'activité de l'élastase des neutrophiles humains, et leur utilité dans le traitement de la BPCO par exemple :(I) où A est un aryle ou un hétéroaryle; D est un oxygène ou un sulfure; R1, R2 et R3 sont indépendamment chacun un hydrogène, un halogène, un nitro ou cyano C1-C6 alkyle, C2-C6 alkényle, Cr2-C6 alkynyle, hydroxy ou Cr1-C6 alkoxy ou C2-C6 alkenyloxy, dans lesquels le C1-C6 akyl et le C1-C6 alkoxy peuvent être de plus substitués avec un à trois radicaux identiques ou différents sélectionnés parmi le groupe consistant d'halogène, d'hydroxy et de Cr1-C4 alkoxy; R et r4 représentant chacun indépendamment un radical de formule -[X]m-[Alk1]p-[Q]n-[Alk2]q-[X1]k-Z où k, m, n, p et q sont indépendamment 0 ou 1; AIk1 et AIk2 représentent chacun indépendamment un C1-C6 alkylène substitué de manière facultative, ou un radical C2-C6 alkenylène pouvant contenir de manière facultative une liaison éther (-0-), thioéther (-S-) ou amine (-NRA-) où RA est un hydrogène ou un C1-C3 alkyl; Q représente (i) -O-, -S-, -S(O)-, -S(O)2-, -S+(RA)-, -N(RA)-, -N+(RA)(RB)-, -C(O)-, -C(O)O-, -OC(O)-, -C(=O)NRA -, -NRAC(=O)-, -S(O2)NRA-, -NRAS(O2)-, -NRAC(=O)NRB-, -NRAC(=NRA)NRB-, -C(=NRD)NRE-, -NREC(=NRD)-, où RA, RB, RD et RE sont indépendamment hydrogène, d-C6 alkyl, ou C3-C6 cycloalkyl, où RA et RB ou RD et RE pris ensemble avec l'azote auquel ils sont attachés forment un anneau monocyclique hétérocyclique de 5 à 7 atomes en anneau pouvant contenir un hétéro-atome supplémentaire sélectionné à partir de N, O et S, ou (ii) un radical mono- ou dicyclique divalent substitué de manière facultative ou hétérocyclique ayant 3 à 6 éléments d'anneau; X représente -(C=O)-, -S(O2)-, -C(O)O-, -(C=O)NRA-, ou -S(O2)NRA-, où RA est un hydrogène,un C1-C6 alkyl, ou un C3-C6 cycloalkyl; X1 représente -O-, -S-, ou -NH; et Z est un hydrogène ou un radical mono- ou dicyclique substitué de manière facultative ou hétérocyclique ayant 3 à 6 éléments d'anneau.
PCT/EP2008/055439 2006-05-04 2008-05-02 Tétrahydroxypyrrolopyrimidinédiones et leur utilisation comme inhibiteurs de l'élastase des neutrophiles humains WO2008135537A1 (fr)

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WO2010078953A1 (fr) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazolo- et tétrazolopyrimidine en tant qu'inhibiteurs de l'élastase neutrophile humaine (hne) pour le traitement de la maladie pulmonaire obstructive chronique (copd)
WO2010086638A1 (fr) * 2009-01-30 2010-08-05 Pulmagen Therapeutics (Inflammation) Limited Pyrrolopyrimidinedione dimère et son utilisation dans le traitement de maladies respiratoires
WO2011110859A1 (fr) * 2010-03-12 2011-09-15 Pulmagen Therapeutics (Inflammation) Limited Dérivés de pyrimidine et leur utilisation dans le traitement de maladies respiratoires telles que la maladie pulmonaire obstructive chronique (mpoc)
WO2011110858A1 (fr) * 2010-03-12 2011-09-15 Pulmagen Therapeutics (Inflammation) Limited Dérivés de pyrimidine et leur utilisation dans le traitement de maladies respiratoires telles que la maladie pulmonaire obstructive chronique (mpoc)
WO2014122160A1 (fr) 2013-02-06 2014-08-14 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation à titre d'inhibiteurs de l'activité élastase neutrophile
WO2014135414A1 (fr) 2013-03-04 2014-09-12 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation en tant qu'inhibiteurs de l'activité élastase de neutrophiles
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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WO2010078953A1 (fr) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazolo- et tétrazolopyrimidine en tant qu'inhibiteurs de l'élastase neutrophile humaine (hne) pour le traitement de la maladie pulmonaire obstructive chronique (copd)
DE102009004197A1 (de) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch anellierte Diaryldihydropyrimidin-Derivate und ihre Verwendung
US9359362B2 (en) 2009-01-09 2016-06-07 Bayer Intellectual Property Gmbh Triazolo and tetrazolo pyrimidine derivatives as HNE inhibitors for treating COPD
US8569314B2 (en) 2009-01-09 2013-10-29 Bayer Intellectual Property Gmbh Triazolo and tetrazolo pyrimidine derivatives as HNE inhibitors for treating COPD
JP2012514615A (ja) * 2009-01-09 2012-06-28 バイエル・ファルマ・アクチェンゲゼルシャフト Ｃｏｐｄの処置用のｈｎｅ阻害剤としてのトリアゾロおよびテトラゾロピリミジン誘導体
US8455505B2 (en) 2009-01-30 2013-06-04 Chiesi Farmaceutici S.P.A. Pyrrolopyrimidinedione and its therapeutic use
WO2010086638A1 (fr) * 2009-01-30 2010-08-05 Pulmagen Therapeutics (Inflammation) Limited Pyrrolopyrimidinedione dimère et son utilisation dans le traitement de maladies respiratoires
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WO2011110859A1 (fr) * 2010-03-12 2011-09-15 Pulmagen Therapeutics (Inflammation) Limited Dérivés de pyrimidine et leur utilisation dans le traitement de maladies respiratoires telles que la maladie pulmonaire obstructive chronique (mpoc)
WO2011110858A1 (fr) * 2010-03-12 2011-09-15 Pulmagen Therapeutics (Inflammation) Limited Dérivés de pyrimidine et leur utilisation dans le traitement de maladies respiratoires telles que la maladie pulmonaire obstructive chronique (mpoc)
RU2604719C2 (ru) * 2010-03-12 2016-12-10 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Производные пиримидина и их применение в лечении респираторных заболеваний, таких как copd
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AU2011225903B2 (en) * 2010-03-12 2016-08-11 Chiesi Farmaceutici S.P.A. Pyrimidine derivatives and their use in the treatment of respiratory diseases such as COPD
US9120802B2 (en) 2010-03-12 2015-09-01 Chiesi Farmaceutici S.P.A. Pyrimidine derivatives and their use in the treatment of respiratory diseases such as COPD
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RU2581839C2 (ru) * 2010-03-12 2016-04-20 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Производные пиримидина и их применение в лечении респираторных заболеваний, таких как copd
WO2014122160A1 (fr) 2013-02-06 2014-08-14 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation à titre d'inhibiteurs de l'activité élastase neutrophile
WO2014135414A1 (fr) 2013-03-04 2014-09-12 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation en tant qu'inhibiteurs de l'activité élastase de neutrophiles
US9115093B2 (en) 2013-03-04 2015-08-25 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
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US9657015B2 (en) 2014-07-31 2017-05-23 Boehringer Ingelheim International Gmbh Substituted bicyclic 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
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