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WO2011095772A2 - Nouveaux agents thérapeutiques iminosucres - Google Patents

Nouveaux agents thérapeutiques iminosucres Download PDF

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Publication number
WO2011095772A2
WO2011095772A2 PCT/GB2011/000139 GB2011000139W WO2011095772A2 WO 2011095772 A2 WO2011095772 A2 WO 2011095772A2 GB 2011000139 W GB2011000139 W GB 2011000139W WO 2011095772 A2 WO2011095772 A2 WO 2011095772A2
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Prior art keywords
compound
disease
composition
alkyl
dnj
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PCT/GB2011/000139
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WO2011095772A3 (fr
Inventor
George William John Fleet
Richard Storer
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Summit Therapeutics Ltd
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Summit Corp PLC
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Priority claimed from GBGB1001809.1A external-priority patent/GB201001809D0/en
Priority claimed from GBGB1006431.9A external-priority patent/GB201006431D0/en
Application filed by Summit Corp PLC filed Critical Summit Corp PLC
Publication of WO2011095772A2 publication Critical patent/WO2011095772A2/fr
Publication of WO2011095772A3 publication Critical patent/WO2011095772A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to carbon-branched iminosugars, to compositions (including pharmaceutical compositions) containing them and to methods of treatment and prophylaxis using the compounds and compositions.
  • N-alkyl derivatives of deoxynojirimycin are drugs and have potential for the treatment of a number of diseases.
  • N-butyl-DNJ miat, Zavesca®, ⁇ / ⁇ - DNJ partially rescues the defective F508del-CFTR function in CF-KM4 cells and is therefore of interests for the chemotherapeutic treatment of cystic fibrosis.
  • the present inventors have developed an efficient synthesis of various carbon-branched iminosugars, including carbon-branched azetidine and pyrrolidine iminosugars such as the carbon-branched pyrrolidine iminosugar isoDAB [1 ,4-dideoxy-2-hydroxymethyl-1 ,4-imino- D-threitol].
  • IsoDAB is a potent and specific inhibitor of a number of a-glucosidases and provides the first example of a carbon branched iminosugar pyrrolidine showing significant glycosidase inhibition.
  • DAB is an excellent inhibitor of glycogen phosphorylase and a moderate inhibitor of glycoprotein processing glucosidases, but isoDAB showed no inhibition of these enzymes.
  • the combination of potency and specificity of isoDAB finds application in various methods of treatment, and in particular isoDAB and related carbon-branched iminosugar pyrrolidines are likely to exhibit an improved protective/therapeutic index compared with known pyrrolidine iminosugar therapeutics.
  • X is selected from H; OH and F;
  • Y is selected from H and CH 2 X;
  • R 1 is selected from H; linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and aralkyi and wherein the optional substitution may be with one or more groups independently selected from: -OH; -F; -CI; -Br; -I; -NH 2 ; alkylamino;
  • dialkylamino linear or branched alkyl, alkenyl, alkynyl and aralkyi; aryl; heteroaryl; linear or branched alkoxy; aryloxy; aralkoxy; -(alkylene)oxy(alkyl); -CN; -N0 2 ; - COOH; -COO(alkyl); -COO(aryl); -C(0)NH(alkyl); -C(0)NH(aryl); sulfonyl;
  • alkylsulfonyl arylsulfonyl; sulfamoyl; alkylsulfamoyl; alkylthio; alkylsulfonamide; arylsulfonamide; -NHNH 2 ; and -NHOH; or a bioisostere, pharmaceutically acceptable salt or derivative thereof.
  • R 1 is selected from H, C 1-18 alkyl (for example, d -9 alkyl, e.g. d. 6 alkyl), C 2 . 18 alkenyl (for example, C 2 -g alkenyl, e.g. C 2-6 alkenyl) and C 2 . 18 alkynyl (for example, C 2 . 9 alkynyl, e.g. C 2 . 6 alkynyl).
  • R may be -H and R 1 selected from C 1-18 alkyl (for example, C 1-g alkyl, e.g. C 1-6 alkyl), C 2-18 alkenyl (for example, C 2 . g alkenyl, e.g.
  • R 1 represents H; C1-15 alkyl, C1-15 alkenyl or C1 -15 alkynyl, optionally substituted with one or more R 2 ; oxygen or an oxygen containing group such that the compound is an N-oxide; C(0)OR 3 ; C(0)NR 3 R 4 ; S0 2 NR 3 ; OH, OR 3 , or formyl.
  • R 1 may represent C1-9 alkyl, optionally substituted with up to 6 OH, NR 3 R 4 , aryl, 0-C1-3 alkyl, 0-C1-3 alkenyl, C0 2 H, NH(NH)NH 2 , CONR 3 R 4 ; C(0)OR 3 ;
  • “comprising,” are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers.
  • the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
  • the term “treatment” or “treating” refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s).
  • treatment refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population.
  • treatment is used synonymously with the term “prophylaxis”.
  • subject (which is to be read to include “individual”, “animal”, “patient” or
  • mammalian where context permits defines any subject, particularly a mammalian subject, for whom treatment is indicated.
  • Mammalian subjects include, but are not limited to, humans, primates, domestic animals, farm animals, pet animals and rodents such as mice, rats, hamsters and guinea pigs.
  • the subject is a human.
  • proteostatic disease is a term of art used to define a set of diseases mediated, at least in part, by deficiencies in proteostasis. The term therefore covers aggregative and misfolding proteostatic diseases, including in particular neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease and Huntington's disease), lysosomal storage disorders, diabetes, emphysema, cancer and cystic fibrosis.
  • neurodegenerative disorders e.g. Parkinson's disease, Alzheimer's disease and Huntington's disease
  • lysosomal storage disorders e.g. Parkinson's disease, Alzheimer's disease and Huntington's disease
  • diabetes emphysema
  • cystic fibrosis e.g., cystic fibrosis.
  • metabolic syndrome is used herein to define conditions characterized by the presence of three or more of the following symptoms: central obesity (waist measurement of more than 40 inches for men and more than 35 inches for women); high levels of triglycerides (150 mg/dL or higher); low levels of HDL (below 40 mg/dL for men and below 50 mg/dL for women) and high blood pressure (130/85 mm Hg or higher).
  • the term therefore includes conditions defined in accordance with the definition of metabolic syndrome by the World Health Organization: (a) fasting plasma glucose above 6.1 mmol/L; (b) blood pressure above140/90 mm Hg; and (c) one or more of the following: (i) plasma triglycerides above 1.7mmol/L; (ii) HDL below 0.9 and 1.0 mmol/L (for men and women, respectively); (iii) a body mass index above 30 kg/m 2 .
  • references herein to the treatment of metabolic syndrome are to be interpreted to include the treatment of any or all of the disorders associated with metabolic syndrome, including in particular obesity (e.g. central obesity) and elevated serum triglycerides.
  • references herein to the treatment of type 1 or type 2 diabetes are to be interpreted to include the treatment of type 1 and type 2 diabetes per se as well as pre-diabetes (incipient diabetes) and insulin resistance.
  • pre-diabetes or "incipient diabetes” defines conditions in which elevated levels of glucose or glycosylated haemoglobin are present in the absence of diabetes.
  • pharmacoperone is a term of art (from “pharmacological chaperone") used to define a class of biologically active small molecules (sometimes also referred to in the art as “chemical chaperones”) that serve as molecular scaffolds, causing otherwise misfolded mutant proteins to fold and route correctly within the cell.
  • ⁇ / ⁇ -DNJ is used sensu stricto to cover N-butyldeoxynojirimycin (a.k.a.
  • Miglustat, ⁇ / ⁇ -DNJ and Zavesca® as well as its pharmaceutically acceptable salts and derivatives.
  • the term is also used sensu lato to cover various derivatives and analogues of deoxynojirimycin (DNJ) which can restore CFTR function, including for example those described in WO2005/046672 and WO2007/123403 (the disclosure of which relating to the structure of the DNJ derivatives is hereby incorporated by reference).
  • DNJ derivatives may have glucosidase inhibitory activity.
  • an effective amount of a compound or composition defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition.
  • the amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge.
  • a therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure.
  • association of the two or more compounds/agents in a combination may be physical or non-physical.
  • Examples of physically associated combined compounds/agents include:
  • compositions e.g. unitary formulations comprising the two or more
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);
  • non-physically associated combined compounds/agents examples include:
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents
  • material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;
  • combination therapy is intended to define therapies which comprise the use of a combination of two or more compounds/agents (as defined above).
  • compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or
  • combination therapy may also differ with respect to the route of administration.
  • the term "pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging.
  • dosing means e.g. measuring device
  • delivery means e.g. inhaler or syringe
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical kit may optionally further comprise instructions for use.
  • the term "pharmaceutical pack" defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging.
  • pharmaceutical packs comprising a combination of two or more compounds/agents
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical pack may optionally further comprise instructions for use.
  • the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the compounds described herein.
  • the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • references to the compounds (e.g. iminosugars) of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers.
  • the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g. by use of dash-wedge structural formulae) the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted. In cases where the
  • the invention contemplates use of an isolated eutomer.
  • bioisostere (or simply isostere) is a term of art used to define drug analogues in which one or more atoms (or groups of atoms) have been substituted with replacement atoms (or groups of atoms) having similar steric and/or electronic features to those atoms which they replace.
  • the substitution of a hydrogen atom or a hydroxyl group with a fluorine atom is a commonly employed bioisosteric replacement.
  • Sila-substitution (C/Si-exchange) is a relatively recent technique for producing isosteres.
  • sila-substituted isosteres may exhibit improved pharmacological properties, and may for example be better tolerated, have a longer half-life or exhibit increased potency (see for example Englebienne (2005) Med. Chem., 1 (3): 215-226).
  • replacement of an atom by one of its isotopes, for example hydrogen by deuterium may also lead to improved pharmacological properties, for example leading to longer half-life (see for example Kushner et al (1999) Can J Physiol Pharmacol.
  • the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention.
  • pharmaceutically acceptable derivative as applied to the compounds of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent compounds of the invention.
  • the pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with mammalian tissues without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio).
  • Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of the parent compounds of the invention.
  • the derivatives may be active per se, or may be inactive until processed in vivo.
  • the derivatives of the invention act as prodrugs.
  • Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo.
  • Other preferred prodrugs are covalently bonded compounds which release the active parent drug according to general formula (I) after cleavage of the covalent bond(s) in vivo.
  • pharmaceutically acceptable salt as applied to the inhibitors of the invention defines any non-toxic organic or inorganic acid addition salt of the free base which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit/risk ratio. Suitable pharmaceutically acceptable salts are well known in the art.
  • Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4- hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p- toluenesulfonic acid).
  • organic carboxylic acids for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic
  • compositions containing the compounds of the invention defines compositions in which the compound of the invention is at least 90% pure, preferably at least 95% pure and most preferably at least 99% pure.
  • alkyl defines a straight or branched saturated hydrocarbon chain.
  • Ci-C 6 alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n- propyl, isopropyl, t-butyl, n-hexyl.
  • d-Cg alkyl refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms.
  • Ci-C 15 alkyl refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms.
  • the alkyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • alkyl may define the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C Cso for straight chain, C 3 -C 30 for branched chain), and more preferably up to 20, 15, 12, 10, 8 or 6.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • aralkyl defines an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • aryl group e.g., an aromatic or heteroaromatic group.
  • Ci-C 4 alkyl has a similar meaning except that it contains from one to four carbon atoms.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl, and 3-hexenyl.
  • C C 6 haloalkyl refers to a C ⁇ e alkyl group as defined above substituted by one or more halogen atoms.
  • alkenyl defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon double bond.
  • Ci-C 6 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • C C 9 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • C C 5 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • alkenyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • alkynyl defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon triple bond.
  • C C 6 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • Ci-C 9 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • C1-C15 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • Preferred is C C 6 alkynyl. Examples include ethynyl, 2-propynyl, and 3-hexynyl.
  • the alkynyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • heterocyclyl defines a saturated or partially saturated 3 to 14 membered ring system (except when alternative numbers of ring atoms are specified) similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O, S, SO or S0 2 .
  • Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine.
  • carbocyclyl means a mono- or polycyclic residue containing 3 or more (e.g. 3-14, 3-10 or 3-8) carbon atoms.
  • the carbocyclyl residues of the invention may be optionally substituted by one or more halogen atoms.
  • Mono- and bicyclic carbocyclyl residues are preferred.
  • the carbocyclyl residues can be saturated or partially unsaturated and include fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and also bridged systems such as norbornyl and adamantyl.
  • cycloalkyls Saturated carbocyclyl residues are preferred and are referred to herein as "cycloalkyls" and the term “cycloalkyl” is used herein to define a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and also bridged systems such as norbornyl and adamantyl.
  • the cycloalkyl residues of the invention may be optionally substituted by one or more halogen atoms.
  • aryl defines a 5-14 (e.g. 5-10) membered aromatic mono-, bi- or tricyclic group at least one ring of which is aromatic.
  • bicyclic aryl groups may contain only one aromatic ring.
  • aromatic moieties are benzene, naphthalene, imidazole and pyridine.
  • the term also includes bicyclic or tricyclic systems in which one or more of the rings has aromatic character. Indane is an example of this type of system.
  • heteroaryl are aryl moieties as defined above which contain heteroatoms (e.g. nitrogen, sulphur and/or oxygen).
  • heteroatoms e.g. nitrogen, sulphur and/or oxygen.
  • the term also includes systems in which a ring having aromatic character is fused to a saturated or partially saturated ring. Examples include pyridine, pyrimidine, furan, thiophene, indole, isoindole, indoline, benzofuran, benzimidazole, benzimidazoline quinoline, isoquinoline,
  • aryl is to be interpreted to include heteroaryl groups as defined above.
  • aryl and heteroaryl groups of the invention may optionally be substituted by one or more halogen atoms.
  • halo refers to fluoro, chloro, bromo or iodo.
  • N-alkyl derivates of the compounds of formula la and lb may be prepared by techniques known to those skilled in the art. Typical approaches involve: (a) reductive amination by hydrogenantion of the amine in the presence of palladium with an aldehyde; (b) reductive amination by sodium cyanoborohydride of the amine with an aldehyde; (c) reductive amination by sodium triacetoxyborohydride of the amine with an aldehyde; and (d) N- alkylation of the amine with an akyl halide or other leaving group such as a tosylate, etc. (all of the preceding in water, alcohols or other suitable solvents).
  • Preferred compounds of the invention are able to rescue mutant CFTR activity.
  • the ability of the compounds of the invention to rescue mutant CFTR activity may be determined by routine assays known to those skilled in the art (an example of which is described in the Exemplification section (Example 3), below).
  • preferred compounds of the invention are CFTR pharmacoperones. Such compounds find application in the treatment of CF.
  • the compounds may act as an indirect chaperone of CFTR via a chaperone effect attendant on binding to a protein (e.g. enzyme) which itself acts as a chaperone or co- chaperone of CFTR.
  • a protein e.g. enzyme
  • the compounds of the invention may bind to (or otherwise inhibit) chaperone proteins such as calnexin and so influence protein trafficking through the Golgi apparatus.
  • chaperone proteins such as calnexin and so influence protein trafficking through the Golgi apparatus.
  • compounds of the invention may prevent the interaction of mutant CFTR polypeptides (e.g. the AF508 CFTR polypeptide) to the chaperone calnexin.
  • preferred compounds of the invention inhibit the interaction of calnexin with CFTR polypeptide. Glycosidase inhibition
  • glycosidase inhibitors i.e. compounds which inhibit one or more glycosidase enzymes.
  • specific inhibitors of a- glucosidases i.e. compounds which inhibit one or more a-glucosidase enzymes but which are inactive against members of other classes of glycosidases.
  • the compounds of the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), nasal, rectal, vaginal and topical (including buccal and sublingual) administration. Preferred is oral administration.
  • the amount of the compound administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular compound selected.
  • the desired dose is preferably presented as a single dose for daily administration.
  • sub-doses administered at appropriate intervals throughout the day may also be employed. These sub-doses may be employed.
  • unit dosage forms for example, containing 0.001 to 100 mg, preferably 0.01 to 10 mg, and most preferably 0.5 to 1.0 mg of active ingredient per unit dosage form.
  • a number of factors are considered by the attending physician, including, but not limited to, the potency and duration of action of the inhibitors used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
  • dosages can also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
  • the effectiveness of a particular dosage of the compound of the invention can be determined by monitoring the effect of a given dosage on the progression of the disease or its prevention.
  • compositions of the invention may be delivered to the respiratory tract and lungs by inhalation. They may be delivered systemically by oral administration.
  • Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
  • ethanesulfonic benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.
  • Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts.
  • Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group I la) salts and other physiologically acceptable metal ions.
  • Such salts can be made from the ions of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.
  • compositions can include stabilizers, antioxidants, colorants and diluents.
  • Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not compromised to such an extent that treatment is ineffective.
  • the compound of the invention can be administered parenterally, for example
  • sterile injectable aqueous or oleaginous suspensions Such suspensions can be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above or other acceptable agents.
  • a sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1 ,3- butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono-or diglycerides.
  • omega-3 polyunsaturated fatty acids can find use in preparation of injectables. Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary
  • buccal and sub-lingual administration including administration in the form of lozenges, pastilles or a chewable gum comprising the inhibitors set forth herein.
  • the inhibitors can be deposited in a flavoured base, usually sucrose, and acacia or tragacanth.
  • Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.
  • Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition.
  • cosolvents include polysorbates 20,60 and 80, polyoxyethylene/polyoxypropylene surfactants (e. g., Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
  • cosolvents are employed at a level of about 0.01 % to about 2% by weight of a
  • compositions and carriers encompass all the foregoing and the like.
  • the above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See for example Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et al., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).
  • compositions of the invention are preferably formulated for oral delivery in tablet form.
  • Formulations for delivery to the respiratory tract are preferably formulated for oral delivery in tablet form.
  • the compounds of the invention can be formulated into a solution and/or a suspension of particles in a carrier appropriate for inhalation into the respiratory tract and the lungs.
  • powders, mists or aerosols with particle sizes of 0.5 to 1 micron may be delivered to the respiratory tract.
  • particle size ranges are commonly achieved by micronisation or spray drying and such delivery methods are described for example in Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et a/., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).
  • the compound of the invention forms part of a powdered composition within a gelatin capsule, blister pack and a multi-dose metering device.
  • the capsule or blister is ruptured within the device enabling the powder to be inhaled.
  • Powdered compositions typically comprise the compounds of the invention blended or mixed with an inert carrier.
  • the inert carrier has a mean particle size substantially larger than that of the drug. This provides, among other advantages, an improvement in the flow properties and dispensing accuracy of the composition.
  • Suitable carriers include calcium carbonate and sugars.
  • the compound of the invention is formulated as an aerosol, for example by preparing a suspension of the compound as a finely divided powder in a liquefied propellant gas.
  • a solution can be prepared which may contain solubilizers and co-solvents.
  • Pressurized metered dose inhalers pMDI are normally used to dispense such formulations to a patient.
  • Suitable propellents include
  • chlorofluorocarbons fluorocarbons and hydrofluoroalkanes.
  • Inhalation devices such as inhalers (including dry powder inhaler and metered dose inhalers (MDIs)) and nebulizers (also known as atomizers) may be used to deliver the compounds of the invention to the respiratory tract and/or lungs.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation.
  • Exemplary nebulizers for delivering an aerosolized solution include the AERxTM (Aradigm), the
  • Ultravent® (Mallinkrodt), the Pari LC PlusTM or the Pari LC StarTM (Pari GmbH, Germany), the DeVilbiss Pulmo-Aide, and the Acorn II® (Marquest Medical Products).
  • 1D isoDAB 16L 1SL 14 Scheme 1 (i) CH 2 0, K 2 C0 3 , MeOH, H 2 0 (ii) NaBH 4 , H 2 0 (iii) Nal0 4 , MeOH, H 2 0, 84% (from 9) (iv) Br 2 , BaC0 3 , H 2 0, 0 ° C to RT, 90% (v) (CF 3 S0 2 ) 2 0, pyridine, CH 2 CI 2 , -30 ° C; then NaN 3> DMF, 67% (vi) DIBALH, CH 2 CI 2 , -78 ° C, 93% (vii) Dowex (50W-X8 hT form) H 2 0:1 ,4-dioxane, 4:1 , 75 °C, 100% (viii) Pd/C (10%), H 2 , H 2 0:AcOH, 9: 1 , 71 %.
  • IsoDAB was synthesized from D-ribose [Scheme 1].
  • the protected azido-L-apiose 15L was the key intermediate for the synthesis of isoDAB 1 D.
  • Reaction of the D-ribose acetonide 9 with formaldehyde and potassium in the presence of potassium carbonate introduced the branching hydroxymethyl group via a Ho crossed aldol reaction gave a mixture of the protected D-hamamelose 10 together with the tetraol 11 , resulting from a crossed Cannizzaro reaction; the mixture was treated by sodium borohydride in water to afford pure 11.
  • Triflouromethanesulfonic anhydride (1 .75 mL, 10.3 mmol) was added dropwise to a solution of 2, 3-0-isopropylidene-L-apiono-1 ,4-lactone (1.29 g, 6.86 mmol) in DCM (30 mL) and pyridine (1.66 mL, 20.6 mmol) at -30°C.
  • TLC analysis (1 :1 EtOAc/cyclohexane) after 1 h showed the complete consumption of starting material (R f 0.70) and formation of a major product (R f 0.77).
  • Diisobutylaluminium hydride solution (1.5M in toluene, 5.0 mL, 7.5 mmol) was added dropwise to a solution of 3-C-azidomethyl-2,3-0-isopropylidene-L-erythrono-1 ,4-lactone (1.28 g, 6.01 mmol) in DCM (10 mL) at -78°C and stirred for 1 h.
  • TLC analysis (1 :1 EtOAc/cyclohexane) showed the complete consumption of starting material (R f 0.77) and formation of a major product (R f 0.70).
  • Excess diisobutylaluminium hydride was quenched with methanol, and the mixture allowed to warm to RT.
  • isoDAB can also be prepared by routes from other sugars.
  • suitable starting monosaccharides include (but are not restricted to) L-TAGATOSE L- lyxose, D-psicose, L-mannose, L-fructose and D-sorbose, , D-ribonolactone, D-gulose, L- lyxonolactone, D-gulonolactone, L-mannonolactone, and suitably protected derivatives of any of the foregoing.
  • protection may be of cis-1 ,2-diols by acetone to acetonides, or any suitable ketone (such as cyclohexanone, pentan-3-one or other ketones) to its corresponding ketal.
  • the key intermediate 4 can also be accessed by the initial preparation of the tosylate 10 which is prepared via direct tosylation of the dithioacetal and then acetonation.
  • compound 12 is formed from 1 by a triflate azide reaction; dedprotection of 12 by TBAF and subsequent tosylation gives 13 which on hydrogenation forms 14.
  • isoDMDP 1 12 11 Scheme 1 (i) Ph 2 CN 2 , toluene (ii) DIBALH, CH 2 CI 2 (Hi) CH 2 0, Na 2 C0 3 , H 2 0 (iv) Br 2 , BaC0 3 , H 2 0 (v) (CF 3 S0 2 ) 2 0, pyridine, CH 2 CI 2 , -30 ° C; then NaN 3 , DMF (vi) LiBH 4 , THF (vii) TBDMSCI, imidazole (viii) (CH 3 S0 2 ) 2 0, pyridine (ix) CF 3 COOH, H 2 0 (x) Pd/C (10%), H 2 , Et 3 N or AcONa (xi) (CF 3 S0 2 ) 2 0, pyridine, CH 2 CI 2
  • the 2,3-acetonide of L-lyxonolactone 1 is the starting material for the synthesis of isoDMDP.
  • the primary alcohol in 1 was protected as the benzhydryl ether by heating with diphenyldiazomethane in toluene to give the full protected lactone 2 which was reduced with DIBALH to afford the lactol 3.
  • a crossed aldol reaction of 3 with formaldehyde and sodium carbonate gave the branched sugar 4 which was oxidized to the corresponding lactone 5 with bromine water in the presence of barium carbonate. Esterification of the alcohol in 5 with triflic anhydride in the presence of pyridine afforded the corresponding trilfate which on treatment with sodium azide in DMF gave 6.
  • the human tracheal gland serous epithelial cell line CF-KM4 is derived from a CF patient homozygous for the AF508 mutation. The details of the generation, characterization, and routine propagation have been described elsewhere (Kammouni et al. (1999) Resp. Cell Mol. Biol. 20(4): 684-91 ).
  • CFTR ion channel functions can be assessed by single-cell fluorescence imaging, using the potential-sensitive probe bis-(1 ,3-diethylthiobarbituric acid)trimethine oxonol
  • Fluorescence intensity is recorded by confocal laser scanning microscopy using Bio-Rad MRC 1024 equipped with 15 mW Ar/Kr gas laser (Hemel Hempstead, UK). Maximal resolution is obtained with Olympus plan apo X60 oil, 1.4 NA, objective lens. Fluorescence signal collection can be performed through the control software Lasersharp 3.2 (Hemel Hempstead, UK). The resolution time is 30 s.
  • Bis-oxonol slowly distributes across biological membrane according to the membrane potential and binds to hydrophobic cell components; since the quantum yield of the dye increases impressively upon the binding, the fluorescence of cells incubated in a medium containing bis-oxonol increases upon depolarization and, conversely, decreases with hyperpolarization (Dall'Asta et al. (1997) Exp. Cell Res. 231 : 260-268).
  • CFTR-dependent current was stimulated by application of Forskolin + Genistein (Fsk+Gst), inducing a depolarization characterized by an increase of the fluorescence, while CFTR-dependent current is inhibited by application of CFTR in h-1 2 characterized by a decrease of the fluorescence.
  • the CF-KM4 cells are treated 2 hours with 100 ⁇ of test compound and then CFTR proteins stimulated by a cocktail of forskolin (Fsk) + genistein (Gst).
  • Fsk forskolin + genistein
  • isoDAB is a potent and specific a-glucosidase inhibitor. Further tests (data not shown) have established that it does not inhibit any cellular ER processing glucosidases. It constitutes the first example of a carbon branched iminosugar pyrrolidine showing significant glycosidase inhibition. It was also determined (data not shown) that isoDAB does not inhibit glycogen phosphorylase (unlike DAB, which is a potent inhibitor). Previous studies with the compounds IE and IG (see above) have indicated that these compounds also have no glycosidase inhibitory activity (Bols et al. (1996) Tetrahedron Letters 37: 2097-2 00).

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Abstract

L'invention concerne des composés de formule (Ia) ou (Ib) qui trouvent des applications pour le traitement ou la prévention : (a) d'une infection ; (b) de troubles immunitaires ; (c) de la néoplasie ; (d) d'une maladie de l'utilisation de l'énergie ; (e) d'une maladie protéostatique ; ou (f) d'un trouble du stockage lysosomal.
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Cited By (2)

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Publication number Priority date Publication date Assignee Title
EP3318277A1 (fr) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibiteurs de la synthase de glucosylcéramide pour le traitement de maladies du motoneurone
US11576924B2 (en) 2017-05-12 2023-02-14 Galectin Sciences, Llc Compounds for the prevention and treatment of diseases and the use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010429A2 (fr) 1999-08-10 2001-02-15 The Chancellor, Masters, And Scholars Of The University Of Oxford Composes n-alkyle a longue chaine et leurs derives oxa
WO2005046672A2 (fr) 2003-11-07 2005-05-26 Centre National De La Recherche Scientifique Utilisation d’inhibiteurs de glucosidase pour une therapie de la mucoviscidose
WO2007123403A1 (fr) 2006-04-24 2007-11-01 Academisch Medisch Centrum Traitement amélioré de la fibrose kystique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515013B2 (en) * 2000-07-13 2003-02-04 Abbott Laboratories 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010429A2 (fr) 1999-08-10 2001-02-15 The Chancellor, Masters, And Scholars Of The University Of Oxford Composes n-alkyle a longue chaine et leurs derives oxa
WO2005046672A2 (fr) 2003-11-07 2005-05-26 Centre National De La Recherche Scientifique Utilisation d’inhibiteurs de glucosidase pour une therapie de la mucoviscidose
WO2007123403A1 (fr) 2006-04-24 2007-11-01 Academisch Medisch Centrum Traitement amélioré de la fibrose kystique

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
"Goodman & Goldman's The Pharmacological Basis of Therapeutics", 1996, APPENDIX, pages: 1707 - 1711
"Handbook of Pharmaceutical Excipients", 1999, AMERICAN PHARMACEUTICAL ASSOCIATION
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS AND WILKINS
ASANO, N., CELL. MOL. LIFE SCI., vol. 66, 2009, pages 1479 - 1492
BOIS ET AL., TETRAHEDRON LETTERS, vol. 37, 1996, pages 2097 - 2100
BOLS ET AL., TETRAHEDRON LETTERS, vol. 37, 1996, pages 2097 - 2100
BUTTERS ET AL., TETRAHEDRON ASYMM., vol. 11, 2000, pages 113 - 125
COX ET AL.: "Iminosugars From Synthesis to Therapeutic Applications", 2007, JOHN WILEY & SONS, article "Medicinal use of iminosugars", pages: 318 - 319
DALL'ASTA ET AL., EXP. CELL RES., vol. 231, 1997, pages 260 - 268
ENGLEBIENNE, MED. CHEM., vol. 1, no. 3, 2005, pages 215 - 226
HAKANSSON ET AL., TETRAHEDRON LETT., vol. 49, 2008, pages 179 - 184
ICHIKAWA ET AL., J. AM. CHEM. SOC., vol. 120, 1998, pages 3007 - 3018
ICHIKAWA ET AL., TETRAHEDRON LETT., vol. 36, 1995, pages 4585 - 4586
J. CHEM. SOC., PERKIN TRANS., vol. 1, 1989, pages 1065
JESPERSON ET AL., ANGEW. CHEM. INT. ED., vol. 33, 1994, pages 1778 - 1779
KAMMOUNI ET AL., RESP. CELL MOL. BIOL., vol. 20, no. 4, 1999, pages 684 - 91
KIBBE ET AL.: "Handbook of Pharmaceutical Excipients", 1999, AMERICAN PHARMACEUTICAL ASSOCIATION
KUSHNER ET AL., CAN J PHYSIOL PHARMACOL., vol. 77, no. 2, 1999, pages 79 - 88
LI, TETRAHEDRON, vol. 65, 2009, pages 3717 - 3727
LIU ET AL., J. CARBOHYDR. CHEM., vol. 23, 2004, pages 223 - 238
MELLOR ET AL., BIOCHEM. J., vol. 366, 2002, pages 225 - 233
NOREZ ET AL., AM. J. RESPIR. CELL MOL. BIOL., vol. 41, no. 2, 2009, pages 217 - 225
NOREZ ET AL., FEBS LETT., vol. 580, 2006, pages 2081 - 2086
RAWLINGS ET AL., CHEMBIOCHEM, vol. 10, 2009, pages 1101 - 1105
SOHOEL ET AL., J. CHEM. SOC., PERKIN TRANS., vol. 1, 2001, pages 1584 - 1585
TACKE; ZILCH, ENDEAVOUR, NEW SERIES, vol. 10, 1986, pages 191 - 197
TETRAHEDRON, vol. 51, 1995, pages 959 - 974

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3318277A1 (fr) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibiteurs de la synthase de glucosylcéramide pour le traitement de maladies du motoneurone
WO2018083223A1 (fr) 2016-11-04 2018-05-11 Icm (Institut Du Cerveau Et De La Moelle Épinière) Inhibiteurs du métabolisme des gangliosides pour le traitement de maladies des motoneurones
US11065238B2 (en) 2016-11-04 2021-07-20 Icm (Institut Du Cerveau Et De La Moelle Épinière) Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases
US11576924B2 (en) 2017-05-12 2023-02-14 Galectin Sciences, Llc Compounds for the prevention and treatment of diseases and the use thereof

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