WO2007107706A2 - Multimeres de composes heterocycliques et leur utilisation - Google Patents

Multimeres de composes heterocycliques et leur utilisation Download PDF

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WO2007107706A2
WO2007107706A2 PCT/GB2007/000919 GB2007000919W WO2007107706A2 WO 2007107706 A2 WO2007107706 A2 WO 2007107706A2 GB 2007000919 W GB2007000919 W GB 2007000919W WO 2007107706 A2 WO2007107706 A2 WO 2007107706A2
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alkyl
compound
ring
formula
optionally substituted
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PCT/GB2007/000919
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WO2007107706A3 (fr
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Harry Finch
Christine Edwards
Nicholas Charles Ray
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Argenta Discovery Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to multimeric heterocyclic compounds which are inhibitors of human neutrophil elastase (HNE), and their use in therapy, for example the treatment of chronic obstructive pulmonary disease (COPD) and other conditions where HNE is implicated.
  • HNE human neutrophil elastase
  • Human neutrophil elastase is a 32 kDa serine proteinase found in the azurophilic granules of neutrophils. It has a role in the degradation of a wide range of extracellular matrix proteins, including fibronectin, laminin, proteoglycans, Type III and Type IV collagens as well as elastin (Bieth, G. In Regulation of Matrix accumulation, Mecham, R. P. (Eds), Academic Press, NY, USA 1986, 217-306). 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.
  • 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, severe asthma, sarcoidosis, bronchiectasis and lung fibrosis. It is also implicated in several 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 obstructive pulmonary disease
  • CF cystic fibrosis
  • ARDS acute respiratory distress syndrome
  • Elevated HNE levels are also correlated with the severity of inflammation in inflammatory bowel disease (Silberer H et al, Clin Lab. 2005;51 (3-4): 117-26) and may play a role in impaired mucosal repair in patients with ulcerative colitis.
  • COPD is an umbrella term encompassing three different pathological conditions, ail of which contribute to limitation of airflow: chronic bronchitis, emphysema and small- airway disease. Generally all three will exist to varying extents in patients presenting with COPD, and ail three may be due to neutrophil-mediated inflammation, as supported by the increased number of neutrophils observed in bronchoalveolar leakage (BAL) fluids of COPD patients (Thompson, A.
  • BAL bronchoalveolar leakage
  • the major pathogenic determinant in COPD has long been considered to be the protease-anti-protease balance (also known as the 'elastase:anti-elastase hypothesis'), in which 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.
  • protease-anti-protease balance also known as the 'elastase:anti-elastase hypothesis'
  • 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 simultaneously with multiple active sites resulting in high-affinity interactions (Handl, H. L. et al. Expert Opin. Ther. Targets 2004, 8, 565-586; Han, Y. F. et al., Bioorg. Med. Chem. 1999, 7, 2569-2575). Also, multiple binding interactions 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.
  • a first aspect of the invention is a covalent conjugate of two or more compounds, each having a structure as defined in any of WO2004/043924, WO2005/021509, WO2005/021512, WO2005/026123, WO2005/026124, WO2006/098683 and WO2006/098684.
  • the covalent conjugate may be one having the formula:
  • each M is independently a compound having a structure as defined in any of WO2004/043924, WO2005/021509, WO2005/021512, WO2005/026123, and WO2005/026124 t is 2 to 20;
  • G is optionally substituted aryl or heteroaryl; C 1 -C 6 alkyl; cycloalkyl; nitrogen; a dendrimer or a group of any of formulae (V) to (VII):
  • Ar is aryl or heteroaryl; and u is 2-20; each L is independently a linker group of Formula (III)
  • L a is a bond or group -C(O)-;
  • L b is a bond or group -C(O)-;
  • R 7 is an alkylene or cycloalkylene group;
  • W is a bond or is selected from the following divalent radicals
  • R 8A is an alkylene or cycloalkylene group
  • R 8B is an alkylene or cycloalkylene group, or a group of Formula A 2 ;
  • R 9A is hydrogen or alkyl; one of R 9B or R 9C is a lone pair and the other is hydrogen or alkyl, or R 9B and
  • R 9C are both alkyl, in which case the nitrogen to which they are attached is quaternary and carries a positive charge. Additionally, R 9B and R 9C may be joined together with the nitrogen to which they are attached to form a ring; R 10A is hydrogen or alkyl;
  • R 10B and R 10C are independently hydrogen or alkyl, or alternatively R 10B and R 10C.
  • R 10C may be joined together to form a ring; m2 is 1-3;
  • a 2 is selected from the groups of the formulae
  • Ar 1 , Ar 2 are independently an aryl or heteroaryl group; or a pharmaceutically acceptable salt, solvate or N-oxide thereof.
  • Compounds of the invention may be described as dimers, when there are two moieties M.
  • the linker L may however carry one or more further moieties M.
  • dimers are preferred.
  • the moieties M be the same.
  • LINKER is a divalent linker radical
  • R 1 is a group of formula Z-[Alk 1 ] m -[X] p -[Alk 2 ] n - wherein: m, n and p are independently 0 or 1;
  • R 2 represents hydrogen or C 1 -C 6 alkyl
  • R 1 and R 2 taken together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring fused to the ring containing X and N, said fused ring being optionally substituted by one or more optional substituents, or one or more optionally substituted C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl groups;
  • R 2 is linked with a carbon or nitrogen atom in the LINKER radical to form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring fused to the ring containing X;
  • R 3 represents hydrogen, or 1 or 2 optional substituents, or 1 or 2 optionally substituted C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl;
  • R 4 represents a radical of formula -[AIk] 8 -Q wherein
  • a is 0 or 1
  • Q is hydrogen, optionally substituted monocyclic carbocyclic or heterocyclic having from 3 to 6 ring atoms;
  • R 4 -NH- represents an optionally substituted monocyclic heterocyclic ring having 5 or 6 ring atoms and linked to the carbonyl via a ring nitrogen. It will be appreciated that any compound of the invention may be used in the form of a prodrug.
  • 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 or cystic fibrosis, asthma, rhinitis, psoriasis, dermatitis, (atopic and non-atopic), Crohn's disease, ulcerative colitis, and irritable bowel disease.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • pulmonary emphysema smoking-induced emphysema or cystic fibrosis
  • asthma rhinitis
  • psoriasis dermatitis
  • Crohn's disease ulcerative colitis
  • irritable bowel disease for example chronic obstructive
  • compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • Preferred compositions are those adapted for pulmonary administration by inhalation.
  • Another aspect of the invention is 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.
  • compounds of the invention may be used in a method of therapy, for the treatment of a patient suffering from a condition or disease as defined above.
  • (C r C 6 )alkyl means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • (CVC 6 )alkylene radical means a divalent saturated hydrocarbon chain having from 1 to 6 carbon atoms .
  • (C 2 -C 6 )alkenyl means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable.
  • the term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
  • divalent (C 2 -C 6 )alkenylene radical means a divalent hydrocarbon chain having from 2 to 6 carbon atoms, and at least one double bond.
  • C 2 -C 6 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond.
  • This term would include for example, ethynyl, 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 2 -C 6 )alkynylene radical means a divalent hydrocarbon chain having from 2 to 6 carbon atoms, and at least one triple bond.
  • 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 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.
  • 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” 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, (Ci-C 6 )alkyl, (C r C 6 )alkoxy, hydroxy, mercapto (CrC 6 )alkylthio, cyclopropyl, phenyl, monocyclic heterocyclyl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), mono- di- or tri-fluoromethyl, mono-, di- or tri-fluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR A , -COR A , -CONH 2 , -CONHR A , -CONR A R B , -SO 2 OH, -SO 2 OR A , -SO 2 R A , -SO 2 NH 2
  • an optional substituent is or includes a phenyl or monocyclic heterocyclyl substituent having 5 or 6 ring atoms
  • that phenyl or heterocyclic ring may be substituted by any of the foregoing substituents except phenyl or monocyclic heterocyclyl having 5 or 6 ring atoms.
  • An "optional substituent” or “substituent” may be one of the foregoing substituent groups.
  • 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-ethyl pipe
  • 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, benzenesulfonic, 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 may be isolated as hydrates or solvates.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • R 2 is hydrogen or CrC 6 alkyl, for example methyl
  • R 3 may represent, for example, 1 or 2 substituents, each independently selected from methyl, trifluoromethyl, fluoro, chloro, bromo, C 1 -C 6 alkyl, -CN, C 1 -C 6 alkoxy, -NO 2 , -NR A R B wherein R A and R B are independently hydrogen or (CrC 6 )alkyl, or R A and R B when attached to the same nitrogen form a cyclic amino group such as morpholinyl, piperidinyl or piperazinyl.
  • R 3 represents a trifluoromethyl substituent in the meta position of the phenyl ring relative to the point of attachment of that phenyl ring to the rest of the molecule.
  • R 6 may also be selected from, for example oxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, oxadiazolyl, furyl, and thienyl, any of which being optionally substituted, for example by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CN, fluoro, chloro, bromo, or trifluoromethyl.
  • R 4 may, for example, be benzyl, optionally substituted in the phenyl ring thereof.
  • R 4 is benzyl, optionally substituted in the 4-position of the phenyl ring thereof by a methylsulfonyl group.
  • L is a radical of formula (A), (B) or (C) as in claim 12.
  • the LINKER radical contains a quaternary nitrogen.
  • dimeric compounds of formula (IA) and (IB) include those of the Examples herein, and especially Examples 19, 33, 17, 21 , 28.
  • 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. 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.
  • 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) (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.
  • the 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. In therapeutic use, 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).
  • 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 ⁇ m.
  • composition In the case of an aerosol-based formulation, a preferred composition is: Compound of the invention 24 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.
  • 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 invention of the present invention can be prepared according to the procedures of the schemes and examples herein, using appropriate materials. 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.
  • G is a group which can be reacted with a bifunctional molecule to effect dimerisation, such as an amino, iodo or carboxylic acid group.
  • the bifunctional molecule bears two other reactive groups, for example amino and carboxylic acid, which react, under suitable conditions, with group G to form a dimer.
  • group A is an optional substituent which can be introduced before or after dimerisation, in one or more steps.
  • MS ionization method Electrospray (positive and negative ion)
  • Micromass Platform LCT with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 ⁇ m particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid.
  • AIBN 2,2'-azobis(2-methylpropionitrile)
  • DIPEA di-isopropylethylamine
  • RT room temperature
  • HATU O-(7-Azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ / ⁇ /'- tetramethyluroniumhexafluorophosphate
  • NBS ⁇ /-bromosuccinimide
  • NIS ⁇ /-iodosuccinimide
  • TFA trifluoroacetic acid
  • NIS 6-methyl-2-oxo- 1-(3-trifluoromethylphenyl)-1 ,2-dihydropyridine-3-carboxylic acid (WO04043924) (10.3 g, 0.035 mol) in a mixture of TFA (30 ml) and DCM (30 ml). Stirring was continued for 1.5 h the reaction mixture was partitioned between water (200 ml) and DCM (200 ml). The organic phase was separated and the aqueous was extracted further with DCM (2 x 100 ml). The organic extracts were combined, washed with sat. aqueous sodium thiosulphate (100 ml), dried (Na 2 SO 4 ) and concentrated to give a beige solid.
  • the organic layer was separated, washed with water (100 ml), dried (Na 2 SO 4 ) and evaporated to give pale yellow oil.
  • the oil was purified on an IsoluteTM Si Il cartridge (50 g) eluting with 40%, DCM in pentane, 70% DCM in pentane, 100% DCM and then 20% Et 2 O in DCM. The required product was isolated as colourless oil.
  • the crude product was purified on an IsoluteTM Si Il cartridge (50 g) eluting with DCM 1 5% EtOAc in DCM, 10% EtOAc in DCM, 15% EtOAc in DCM and then 20% EtOAc in DCM.
  • the desired product was isolated as a white solid.
  • Example 1 A solution of Example 1 (238 mg, 0.217 mmol) in DME (9 ml) was split into two batches and to each was added 3,5-dimethylisoxazole-4-boronic acid (306 mg, 2.17 mmol), caesium carbonate (2.12 g, 6.51 mmol), water (0.5 ml) and Pd(PPh 3 ) 4 (13 mg, 0.011 mmol).
  • the reaction vessels were de-gassed and then heated at 150 g C for 15 min in the microwave. Further amounts of boronic acid (150 mg, 1.064 mmol) and catalyst (8 mg, 0.007 mmol) were added and heating was continued for 10 min.
  • Example 3 was prepared from Intermediate 9 using a procedure similar to that used in the synthesis of Example 2.
  • Example 5 was prepared from 6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1 ,2- dihydropyridine-3-carboxylic acid (WO04043924) and 3,3'-diamino- ⁇ /-methyl- dipropylamine. Purification was achieved using HPLC system 1 giving the formate salt.
  • Example 6 was prepared from 6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1 ,2- dihydropyridine-3-carboxylic acid (WO04043924) and Intermediate 27.
  • the crude product was loaded onto an IsoluteTM SCX-2 cartridge (2 g) which was flushed with MeOH.
  • the product was then eluted with 2M NH 3 in MeOH to give a white solid.
  • Example 7 was prepared from Intermediate 14 and 2,2'-diamino- ⁇ /- methyldiethylamine. Purification was accomplished on a RediSepTM silica cartridge eluting with 0-10% MeOH in DCM.
  • Example 8 was prepared from Intermediate 14 and 3,3'-diamino-/V- methyldipropylamine. Purification on a RediSepTM silica cartridge eluting with 1-10% MeOH in DCM, gave a cream foam.
  • Example 9 was prepared from 5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-(3- trifluoromethylphenyl)-1 ,2-dihydropyridine-3-carboxylic acid (WO05026123) and 3,3'- diamino- ⁇ /-methyldipropylamine. Purification was achieved using HPLC system 1 to afford the free base.
  • Example 10 was prepared from 5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-(3- trifluoromethylphenyl)-1 ,2-dihydropyridine-3-carboxylic acid (WO05026123) and 2,2'- diamino- ⁇ /-methyldiethylamine. Purification was achieved using a RediSepTM silica cartridge eluting with DCM then DCM/EtOH/NH 4 OH (400:8:1), followed by (200:8:1) and (100:8:1). Further purification on a RediSepTM C-18 silica cartridge eluting with 0- 100% MeOH/H 2 O gave a white solid. Yield: (28%) LC-MS (Method 3): Rt 8.98 min, m/z 866.39 [MH + ]
  • Example 11 was prepared from 5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-(3- trifluoromethylphenyl)-1,2-dihydropyridine-3-carboxylic acid (WO05026123) and Intermediate 33. Purification was achieved using HPLC system 1 and ion exchange (IsoluteTM SCX-2) gave Example 11 as the free base. Yield: 34%
  • Example 12 was prepared from Intermediate 13 and 3,3'-diamino- ⁇ /- methyldipropylamine. Purification was achieved using HPLC system 1 giving the free base.
  • Example 13 was prepared from Intermediate 13 and Intermediate 27. Purification was achieved using HPLC system 1 giving the free base.
  • Example 14 was prepared from 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3- trifluoromethyl-phenyl)-1 ,2-dihydropyridine-3-carboxylic acid (WO05026123) and Intermediate 27. Purification was achieved using HPLC system 1 giving the free base after ion exchange (IsoluteTM SCX-2).
  • Example 15 was prepared from Intermediate 28 and 3,3'-diamino-/V- methyldipropylamine. Purification was achieved using HPLC system 1 giving the free base.
  • Example 16 was prepared from Intermediate 28 and 2,2'-diamino- ⁇ /- methyldiethylamine. Purification was achieved using HPLC system 1 giving the free base.
  • Example 17 was prepared from Intermediate 20 and 3,3'-diamino-N- methylpropylamine. Purification was achieved using HPLC system 1 giving the formate salt.
  • Example 18 was prepared from Intermediate 21 and 3,3'-diamino- ⁇ /- methylpropylamine. Purification was achieved using HPLC system 1 giving the formate salt.
  • Example 19 was prepared from Intermediate 24 and 3,3'-diamino- ⁇ /- methylpropylamine. Purification was achieved using HPLC system 1 giving the formate salt.
  • Example 20 was prepared from Intermediate 25 and 3,3'-diamino- ⁇ /- methylpropylamine. Purification was achieved using HPLC system 1 giving the formate salt.
  • Example 21 was prepared from 5-(4-methanesulfonylbenzylcarbamoyl)-2-methyl-6- oxo-1-(3-trifluoromethylphenyl)-1 ,6-dihydropyridine-3-carboxylic acid (WO05026123) and 3,3'-diamino- ⁇ /-methylpropylamine. Purification was achieved using HPLC system 1 and the free base was obtained by ion exchange (IsoluteTM SCX-2).
  • Example 22 was prepared from 5-(4-methanesulfonylbenzylcarbamoyl)-2-methyl-6- oxo-1 -(3-trifluoromethylphenyl)-1 ,6-dihydropyridine-3-carboxylic acid (WO05026123) and Intermediate 27. Purification was achieved using HPLC system 1 and the free base was obtained after ion exchange (IsoluteTM SCX-2). Yield: (41%) LC-MS (Method 4): Rt 8.61 min, m/z 1464.45 [MH + ]
  • Example 23 Example 23
  • Example 23 was prepared from 5-amino-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)- 1 ⁇ -dihydropyridine-S-carboxylic acid 4-methanesulfonylbenzylamide (WO 2005026124) and 3,6,9-trioxaundecanoic acid.
  • the crude product was purified using a RediSepTM silica cartridge, eluting with 0-10% MeOH in DCM, followed by trituration with Et 2 O.
  • Example 23 was obtained as a cream solid.
  • Example 25 was prepared from 5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-(3- trifluoromethylphenyl)-1 ,2-dihydropyridine-3-carboxylic acid (WO05026123) and ⁇ 3- [/V-(3-fe/t-butoxycarbonylaminopropyI)-/V l -(2,2,2-trifluoroacetyl)guanidino]propyl ⁇ - carbamic acid te/t-butyl ester (J. Org. Chem., 2003, 68, 9416) using a similar procedure to that used in the synthesis of Example 24. Purification was achieved using HPLC system 1 and the free base was obtained using an IsoluteTM SCX-2 cartridge.
  • Example 4 (929 mg, 1.38 mmol) was dissolved in acetic acid (25 ml) and a 1.08M solution of bromine in acetic acid (3.8 ml, 4.13 mmol) was added. After 17 h, a further portion of bromine solution (1 ml) was added and stirring was continued for 4 h. The volatiles were evaporated and the residue was purified on a RediSepTM silica cartridge eluting with 0-8% MeOH in DCM. Trituration with Et 2 O gave a white solid.
  • Example 12 (13 mg, 0.016 mmol) was dissolved in acetonitrile (2 ml) and iodomethane (1 ml) was added. The solution was heated at 100 Q C for 20 min in the microwave. The volatiles were evaporated and the product was purified on an IsoluteTM Al-N cartridge (2 g) eluting with DCM then 1% MeOH in DCM. After evaporation the pure product was dissolved in acetonitrile/water and freeze-dried to give a cream solid.
  • Example 28 was prepared from Example 22 Yield: (60%) LC-MS (Method 4): Rt 8.63 min, m/z 1477.85 [M + ]
  • Example 29 was prepared from Example 21. Yield: (76%) LC-MS (Method 4): Rt 7.94 min, m/z 1140.00 [M + ]
  • Example 30
  • Example 30 was prepared from Example 8. Yield: (23%) LC-MS (Method 3): Rt 9.30 min, m/z 970.14 [M + ]
  • Example 31 was prepared from Example 6. Yield: (63%)
  • Example 7 (200 mg, 0.215 mmol) was dissolved in acetonitrile (15 ml) and a 30% solution of bromomethane in acetonitrile (7 ml) was added. The solution was heated for 42 h at 80 9 C in a steal reaction vessel. A further portion of bromomethane solution (7 ml) was added and heating was continued for 18 h. The volatiles were evaporated and the product was purified on an IsoluteTM Al-N cartridge (10 g) eluting with 0-5% MeOH in DCM. Trituration with EtOAc gave a pale yellow solid. Yield: (55%) LC-MS (Method 3): Rt 9.36 min, m/z 942.02 [M + ] Example 33
  • Fluorescent peptide substrate Assays were performed in 96-well plates at a total assay volume of 100 ⁇ 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.
  • Assays were performed in 96-well plate at a total assay volume of 100 ⁇ 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 0.2 mM sodium azide).
  • the enzymatic reaction was started by adding the enzyme.
  • the enzymatic reaction was performed at RT and read after 120 minutes. Fluorescence was read on the FLEXstation (Molecular Devices) using 485 nm excitation and 530 nm emission filters.
  • the potency of the compounds was determined from a concentration series of 10 concentrations in range from 25000 nM to 1nM. The results are means of two independent experiments, each performed in duplicate.
  • the actual IC50 obtained for the compound of Example 3 was 49nM.
  • the activity of the parent monomer (structure X below - disclosed in WO 2005/026123 (Example 11)) was found to be 6 nM in the same assay.
  • the HNE inhibitory activity of the monomer is substantially retained in the dimer.
  • the somewhat reduced intrinsic inhibitory activity of the dimer is tolerable since the dimer is primarily designed for pulmonary administration, where prolongation of activity relative to, for example, oral or even pulmonary administration of the monomer, is expected.

Abstract

La présente invention concerne des conjugués covalents de deux composés ou plus, chacun doté d'une structure telle que définie dans l'un des documents WO2004/043924, WO2005/021509, WO2005/021512, WO2005/026123, WO2005/026124, WO2006/098683 et WO2006/098684. Lesdits conjugués sont des inhibiteurs de l'élastase neutrophile humaine et sont notamment utiles dans le traitement de la bronchopneumopathie chronique obstructive. L'invention concerne des dimères de formule (IA) ou (IB): dans lesquelles le LIEUR et les substituants variables sont des types particuliers desdits multimères.
PCT/GB2007/000919 2006-03-17 2007-03-16 Multimeres de composes heterocycliques et leur utilisation WO2007107706A2 (fr)

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CN106459054A (zh) * 2014-06-12 2017-02-22 奇斯药制品公司 新的化合物
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WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose

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US8501784B2 (en) 2003-09-18 2013-08-06 Astrazeneca Ab 2-pyridone derivatives as neutrophil elastase inhibitors and their use
US7998984B2 (en) 2006-05-08 2011-08-16 Astrazeneca Ab 2-pyridone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial
US8114881B2 (en) 2006-05-08 2012-02-14 Astrazeneca Ab 2-pyrazinone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial
WO2008030158A1 (fr) * 2006-09-04 2008-03-13 Astrazeneca Ab Composés hétérocycliques multimériques utilisés comme inhibiteurs de l'élastase neutrophile
WO2009037413A1 (fr) * 2007-09-19 2009-03-26 Argenta Discovery Limited Dimères de 5-[(4-cyanophényl)sulfinyl]-6-méthyl-2-oxo-1-[3-(trifluorométhyl)phényl]-1,2-dihydropyridine-3-carboxamide en tant qu'inhibiteurs de l'élastase des neutrophiles humains pour traiter des maladies respiratoires
US8466284B2 (en) 2007-11-06 2013-06-18 Astra Zeneca Ab Some 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase
US8232296B2 (en) 2009-02-20 2012-07-31 Astrazeneca Ab Salt 628
WO2011039528A1 (fr) 2009-10-02 2011-04-07 Astrazeneca Ab Composés 2-pyridones utilisés comme inhibiteurs d'élastase de neutrophile
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US9656972B2 (en) 2013-07-02 2017-05-23 The California Institute For Biomedical Research Compounds for treatment of cystic fibrosis
US9221807B2 (en) * 2014-02-21 2015-12-29 Boehringer Ingelheim International Gmbh Substituted pyridones and pyrazinones and their use as inhibitors of neutrophil elastase activity
US20150239875A1 (en) * 2014-02-21 2015-08-27 Boehringer Ingelheim International Gmbh Substituted pyridones and pyrazinones and their use as inhibitors of neutrophil elastase activity
WO2015179823A3 (fr) * 2014-05-23 2016-05-19 The California Institute For Biomedical Research Inhibiteurs d'alpha (v) bêta 6, localisés dans les poumons
CN106459054A (zh) * 2014-06-12 2017-02-22 奇斯药制品公司 新的化合物
CN106459065A (zh) * 2014-06-12 2017-02-22 奇斯药制品公司 四氢三唑并嘧啶衍生物、含有它的药物组合物及其用途
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WO2016112120A1 (fr) * 2015-01-07 2016-07-14 The California Institute For Biomedical Research Composés destinés au traitement de la mucosviscidose
CN109311850A (zh) * 2016-05-31 2019-02-05 奇斯药制品公司 作为人嗜中性粒细胞弹性蛋白酶抑制剂的咪唑酮化合物
CN109311850B (zh) * 2016-05-31 2021-11-19 奇斯药制品公司 作为人嗜中性粒细胞弹性蛋白酶抑制剂的咪唑酮化合物
WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose

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