WO2017175185A1 - Dérivés d'acide hétéroaryl butanoïque utilisés en tant qu'inhibiteurs de la lta4h - Google Patents

Dérivés d'acide hétéroaryl butanoïque utilisés en tant qu'inhibiteurs de la lta4h Download PDF

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Publication number
WO2017175185A1
WO2017175185A1 PCT/IB2017/052003 IB2017052003W WO2017175185A1 WO 2017175185 A1 WO2017175185 A1 WO 2017175185A1 IB 2017052003 W IB2017052003 W IB 2017052003W WO 2017175185 A1 WO2017175185 A1 WO 2017175185A1
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compound
pharmaceutically acceptable
acceptable salt
disease
syndrome
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PCT/IB2017/052003
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English (en)
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Gebhard Thoma
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Novartis Ag
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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
    • 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]

Definitions

  • the present invention describes novel heteroaryl butanoic acid derivatives which especially modulate leukotriene A4 hydrolase (LTA4H).
  • the present invention also relates to pharmaceutical compositions comprising said novel heteroaryl butanoic acid derivatives, methods of using said compounds in the treatment of various diseases and disorders, and processes for preparing the said novel compounds.
  • the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, and to their use in modulating LTA4H.
  • the compounds of the invention may be useful in the treatment of diseases and/or disorders related to LTA4H.
  • diseases and / or disorders typically include acute and chronic inflammation and autoinflammatory disorders such as inflammatory bowel disease, neutrophilic dermatoses, allergy, fibrotic diseases, vasculitides, arthritides,
  • the present invention further relates to pharmaceutical compositions comprising said novel heteroaryl butanoic acid derivatives of formula (I), methods of using said compounds in the treatment of various diseases and disorders, and processes for preparing the said novel compounds.
  • Leukotriene A4 hydrolase catalyzes the hydrolysis of LTA4 to produce LTB4.
  • LTB4 stimulates an array of pro-inflammatory responses for example where leukocyte chemotaxis or cytokine release may be implicated.
  • Inhibition of LTA4H furthermore elevates biosynthesis of anti-inflammatory, pro-resolving lipoxin A4 which can promote resolution of chronic inflammation.
  • LTA4H inhibition may therefore be of benefit in diseases where chronic, non-resolving inflammation might be a critical component of the pathology and appear to include a broad range of autoinflammatory and autoimmune diseases (see for example Anne M Fourie, Current Opinion in Invest. Drugs 2009, 10, 1 173 - 1 182).
  • WO2015/092740 describes LTA4H modulators exhibiting some structural similarity. Summary of the invention
  • the present invention relates to novel compounds of formula (I) and/or pharmaceutically acceptable salts thereof, and to their use in inhibiting LTA4H, and may further include the treatment of diseases and/or disorders such as allergy, pulmonary, fibrotic, inflammatory, cardiovascular diseases including atherosclerosis, myocardial infarction and stroke, and cancer.
  • diseases and/or disorders such as allergy, pulmonary, fibrotic, inflammatory, cardiovascular diseases including atherosclerosis, myocardial infarction and stroke, and cancer.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof;
  • pyridyl optionally substituted one or more times by halogen, hydroxyl, oxo, C- ⁇ alkyl optionally substituted by hydroxyl, or C C 6 alkoxy;
  • welded bond refers to the racemic and/or chiral (S)- or (R)- forms.
  • the present invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described above.
  • Embodiment 2 of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is 2-pyridyl optionally substituted one or more times by halogen, hydroxyl, oxo or C C 6 alkyl optionally substituted by hydroxyl.
  • Embodiment 3 of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is 2-pyridyl substituted one or more times by halogen, hydroxyl, or oxo.
  • Embodiment 4 of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R- ⁇ is 2-pyridyl substituted one or more times by halogen.
  • Embodiment 5 relates to a compound of formula (I) in accordance to the embodiments 1
  • Embodiment 6 relates to a compound of formula (I) in accordance to the embodiments 1
  • Embodiment 7 relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof in accordance to embodiment 1 , wherein the compound is selected from:
  • Embodiment 8 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 7 and one or more pharmaceutically acceptable carriers.
  • Embodiment 9 relates to a combination comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.
  • Embodiment 10 relates to a method of modulating LTA4H activity in a subject in need thereof, wherein the method comprises administering to said subject a therapeutically effective amount of the compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, or alternatively said method comprises administering a pharmaceutical composition of embodiment 8, or alternatively said method comprises administering a combination of embodiment 9.
  • Embodiment 1 1 relates to a compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for inhibiting LTA4H activity.
  • C C 6 alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 6 carbon atoms. Unless otherwise provided, it refers to hydrocarbon moieties having 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 to 2 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, / ' so-propyl, n-butyl, sec-butyl, / ' so-butyl, fe/f-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.
  • C C 6 alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, fe/f-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
  • alkoxy groups have about 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 to 2 carbon atoms.
  • halogen refers to fluoro, chloro, bromo, and iodo.
  • salt refers to an acid addition or base addition salt of a compound of the invention.
  • Salts include in particular “pharmaceutically acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids, e.g., acetate, chloride/hydrochloride, citrate, fumarate, tartrate, tosylate and trifluoroacetate salts.
  • inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts may be derived include, for example, acetic acid, fumaric acid, tartaric acid, citric acid, toluenesulfonic acid, and the like.
  • Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.
  • Inorganic bases from which salts may be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts may be derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, diethanolamine, diethylamine, lysine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention may be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 l respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labeled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, d 6 -DMSO.
  • Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term "a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by LTA4H, or (ii) associated with LTA4H activity, or (iii)
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of LTA4H; or reducing or inhibiting the expression of LTA4H partially or completely.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treatment refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • any asymmetric atom (e.g. , carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in c/ ' s- (Z)- or trans- (£)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (c/ ' s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • the term "possible isomers" shall not include positional isomers.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g. , by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g. , by fractional crystallization of a salt formed with an optically active acid, e.g. , tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g. , high pressure liquid chromatography (HPLC) using a
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present invention
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g. , lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g. , magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g. , starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g. , lactose, dex
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g. , for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g. , vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • Agents of the invention may be prepared by a reaction sequence of the reaction scheme (I).
  • a reducing agent e.g. NaBH 4 in a solvent such as DME at low temperature
  • Compound B may be transformed into a nitrile C, for example by reacting compound B with an appropriate sulfonic acid chloride (e.g. p-toluene sulfonylchloride) to convert the alcohol functionality of compound B into a suitable leaving group (e.g. tolylate), followed by reacting it with a nitrile reagent e.g. NaCN in a solvent, e.g. DMSO at elevated temperature.
  • a nitrile reagent e.g. NaCN in a solvent, e.g. DMSO at elevated temperature.
  • the nitrile C thus obtained may be reacted with an azide, e.g. NaN 3 in a solvent, such as DMF at elevated temperature, e.g. 1 10°C to yield the tetrazole compound D.
  • the tetrazole compound D may then be reacted via cross coupling reaction with an arylboronic acid E in a solvent, such as DCM in the presence of a Cu catalyst (e.g. [Cu(OH)(TMEDA)] 2 CI 2 ), a base (e.g. K 2 C0 3 ) and oxygen to furnish the protected target compound F.
  • a Cu catalyst e.g. [Cu(OH)(TMEDA)] 2 CI 2
  • a base e.g. K 2 C0 3
  • oxygen e.g.
  • Deprotection of a compound F may then yield a compound in accordance to formula (I) as defined in the main embodiment of the present invention.
  • An arylboronic acid derivative E may be prepared by a reaction sequence shown in scheme (II).
  • An iodophenol G may be reacted with an fluoropyridine H in a solvent, such as DMF in the presence of a base, e.g. K 2 C0 3 to give an ether J which may be transformed into a boronate ester K for example by the treatment with B 2 pin 2 in a solvent, such as DMSO in the presence of a catalyst, e.g. Pd(dppf)CI 2 and a base, e.g. KOAc at elevated temperatures, e.g. 80°C.
  • Ester cleavage of J typically in the presence of a solvent such as dioxane and typically in the presence of an acid, such as HCI, may furnish the arylboronic acid E as shown below in scheme (II).
  • NMM N-methyl morpholine
  • composition of mobile phase A: 0.1 % TFA in H20, B: 0.1 % TFA in ACN Flow: 1 ml/min
  • UV-PDA 210 - 450 nM
  • composition of mobile phase A: 0.018% HCI in H 2 0, B: ACN
  • reaction mixture was diluted with water (100 mL) and extracted with EtOAc 500mL (250 mL x 2), the combined organic layers were washed with brine (200 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to yield a residue comprising compound 2 (10.0 g, 70% yield) as a white oil.
  • Example 2 was prepared by a procedure analogous to the synthesis of Example 1 using (R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid instead of (S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid and the final product was isolated as free base.
  • LCMS (conditions B): RT 0.79 min
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof exhibit valuable pharmacological properties, e.g. properties susceptible to LTA4H, e.g. as indicated in tests as provided in the next sections and are therefore indicated for therapy related to LTA4H.
  • pharmacological properties e.g. properties susceptible to LTA4H, e.g. as indicated in tests as provided in the next sections and are therefore indicated for therapy related to LTA4H.
  • Leukotriene A4 hydrolase catalyzes the vinylogous hydrolysis of the epoxide, leukotriene A4 (LTA4) into the pro-inflammatory mediator LTB4.
  • LTA4H is also able to catalyze the hydrolysis of di- and tripeptide substrates, as well as the chromogenic 7- amino-4-methylcoumarin (AMC) derivatives of amino acids.
  • the AMC derivative of Arginine (Arg-AMC) can be used as a surrogate substrate for LTA4H and enables the measurement of enzyme activity and compound IC 50 values by monitoring the fluorescence intensity upon AMC release.
  • compounds are delivered as 10 mM stock solutions in 90% DMSO (10% water) in matrix tubes. From this, a 1 :5 dilution series is prepared with a starting concentration of 10 mM going down to 0.64 ⁇ .
  • 0.5 ⁇ _ of compound solution is transferred to each well and 24.5 ⁇ _ of assay buffer (50 mM Tris buffer, pH 7.5, 150 mM NaCI, 10 mM CaCI 2 ) is added to the well followed by 25 ⁇ _ of enzyme solution (36 nM human LTA4H in assay buffer). The enzyme compound mixture is incubated at room temperature for 15 min prior to the addition of 50 ⁇ _ substrate solution.
  • a final substrate concentration of 600 ⁇ , which is around the K M value of Arg-AMC, at a final enzyme concentration of 9 nM is chosen.
  • AMC at varying concentrations (0.00128 - 100 ⁇ ) in assay buffer is used as a standard curve.
  • Raw data is converted to rate (moles per minute) using the AMC calibration curve calculated from the AMC standards.
  • the data is analyzed in GraphPad Prism (GraphPad software Inc.) using non-linear regression to determine IC 50 values of LTA4H inhibitors.
  • hWB human whole blood assay
  • LTA4H inhibitor compounds or vehicle control 0.5 % Tween 80, 0.5% Methylcellulose
  • vehicle control 0.5 % Tween 80, 0.5% Methylcellulose
  • mice are terminally bled and blood is collected in heparinized tubes. Collected blood is diluted 1 :3 in RPMI medium, added in 96-well round bottom cell culture plates and incubated with 10 ⁇ g ml calcium ionophore A23187 (Sigma) or equal volume DMSO (control) for 15 min at 37°C in a humidified incubator. Incubation is terminated by centrifugation at 300 g for 10 min at 22°C.
  • Plasma supernatant is taken, diluted 1 : 10 in assay buffer and transferred to a 96 well plate for eicosanoid determination by ELISA (Assay designs) according to the manufacturer ' s protocol. Percent inhibition of LTB4 release in comparison to vehicle control was calculated and is shown for the tested compounds in table 2. (For the sake of clarity: The bigger the numeric value in table 2, the stronger is the inhibition)
  • the compounds of the invention are especially inhibitors of LTA4H-activity and are therefore useful in treating diseases and disorders which are typically ameliorated by the inhibition of LTA4H.
  • diseases and conditions may include inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation.
  • the compounds may be useful in the treatment of the following diseases or disorders: acute or chronic inflammation, anaphylactic reactions, allergic reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex- mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases (including ulcerative colitis, Crohn's disease and post-surgical trauma), gastrointestinal ulcers, neutrophilic dermatoses (including but not limited to Pyoderma gangrenosum, Sweefs syndrome, severe acne and neutrophilic urticaria), immune- complex-mediated glomerulonephritis, autoimmune diseases (including insulin- dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus), vasculitides (including but not limited to cutaneous vasculitis, Behcets disease and Henoch Schonlein Purpura), cardiovascular disorders (including, but not limited to hypertension, atherosclerosis, aneury
  • Compounds of the invention are especially useful in the treatment of acute or chronic inflammation especially autoinflammatory disorders such as sterile neutrophilic inflammatory disorders, inflammatory bowel disease (including ulcerative colitis and Crohn ' s disease), neutrophilic dermatoses (including Pyoderma gangrenosum and severe acne), vasculitides, rheumatoid arthritis, gout and cardiovascular diseases .
  • autoinflammatory disorders such as sterile neutrophilic inflammatory disorders, inflammatory bowel disease (including ulcerative colitis and Crohn ' s disease), neutrophilic dermatoses (including Pyoderma gangrenosum and severe acne), vasculitides, rheumatoid arthritis, gout and cardiovascular diseases .
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or different route of
  • the compounds of the invention may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of alio- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent.
  • the compounds of the invention may be used in combination with a COX inhibitor; a Cysteinyl-Leukotriene Receptor antagonist e.g.
  • Montelukast a leukotriene C4 synthase (LTC4S) inhibitor; a statin; a calcineurin inhibitor, e.g. cyclosporin A; a rmTOR inhibitor, e.g. rapamycin; an ascomycin having immunosuppressive properties, e.g.ASM981 ; or an IL-1 beta inhibitor.
  • LTC4S leukotriene C4 synthase
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of formula (I) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by LTA4H.
  • Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I).
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for

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Abstract

La présente invention concerne de nouveaux dérivés d'acide hétéroaryl-butanoïque qui s'avèrent être de bons inhibiteurs de la leucotriène A4 hydrolase (LTA4H). La présente invention concerne également des compositions pharmaceutiques comprenant ces nouveaux dérivés d'acide hétéroaryl-butanoïque, des procédés d'utilisation de ces composés dans le traitement de diverses maladies et de divers troubles, et des procédés de préparation de ces nouveaux composés.
PCT/IB2017/052003 2016-04-08 2017-04-07 Dérivés d'acide hétéroaryl butanoïque utilisés en tant qu'inhibiteurs de la lta4h WO2017175185A1 (fr)

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CN113395996A (zh) * 2019-02-08 2021-09-14 阿斯利康(瑞典)有限公司 精氨酸酶抑制剂及其使用方法
WO2022219546A1 (fr) * 2021-04-16 2022-10-20 Novartis Ag Dérivés d'hétéroaryl-aminopropanol en tant qu'inhibiteurs de lta4h
CN115785014A (zh) * 2022-12-27 2023-03-14 瑞石生物医药有限公司 四唑衍生物及其用途

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113395996A (zh) * 2019-02-08 2021-09-14 阿斯利康(瑞典)有限公司 精氨酸酶抑制剂及其使用方法
CN113395996B (zh) * 2019-02-08 2024-05-28 阿斯利康(瑞典)有限公司 精氨酸酶抑制剂及其使用方法
WO2022219546A1 (fr) * 2021-04-16 2022-10-20 Novartis Ag Dérivés d'hétéroaryl-aminopropanol en tant qu'inhibiteurs de lta4h
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CN115785014A (zh) * 2022-12-27 2023-03-14 瑞石生物医药有限公司 四唑衍生物及其用途

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