WO2022234287A1 - Imidazopyridazine derivatives useful as trk inhibitors - Google Patents

Imidazopyridazine derivatives useful as trk inhibitors Download PDF

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WO2022234287A1
WO2022234287A1 PCT/GB2022/051151 GB2022051151W WO2022234287A1 WO 2022234287 A1 WO2022234287 A1 WO 2022234287A1 GB 2022051151 W GB2022051151 W GB 2022051151W WO 2022234287 A1 WO2022234287 A1 WO 2022234287A1
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compound
compounds
formula
halo
trk
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PCT/GB2022/051151
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French (fr)
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Jane MCGUFFOG
Edward BALMOND
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Benevolentai Bio Limited
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to certain imidazo[1,2-b]pyridazine compounds and pharmaceutically acceptable salts of such compounds.
  • the invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk) activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk.
  • Tropomyosin-related kinases are a family of receptor tyrosine kinases activated by neurotrophins, a group of soluble growth factors including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin- 3 (NT-3) and Neurotrophin-4/5 (NT-4/5).
  • the Trk receptors include three family members TrkA, TrkB and TrkC that bind to and mediate the signal transduction derived from the Neurotrophins.
  • NGF activates TrkA, BDNF and NT-4/5 activate TrkB and NT3 activates TrkC.
  • Tropomyosin-related kinases have been implicated in the following diseases: atopic dermatitis, psoriasis, eczema and prurigo nodularis, acute and chronic itch, pruritus, inflammation, cancer, restenosis, atherosclerosis, thrombosis, pruritus, lower urinary tract disorder, inflammatory lung diseases such as asthma, allergic rhinitis, lung cancer, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, fibrosis, neurodegenerative disease, diseases disorders and conditions related to dysmyelination or demyelination, certain infectious diseases such as Trypanosoma cruzi infection, (Chagas disease), cancer related pain, chronic pain, neuroblastoma, ovarian cancer, colorectal cancer, melanoma, head and neck cancer, gastric carcimoma, lung carcinoma, breast cancer, glioblastoma,
  • X is a direct bond or -(CR 6 R 7 )-;
  • Y is a direct bond or selected from wherein * denotes the point of attachment to X and ** denotes the point of attachment to Z;
  • Z is a direct bond or selected from -CH 2 -, -C(O)-, and -S(C> 2 )-;
  • R 1 is -OR, wherein R is an optionally substituted oxane or oxolane;
  • R 2 is selected from H and -SMe
  • R 3 is selected from H and halo
  • R 4 is selected from H and (Ci-C3)alkyl
  • R 5 is selected from H, -OH and halo;
  • R 6 and R 7 are each independently selected from H and (Ci-C3)alkyl;
  • each R 8 is independently selected from halo and (Ci-C3)alkoxy;
  • each R 9 is independently selected from halo;
  • m is 1 or 2;
  • n is 1 or 2;
  • p is 1 or 2; provided that the sum of m, n, and p is from 2 to 4; q is 0, 1, 2, 3 or 4; and r is 0, 1, 2, or 3.
  • Such compounds are the compounds of the invention, or “the compounds”.
  • a feature of the first aspect of the invention is that the compound of Formula (I) is a compound is of Formula (IA).
  • the groups X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, m, n, p, q, and r, are as defined for the compound of Formula (I).
  • the compound of Formula (I) is preferably a compound of Formula (IB).
  • Y is a direct bond
  • X is a direct bond
  • both are a direct bond.
  • the term “direct bond” means that the two adjacent groups are connected directly to each other via a bond. In effect, the particular group is absent from the molecule.
  • Z is a direct bond or selected from -CH2-, -C(O)-, and -S(C>2)-, however, it is preferable that Z is -CH2-.
  • the compound of Formula (I) is a compound is of Formula (IC).
  • the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R, and q are as defined for the compound of Formula (I).
  • R 3 is selected from H and halo. It is preferable that R 3 is selected from H and F.
  • R 2 is -SMe and R 3 is F.
  • R 4 is selected from H and (Ci-C3)alkyl. It is preferable that R 4 in Formulae (I), (IA), (IB), and (IC) is H.
  • the compound of Formula (I) is a compound is of Formula (ID).
  • the groups R 1 , R 9 , R, and q are as defined for the compound of Formula (I).
  • the compound of Formula (I) may be of Formula (ID’).
  • the groups R 1 , R 9 , R, and q are as defined for the compound of Formula (I).
  • An important feature of the compounds of the invention is the presence of an optionally substituted oxane or oxolane group at position R. This group is linked to the remainder of the compounds through an “-0-” group. This is in line with the definition of group R 1 which is “-OR”.
  • the oxane or oxolane of group R may be substituted by one or more suitable groups.
  • Particular groups that may be substituted on the oxane or oxolane is one or more of halo, (CrC3)alkyl, -NR 10 R 11 , -OR 12 , -COOH, -CHO, and -CH2OR 12 , wherein the (Ci-C3)alkyl is optionally substituted with one or more halo (preferably one or more F).
  • R 10 and R 11 are independently selected from H and (Ci-C3)alkyl optionally substituted with one or more halo.
  • R 10 and R 11 can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle, wherein the 5- or 6-membered heterocycle is optionally substituted with one or more groups selected from C1-C6 alkyl, halo, -OH, and -NH2, wherein the Ci- O d alkyl optionally substituted with one or more halo (preferably one or more F).
  • R 12 is independently selected from H and (CrC3)alkyl optionally substituted with one or more halo.
  • R 1 is a sugar, such as a monosaccharide (i.e. a carbohydrate consisting of one sugar unit) or a derivative thereof. They may be linear or cyclic compounds. It may be a pentose or hexose or a derivative thereof. Particularly, R 1 may be selected from the list consisting of allose, aldose, glucose, mannose, idose, galactose, talose, fructose, ribose, deoxyribose, or a derivative thereof. These groups may be joined to the reminder of the compound through an “-0-” group attached to a ring carbon adjacent to the oxygen atom in the oxane or oxolane ring. Any suitable derivative may be used, but it is preferred that the derivative is a uronic acid derivative. Uronic acids are a class of sugar acids in which the terminal carbon's hydroxyl group has been oxidized to a carboxylic acid.
  • R 1 is and most preferable that R 1 is
  • a compound of the invention has one of the following structures.
  • the most preferred compound has the following structure.
  • oxane is synonymous with tetrahydropyran and is represented by the following formula.
  • oxolane is synonymous with tetrahydrofuran and is represented by the following formula.
  • halo refers to fluoro, chloro, bromo, and iodo. It is preferable that halo is fluoro, which may be denoted as F.
  • (Ci-C3)alkyl refers to a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2 or 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, and cyclopropyl.
  • (Ci-C4)alkyl refers to a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, and include, in addition to the aforementioned, n-butyl, t butyl, iso butyl, cyclobutyl, methyl-cyclopropyl, amongst others.
  • (Ci-C3)alkoxy refers to (Ci-C 3 )alkyl-0-, wherein
  • (CrC3)alkyl is defined herein above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, and propoxy.
  • the groups -C(O)- and -S(C> 2 )- respectfully represent the two groups
  • the compounds of the invention may be present as their pharmaceutically acceptable salts.
  • a "pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by one of the aforementioned Formulae, that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, generally, G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S.M.
  • compositions of the invention are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoromethylsulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are 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 can 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, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • Examples of pharmaceutically acceptable salts particularly include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates,
  • any formula given herein is intended to refer also to hydrates and solvates of compounds of the invention, and mixtures thereof, even if such forms are not listed explicitly.
  • a compound of the invention, or pharmaceutically acceptable salt of a compound of the invention may be obtained as a solvate.
  • Solvates include those formed from the interaction or complexation of compounds of the invention with one or more solvents, either in solution or as a solid or crystalline form.
  • the solvent may be water, which case the solvates are hydrates.
  • certain crystalline forms of a compound of the invention, or a pharmaceutically acceptable salt of a compound of the invention may be obtained as co-crystals.
  • a compound of the invention, or a pharmaceutically acceptable salt of a compound of the invention may be obtained in a crystalline form.
  • a compound of the invention may be obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form.
  • a compound of the invention may convert in solution between one or more crystalline forms and/or polymorphic forms.
  • Compounds of the invention 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 the invention by known co-crystal forming procedures.
  • Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the invention 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 the invention.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centres and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • tautomeric isomerism (‘tautomerism’) can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, by chromatography and fractional crystallisation.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% ethanol, typically from 2 to 20%. Concentration of the eluate affords the enriched mixture.
  • Stereoisomers may be separated by conventional techniques known to those skilled in the art (see, for example, “Stereochemistry of Organic Compounds ” by E L Eliel (Wiley, New York, 1994)).
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral centre of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic” mixture.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration.
  • Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples of tautomers include but are not limited to those compounds defined in the claims. 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 bonds may, if possible, be present in cis- (Z)- or trans- (E)- 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 ( cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. 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 chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • the invention also relates to pharmaceutically acceptable prodrugs of a compound of the invention and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prod rugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the invention following administration of the prodrug to a subject.
  • the compounds of the present invention may themselves be active and/or act as prodrugs which convert in vivo to active compounds.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action.
  • the linkage between the drug moiety and the transport moiety is a covalent bond
  • the prodrug is inactive or less active than the drug compound
  • any released transport moiety is acceptably non-toxic.
  • the release of the transport moiety should be rapid.
  • it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
  • prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
  • Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the oo-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally
  • amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the invention may also be N-oxides. It will be understood that an N-oxide, or “amine oxide”, is a compound that contains an N-0 coordinate covalent bond. Examples of an N-oxide group include functional groups is:
  • the present invention also relates to pharmaceutically active metabolites of a compound of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of the invention, or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g. Bertolini, et al., J Med Chem. 1997, 40, 201 1 -2016; Shan, et al., J Pharm Sci.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, respectively.
  • isotopically labelled compounds are useful in metabolic studies (preferably 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 subjects.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • Substitution with positron emitting isotopes can be useful in PET studies for examining substrate receptor occupancy.
  • an 18 F or 11 C labelled compound may be particularly preferred for PET studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Certain isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopically labelled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • 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).
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de acetone, d 6 -DMSO.
  • ratios of solvents are given, the ratios are by volume.
  • Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution.
  • Compounds prepared according to the schemes above may alternately be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures or as mixtures of diastereomers or regioisomers.
  • single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation.
  • separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation.
  • regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compound of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
  • Compounds of the invention may be prepared from the compounds of Formulae (II), (III), (IV), (V), (VI), and (VII) as illustrated by Scheme 1.
  • PG 1 is (CrC4)alkyl, preferably Me or Et.
  • R 1A is OH.
  • the amine of Formula (III) is commercially available or may be prepared by analogy to methods known in the literature or as illustrated in Scheme 6 of WO 2020/039209 (which is incorporated herein in its entirety by reference).
  • the chloride of Formula (IV) is commercially available or may be prepared by analogy to methods known in the literature.
  • Compounds of Formula (VI) are commercially available or may be prepared in chiral form by analogy with the methods described by Brinner et. al. ( Org . Biomol. Chem., 2005,3, 2109-2113) or Fan et.al. (WO 2012/034091).
  • compounds of Formula (VI) may be prepared by analogy with the methods described by Huihui et. al. (J.A.C.S., 2016, 138, 5016-5019).
  • the compound of Formula (V) may be prepared by treatment of the amine of Formula (VI) with the chloride of Formula (IV), in the presence of an inorganic base in a polar aprotic solvent at elevated temperature.
  • Preferred conditions comprise treatment of the compound of Formula (IV) with the amine of Formula (VI) in the presence of KF in a solvent such as DMSO at elevated temperature, typically 130°C.
  • the compound of Formula (II) may be prepared by the hydrolysis of the compound of Formula (V) under suitable acidic or basic conditions in a suitable aqueous solvent. Preferred conditions comprise the treatment of the ester of Formula (V) with KOH in aqueous EtOH at room temperature.
  • the compound of Formula (VII) may be prepared by an amide bond formation of the acid of Formula (II) and the amine of Formula (III) in the presence of a suitable coupling agent and organic base in a suitable polar aprotic solvent.
  • Preferred conditions comprise the reaction of the acid of Formula (II) with the amine of Formula (III) in the presence of HATU or TPTU, in the presence of a suitable organic base, typically DIPEA in a suitable solvent, such as DMF at room temperature.
  • a suitable solvent such as DMF at room temperature.
  • an appropriate phenol protecting group strategy as selected by a person skilled in the art, may be employed, such as for example a silyl protecting group, if required.
  • the compounds of the invention may be formed by coupling Formula (VII) with an appropriate optionally substituted hydroxyl-oxane or hydroxyl-oxolane. This coupling may be achieved using BF 3 .0Et 2 . If R 1 is a monosaccharide, then a suitable protecting group methodology may be used, such as acetylation of hydroxyl groups. If the monosaccharide is a uronic acid derivative, then the carboxylic acid may be protected with PG 1 . The monosaccharide may be deprotected using known methodologies, such as stirring the compound in the presence of lithium hydroxide monohydrate in a THF/water mixture.
  • a compound of Formula (I) may be prepared from the compounds of Formulae (II), (III), (VII) and (VIII) as illustrated by Scheme 2.
  • Scheme 2 The compound of Formula (VII) may be prepared by formation of the acid chloride of Formula (VIII) from the acid of Formula (II), typically using oxalyl chloride and DMF in DCM at room temperature and the subsequent amide bond formation of the acid chloride of Formula (VIII) and the amine of Formula (III) in the presence of a suitable organic base, typically triethylamine at 0°C.
  • the compound of Formula (I) may be obtained from Formula (VII) as set out in Scheme 1.
  • the compound of Formula (VII) may be prepared as set out in WO 2020/039209 (the content of which is incorporated herein in its entirety by reference).
  • Schemes 1 to 6 and the intermediates and examples therein may be used to prepare the compounds of the present invention.
  • the above general schemes may be used to prepare compounds of the present invention.
  • the desired specific compounds can be prepared by selecting the appropriate starting materials, reactants and reaction conditions.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as 'Greene’s Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fifth edition, (John Wiley and Sons, 2014), in particular Chapter 3 (“ Protection for Phenols”) and Chapter 5 (“ Protection for the Carboxyl group”), incorporated herein by reference, which also describes methods for the removal of such groups , in J. F. W.
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted into the free compounds in accordance with methods known to those skilled in the art.
  • Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or A/-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride,
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • the compounds of the invention exhibit valuable pharmacological properties, e.g. Trk modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • Trk modulating properties e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • the compounds of the invention hereinafter alternately referred to as "agents of the invention", are useful in the treatment or prevention of a condition or disorder which is mediated by Trk.
  • the compounds of the present invention are useful for the treatment of disorders or conditions mediated by the high affinity neurotrophin receptors TrkA, TrkB and TrkC, and the actions of their cognate neurotrophin ligands - NGF, BDNF/NT-4/5, NT-3 - on these receptor tyrosine kinases.
  • the compounds are useful for treating or preventing conditions of skin (dermal) inflammation and itch (pruritus) that are mediated by the high affinity neurotrophin receptors TrkA, TrkB and TrkC, and associated with inflammation and nerve hypersensitivity, in particular atopic dermatitis.
  • NGF, BDNF, NT-3 and NT-4/5 levels are higher in the lesional skin cells and plasma of atopic dermatitis patients compared to normal subjects and levels correlate with disease severity (Yamaguchi et al, J Dermatol Sci. 2009, 53(1):48-54; Toyoda et al, Br J Dermatol 2002, 147:71-79; Raap et al, J Allergy Clin Immunol. 2005, 115:1268- 75; Raap et al, Allergy. 2006, 61(12):1416-8). Trk levels are also upregulated in atopic dermatitis lesional skin cells (Dou et al, Arch Dermatol Res.
  • Trk A/NGF neurotrophin receptors and their endogenous ligands, in particular Trk A/NGF have been shown to sensitize primary afferent nerves and mediate dermal hyperinnervation, thereby contributing to peripheral itch sensitization and pruritus in particular in atopic dermatitis (Tominaga et al, J Dermatol. 2014, 41(3):205-12; Roggenkamp D et al, J Invest Dermatol 2012, 132: 1892-1900; Grewe et al, J Invest Dermatol 2000, 114:1108-1112).
  • the compounds of the present invention may be used for the treatment or prevention of skin pathologies or conditions including diseases of dermatitis such as atopic dermatitis (eczema), contact dermatitis, allergic dermatitis; diseases of pruritus such as urticaria (Rossing et al, Clin Exp Allergy. 2011, 41 (10): 1392-9), Cutaneous T-cell lymphoma (CTCL) -associated pruritus including Sezary syndrome (Suga et al, Acta Derm Venereol. 2013, 93(2):144-9; Saulite et al, Biomed Res Int.
  • diseases of dermatitis such as atopic dermatitis (eczema), contact dermatitis, allergic dermatitis; diseases of pruritus such as urticaria (Rossing et al, Clin Exp Allergy. 2011, 41 (10): 1392-9), Cutaneous T-cell lymphoma (CTCL)
  • Trk diseases or disorders which are mediated by Trk, in particular Trk A, B, and C, include, but are not limited to: diseases of pruritus and itch; autoimmune diseases of the skin; diseases of skin pain and neuropathy; and diseases of dermatitis.
  • Diseases of pruritus and itch include, but are not limited to: skin diseases, eczematous; dermatitis, atopic; eczema; dermatitis, contact; dermatitis, allergic contact; dermatitis, irritant; dermatitis, photoallergic; dermatitis, phototoxic; psoriasis; pruritus; pruritus ani; pruritus, hereditary localized; Sjogrens syndrome associated pruritis; idiopathic pruritus; sclerosis multiplex pruritus; prurigo nodularis; brachioradial pruritus; acute itch; chronic itch; diabetes pruritus; iron deficiency anaemia pruritus; polycythemia vera pruritus; graft-versus-host-disease; uraemic pruritus; cholestatic pruritus; pruritic urticarial papules and plaques of pregnancy; pemphigo
  • Autoimmune diseases of the skin include, but are not limited to: autoimmune disease of skin and connective tissue; autoimmune disease with skin involvement; autoimmune bullous skin disease; pemphigoid, bullous.
  • Diseases of skin pain and neuropathy include but are not limited to: diabetic neuropathies; neuralgia; painful neuropathy; nerve compression syndromes; neuritis; sensory peripheral neuropathy; alcoholic neuropathy; radiculopathy; complex regional pain syndromes; polyneuropathy due to drug; plantar nerve lesion; polyradiculopathy; sciatic neuropathy;trigeminal neuralgia.
  • Diseases of dermatitis include, but are not limited to: skin diseases, eczematous; dermatitis, atopic; eczema; dermatitis, contact; dermatitis, allergic contact; dermatitis, irritant; dermatitis, photoallergic; dermatitis, phototoxic; chronic irritative hand dermatitis; dermatitis, occupational; fiberglass dermatitis; dermatitis, toxicodendron; eczema, dyshidrotic; eczematous dermatitis of eyelid; allergic contact dermatitis of eyelid; hand and foot dermatitis; digital dermatitis; dermatitis, exfoliative; radiodermatitis; dermatitis herpetiformis; juvenile dermatitis herpetiformis; autoimmune progesterone dermatitis; dermatitis, seborrheic; pityriasis lichenoides; blepharitis; nummular dermatitis; Seborrhea
  • condition or disorder which is mediated by Trk in particular Trk A, B, and C, may be atopic dermatitis.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • the invention includes an agent of the invention for use as a pharmaceutical.
  • the invention provides an agent of the invention for treating or preventing a condition or disorder which is mediated by Trk, in particular Trk A, B, and C.
  • the invention provides the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition or disorder which is mediated by Trk, in particular Trk A, B, and C.
  • the invention provides a method for preventing or treating a condition which is mediated by Trk, in particular Trk A, B, and C, which comprises administering to a subject in need thereof a therapeutically effective amount of an agent of the invention.
  • the invention also provides as a further aspect a method for preventing or treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, more particularly atopic dermatitis, which comprises administering to a subject, particularly a human subject, in need thereof a therapeutically effective amount of an agent of the invention.
  • the invention provides an agent of the invention for preventing or treating a condition or disorder which is mediated by Trk, in particular T rk A, B, and C, more particularly atopic dermatitis.
  • the invention provides the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, more particularly atopic dermatitis.
  • a “disorder” or a “disease” refers to an underlying pathological disturbance in a symptomatic or asymptomatic organism relative to a normal organism, which may result, for example, from infection or an acquired or congenital genetic imperfection.
  • a “condition” refers to a state of the mind or body of an organism which has not occurred through disease, e.g. the presence of a moiety in the body such as a toxin, drug or pollutant.
  • 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 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.
  • Prevention of a condition or disorder refers to delaying or preventing the onset of a condition or disorder or reducing its severity, as assessed by the appearance or extent of one or more symptoms of said condition or disorder.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ( e.g ., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. It is preferable that the subject is a primate, and most preferable that the subject is a human.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • a therapeutically effective amount of an agent of the invention refers to an amount of the agent of the 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 agent of the invention that, when administered to a subject, is effective to at least partially alleviating, inhibiting, preventing and/or ameliorating a condition or disorder which is mediated by TrK, in particular Trk A, B, and C.
  • a therapeutically effective amount refers to the amount of the agent of the 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 inhibiting Trk activity, in particular Trk A, B, and C.
  • the condition or disorder which is mediated by Trk is selected from diseases of pruritus and itch; autoimmune diseases of the skin; diseases of skin pain and neuropathy; and diseases of dermatitis.
  • condition or disorder which is mediated by Trk is atopic dermatitis.
  • the agents of the invention which inhibit Trk, in particular Trk A, B, and C, have various clinical applications and thus a further aspect of the invention provides pharmaceutical compositions containing agents of the invention.
  • the use of these agents as a medicament forms a further aspect of the invention.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention and a pharmaceutically acceptable excipient.
  • compositions as described herein for use as a medicament in particular for use in treating or preventing disorders or conditions mediated by Trk, in particular Trk A, B, and C, such as the conditions described herein, and methods of treatment or prophylaxis using such compositions and use of said agents for the preparation of a medicament for treating or preventing such disorders or conditions, form further aspects of the invention.
  • “Pharmaceutically acceptable” refers to ingredients that are compatible with other ingredients of the compositions as well as physiologically acceptable to the recipient.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • 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, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavouring 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.
  • compositions according to the invention may be formulated in conventional manner using readily available ingredients.
  • the active ingredient may be incorporated, optionally together with other active substances, with one or more conventional carriers, diluents and/or excipients, to produce conventional galenic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
  • 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).
  • the pharmaceutical 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.
  • compositions When pharmaceutical compositions are tablets or gelatin capsules, they may comprise the active ingredient together (compound of the invention) with a) diluents, e.g., lactose, polylactone, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; 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
  • 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 an agent 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.
  • Certain injectable 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.
  • the pharmaceutical composition may be a topical composition.
  • compositions for topical application to the skin or mucosa include aqueous solutions, suspensions, ointments, creams, gels, hydrogels, microemulsions, dusting powders, dressings, foams, films, skin patches, wafers, implants, fibres, bandages 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 atopic dermatitis. 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 preservatives.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).]
  • compositions for transdermal application include an effective amount of an agent 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.
  • the topical pharmaceutical compositions may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the topical pharmaceutical compositions of the invention may be administered separately, by the same or different route of administration, or together in the same topical pharmaceutical composition as the other agents.
  • the compound of Formula (I) may be present in the topical composition in an amount of from about 0.008% to about 30% by weight of the composition, in combination with an excipient system.
  • the excipient system may be present in the topical composition in an amount of less than about 99.99 % by weight of the composition.
  • the amount of the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the topical composition may depend on the amount required to be delivered to a subject to effectively treat or prevent a specific disease or condition.
  • the amount of the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the topical composition is preferably from about 0.01% to about 20%, more preferably from about 0.05% to about 5%, by weight of the composition.
  • the topical pharmaceutical composition may take any suitable form, such as an ointment, aqueous gel, non-aqueous gel, cream, solution (such as aqueous solution), suspension, emulsion (such as microemulsion), dusting powder, dressing, foam, film, skin patch, wafer, implant, fibre, bandage, sprayable formulation e.g. for delivery by aerosol or the like.
  • the exact form may be dependent upon the intended use.
  • the components that make up the excipient system will dictate the form of the topical composition.
  • the excipient system comprises one or more pharmaceutically acceptable excipients.
  • the topical pharmaceutical composition is an ointment, aqueous gel, non-aqueous gel, or cream.
  • the excipient system may comprise one or more carriers suitable for transdermal delivery of the compound of Formula (I) including absorbable pharmacologically acceptable solvents (such as those defined below) to assist delivery to therapeutically relevant compartments of the skin, such as the epidermis and dermis.
  • the topical pharmaceutical composition may be part of a transdermal devices in the form of a bandage comprising a backing member, a reservoir containing the topical pharmaceutical composition, 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.
  • the excipient system may comprise polyethylene glycol (PEG). It is preferable that the PEG selected from PEG 100 to PEG 900, and more preferably PEG 400. The inclusion of PEG as part of the excipient system may help to increase active pharmaceutical ingredient (API) loading in the composition.
  • API active pharmaceutical ingredient
  • PEG may also increase chemical stability of the API in the composition, and physical stability of the composition, compared to other composition bases, particularly when a high purity grade of PEG 400 is used, such as super-refined PEG 400, such as that supplied by Croda.
  • BHT or ascorbic acid, (preferably BHT) may also be included in the topical composition to further increase stability of the composition, particularly the stability of the API.
  • the PEG may be present in any suitable amount, such as from about 1% to about 60%, more preferably from about 5% to about 50%, by weight of the composition.
  • the excipient system may comprise glycol, polyol, dialkyl glycol monoalkyl ether or a combination thereof. It is preferably that the glycol, polyol, dialkyl glycol monoalkyl ether or a combination thereof is present in an amount of from about 10% to about 70%, more preferably about 20% to about 60%, by weight of the composition.
  • glycol means a chemical compound that comprise two hydroxyl groups. Such compounds include, but are not limited to, ethylene glycol, propylene glycol (propane-1, 2-diol), and propane-1, 3-diol, butylene glycol (such as 1,2- butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 2-methyl-1, 2-propanediol and 2-methyl-1, 3-propanediol). It is preferred that the glycol is propylene glycol, i.e. propane-1, 2-diol.
  • polyol means a chemical compound that contains three or more hydroxyl groups. Such compounds include, but are not limited to, glycerol, butanetriol, pentanetirol, and polyethylene triols, in particular containing from 4 to 8 ethylene oxide units, and their mixtures.
  • dialkyl glycol monoalkyl ether includes, but is not limited to, diethylene glycol monoethyl ether (Transcutol P).
  • compositions that may benefit from a higher loading of API before they become saturated.
  • such compositions may comprise the compound of Formula (I) in amounts in excess of 5% by weight of the composition without crystallisation of API. This has the advantage of providing topical compositions that are able to deliver higher dosages of API to a subject in need thereof.
  • the excipient system may comprise
  • PEG selected from PEG 100 to PEG 900, preferably PEG 400, and preferably wherein the PEG is present in an amount of from about 1% to about 60%, more preferably from about 5% to about 50%, by weight of the composition;
  • glycol in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition, preferably the glycol is propylene glycol; and/or
  • dialkyl glycol monoalkyl ether in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition, preferably the dialkyl glycol monoalkyl ether is diethyl glycol monoethyl ether.
  • a particularly high loading of a compound of Formula (I) may be dissolved in these topical compositions before said compound crystallises.
  • excipient system may optionally comprise, in addition to components (A) and (C), the additional component
  • (D) polyol in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition.
  • the polyol is glycerol.
  • the topical composition may be an ointment, aqueous gel, non- aqueous gel, or cream dependent upon the components that form the excipient system, and that the skilled person will know the types of excipients to add to form each of those formulations.
  • particularly beneficial ointment- based topical compositions may comprise, as part of the excipient system, an oleaginous base, such as petroleum jelly, PEG selected from PEG 1000 to PEG 10000, yellow wax (such as that purified from the honeycomb of bees), and/or white wax (i.e. purified from yellow wax).
  • the oleaginous base may be present in an amount of from about 20% to about 30% by weight of the composition.
  • PEG is included and that it is PEG 3350 and/or PEG 4000.
  • Particularly beneficial non-aqueous gel-based topical compositions may comprise, as part of the excipient system, a gelling agent in an amount of from about 0.5% to about 5%, preferably from about 1% to about 3%, by weight of the composition.
  • a gelling agent in an amount of from about 0.5% to about 5%, preferably from about 1% to about 3%, by weight of the composition.
  • Any suitable getting agent may be used, such as hydroxypropylcellulose MF (HPC MF) and/or hydroxypropylcellulose (HPC GF).
  • HPC MF hydroxypropylcellulose MF
  • HPC GF hydroxypropylcellulose
  • water in an amount of from about 10% to about 30% by weight of the composition may be added.
  • a preservative such as benzyl alcohol
  • the preservative may be present in any suitable amount, however, an amount of from about 0.1% to about 5% by weight of the composition is typical.
  • Particularly beneficial cream-based topical compositions may comprise, as part of the excipient system, water, oil phase, emollient, emulsifier, and optionally a preservative.
  • the water may be present in an amount of from about 20% to about 35% by weight of the composition
  • the oil phase preferably in an amount of from about 0.5% to about 25% by weight of the composition
  • the emollient preferably in an amount of from about 5% to about 15% by weight of the composition
  • the emulsifier preferably in an amount of from about 2% to about 10% by weight of the composition.
  • the preservative may be present in an amount of from about 0.1% to about 5% by weight of the composition.
  • Particularly suitable emollients are cetostearyl alcohol and/or Span 60.
  • a particularly suitable emulsifier is Tween, such as Tween 80.
  • a particularly suitable preservative is benzyl alcohol.
  • oil phases useful in the topical compositions are those that comprise one or more triglycerides, such as crodamol GTCC; liquid paraffin, or a combination thereof.
  • the topical compositions may have increased stability (both chemical and physical stability). Ointments, aqueous gels and non-aqueous gels may exhibit further enhanced stability. Therefore, a particular feature the invention is that the pharmaceutical composition is a topical composition that comprises an excipient system that comprises
  • an oleaginous base such as petroleum jelly, and/or PEG selected from PEG 1000 to PEG 10000 in an amount of from about 20% to about 30% by weight of the composition, preferably the PEG is PEG 3350 or PEG 4000; or
  • a gelling agent in an amount of from about 0.5% to about 5%, preferably from about 1% to about 3%, by weight of the composition, preferably the gelling agent is HPC MF or HPC GF, and optionally wherein the excipient system further comprises
  • the excipient system may comprise low molecular weight alcohol, i.e. Ci to Cs alcohol, such as methanol, ethanol, propanol, butanol, pentanol or a combination thereof. It is preferable that the low molecular weight alcohol is ethanol. When present, the low molecular weight alcohol may be in the excipient system in an amount of from about 2% to about 8% by weight of the composition.
  • the excipient system may comprise an antioxidant, preferably BHT or ascorbic acid. This may be present in any suitable amount, such as from about 0.01% to about 0.5%, preferably from about 0.05% to about 0.2%, by weight of the composition. The antioxidant may further increase stability of the topical composition, particularly the chemical stability of the composition.
  • the excipient system may comprise a UV filter. Any suitable UV filter may be used, such as octisalate.
  • the UV filter may be present in any suitable amounts, such as from about 4% to about 8% by weight of the composition.
  • a specific ointment-based topical composition may comprise
  • glycerol in an amount of from about 12% to about 22% by weight of the composition
  • PEG selected from PEG 1000 to PEG 10000 in an amount of from about 20% to 30% by weight of the composition, preferably the PEG is PEG 3350 or PEG 4000;
  • a specific aqueous gel and non-aqueous gel-based topical compositions may comprise
  • PEG 400 preferably SR PEG 400, in an amount of from about 25% to about 45% by weight of the composition
  • glycerol in an amount of from about 17% to about 23% by weight of the composition
  • a gelling agent in an amount of from about 1% to about 3%, by weight of the composition, preferably the gelling agent is HPC MF and/or HPC GF; and
  • antioxidant preferably BHT, in an amount of from about 0.05% to about 0.5% by weight of the composition.
  • a specific cream-based topical composition may comprise (A) the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof present in an amount of from about 0.3% to about 1.5% by weight of the composition;
  • glycerol in an amount of from about 5% to about 15% by weight of the composition
  • an oil phase comprising one or more triglycerides, such as crodamol GTCC; liquid paraffin, or a combination thereof in an amount of from about 0.5% to about 25%, preferably from about 3% to about 9%, by weight of the composition;
  • cetostearyl alcohol in an amount of from about 5% to about 15% by weight of the composition
  • Span 60 in an amount of from about 0.2% to about 1% by weight of the composition.
  • (x) optionally an antioxidant, preferably BHT or ascorbic acid, in an amount of from about 0.05% to about 0.5% by weight of the composition;
  • (xii) optionally a UV filter, such as octisalate, preferably in an amount of from about 4% to about 8% by weight of the composition.
  • a UV filter such as octisalate
  • the topical compositions may be formed by any suitable method, such as bringing the ingredients together in a mixer and mixing them until a homogeneous composition is formed.
  • One preferred method of forming a topical pharmaceutical composition involves combining the compound of Formula (I) with one or more of the components of the excipient system to dissolve said compound, and then adding the remaining components of the excipient system in a mixer. It may be preferable to mix the compound of Formula (I) with a mixture comprising PEG selected from PEG 100 to PEG 900, such as PEG 400, to dissolve said compound prior to the addition of the remaining components of the excipient system.
  • the compound of Formula (I) may be mixed with a mixture comprising PEG 400, propylene glycol, glycerol, and dialkyl glycol monoalkyl ether, to dissolve said compound prior to mixing with the remaining components of the excipient system.
  • Certain excipients, such as PEG 3350 may require heating (for instance to 65 °C) to liquefy the excipient so that it may be combined with the other components. The exact method of forming the topical pharmaceutical composition will be easily ascertained by the skilled person.
  • 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
  • Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.0001 to 30 g/kg, typically 0.01 to 10 g per patient, while for oral administration suitable daily doses are of the order of 0.01 to 100 g/kg.
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the agents of the 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.
  • the agent of the invention may be administered either simultaneously with, or before or after, one or more other therapeutic agents.
  • the agent of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • the invention includes a product comprising a compound of the invention 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 condition or disorder which is mediated by Trk, in particular Trk A, B, and C.
  • Products provided as a combined preparation include a composition comprising the agent of the invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or the agent of the invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising an agent of the invention 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 an agent of the invention.
  • 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 topical, 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 administration.
  • the agent of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the agent of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the agent of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the agent of the invention and the other therapeutic agent.
  • the invention provides the use of an agent of the invention for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the medicament is administered with a compound of the invention.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
  • the invention also provides a compound of the invention for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the compound of the invention is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the other therapeutic agent is prepared for administration with a compound of the invention.
  • the invention also provides a compound of the invention for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein agent of the invention is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the other therapeutic agent is administered with a compound of the invention.
  • the invention also provides the use of a compound of the invention for treating a condition or disorder which is mediated by T rk, in particular T rk A, B, and C, wherein the subject has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the subject has previously (e.g. within 24 hours) been treated with a compound of the invention.
  • a compound of the invention is administered alongside one or more other therapeutically active agents.
  • the compounds of the invention may therefore be used in combination with one or more further agents for the treatment of atopic dermatitis, such as: one or more topical and/or oral corticosteroids; one or more antihistamines; one or more antibiotics; one or more topical calcineurin inhibitors such as tacrolimus and/or pimecrolimus; one or more systemic immunosuppressants such as cyclosporin, methotrexate, interferon gamma-1 b, mycophenolate mofetil and/or azathioprine; one or more PDE4 inhibitors such as crisaborole; one or more monoclonal antibodies such as dupilumab.
  • an agent of the invention may be administered to a subject, particularly a human subject, wherein the subject is being treated with phototherapy for a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis.
  • a compound of the invention may also be administered to a subject, particularly a human subject, wherein the subject has previously ( e.g . within 24 hours) been treated with phototherapy for a condition or disorder in which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis.
  • a subject particularly a human subject may also be treated with phototherapy for a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis wherein a compound of the invention has previously (e.g. within 24 hours) been administered to a subject.
  • Trk in particular Trk A, B, and C
  • atopic dermatitis wherein a compound of the invention has previously (e.g. within 24 hours) been administered to a subject.
  • the invention includes as a further aspect a combination of an agent of the invention with one or more further agents for the treatment of atopic dermatitis, such as: one or more topical and/or oral corticosteroids; one or more antihistamines; one or more antibiotics; one or more topical calcineurin inhibitors such as tacrolimus and/or pimecrolimus; one or more systemic immunosuppressants such as cyclosporin, methotrexate, interferon gamma-1 b, mycophenolate mofetil and/or azathioprine; one or more PDE4 inhibitors such as crisaborole; one or more monoclonal antibodies such as dupilumab; and phototherapy.
  • atopic dermatitis such as: one or more topical and/or oral corticosteroids; one or more antihistamines; one or more antibiotics; one or more topical calcineurin inhibitors such as tacrolimus and/or pimecrolimus;
  • the compounds of Formula (VII) may be prepared as set out in WO 2020/039209 (the content of which is incorporated herein in its entirety by reference). However, they may be synthesised using the methods described herein, or other methods, which are known in the art.
  • organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism.
  • chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the preferred embodiments encompasses any tautomeric form of the drawn structure.
  • HTRF® KinEASETM kinase kits from Cisbio were used. Assays were carried out in low volume, black 384-well plates. Recombinant Human TRK enzymes (Invitrogen) were incubated in the presence or absence of the compound (11-point dose response with FAC as 10 mM) for 30 minutes at 23 °C. Kinase reaction was started by addition of ATP to a mixture containing the enzyme (NTRK1-4nM, NTRK2-1nM, NTRK3-10nM) and substrate (1 mM).
  • the compounds of the present invention exhibit Trk inhibition activity, expressed as an IC50 value, of less than 1 mM.
  • Preferred examples have IC50 values of less than 200 nM and particularly preferred examples have IC50 values of less than 50 nM.
  • the IC50 value for Example 2 is below 0.70 nM in each of TrkA, TrkB and TrkC. The compounds of the invention can therefore be used in the treatments and methods discussed above.

Abstract

The present invention relates to imidazo[1,2-b]pyridazine compounds and pharmaceutically acceptable salts thereof. The invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk) activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk. (I)

Description

IMIDAZOPYRIDAZINE DERIVATIVES USEFUL AS TRK INHIBITORS
The present invention relates to certain imidazo[1,2-b]pyridazine compounds and pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk) activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk.
Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins, a group of soluble growth factors including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin- 3 (NT-3) and Neurotrophin-4/5 (NT-4/5). The Trk receptors include three family members TrkA, TrkB and TrkC that bind to and mediate the signal transduction derived from the Neurotrophins. NGF activates TrkA, BDNF and NT-4/5 activate TrkB and NT3 activates TrkC.
Tropomyosin-related kinases have been implicated in the following diseases: atopic dermatitis, psoriasis, eczema and prurigo nodularis, acute and chronic itch, pruritus, inflammation, cancer, restenosis, atherosclerosis, thrombosis, pruritus, lower urinary tract disorder, inflammatory lung diseases such as asthma, allergic rhinitis, lung cancer, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, fibrosis, neurodegenerative disease, diseases disorders and conditions related to dysmyelination or demyelination, certain infectious diseases such as Trypanosoma cruzi infection, (Chagas disease), cancer related pain, chronic pain, neuroblastoma, ovarian cancer, colorectal cancer, melanoma, head and neck cancer, gastric carcimoma, lung carcinoma, breast cancer, glioblastoma, medulloblastoma, secratory breast cancer, salivary gland cancer, papillary thyroid carcinoma, adult myeloid leukaemia, tumour growth and metastasis and interstitial cystitis. (C. Potenzieri and B. J. Undem, Clinical & Experimental Allergy, 2012 (42) 8-19; Yamaguchi J, Aihara M, Kobayashi Y, Kambara T, Ikezawa Z, J Dermatol Sci. 2009;53:48-54; Dou YC, Hagstromer L, Emtestam L, Johansson O., Arch Dermatol Res. 2006;298:31-37; Johansson O, Liang Y, Emtestam L., Arch Dermatol Res. 2002;293:614-619; Grewe M, Vogelsang K, Ruzicka T, Stege H, Krutmann J., J Invest Dermatol. 2000;114:1108-1112; Urashima R, Mihara M .Virchows Arch. 1998;432:363-370; Kinkelin I, Motzing S, Koltenzenburg M, Brocker EB., Cell Tissue Res. 2000;302:31-37; Tong Liu & Ru- Rong Ji, Pflugers Arch - Eur J Physiol, DOI 10.1007/s00424-013-1284-2, published online 1 May 2013.); International Patent Application publication numbers WO2012/158413, WO2013/088256, WO2013/088257 and W02013/161919,
(Brodeur, G. M., Nat. Rev. Cancer 2003, 3, 203-216), (Davidson. B. , et al. , Clin. Cancer Res. 2003, 9, 2248-2259), (Bardelli, A , Science 2003, 300, 949), (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (I), pp. 32-36), Yilmaz.T. , et al. , Cancer Biology and Therapy 2010, 10 (6), pp. 644-653), (Du, J. et al. .World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), (Ricci A, et al., American Journal of Respiratory Cell and Molecular Biology 25 (4), pp. 439-446), (Jin, W. , et al., Carcinogenesis 2010, 31 (11), pp. 1939-1947), (Wadhwa, S. , et al., Journal of Biosciences 2003, 28 (2), pp. 181-188), (Gruber-Olipitz, M. , et al. , Journal of
Proteome Research 2008, 7 (5), pp. 1932-1944), (Euthus, D. M. et al. , Cancer Cell 2002, 2 (5), pp. 347-348), (Li, Y. -G. , et al., Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp. 428-430), (Greco, A , et al. , Molecular and Cellular Endocrinology 2010, 321 (I), pp. 44-49), (Eguchi, M., et al., Blood 1999, 93 (4), pp. 1355-1363), (Nakagawara, A (2001) Cancer Letters 169: 107-114; Meyer, J. et al.
(2007) Leukemia, 1-10; Pierottia, M. A and Greco A, (2006) Cancer Letters 232:90- 98; Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351 ), (FreundMichel, V; Frossard, N. , Pharmacology ck Therapeutics (2008) 117(1), 52-76), (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21), (Di Mola, F. F, et. al. Gut (2000) 46(5), 670-678) (Dou, Y. -C. ,et. al. Archives of Dermatological Research
(2006) 298(1), 31-37), (Raychaudhuri, S. P. , et al. , J. Investigative Dermatology
(2004) 122(3), 812-819) and (de Melo-Jorge, M. et al. , Cell Host ck Microbe (2007) 1 (4), 251-261). In a first aspect of the invention there is provided a compound of Formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N- oxide, and/or prodrug thereof, wherein
X is a direct bond or -(CR6R7)-; Y is a direct bond or selected from
Figure imgf000004_0001
wherein * denotes the point of attachment to X and ** denotes the point of attachment to Z;
Z is a direct bond or selected from -CH2-, -C(O)-, and -S(C>2)-; R1 is -OR, wherein R is an optionally substituted oxane or oxolane;
R2 is selected from H and -SMe;
R3 is selected from H and halo;
R4 is selected from H and (Ci-C3)alkyl;
R5 is selected from H, -OH and halo; R6 and R7 are each independently selected from H and (Ci-C3)alkyl; each R8 is independently selected from halo and (Ci-C3)alkoxy; each R9 is independently selected from halo; m is 1 or 2; n is 1 or 2; p is 1 or 2; provided that the sum of m, n, and p is from 2 to 4; q is 0, 1, 2, 3 or 4; and r is 0, 1, 2, or 3. Such compounds are the compounds of the invention, or “the compounds”.
A feature of the first aspect of the invention is that the compound of Formula (I) is a compound is of Formula (IA). In Formula (IA), the groups X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R, m, n, p, q, and r, are as defined for the compound of Formula (I).
In a more specific feature, the compound of Formula (I) is preferably a compound of Formula (IB).
Figure imgf000005_0001
In Formula (IB), the groups X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R, m, n, p, q, and r, are as defined for the compound of Formula (I).
In the compounds of the invention, such as those defined by Formulae (I), (IA) and (IB), it is preferable that Y is a direct bond, and/or X is a direct bond. With regard to groups X and Y it is most preferable that both are a direct bond. As used herein, the term “direct bond” means that the two adjacent groups are connected directly to each other via a bond. In effect, the particular group is absent from the molecule. In the compounds of the invention, Z is a direct bond or selected from -CH2-, -C(O)-, and -S(C>2)-, however, it is preferable that Z is -CH2-.
In view of the above, in a specific feature of the first aspect of the invention, the compound of Formula (I) is a compound is of Formula (IC). In Formula (IC), the groups R1, R2, R3, R4, R5, R9, R, and q are as defined for the compound of Formula (I).
In the compounds of the invention, R3 is selected from H and halo. It is preferable that R3 is selected from H and F.
In a particular feature of the first aspect of the invention, such as those defined by Formulae (I), (IA), (IB), and (IC), R2 is -SMe and R3 is F.
In the compounds of the invention, R4 is selected from H and (Ci-C3)alkyl. It is preferable that R4 in Formulae (I), (IA), (IB), and (IC) is H. In view of the above, in a specific feature of the first aspect of the invention, the compound of Formula (I) is a compound is of Formula (ID).
Figure imgf000006_0001
In Formula (ID), the groups R1, R9, R, and q are as defined for the compound of Formula (I).
The compound of Formula (I) may be of Formula (ID’). In Formula (ID’), the groups R1, R9, R, and q are as defined for the compound of Formula (I).
An important feature of the compounds of the invention is the presence of an optionally substituted oxane or oxolane group at position R. This group is linked to the remainder of the compounds through an “-0-” group. This is in line with the definition of group R1 which is “-OR”.
The oxane or oxolane of group R may be substituted by one or more suitable groups. Particular groups that may be substituted on the oxane or oxolane is one or more of halo, (CrC3)alkyl, -NR10R11, -OR12, -COOH, -CHO, and -CH2OR12, wherein the (Ci-C3)alkyl is optionally substituted with one or more halo (preferably one or more F).
R10 and R11 are independently selected from H and (Ci-C3)alkyl optionally substituted with one or more halo. Alternatively, R10 and R11 can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle, wherein the 5- or 6-membered heterocycle is optionally substituted with one or more groups selected from C1-C6 alkyl, halo, -OH, and -NH2, wherein the Ci- Od alkyl optionally substituted with one or more halo (preferably one or more F).
R12 is independently selected from H and (CrC3)alkyl optionally substituted with one or more halo.
It is preferable that R1 is a sugar, such as a monosaccharide (i.e. a carbohydrate consisting of one sugar unit) or a derivative thereof. They may be linear or cyclic compounds. It may be a pentose or hexose or a derivative thereof. Particularly, R1 may be selected from the list consisting of allose, aldose, glucose, mannose, idose, galactose, talose, fructose, ribose, deoxyribose, or a derivative thereof. These groups may be joined to the reminder of the compound through an “-0-” group attached to a ring carbon adjacent to the oxygen atom in the oxane or oxolane ring. Any suitable derivative may be used, but it is preferred that the derivative is a uronic acid derivative. Uronic acids are a class of sugar acids in which the terminal carbon's hydroxyl group has been oxidized to a carboxylic acid.
Based upon the above, it is preferable that R1 is
Figure imgf000008_0001
and most preferable that R1 is
Figure imgf000008_0002
The most preferred R1 group in the compounds of the invention is
Figure imgf000008_0003
Based upon all of the above, a compound of the invention has one of the following structures.
Figure imgf000008_0004
The most preferred compound has the following structure.
Figure imgf000009_0003
In the features of the first aspect of the invention mentioned herein, where only certain variables are defined, it is intended that the remainder of the variables are as defined in any other feature herein. Thus, the invention provides for the combination of limited or optional definitions of variables.
As used herein, "optionally substituted" means the group referred to can be unsubstituted, or substituted at one, two, three, four, five, six or more positions by any one or any combination of the substituents, such as those listed thereafter. The term “oxane” is synonymous with tetrahydropyran and is represented by the following formula.
Figure imgf000009_0001
The term “oxolane” is synonymous with tetrahydrofuran and is represented by the following formula.
Figure imgf000009_0002
As used herein, the term “halo” refers to fluoro, chloro, bromo, and iodo. It is preferable that halo is fluoro, which may be denoted as F. As used herein, the term “(Ci-C3)alkyl” refers to a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2 or 3 carbon atoms.
Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, and cyclopropyl. By extension, “(Ci-C4)alkyl” refers to a fully saturated branched, unbranched or cyclic hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, and include, in addition to the aforementioned, n-butyl, t butyl, iso butyl, cyclobutyl, methyl-cyclopropyl, amongst others. As used herein, the term “(Ci-C3)alkoxy” refers to (Ci-C3)alkyl-0-, wherein
(CrC3)alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, and propoxy.
The groups -C(O)- and -S(C>2)- respectfully represent the two groups
Figure imgf000010_0001
Throughout this specification and in the claims that follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, should be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The compounds of the invention may be present as their pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by one of the aforementioned Formulae, that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, generally, G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S.M. Berge, et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1 -19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound of the invention, may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate , trifluoroacetate and trifluoromethylsulfonate salts.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoromethylsulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are 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 can 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, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
Examples of pharmaceutically acceptable salts particularly include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y- hydroxy butyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.
Additionally, any formula given herein is intended to refer also to hydrates and solvates of compounds of the invention, and mixtures thereof, even if such forms are not listed explicitly. A compound of the invention, or pharmaceutically acceptable salt of a compound of the invention, may be obtained as a solvate. Solvates include those formed from the interaction or complexation of compounds of the invention with one or more solvents, either in solution or as a solid or crystalline form. The solvent may be water, which case the solvates are hydrates. In addition, certain crystalline forms of a compound of the invention, or a pharmaceutically acceptable salt of a compound of the invention, may be obtained as co-crystals. A compound of the invention, or a pharmaceutically acceptable salt of a compound of the invention, may be obtained in a crystalline form.
A compound of the invention, may be obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form. A compound of the invention may convert in solution between one or more crystalline forms and/or polymorphic forms. Compounds of the invention 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 the invention by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the invention 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. Hence the invention further provides co-crystals comprising a compound of the invention.
Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centres and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base addition salts wherein the counter ion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Where a compound of the invention contains for example, a keto or guanidine group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. It follows that a single compound may exhibit more than one type of isomerism. Examples of types of potential tautomerisms shown by the compounds of the invention include; amide o hydroxyl-imine and keto o enol tautomersims. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, by chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or other derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% ethanol, typically from 2 to 20%. Concentration of the eluate affords the enriched mixture.
Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art (see, for example, “Stereochemistry of Organic Compounds ” by E L Eliel (Wiley, New York, 1994)).
As used herein, the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral centre of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration.
All tautomeric forms are also intended to be included. Tautomers are one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples of tautomers include but are not limited to those compounds defined in the claims. 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. In certain embodiments, 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 bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
Accordingly, as used herein 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 ( cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. 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. In particular, 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 chiral adsorbent.
Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
The invention also relates to pharmaceutically acceptable prodrugs of a compound of the invention and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).
A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prod rugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the invention following administration of the prodrug to a subject. The compounds of the present invention may themselves be active and/or act as prodrugs which convert in vivo to active compounds. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action.
Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein. Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the oo-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
The compounds of the invention may also be N-oxides. It will be understood that an N-oxide, or “amine oxide”, is a compound that contains an N-0 coordinate covalent bond. Examples of an N-oxide group include functional groups is: The present invention also relates to pharmaceutically active metabolites of a compound of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of the invention, or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g. Bertolini, et al., J Med Chem. 1997, 40, 201 1 -2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991). Any formula given herein is also intended to represent unlabelled forms as well as isotopically labelled forms of the compounds. Isotopically labelled 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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), 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 subjects. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in PET studies for examining substrate receptor occupancy. In particular, an 18F or 11C labelled compound may be particularly preferred for PET studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Certain isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Isotopically labelled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the invention. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If 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. D2O, de acetone, d6-DMSO.
Exemplary compounds of the invention, and exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Reactions may be performed between the melting point and the reflux temperature of the solvent, or at higher temperatures by using seal reaction vessels, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.
All of the derivatives of the compounds of the invention, and in particular the above- mentioned Formulae, can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of the Formulae, in addition to any novel intermediates used therein.
The routes below, including those mentioned in the Examples and Intermediates, illustrate methods of synthesising the compounds of the invention. The skilled person will appreciate that the compound of the invention, and intermediates thereto, could be made by methods other than those specifically described herein, for example by adaptation of the methods described herein, for example by methods known in the art. Suitable guides to synthesis, functional group interconversions, use of protecting groups, etc., are for example: “Comprehensive Organic Transformations ” by RC Larock, VCH Publishers Inc. (1989); “Advanced Organic Chemistry’ by J. March, Wiley Interscience (1985); “Designing Organic Synthesis ” by S Warren, Wiley Interscience (1978); “Organic Synthesis - The Disconnection Approach" by S Warren, Wiley Interscience (1982); “Guidebook to Organic Synthesis ” by RK Mackie and DM Smith, Longman (1982); “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, Fifth Ed, John Wiley and Sons, Inc. (2014); and “Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag (1994); and any updated versions of these standard works.
In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect phenol or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in a conventional manner. See, for example, those described in 'Greene’s Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fifth edition, (John Wiley and Sons, 2014), in particular Chapter 3 (“ Protection for Phenols") Chapter 5 (“ Protection for the Carboxyl group”), and Chapter 7 (“Protection for the Amino Group”), incorporated herein by reference, which also describes methods for the removal of such groups.
In the general synthetic methods below, unless otherwise specified, the substituents are as defined above with reference to the compound of the various formulae above.
Where ratios of solvents are given, the ratios are by volume.
The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of the compound of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures or as mixtures of diastereomers or regioisomers. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.
The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compound of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of the compound of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention
Compounds of the invention, such as those of Formula (I), may be prepared from the compounds of Formulae (II), (III), (IV), (V), (VI), and (VII) as illustrated by Scheme 1.
Scheme 1
PG1 is (CrC4)alkyl, preferably Me or Et. R1A is OH.
The amine of Formula (III) is commercially available or may be prepared by analogy to methods known in the literature or as illustrated in Scheme 6 of WO 2020/039209 (which is incorporated herein in its entirety by reference).
The chloride of Formula (IV) is commercially available or may be prepared by analogy to methods known in the literature.
Compounds of Formula (VI) are commercially available or may be prepared in chiral form by analogy with the methods described by Brinner et. al. ( Org . Biomol. Chem., 2005,3, 2109-2113) or Fan et.al. (WO 2012/034091). Alternatively, compounds of Formula (VI) may be prepared by analogy with the methods described by Huihui et. al. (J.A.C.S., 2016, 138, 5016-5019). The compound of Formula (V) may be prepared by treatment of the amine of Formula (VI) with the chloride of Formula (IV), in the presence of an inorganic base in a polar aprotic solvent at elevated temperature. Preferred conditions, comprise treatment of the compound of Formula (IV) with the amine of Formula (VI) in the presence of KF in a solvent such as DMSO at elevated temperature, typically 130°C.
The compound of Formula (II) may be prepared by the hydrolysis of the compound of Formula (V) under suitable acidic or basic conditions in a suitable aqueous solvent. Preferred conditions comprise the treatment of the ester of Formula (V) with KOH in aqueous EtOH at room temperature.
The compound of Formula (VII) may be prepared by an amide bond formation of the acid of Formula (II) and the amine of Formula (III) in the presence of a suitable coupling agent and organic base in a suitable polar aprotic solvent. Preferred conditions, comprise the reaction of the acid of Formula (II) with the amine of Formula (III) in the presence of HATU or TPTU, in the presence of a suitable organic base, typically DIPEA in a suitable solvent, such as DMF at room temperature. Due to the hydroxyl group R1A, an appropriate phenol protecting group strategy, as selected by a person skilled in the art, may be employed, such as for example a silyl protecting group, if required.
The compounds of the invention, such as those of Formula (I), may be formed by coupling Formula (VII) with an appropriate optionally substituted hydroxyl-oxane or hydroxyl-oxolane. This coupling may be achieved using BF3.0Et2. If R1 is a monosaccharide, then a suitable protecting group methodology may be used, such as acetylation of hydroxyl groups. If the monosaccharide is a uronic acid derivative, then the carboxylic acid may be protected with PG1. The monosaccharide may be deprotected using known methodologies, such as stirring the compound in the presence of lithium hydroxide monohydrate in a THF/water mixture.
Alternatively, a compound of Formula (I) may be prepared from the compounds of Formulae (II), (III), (VII) and (VIII) as illustrated by Scheme 2. Scheme 2 The compound of Formula (VII) may be prepared by formation of the acid chloride of Formula (VIII) from the acid of Formula (II), typically using oxalyl chloride and DMF in DCM at room temperature and the subsequent amide bond formation of the acid chloride of Formula (VIII) and the amine of Formula (III) in the presence of a suitable organic base, typically triethylamine at 0°C. The compound of Formula (I) may be obtained from Formula (VII) as set out in Scheme 1.
In addition to the above, the compound of Formula (VII) may be prepared as set out in WO 2020/039209 (the content of which is incorporated herein in its entirety by reference). In particular, Schemes 1 to 6 and the intermediates and examples therein may be used to prepare the compounds of the present invention. The above general schemes may be used to prepare compounds of the present invention. The desired specific compounds can be prepared by selecting the appropriate starting materials, reactants and reaction conditions.
The starting materials and reagents in the above scheme are all either available commercially or can be prepared following literature precedents.
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as 'Greene’s Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fifth edition, (John Wiley and Sons, 2014), in particular Chapter 3 (“ Protection for Phenols") and Chapter 5 (“ Protection for the Carboxyl group”), incorporated herein by reference, which also describes methods for the removal of such groups , in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.- D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage).
Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
Mixtures of isomers obtainable according to the invention can be separated in a manner known to those skilled in the art into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
The following applies in general to all processes mentioned herein before and hereinafter. All the above-mentioned process steps can be carried out under reaction conditions that are known to those skilled in the art, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 °C to about 190 °C, including, for example, from approximately -80 °C to approximately 150 °C, for example at from -80 to -60 °C, at room temperature, at from -20 to 40 °C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps".
The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or A/-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.
The compounds of the invention exhibit valuable pharmacological properties, e.g. Trk modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
Having regard to their ability to inhibit Trk activity, the compounds of the invention, hereinafter alternately referred to as "agents of the invention", are useful in the treatment or prevention of a condition or disorder which is mediated by Trk.
In particular, the compounds of the present invention are useful for the treatment of disorders or conditions mediated by the high affinity neurotrophin receptors TrkA, TrkB and TrkC, and the actions of their cognate neurotrophin ligands - NGF, BDNF/NT-4/5, NT-3 - on these receptor tyrosine kinases. Particularly the compounds are useful for treating or preventing conditions of skin (dermal) inflammation and itch (pruritus) that are mediated by the high affinity neurotrophin receptors TrkA, TrkB and TrkC, and associated with inflammation and nerve hypersensitivity, in particular atopic dermatitis.
Infiltration and activation of immune cells in the skin (including T-cell, mast cells, eosinophils) play a key role in inflammatory skin pathologies (llkovitch D. J Leukoc Biol. 2011, 89(1 ):41 -9; Kim et al, Int J Mol Sci. 2016,17(8)). Trk A, B, and C and their cognate endogenous neurotrophin ligands have been demonstrated to play a role in the immunological and neurogenic mechanisms associated with skin pathologies (Botchkarev et al, J Invest Dermatol. 2006, 126(8) : 1719-27. ; Truzzi et al, Dermatoendocrinol. 2011, 3(1):32-6; Minnone et al, Int J Mol Sci. 2017, 11 ; 18(5)), and mediate inflammatory functions of skin resident immune cells, particularly those involved in atopic dermatitis pathology (Raap et al, Clin Immunol. 2005, (5):419-24), including T-cells (Sekimoto et al, Immunol Lett. 2003, 88(3):221-6; Matsumura et al, J Dermatol Sci. 2015,78(3):215-23), mast cells (Quarcoo et al, J Occup Med Toxicol. 2009, Apr 22;4:8.), and eosinophils (Raap et al, J Allergy Clin Immunol. 2005, 115:1268-75; Raap et al, Clin Exp Allergy.2008, 38(9): 1493-8).
NGF, BDNF, NT-3 and NT-4/5 levels are higher in the lesional skin cells and plasma of atopic dermatitis patients compared to normal subjects and levels correlate with disease severity (Yamaguchi et al, J Dermatol Sci. 2009, 53(1):48-54; Toyoda et al, Br J Dermatol 2002, 147:71-79; Raap et al, J Allergy Clin Immunol. 2005, 115:1268- 75; Raap et al, Allergy. 2006, 61(12):1416-8). Trk levels are also upregulated in atopic dermatitis lesional skin cells (Dou et al, Arch Dermatol Res. 2006, (1 ):31 -7; Raap et al, Clin Exp Allergy. 2008, 38(9): 1493-8). In addition, the high affinity neurotrophin receptors and their endogenous ligands, in particular Trk A/NGF have been shown to sensitize primary afferent nerves and mediate dermal hyperinnervation, thereby contributing to peripheral itch sensitization and pruritus in particular in atopic dermatitis (Tominaga et al, J Dermatol. 2014, 41(3):205-12; Roggenkamp D et al, J Invest Dermatol 2012, 132: 1892-1900; Grewe et al, J Invest Dermatol 2000, 114:1108-1112). In preclinical mouse models of atopic dermatitis, inhibition of Trk signalling with small molecule compounds that have Trk inhibitory activity, reduced dermatitis and scratching behaviour, with concomitant decreases in nerve fibres in the epidermis (Takano et al, Br J Dermatol. 2007, 156(2):241-6; Narayanan et al, PLoS One. 2013, 26;8(12)).
The compounds of the present invention may be used for the treatment or prevention of skin pathologies or conditions including diseases of dermatitis such as atopic dermatitis (eczema), contact dermatitis, allergic dermatitis; diseases of pruritus such as urticaria (Rossing et al, Clin Exp Allergy. 2011, 41 (10): 1392-9), Cutaneous T-cell lymphoma (CTCL) -associated pruritus including Sezary syndrome (Suga et al, Acta Derm Venereol. 2013, 93(2):144-9; Saulite et al, Biomed Res Int. 2016 doi: 10.1155/2016/9717530); Psoriasis (Raychaudhuri et al, Prog Brain Res. 2004, 146:433-7); diseases of skin pain and neuropathy (Hirose et al, Pain Pract. 2016, 16(2):175-82; Wang et al, J Neurosci. 2009, 29(17):5508-15).
In particular, conditions or disorders which are mediated by Trk, in particular Trk A, B, and C, include, but are not limited to: diseases of pruritus and itch; autoimmune diseases of the skin; diseases of skin pain and neuropathy; and diseases of dermatitis.
Diseases of pruritus and itch include, but are not limited to: skin diseases, eczematous; dermatitis, atopic; eczema; dermatitis, contact; dermatitis, allergic contact; dermatitis, irritant; dermatitis, photoallergic; dermatitis, phototoxic; psoriasis; pruritus; pruritus ani; pruritus, hereditary localized; Sjogrens syndrome associated pruritis; idiopathic pruritus; sclerosis multiplex pruritus; prurigo nodularis; brachioradial pruritus; acute itch; chronic itch; diabetes pruritus; iron deficiency anaemia pruritus; polycythemia vera pruritus; graft-versus-host-disease; uraemic pruritus; cholestatic pruritus; pruritic urticarial papules and plaques of pregnancy; pemphigoid gestationis; senile pruritus; HIV associated pruritus; shingles; herpes zoster oticus; larva migrans; tinea corporis; tungiasis; exanthema; Fox-Fordyce disease; skin diseases, parasitic; skin diseases, bacterial; cutaneous T-cell; lymphoma-associated pruritus; Sezary syndrome; mycosis fungoides; colorectal cancer; melanoma; head and neck cancer; drug eruption pruritus (iatrogenic); drug reactions; urticarial; vibratory urticarial; physical urticarial; familial cold urticarial; allergic urticarial; dermatographia; dermatitis herpetiformis; Grover disease.
Autoimmune diseases of the skin include, but are not limited to: autoimmune disease of skin and connective tissue; autoimmune disease with skin involvement; autoimmune bullous skin disease; pemphigoid, bullous.
Diseases of skin pain and neuropathy include but are not limited to: diabetic neuropathies; neuralgia; painful neuropathy; nerve compression syndromes; neuritis; sensory peripheral neuropathy; alcoholic neuropathy; radiculopathy; complex regional pain syndromes; polyneuropathy due to drug; plantar nerve lesion; polyradiculopathy; sciatic neuropathy;trigeminal neuralgia.
Diseases of dermatitis include, but are not limited to: skin diseases, eczematous; dermatitis, atopic; eczema; dermatitis, contact; dermatitis, allergic contact; dermatitis, irritant; dermatitis, photoallergic; dermatitis, phototoxic; chronic irritative hand dermatitis; dermatitis, occupational; fiberglass dermatitis; dermatitis, toxicodendron; eczema, dyshidrotic; eczematous dermatitis of eyelid; allergic contact dermatitis of eyelid; hand and foot dermatitis; digital dermatitis; dermatitis, exfoliative; radiodermatitis; dermatitis herpetiformis; juvenile dermatitis herpetiformis; autoimmune progesterone dermatitis; dermatitis, seborrheic; pityriasis lichenoides; blepharitis; nummular dermatitis; Seborrhea-Like Dermatitis with Psoriasiform Elements; infective dermatitis associated with HTLV-1; psoriasis; generalized pustular psoriasis; skin diseases, papulosquamous; parapsoriasis; keratosis; hyperkeratosis, epidermolytic; skin sarcoidosis; skin atrophy; erythematosquamous dermatosis; poikiloderma with neutropenia; erythema multiforme; angiolymphoid hyperplasia with eosinophilia; keratosis palmoplantaris striata 3; acne vulgaris; lamellar ichthyosis; lichen disease; lichen planus; actinic lichen planus; lichen planus, oral; lichen planus follicularis; lichen sclerosus et atrophicus; lichen nitidus; lichen sclerosus; lichen simplex chronicus; scleroderma, limited; keratosis linearis with ichthyosis congenita and sclerosing keratoderma; erythrokeratoderma, reticular; keratosis palmoplantaris papulose; skin diseases, genetic; autosomal recessive congenital ichthyosis; autosomal recessive congenital ichthyosis 1; autosomal recessive congenital ichthyosis 2; autosomal recessive congenital ichthyosis 3; autosomal recessive congenital ichthyosis 4A; autosomal recessive congenital ichthyosis 5; autosomal recessive congenital ichthyosis 6; autosomal recessive congenital ichthyosis 7; autosomal recessive congenital ichthyosis 8 autosomal recessive congenital ichthyosis 9; autosomal recessive congenital ichthyosis 10; autosomal recessive congenital ichthyosis 11.
More particularly, the condition or disorder which is mediated by Trk, in particular Trk A, B, and C, may be atopic dermatitis.
Treatment in accordance with the invention may be symptomatic or prophylactic.
Thus in a further aspect the invention includes an agent of the invention for use as a pharmaceutical.
Therefore according to a further aspect, the invention provides an agent of the invention for treating or preventing a condition or disorder which is mediated by Trk, in particular Trk A, B, and C.
Therefore according to a further aspect, the invention provides the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition or disorder which is mediated by Trk, in particular Trk A, B, and C.
Therefore according to a further aspect, the invention provides a method for preventing or treating a condition which is mediated by Trk, in particular Trk A, B, and C, which comprises administering to a subject in need thereof a therapeutically effective amount of an agent of the invention.
In accordance with the foregoing, the invention also provides as a further aspect a method for preventing or treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, more particularly atopic dermatitis, which comprises administering to a subject, particularly a human subject, in need thereof a therapeutically effective amount of an agent of the invention. In another aspect the invention provides an agent of the invention for preventing or treating a condition or disorder which is mediated by Trk, in particular T rk A, B, and C, more particularly atopic dermatitis.
In another aspect the invention provides the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, more particularly atopic dermatitis.
As referred to herein a “disorder” or a “disease” refers to an underlying pathological disturbance in a symptomatic or asymptomatic organism relative to a normal organism, which may result, for example, from infection or an acquired or congenital genetic imperfection.
A "condition" refers to a state of the mind or body of an organism which has not occurred through disease, e.g. the presence of a moiety in the body such as a toxin, drug or pollutant.
As used herein, 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). In another embodiment “treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, "treating" or "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. In yet another embodiment, “treat”, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
"Prevention" of a condition or disorder refers to delaying or preventing the onset of a condition or disorder or reducing its severity, as assessed by the appearance or extent of one or more symptoms of said condition or disorder. As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ( e.g ., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. It is preferable that the subject is a primate, and most preferable that the subject is a human.
As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
The term "a therapeutically effective amount" of an agent of the invention refers to an amount of the agent of the 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. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the agent of the invention that, when administered to a subject, is effective to at least partially alleviating, inhibiting, preventing and/or ameliorating a condition or disorder which is mediated by TrK, in particular Trk A, B, and C. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the agent of the 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 inhibiting Trk activity, in particular Trk A, B, and C.
In a feature of the present invention, the condition or disorder which is mediated by Trk, in particular Trk A, B, and C, is selected from diseases of pruritus and itch; autoimmune diseases of the skin; diseases of skin pain and neuropathy; and diseases of dermatitis.
It is preferable that the condition or disorder which is mediated by Trk, in particular Trk A, B, and C, is atopic dermatitis.
As described above, the agents of the invention, which inhibit Trk, in particular Trk A, B, and C, have various clinical applications and thus a further aspect of the invention provides pharmaceutical compositions containing agents of the invention. The use of these agents as a medicament forms a further aspect of the invention.
The active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
Thus, in a further aspect the present invention provides a pharmaceutical composition comprising an agent of the invention and a pharmaceutically acceptable excipient.
Pharmaceutical compositions as described herein for use as a medicament, in particular for use in treating or preventing disorders or conditions mediated by Trk, in particular Trk A, B, and C, such as the conditions described herein, and methods of treatment or prophylaxis using such compositions and use of said agents for the preparation of a medicament for treating or preventing such disorders or conditions, form further aspects of the invention.
"Pharmaceutically acceptable" as referred to herein refers to ingredients that are compatible with other ingredients of the compositions as well as physiologically acceptable to the recipient.
A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
As used herein, 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, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavouring 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.
Pharmaceutical compositions according to the invention may be formulated in conventional manner using readily available ingredients. Thus, the active ingredient may be incorporated, optionally together with other active substances, with one or more conventional carriers, diluents and/or excipients, to produce conventional galenic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, 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). The pharmaceutical 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.
When pharmaceutical compositions are tablets or gelatin capsules, they may comprise the active ingredient together (compound of the invention) with a) diluents, e.g., lactose, polylactone, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; 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.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of an agent 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. These 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. For example, 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. Certain injectable 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.
It is most preferred that the compounds of the invention are administered topically. Therefore, the pharmaceutical composition may be a topical composition.
Suitable compositions for topical application to the skin or mucosa (e.g., to the skin and eyes), that is dermally or transdermally, include aqueous solutions, suspensions, ointments, creams, gels, hydrogels, microemulsions, dusting powders, dressings, foams, films, skin patches, wafers, implants, fibres, bandages or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of atopic dermatitis. 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 preservatives.
Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).]
Suitable compositions for transdermal application include an effective amount of an agent 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. For example, 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.
The topical pharmaceutical compositions may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The topical pharmaceutical compositions of the invention may be administered separately, by the same or different route of administration, or together in the same topical pharmaceutical composition as the other agents.
The compound of Formula (I) may be present in the topical composition in an amount of from about 0.008% to about 30% by weight of the composition, in combination with an excipient system. The excipient system may be present in the topical composition in an amount of less than about 99.99 % by weight of the composition. The amount of the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the topical composition may depend on the amount required to be delivered to a subject to effectively treat or prevent a specific disease or condition. The amount of the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the topical composition is preferably from about 0.01% to about 20%, more preferably from about 0.05% to about 5%, by weight of the composition. This may deliver to a subject a suitable amount of the compound of Formula (I) that is required to treat or prevent most diseases or conditions. The topical pharmaceutical composition may take any suitable form, such as an ointment, aqueous gel, non-aqueous gel, cream, solution (such as aqueous solution), suspension, emulsion (such as microemulsion), dusting powder, dressing, foam, film, skin patch, wafer, implant, fibre, bandage, sprayable formulation e.g. for delivery by aerosol or the like. The exact form may be dependent upon the intended use. The components that make up the excipient system will dictate the form of the topical composition. The excipient system comprises one or more pharmaceutically acceptable excipients. The types of components that lead to the formation of each of the types of topical composition are well known to those skilled in the art. It is preferable that the topical pharmaceutical composition is an ointment, aqueous gel, non-aqueous gel, or cream. The excipient system may comprise one or more carriers suitable for transdermal delivery of the compound of Formula (I) including absorbable pharmacologically acceptable solvents (such as those defined below) to assist delivery to therapeutically relevant compartments of the skin, such as the epidermis and dermis. For example, the topical pharmaceutical composition may be part of a transdermal devices in the form of a bandage comprising a backing member, a reservoir containing the topical pharmaceutical composition, 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. The excipient system may comprise polyethylene glycol (PEG). It is preferable that the PEG selected from PEG 100 to PEG 900, and more preferably PEG 400. The inclusion of PEG as part of the excipient system may help to increase active pharmaceutical ingredient (API) loading in the composition. PEG may also increase chemical stability of the API in the composition, and physical stability of the composition, compared to other composition bases, particularly when a high purity grade of PEG 400 is used, such as super-refined PEG 400, such as that supplied by Croda. BHT or ascorbic acid, (preferably BHT) may also be included in the topical composition to further increase stability of the composition, particularly the stability of the API. The PEG may be present in any suitable amount, such as from about 1% to about 60%, more preferably from about 5% to about 50%, by weight of the composition. The excipient system may comprise glycol, polyol, dialkyl glycol monoalkyl ether or a combination thereof. It is preferably that the glycol, polyol, dialkyl glycol monoalkyl ether or a combination thereof is present in an amount of from about 10% to about 70%, more preferably about 20% to about 60%, by weight of the composition.
As used herein, “glycol” means a chemical compound that comprise two hydroxyl groups. Such compounds include, but are not limited to, ethylene glycol, propylene glycol (propane-1, 2-diol), and propane-1, 3-diol, butylene glycol (such as 1,2- butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 2-methyl-1, 2-propanediol and 2-methyl-1, 3-propanediol). It is preferred that the glycol is propylene glycol, i.e. propane-1, 2-diol.
As used herein, “polyol” means a chemical compound that contains three or more hydroxyl groups. Such compounds include, but are not limited to, glycerol, butanetriol, pentanetirol, and polyethylene triols, in particular containing from 4 to 8 ethylene oxide units, and their mixtures.
As used herein, “dialkyl glycol monoalkyl ether” includes, but is not limited to, diethylene glycol monoethyl ether (Transcutol P).
Without wishing to be bound by theory, is it believed that the combination of PEG (preferably PEG 400), Transcutol P and propylene glycol (propane-1 ,2-diol) in the excipient system leads to topical compositions that may benefit from a higher loading of API before they become saturated. For instance, such compositions may comprise the compound of Formula (I) in amounts in excess of 5% by weight of the composition without crystallisation of API. This has the advantage of providing topical compositions that are able to deliver higher dosages of API to a subject in need thereof.
In view of the above, the excipient system may comprise
(A) PEG selected from PEG 100 to PEG 900, preferably PEG 400, and preferably wherein the PEG is present in an amount of from about 1% to about 60%, more preferably from about 5% to about 50%, by weight of the composition;
(B) glycol in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition, preferably the glycol is propylene glycol; and/or
(C) dialkyl glycol monoalkyl ether in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition, preferably the dialkyl glycol monoalkyl ether is diethyl glycol monoethyl ether.
A particularly high loading of a compound of Formula (I) may be dissolved in these topical compositions before said compound crystallises.
A further feature is that the excipient system may optionally comprise, in addition to components (A) and (C), the additional component
(D) polyol in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the composition. When present, it is preferable that the polyol is glycerol.
As mentioned, the topical composition may be an ointment, aqueous gel, non- aqueous gel, or cream dependent upon the components that form the excipient system, and that the skilled person will know the types of excipients to add to form each of those formulations. Notwithstanding this, particularly beneficial ointment- based topical compositions may comprise, as part of the excipient system, an oleaginous base, such as petroleum jelly, PEG selected from PEG 1000 to PEG 10000, yellow wax (such as that purified from the honeycomb of bees), and/or white wax (i.e. purified from yellow wax). The oleaginous base may be present in an amount of from about 20% to about 30% by weight of the composition. In this regard, it is preferable that PEG is included and that it is PEG 3350 and/or PEG 4000.
Particularly beneficial non-aqueous gel-based topical compositions may comprise, as part of the excipient system, a gelling agent in an amount of from about 0.5% to about 5%, preferably from about 1% to about 3%, by weight of the composition. Any suitable getting agent may be used, such as hydroxypropylcellulose MF (HPC MF) and/or hydroxypropylcellulose (HPC GF). If an aqueous gel-based topical composition is required then, in addition to the gelling agent, water in an amount of from about 10% to about 30% by weight of the composition may be added. In such cases it is optional, and preferable, that a preservative, such as benzyl alcohol, is added to the excipient system. The preservative may be present in any suitable amount, however, an amount of from about 0.1% to about 5% by weight of the composition is typical.
Particularly beneficial cream-based topical compositions may comprise, as part of the excipient system, water, oil phase, emollient, emulsifier, and optionally a preservative. Preferably, the water may be present in an amount of from about 20% to about 35% by weight of the composition, the oil phase preferably in an amount of from about 0.5% to about 25% by weight of the composition, the emollient preferably in an amount of from about 5% to about 15% by weight of the composition, the emulsifier preferably in an amount of from about 2% to about 10% by weight of the composition. When present, the preservative may be present in an amount of from about 0.1% to about 5% by weight of the composition.
Particularly suitable emollients are cetostearyl alcohol and/or Span 60. A particularly suitable emulsifier is Tween, such as Tween 80. A particularly suitable preservative is benzyl alcohol.
The skilled person will understand the breadth of compounds that may form the oil phase. Typical oil phases useful in the topical compositions are those that comprise one or more triglycerides, such as crodamol GTCC; liquid paraffin, or a combination thereof.
The topical compositions may have increased stability (both chemical and physical stability). Ointments, aqueous gels and non-aqueous gels may exhibit further enhanced stability. Therefore, a particular feature the invention is that the pharmaceutical composition is a topical composition that comprises an excipient system that comprises
(a) an oleaginous base, such as petroleum jelly, and/or PEG selected from PEG 1000 to PEG 10000 in an amount of from about 20% to about 30% by weight of the composition, preferably the PEG is PEG 3350 or PEG 4000; or
(b) a gelling agent in an amount of from about 0.5% to about 5%, preferably from about 1% to about 3%, by weight of the composition, preferably the gelling agent is HPC MF or HPC GF, and optionally wherein the excipient system further comprises
(i) water in an amount of from about 10% to about 30% by weight of the composition; and
(ii) benzyl alcohol in an amount of from about 0.1% to about 5% by weight of the composition.
The excipient system, particular that of non-aqueous gel-based compositions, may comprise low molecular weight alcohol, i.e. Ci to Cs alcohol, such as methanol, ethanol, propanol, butanol, pentanol or a combination thereof. It is preferable that the low molecular weight alcohol is ethanol. When present, the low molecular weight alcohol may be in the excipient system in an amount of from about 2% to about 8% by weight of the composition. The excipient system may comprise an antioxidant, preferably BHT or ascorbic acid. This may be present in any suitable amount, such as from about 0.01% to about 0.5%, preferably from about 0.05% to about 0.2%, by weight of the composition. The antioxidant may further increase stability of the topical composition, particularly the chemical stability of the composition.
The excipient system may comprise a UV filter. Any suitable UV filter may be used, such as octisalate. The UV filter may be present in any suitable amounts, such as from about 4% to about 8% by weight of the composition.
A specific ointment-based topical composition may comprise
(A) the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof present in an amount of from about 1 % to about 5% by weight of the composition;
(B) the excipient system which comprises
(i) PEG 400 in an amount of from about 15% to about 35% by weight of the composition;
(ii) glycerol in an amount of from about 12% to about 22% by weight of the composition;
(iii) propylene glycol in an amount of from about 5% to about 15% by weight of the composition;
(iv) diethyl glycol monoethyl ether in an amount of from about 5% to about 25% by weight of the composition;
(v) PEG selected from PEG 1000 to PEG 10000 in an amount of from about 20% to 30% by weight of the composition, preferably the PEG is PEG 3350 or PEG 4000; and
(vi) an antioxidant, preferably BHT, in an amount of from about 0.05% to about 0.5% by weight of the composition. A specific aqueous gel and non-aqueous gel-based topical compositions may comprise
(A) the compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof present in an amount of from about 0.5% to about 4% by weight of the composition;
(B) the excipient system which comprises
(i) PEG 400, preferably SR PEG 400, in an amount of from about 25% to about 45% by weight of the composition;
(ii) glycerol in an amount of from about 17% to about 23% by weight of the composition;
(iii) propylene glycol in an amount of from about 17% to about 23% by weight of the composition;
(iv) diethyl glycol monoethyl ether in an amount of from about 7% to about 13% by weight of the composition; and
(v) either
(a) low molecular weight alcohol, preferably ethanol, in an amount of from about 2% to about 8% by weight of the composition; or
(b) water in an amount of from about 10% to about 30% by weight of the composition; and benzyl alcohol in an amount of from about 0.1% to about 5% by weight of the composition;
(vi) a gelling agent in an amount of from about 1% to about 3%, by weight of the composition, preferably the gelling agent is HPC MF and/or HPC GF; and
(vii) optionally an antioxidant, preferably BHT, in an amount of from about 0.05% to about 0.5% by weight of the composition.
A specific cream-based topical composition may comprise (A) the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof present in an amount of from about 0.3% to about 1.5% by weight of the composition;
(B) the excipient system which comprises (i) PEG 400, preferably SR PEG 400, in an amount of from about 5% to about 15% by weight of the composition;
(ii) glycerol in an amount of from about 5% to about 15% by weight of the composition;
(iii) propylene glycol in an amount of from about 7% to about 13% by weight of the composition;
(iv) diethyl glycol monoethyl ether in an amount of from about 12% to about 17% by weight of the composition;
(v) water in an amount of from about 20% to about 35% by weight of the composition;
(vi) an oil phase comprising one or more triglycerides, such as crodamol GTCC; liquid paraffin, or a combination thereof in an amount of from about 0.5% to about 25%, preferably from about 3% to about 9%, by weight of the composition;
(vii) cetostearyl alcohol in an amount of from about 5% to about 15% by weight of the composition; and
(viii) Span 60 in an amount of from about 0.2% to about 1% by weight of the composition; and
(ix) optionally Tween 80 in an amount of from about 2% to about 10% by weight of the composition;
(x) optionally an antioxidant, preferably BHT or ascorbic acid, in an amount of from about 0.05% to about 0.5% by weight of the composition;
(xi) optionally benzyl alcohol in an amount of from about 0.1% to about 5% by weight of the composition; and
(xii) optionally a UV filter, such as octisalate, preferably in an amount of from about 4% to about 8% by weight of the composition.
The skilled person will understand the processes that may be used to form the topical pharmaceutical compositions. The topical compositions may be formed by any suitable method, such as bringing the ingredients together in a mixer and mixing them until a homogeneous composition is formed. One preferred method of forming a topical pharmaceutical composition involves combining the compound of Formula (I) with one or more of the components of the excipient system to dissolve said compound, and then adding the remaining components of the excipient system in a mixer. It may be preferable to mix the compound of Formula (I) with a mixture comprising PEG selected from PEG 100 to PEG 900, such as PEG 400, to dissolve said compound prior to the addition of the remaining components of the excipient system. In a more preferred method, the compound of Formula (I) may be mixed with a mixture comprising PEG 400, propylene glycol, glycerol, and dialkyl glycol monoalkyl ether, to dissolve said compound prior to mixing with the remaining components of the excipient system. Certain excipients, such as PEG 3350, may require heating (for instance to 65 °C) to liquefy the excipient so that it may be combined with the other components. The exact method of forming the topical pharmaceutical composition will be easily ascertained by the skilled person.
As used herein 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.
Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of 0.0001 to 30 g/kg, typically 0.01 to 10 g per patient, while for oral administration suitable daily doses are of the order of 0.01 to 100 g/kg.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the agents of the 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.
The invention further provides pharmaceutical 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. Such 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.
The agent of the invention may be administered either simultaneously with, or before or after, one or more other therapeutic agents. The agent of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
The invention includes a product comprising a compound of the invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a condition or disorder which is mediated by Trk, in particular Trk A, B, and C. Products provided as a combined preparation include a composition comprising the agent of the invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or the agent of the invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising an agent of the invention and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains an agent of the invention. In one embodiment, the kit comprises means for separately retaining said compositions, such as 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 topical, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the agent of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the agent of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the agent of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the agent of the invention and the other therapeutic agent.
Accordingly, the invention provides the use of an agent of the invention for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the medicament is administered with a compound of the invention.
The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention. The invention also provides a compound of the invention for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the compound of the invention is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the other therapeutic agent is prepared for administration with a compound of the invention. The invention also provides a compound of the invention for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein agent of the invention is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the other therapeutic agent is administered with a compound of the invention.
The invention also provides the use of a compound of the invention for treating a condition or disorder which is mediated by T rk, in particular T rk A, B, and C, wherein the subject has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, wherein the subject has previously (e.g. within 24 hours) been treated with a compound of the invention.
In one embodiment, a compound of the invention is administered alongside one or more other therapeutically active agents. For example, the compounds of the invention may therefore be used in combination with one or more further agents for the treatment of atopic dermatitis, such as: one or more topical and/or oral corticosteroids; one or more antihistamines; one or more antibiotics; one or more topical calcineurin inhibitors such as tacrolimus and/or pimecrolimus; one or more systemic immunosuppressants such as cyclosporin, methotrexate, interferon gamma-1 b, mycophenolate mofetil and/or azathioprine; one or more PDE4 inhibitors such as crisaborole; one or more monoclonal antibodies such as dupilumab.
A skilled person will appreciate that an agent of the invention may be administered to a subject, particularly a human subject, wherein the subject is being treated with phototherapy for a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis. A compound of the invention may also be administered to a subject, particularly a human subject, wherein the subject has previously ( e.g . within 24 hours) been treated with phototherapy for a condition or disorder in which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis. A subject, particularly a human subject may also be treated with phototherapy for a condition or disorder which is mediated by Trk, in particular Trk A, B, and C, such as atopic dermatitis wherein a compound of the invention has previously (e.g. within 24 hours) been administered to a subject.
Accordingly, the invention includes as a further aspect a combination of an agent of the invention with one or more further agents for the treatment of atopic dermatitis, such as: one or more topical and/or oral corticosteroids; one or more antihistamines; one or more antibiotics; one or more topical calcineurin inhibitors such as tacrolimus and/or pimecrolimus; one or more systemic immunosuppressants such as cyclosporin, methotrexate, interferon gamma-1 b, mycophenolate mofetil and/or azathioprine; one or more PDE4 inhibitors such as crisaborole; one or more monoclonal antibodies such as dupilumab; and phototherapy.
If a chemical structure and the associated chemical name do not agree, then the chemical structure takes precedence, unless it is readily understood that the converse is true.
EXAMPLES
As mentioned above, the compounds of Formula (VII) may be prepared as set out in WO 2020/039209 (the content of which is incorporated herein in its entirety by reference). However, they may be synthesised using the methods described herein, or other methods, which are known in the art.
It should be understood that the organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the preferred embodiments encompasses any tautomeric form of the drawn structure.
It is understood that the invention is not limited to the embodiments set forth herein for illustration, but embraces all such forms thereof as come within the scope of the above disclosure.
The following abbreviations have been used.
Ac Acetyl
DCM Dichloromethane
ES+ electrospray ionization
Et ethyl
EtOAc ethyl acetate
EtOH ethanol h hour(s)
HPLC High Performance Liquid Chromatography
LCMS Liquid Chromatography Mass Spectrometry
M molar
MeCN acetonitrile
MeOH methanol
[MH]+ protonated molecular ion
Min minute(s) mol molar
Rt retention time rt room temperature
TFA trifluoroacetic acid
THF Tetrahydrofuran
UPLC Ultra Performance Liquid Chromatography
UV Ultraviolet Intermediate 1
4-Fluoro-2-iodo-1-(methylsulfanyl)benzene 2-Bromo-4-fluoro-1-(methylsulfanyl)benzene (0.5 g, 2.26 mmol) was added dropwise to a suspension of activated Mg turnings (1.92 g, 79 mmol) under N2 in dry THF (80 ml) and the reaction warmed until Grignard formation had initiated. The remaining 2-bromo-4-fluoro-1-(methylsulfanyl)benzene (17 g, 76.89 mmol) was added dropwise, so as to maintain the temperature below 50°C and after complete addition, the reaction was allowed to cool to rt and stirred for 16 h. The solution was added via cannula to an ice-cooled solution of iodine (24.11 g, 94.99 mmol) in dry THF (80 ml_) maintaining the temperature below 10 °C. The reaction was stirred at 0°C for 1 h, at rt for 1 h, then poured into an ice-cold sat. NH4CI soln. (300 ml_). The mixture was concentrated in vacuo to remove organic solvents then extracted with Et2<D (3 x 300 ml_). The combined organic layers were washed with a sat. Na2S2C>3 solution, dried (Na2SC>4), and concentrated in vacuo to afford the title compound as a brown oil (21.5 g, 83%).
1H NMR (CDC , 396 MHz): d: 7.55 (m, 1H), 7.08-7.11 (m, 2H), 2.45 (s, 3H). Intermediate 2
1 -fert-Butyl 2 (1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl) (2S,4S)-4- fluoropyrrolidine-1,2-dicarboxylate
Figure imgf000055_0001
A solution of (2S,4S)-1-(fe/f-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.07 g, 4.6 mmol) in EtOAc (12.5 ml_) was added to a stirred mixture of N- hydroxyphthalimide (0.75 g, 4.6 mmol) and N,N'-dicyclohexylcarbodiimide (0.95 g, 4.6 mmol) in EtOAc (12.5 ml) under I\l2(g) and the reaction stirred at rt for 4 h. The mixture was filtered through a plug of silica, washed with EtOAc (50 ml_) and the filtrate concentrated in vacuo. The resulting oil was re-dissolved in EtOAc (20 ml_), washed with sat. aq. NaHCC>3 (4 x 30 mL) and the organic layer dried (MgSCL), filtered and evaporated under reduced pressure to afford the title compound as a white solid (1.55 g, 89 %). LCMS m/z = 278.9 [M-Boc]+
Intermediate 3 ferf -Butyl (2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidine-1- carboxylate
Figure imgf000056_0001
Dry N,N-dimethylacetamide (4 mL) was added to nickel dibromide glyme complex (0.09 g, 0.291 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.08 g, 0.298 mmol) under N2. The mixture was stirred for 15 min, then 4-fluoro-2-iodo-1- (methylsulfanyl)benzene (Intermediate 1, 0.51 g, 1.49 mmol), 1-te/f-butyl 2-(1 ,3- dioxo-2,3-dihydro-1H-isoindol-2-yl) (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (Intermediate 2, 0.62 g, 1.64 mmol) and zinc dust (0.251 g, 3.84 mmol) were added and the reaction mixture was stirred at 28 °C for 17 h. The mixture was filtered through a plug of silica and washed with diethyl ether (75 ml). The collected solution was extracted with brine (4 x 75 ml), the organic layers were combined, dried (MgSCL), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with heptanes: EtOAc, 100:0 to 90:10 to afford the title compound as a yellow oil (0.24 g, 36%).
LCMS m/z = 230.1 [M-Boc]+
Intermediate 4
(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidine To a solution of tert- butyl (2R,4S)-4-fluoro-2-[5-fluoro-2-
(methylsulfanyl)phenyl]pyrrolidine-1-carboxylate (Intermediate 3, 1.21 g, 3.67 mmol) in MeOH (15 ml_) was added HCI (4M solution in dioxane, 10 ml_) and the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo to afford a dark brown oil which was taken up in MeOH (2 ml_) and loaded onto an SCX cartridge and flushed with 7N ammonium hydroxyde in MeOH. The combined solution was concentrated in vacuo to afford the title compound as a dark orange oil (0.4 g, 53%).
LCMS m/z = 230.0 [M+H]+
Intermediate 5
Ethyl 6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1- yl]imidazo[1,2-b]pyridazine-3-carboxylate
Figure imgf000057_0001
Ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (89 mg, 0.40 mmol), KF (253 mg, 4.36 mmol) and (2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidine (Intermediate 4, 100 mg, 0.38 mmol) were suspended in dry degassed DMSO (5 ml_). The reaction was heated at 130°C for 20 h. The mixture was diluted with EtOAc (20 ml_), washed with water (15 ml_) and brine (2 x 15 ml_), dried (Na2S04), filtered and evaporated to dryness to afford the title compound as a light yellow solid (174 mg, 85%).
LCMS m/z = 419.0 [M+H]
Intermediate 6 6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1- yl]imidazo[1,2-b]pyridazine-3-carboxylic acid
Figure imgf000058_0001
To a solution of ethyl 6-[(2R,4S)-4-fluoro-2-[5-fluoro-2- (methylsulfanyl)phenyl]pyrrolidin-1 -yl]imidazo[1 ,2-b]pyridazine-3-carboxylate
(Intermediate 5, 174 g, 0.42 mmol) in EtOH (897 mI_) and water (143 mI_) was added KOH (117 mg, 2.08 mmol). The reaction was stirred at rt for 15 min, then diluted with water (20 ml_) and washed with EtOAc (2 x 20 ml_). The water was acidified to pH 4, then extracted with EtOAc (3 x 20 ml_) and concentrated in vacuo to afford the title compound as a light yellow vitreous solid (94 mg, 50%).
LCMS m/z = 391 [M+H]+
Intermediate 7 6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1 -yl]-N-[(3- hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboxamide
Figure imgf000058_0002
To a solution of 6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1- yl]imidazo[1,2-b]pyridazine-3-carboxylic acid (Intermediate 6, 40 mg, 0.102 mmol) in dry DCM (0.73 ml_) at rt were added TPTU (365 mg, 0.122 mmol), 3- hydroxybenzylamine (138 mg, 0.122 mmol) and DIPEA (0.035 ml, 0.204 mmol) and the reaction mixture stirred at rt for 2 h. The reaction was diluted with DCM (15ml), washed with saturated NaHCC>3 solution (10 ml_), saturated NH4CI solution (10 ml_) and saturated brine solution (10 ml_). The organic phase was dried over MgSCU, concentrated in vacuo and purified by column chromatography (1-6 % MeOH in DCM) to afford the title compound as a colourless solid (281 mg, 55 %). LCMS m/z = 496 [M+H]+
1H NMR (MeOD-cU, 396 MHz): d: 8.95 (s, 1 H), 8.73 (d, 1 H), 8.06 (m, 2H), 7.82-7.77 (m, 3H), 7.63-7.56 (m, 3H), 6.38-6.17 (m, 2H), 5.47-5.37 (m, 2H), 4.95-4.82 (m, 2H),
3.94-3.85 (m, 1H), 3.31 (s, 3H), 3.09-2.89 (m, 1 H).
Example 1
Methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-[3-[[[6-(2R,4S)-4-fluoro-2-(5-fluoro-2- methylsulfanyl-phenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3- carbonyl]amino]methyl]phenoxy]tetrahydropyran-2-carboxylate
Figure imgf000059_0001
2,3,4-Tri-O-acetyl-a-D-glucuronide methyl ester trichloroacetimidate (362mg, 757mol) and 6-[(2R,4S)-4-fluoro-2-(5-fluoro-2-methylsulfanyl-phenyl)pyrrolidine-1- yl]-N-[(3-hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboxamide (Intermediate 7, 250 mg, 505 pmol) were dissolved in DCM (7 ml_), BF3.0Et2 (31.1 mI_, 252 pmol) was added dropwise at 0 °C and the reaction mixture was stirred for 2h. BF3.0Et2 (200 mI_, 1.62 mmol) was added dropwise at 0 °C and the reaction mixture was stirred for 30min. The reaction mixture was quenched with saturated aqueous NaHCC>3 (7 ml_) and the organic phase was dried (MgSCL) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound as a white solid (256 mg, 58%). LCMS (ES+): 812.2 [MH]+.
Example 2
(2S,3S,4S,5R,6S)-6-[3-[[[6-[(2R,4S)-4-fluoro-2-(5-fluoro-2-methylsulfanyl- phenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3- carbonyl]amino]methyl]phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2- carboxylic acid
Figure imgf000060_0001
A solution of lithium hydroxide monohydrate (51.2 mg, 1.22 mmol) in water (1 ml_) was added to a solution of Example 1 (256 mg, 0.29 mmol) in THF/water (2:1, 3 ml_) at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 4h. Acetic acid (100 mI_, 1.75 mmol) was added and the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give the title compound (119 mg, 60% yield) as a white solid.
LCMS (ES+): 672.1 [MH]+.
UPLC: Rt 4.16min, 99.1% purity.
In vitro assays
A suitable assay for determining the Trk inhibition activity of a compound is detailed herein below.
To determine the IC50 of small molecule compounds for the Human TRK receptors, HTRF® KinEASE™ kinase kits from Cisbio were used. Assays were carried out in low volume, black 384-well plates. Recombinant Human TRK enzymes (Invitrogen) were incubated in the presence or absence of the compound (11-point dose response with FAC as 10 mM) for 30 minutes at 23 °C. Kinase reaction was started by addition of ATP to a mixture containing the enzyme (NTRK1-4nM, NTRK2-1nM, NTRK3-10nM) and substrate (1 mM). Kinase reaction was allowed to carry on for 10 to 45 minutes at 23 °C after which it was stopped by addition of the detection mix (supplied by vendor) containing EDTA, TK-Ab- labelled with Eu3+-cryptate (1:200 dilutions) and Streptavidin-XL665 (250nM). Assay plates were incubated in this detection mix for 60 minutes at 23 °C. The resulting TR-FRET signal, calculated as the fluorescence ratio at 665/620 nm, was read on an Envision and was proportional to the level of phosphorylation of the peptide in the presence or absence of the compound.
The uniformity of the plates were assured with Z’ value [1-{3*(SDHPE+SDZPE)/ (ZPE-HPE)}]. The percent (%) effect i.e. Inhibition of compound was calculated in comparison to the signal in the positive (HPE) and negative control (ZPE) wells within each assay plate. The endpoint value % Inhibition for the Standard compound was evaluated in each experiment as a quality control measure. IC50 was determined by plotting compound inhibition at respective dose in Graphpad prism5 using four parameter logistic curve fit.
Using the assay described above, the compounds of the present invention exhibit Trk inhibition activity, expressed as an IC50 value, of less than 1 mM. Preferred examples have IC50 values of less than 200 nM and particularly preferred examples have IC50 values of less than 50 nM. The IC50 value for Example 2 is below 0.70 nM in each of TrkA, TrkB and TrkC. The compounds of the invention can therefore be used in the treatments and methods discussed above.

Claims

Claims
1. A compound of Formula (I)
Figure imgf000062_0001
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N- oxide, and/or prodrug thereof, wherein
X is a direct bond or -(CR6R7)-;
Y is a direct bond or selected from
Figure imgf000062_0002
wherein * denotes the point of attachment to X and ** denotes the point of attachment to Z;
Z is a direct bond or selected from -CH2-, -C(O)-, and -S(C>2)-;
R1 is -OR, wherein R is an optionally substituted oxane or oxolane; R2 is selected from H and -SMe;
R3 is selected from H and halo;
R4 is selected from H and (Ci-C3)alkyl;
R5 is selected from H, -OH and halo;
R6 and R7 are each independently selected from H and (Ci-C3)alkyl; each R8 is independently selected from halo and (Ci-C3)alkoxy; each R9 is independently selected from halo; m is 1 or 2; n is 1 or 2; p is 1 or 2; provided that the sum of m, n, and p is from 2 to 4; q is 0, 1, 2, 3 or 4; and r is 0, 1, 2, or 3.
2. The compound as claimed in claim 1, wherein the compound is of Formula
(IA) wherein
Figure imgf000063_0001
are as defined in claim 1.
3. The compound as claimed in claim 1 or claim 2, wherein the compound is of Formula wherein X,
Figure imgf000063_0002
are as defined in claim 1.
4. The compound as claimed in any one of claims 1 to 3, wherein Y is a direct bond.
5. The compound as claimed in any one of claims 1 to 4, wherein X is a direct bond.
6. The compound as claimed in any one of claims 1 to 5, wherein the compound is of Formula (IC)
Figure imgf000063_0003
wherein R1, R2, R3, R4, R5, R9, R, and q are as defined in claim 1.
7. The compound as claimed in any one of claims 1 to 6, wherein the compound is of Formula (ID)
Figure imgf000064_0001
wherein R1, R9, R, and q and are as defined in claim 1.
8. The compound as claimed in any one of claims 1 to 7, wherein R is an oxane or oxolane that is substituted with one or more groups selected from the group consisting of halo, (Ci-C3)alkyl, -NR10R11, -OR12, -COOH, -CHO, and
-CH2OR12, wherein the (Ci-C3)alkyl is optionally substituted with one or more halo; wherein R10 and R11 are independently selected from H and (Ci-C3)alkyl optionally substituted with one or more halo, or R10 and R11 can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle, wherein the 5- or 6-membered heterocycle is optionally substituted with one or more groups selected from C1-C6 alkyl optionally substituted with one or more halo, halo, -OH, and -NH2; and each R12 is independently selected from H and (Ci-C3)alkyl optionally substituted with one or more halo.
9. The compound as claimed in any one of claims 1 to 8, wherein R1 is selected from the list consisting of allose, aldose, glucose, mannose, idose, galactose, talose, fructose, ribose, deoxyribose, or a derivative thereof, preferably joined to the reminder of the compound through an -O- group attached to a ring carbon adjacent to the oxygen atom in the oxane or oxolane ring.
10. The compound as claimed in claim 9, wherein R1 is a sugar acid, preferably a uronic acid derivative.
11. The compound as claimed in any one of claims 1 to 10, wherein R1 is
12. The compound as claimed in any one of claims 1 to 11, wherein the compound is
Figure imgf000065_0001
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and one or more pharmaceutically acceptable excipients.
14. The pharmaceutical composition according to claim 13 in combination with one or more other therapeutic agents.
15. A compound according to any one of claims 1 to 12 for use as a pharmaceutical.
16. A compound according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13 or claim 14, for use in treating or preventing a condition or disorder which is mediated by Trk.
17. Use of a compound as defined in any one of claims 1 to 12 in the manufacture of a medicament for treating or preventing a condition or disorder which is mediated by Trk.
18. A method for preventing or treating a condition or disorder which is mediated by Trk which comprises administering to a subject a therapeutically effective amount of the compound as defined in any one of claims 1 to 12.
19. The compound or pharmaceutical composition for use according to claim 16, the use according to claim 17, or the method according to claim 18, wherein the condition or disorder is mediated by TrkA, TrkB, and/or TrkC.
20. The compound or pharmaceutical composition for use according to claim
16 or claim 19, the use according to claim 17 or claim 19, or the method according to claim 18 or claim 19, wherein the condition or disorder is atopic dermatitis.
21. The compound or pharmaceutical composition for use according to claims 16, 19 or 20, the use according to claims 17, 19 or 20, or the method according to claims 18, 19 or 20, wherein the compound is administered topically.
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