WO2004016600A1 - Novel use of benzothiazole derivatives - Google Patents

Novel use of benzothiazole derivatives Download PDF

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Publication number
WO2004016600A1
WO2004016600A1 PCT/SE2003/001271 SE0301271W WO2004016600A1 WO 2004016600 A1 WO2004016600 A1 WO 2004016600A1 SE 0301271 W SE0301271 W SE 0301271W WO 2004016600 A1 WO2004016600 A1 WO 2004016600A1
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WIPO (PCT)
Prior art keywords
benzothiazol
phenol
pyrrolidin
benzothiazole
chloro
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PCT/SE2003/001271
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French (fr)
Inventor
Peter Sjö
Peter Storm
Original Assignee
Astrazeneca Ab
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Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to BR0313407-5A priority Critical patent/BR0313407A/en
Priority to MXPA05001585A priority patent/MXPA05001585A/en
Priority to CA002495492A priority patent/CA2495492A1/en
Priority to AU2003248587A priority patent/AU2003248587A1/en
Priority to EP03788208A priority patent/EP1539723B1/en
Priority to JP2004528996A priority patent/JP2006504672A/en
Priority to US10/524,124 priority patent/US20060106015A1/en
Priority to DE60305514T priority patent/DE60305514D1/en
Publication of WO2004016600A1 publication Critical patent/WO2004016600A1/en
Priority to IL16641205A priority patent/IL166412A0/en
Priority to NO20051263A priority patent/NO20051263L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to the use of benzothiazole derivatives as inhibitors of the kinase Itk. Certain novel benzothiazole derivatives are also disclosed together with processes for their preparation, intermediates thereto, pharmaceutical compositions comprising them, and their use in therapy.
  • Itk Inducible T cell Kinase
  • Tec cytosolic protein tyrosine kinases.
  • this family also includes Btk, Tec, Bmx, and Txk. These kinases regulate various immune cell functions that integrate signals given by the other cytosolic tyrosine kinases as well as serine/threonine kinases, lipid kinases, and small G proteins.
  • Tec-family kinases have the following general structure: a N-terminal pleckstrin-homology (PH) domain, a Tec-homology domain that includes a Btk motif and one or two proline- rich (PR) motifs, a SH3 domain, a SH2 domain and a c-terminal catalytic (SHI) domain. These kinases are expressed exclusively in hematopoietic tissues, with the exception of Tec and Bmx that have also been detected in endothelial cells. The cellular distribution is different for the Tec-family members. For example, Itk is expressed by T cells, NK cells and mast cells, whereas Btk is expressed by all hematopoietic cells except T cells.
  • hematopoietic cells may express one or several Tec-family kinases.
  • T cells express Itk, Tec and Txk
  • mast cells express Btk, Itk and Tec.
  • Btk is by far the most extensively studied among the Tec-family kinases, due to its association with X-linked agammaglobulinemia (XLA), and Btk is currently the only Tec- family kinase with a known human phenotype.
  • XLA patients are virtually devoid of mature B cells and their Ig levels are strongly reduced.
  • T helper 2 (Th2) differentiation is disrupted in these mice, whereas Thl differentiation is apparently intact.
  • Th2 T helper 2
  • signalling through T cell receptors and B cell receptors leads to activation of Itk and Btk, respectively.
  • Downstream of Itk and Btk a number of different messengers are engaged; scaffolding proteins (SLP-76, LAT, SLP-65), Src kinases, MAP kinases, and
  • PLC- ⁇ activation that leads to IP3 generation and sustained Ca 2+ flux, and subsequently activation of transcription factors.
  • PLC- ⁇ l has been suggested as a direct substrate for Itk.
  • Itk In T cells, Itk (and Tec) may also mediate signalling through the CD28 co-receptor.
  • Tec -family kinases can also be regulated by PH domain-mediated plasma membrane localization, and by Src-family-mediated phosphorylation of critical tyrosine residues.
  • Itk, Btk and Txk have recently been shown to translocate to the nucleus after activation.
  • Itk inhibitors may be used as pharmaceutical agents for the treatment of mast cell-driven or basophil-driven conditions or diseases.
  • Itk as a target for inhibiting several key events in both acute and late phase allergic reactions common to allergic rhinitis and asthma.
  • Certain 2-(2-hydroxyphenyl)benzothiazole derivatives have been previously disclosed in the literature but no such compounds have been disclosed to have utility as kinase inhibitors, particularly not as inhibitors of the kinase Itk.
  • the present invention discloses certain 2-aryl benzothiazole derivatives that have activity as Itk inhibitors and are thereby useful as pharmaceuticals.
  • the present invention provides the use of a compound of formula (I)
  • a and D independently represent CH or N;
  • R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy;
  • R represents hydroxy, amino, CI to 6 alkyl, CI to 6 alkoxy, carbamoyl
  • alkyl or alkoxy group being optionally further substituted by one or more groups independently selected from hydroxy and NR R ;
  • R , R , R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected
  • R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further
  • R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
  • the compounds of formula (I) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
  • B represents CH and X represents O.
  • a and D each represent CH.
  • R represents hydrogen, halogen or CI to 6 alkoxy. In another embodiment, R represents -CONR R or CI to 6 alkyl substituted by NR R
  • the substituent R is located at the 5- or 6-position of the
  • the invention provides the use of a compound of formula (I) wherein
  • R represents -CONR R or CI to 6 alkyl substituted by
  • the present invention specifically includes the use of the following compounds: 2-(4-chloro-2-hydroxyphenyl)-l ,3-benzothiazole-6-carboxylic acid;
  • CI to 6 alkyl denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl.
  • CI to 6 alkoxy referred to herein denotes an oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, i-butoxy and s-butoxy.
  • halogen referred to herein denotes fluorine, chlorine, bromine and iodine.
  • aryl referred to herein denotes a C6 to 10 carbocyclic aromatic ring system. Examples include phenyl, naphthyl and indanyl.
  • 9 heteroatom selected from O and NR include pyrrolidine, piperidine, morpholine and piperazine
  • the present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts.
  • Suitable salts include those formed with both organic and inorganic acids.
  • Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question.
  • preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
  • a more particular aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • a method of treating, or reducing the risk of, diseases or conditions in which inhibition of kinase Itk activity is beneficial which comprises administering to a person suffering from or at risk of said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • AIDS Acquired Immunodeficiency Syndrome
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, late asthma and airways hyper-responsiveness);
  • bronchitis acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; sinusitis,
  • COPD chronic obstructive pulmonary disease
  • asthma such
  • Th2-driven and/or mast cell-driven and/or basophil-driven conditions or diseases We are particularly interested in Th2-driven and/or mast cell-driven and/or basophil-driven conditions or diseases.
  • a more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of Th2-driven and/or mast cell-driven and/or basophil driven diseases or conditions; and a method of treating, or reducing the risk of, Th2-driven and/or mast cell-driven and/or basophil driven diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment or prevention of a reversible obstructive airway disease, especially asthma which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a human that is suffering from or susceptible to the disease.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a reversible obstructive airway disease, especially asthma.
  • a method for the treatment or prevention of rhinitis which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a human that is suffering from or susceptible to rhinitis, especially allergic rhinitis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of rhinitis, especially allergic rhinitis.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the dose of the compound to be administered will depend on the compound employed, the disease being treated, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).
  • the compounds of formula (I) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of diseases or conditions in which inhibition of kinase Itk activity is beneficial.
  • the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • a pharmaceutical formulation comprising preferably less than 95% by weight and more preferably less than 50% by weight of a compound of formula (I) in admixture with a pharmaceutically acceptable diluent or carrier.
  • the compounds may be administered topically, for example, to the lungs and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, for example, by oral administration in the form of tablets, pills, capsules, syrups, powders or granules; or by parenteral administration, for example, in the form of sterile parenteral solutions or suspensions; or by rectal administration, for example, in the form of suppositories.
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or an other polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active compound with or without a carrier substance, is delivered to the patient.
  • the active compound may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, par
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum, titanium dioxide, and the like.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • a and D independently represent CH or N;
  • R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy;
  • .3 4 NR R represents a 5 to 7 membered azacyclic ring optionally incorporating one further
  • R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from
  • R 7 8 7 8 R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further
  • R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
  • B in formula (la) represents CH and X represents O.
  • a and D in formula (la) each represent CH.
  • R in formula (la) represents hydrogen, halogen or CI to 6 alkoxy.
  • R in formula (la) represents -CONR R or CI to 6 alkyl substituted by NR R .
  • the substituent R in formula (la) is located at the 6-position of the benzothiazole ring system.
  • the invention provides a compound of formula (la) wherein A and D each represent CH; B represents CH and X represents O; R represents hydrogen, halogen or CI to 6 alkoxy, R represents -CONR R or CI to 6 alkyl substituted by NR R ; and
  • novel compounds of formula (la) include those described within the Examples section of the present specification, either as such, or as the corresponding free bases, or as pharmaceutically acceptable salts thereof.
  • the invention provides a process for the preparation of a compound of formula (la) which comprises:
  • R is as defined in formula (la); or (b) oxidative cyclisation of a compound of formula (IN)
  • the reaction may be achieved by heating together a mixture of compounds (II) and (HI) in an oxidizing solvent, for example, nitrobenzene, at an elevated temperature, for example, at about 185 °C.
  • an oxidizing solvent for example, nitrobenzene
  • reaction may be achieved by suspending the compound of formula (IN) in aqueous base and then heating it together with a suitable oxidising agent such as potassium ferricyanide.
  • R , A, B, D and X are as defined in formula (la), with an amine of the general formula (NI) H ⁇ R 3 R 4 (NI)
  • a compound of formula (N) with a compound of general formula (NI) will in general be well known to the man skilled in the art.
  • the two compounds may be coupled together in the presence of a coupling agent, for example, HATU.
  • Salts of compounds of formula (la) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying.
  • Suitable solvents include, for example, water, dioxan, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof.
  • the reaction may be a metathetical process or it may be carried out on an ion exchange resin.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
  • the compounds of formula (la) may exist in enantiomeric or diastereoisomeric forms or mixtures thereof, all of which are included within the scope of the invention.
  • the various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC.
  • the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions that will not cause racemisation.
  • Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures thereof.
  • the compounds of formula (la), and their pharmaceutically acceptable salts are useful because they possess pharmacological activity in animals.
  • the compounds of formula (la) have activity as pharmaceuticals, in particular as modulators of kinase activity, especially Itk kinase activity, and as such are predicted to be useful in therapy. They may be used in the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • the compounds of formula (la) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of formula (la) in admixture with a pharmaceutically acceptable diluent, adjuvant or carrier.
  • a pharmaceutically acceptable diluent, adjuvant or carrier particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (la) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150 x 4.6 mm) and a gradient (containing 0.1% trifluoroacetic acid) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 60 °C. Products were dried under reduced pressure at about 40 °C.
  • N-aryl-benzamide which was synthesised by known methods (see, for example, J. Med. Chem. 1999, 42, 4172) (53.6 mmol) was dissolved in dry toluene (200 mL). Lawesson's reagent (32.2 mmol) was added and the reaction mixture was heated to 80 °C for 1 h under an inert atmosphere. TLC (toluene : ethyl acetate, 2: 1) showed a distinct yellow spot from the product. The reaction mixture was evaporated to dryness and purified via column chromatography (toluene : ethyl acetate, 9:1) and used directly in the next step.
  • N-Aryl-thiobenzamide (40 mmol) was suspended in 1.5M sodium hydroxide solution (270 mL, 400 mmol). The suspension was slowly added (30 minutes) to a warm (80 °C) 1.8M aqueous solution of K 3 [Fe(CN) 6 ] (160 mmol). The reaction mixture was stirred for another 30 minutes before it was diluted with water (500 mL) and extracted with ethyl acetate. After evaporation of the solvent, the crude product was purified by column chromatography (toluene : ethyl acetate, 10: 1) and recrystallised.
  • Example 22 5-Ethoxy-4-r6- ⁇ yrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2- yIlpyridin-3-ol
  • a mixture of 3,5-diethoxy-4-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridine (prepared according to the general method 1) (0.200 g, 0.503 mmol) and BBr 3 (1 ml, IM solution in dichloromethane) was refluxed overnight in dichloromethane (20 ml). After cooling to room temperature, water (5 ml) was added. The organic phase was washed with brine and dried (Na 2 SO 4 ). The crude material isolated upon evaporation was purified by column chromatography (methanol : dichloromethane, 5:95), delivering the title product (0.046 g, 25%).
  • the 2-arylbenzothiazole-6-carboxamide (0.2 mmol) was dissolved in tetrahydrofuran. After cooling to 0 °C, a IM solution of lithium aluminium hydride in tetrahydrofuran (0.4 mmol) was added dropwise. The ice-bath was removed and the reaction mixture stirred at room temperature until completion of the reduction (LC-MS). Water (0.5 ml) was added followed by dichloromethane (30 ml). After washing with brine, drying and evaporation, the crude title product was purified by column chromatography (methanol : dichloromethane, 5:95).
  • Example 32 4-Bromo-2-r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-vnphenol From 4-bromo-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol (0.062 g, 0.154 mmol), the title compound was isolated (0.024 g, 40%).
  • 3-Amino-pyrazine-2-carbaldehyde 3-Aminopyrazine-2-carboxylic acid methyl ester (3.0 g, 20 mmol) was suspended in tetrahydrofuran (100 ml) under a nitrogen atmosphere and cooled to 0 °C. Lithium aluminium hydride as a 1.0M solution in tetrahydrofuran (20 ml, 20 mmol) was added dropwise over 30 minutes whereupon the solution was stirred for another 30 minutes.
  • the title compound was prepared by a route analogous to those used for Examples 51 and 54.
  • This compound was prepared according to the general method described above.
  • the regioisomers were separated by HPLC-C 18 .
  • the Itk kinase assay utilized recombinant human Itk kinase domain fused with GST (Glutathione S-Transf erase).
  • the protein was expressed in High five insect cells, purified in one step on an affinity chromatography glutathione column and stored in 50 mM Tris/HCl (pH 7.6), 150 mM NaCl, 5% (w/v) mannitol, 1 mM DTT, 30% glycerol at -70 °C.
  • the kinase substrate used in the assay was a biotinylated peptide derived from the Src- optimal substrate (Nair et al, J. Med.
  • test compounds or controls; 1 ⁇ L in 100% DMSO
  • Test compounds were added to black 96-well flat-bottomed plates (Greiner 655076) followed by 20 ⁇ L Itk in assay buffer and the reaction was started by adding 20 ⁇ L ATP and peptide substrate in assay buffer.
  • the assay buffer constitution during phosphorylation was: 50 mM HEPES (pH 6.8), 10 mM MgCl 2 , 0.015% Brij 35, 1 mM DTT, 10% glycerol, 160 ng/well Itk, 2 ⁇ M peptide substrate and 50 ⁇ M ATP.
  • the assay was stopped after 50 minutes (RT) by adding ,150 ⁇ L ice-cold Stop solution (50 mM Tris/HCl, pH 7.5, 10 mM EDTA, 0.9% NaCl and 0.1% BSA) together with LANCE reagents (2 nM PT66-Eu 3+ , Wallac AD0069 and 5 ⁇ g/ml Streptavidin-APC, Wallac AD0059. Both concentrations were final in stopped assay solution).
  • the plates were measured on a Wallac 1420 Victor 2 instrument with TRF settings after lh incubation, and the ratio (665 signal/615 signal)*10000 was used to calculate the inhibition values. IC50 values were determined using XLfit.

Abstract

The use of compounds of formula (I) wherein X, A, B, D, R1 and R2 are as defined in the Specification and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which inhibition of kinase Itk activity is beneficial is disclosed. Certain novel compounds of formula (I), together with processes for their preparation, compositions containing them and their use in therapy are also disclosed.

Description

NOVEL USE OF BENZOTHIAZOLE DERIVATIVES.
Field of the Invention
This invention relates to the use of benzothiazole derivatives as inhibitors of the kinase Itk. Certain novel benzothiazole derivatives are also disclosed together with processes for their preparation, intermediates thereto, pharmaceutical compositions comprising them, and their use in therapy.
Background of the Invention Inducible T cell Kinase (Itk) is a member of the Tec-family of cytosolic protein tyrosine kinases. In mammalians, this family also includes Btk, Tec, Bmx, and Txk. These kinases regulate various immune cell functions that integrate signals given by the other cytosolic tyrosine kinases as well as serine/threonine kinases, lipid kinases, and small G proteins. Tec-family kinases have the following general structure: a N-terminal pleckstrin-homology (PH) domain, a Tec-homology domain that includes a Btk motif and one or two proline- rich (PR) motifs, a SH3 domain, a SH2 domain and a c-terminal catalytic (SHI) domain. These kinases are expressed exclusively in hematopoietic tissues, with the exception of Tec and Bmx that have also been detected in endothelial cells. The cellular distribution is different for the Tec-family members. For example, Itk is expressed by T cells, NK cells and mast cells, whereas Btk is expressed by all hematopoietic cells except T cells. Thus, hematopoietic cells may express one or several Tec-family kinases. For example, T cells express Itk, Tec and Txk, and mast cells express Btk, Itk and Tec. Btk is by far the most extensively studied among the Tec-family kinases, due to its association with X-linked agammaglobulinemia (XLA), and Btk is currently the only Tec- family kinase with a known human phenotype. XLA patients are virtually devoid of mature B cells and their Ig levels are strongly reduced.
Itk"7" mice show defects in T cell activation and differentiation. T helper 2 (Th2) differentiation is disrupted in these mice, whereas Thl differentiation is apparently intact. In T and B cells, signalling through T cell receptors and B cell receptors leads to activation of Itk and Btk, respectively. Downstream of Itk and Btk a number of different messengers are engaged; scaffolding proteins (SLP-76, LAT, SLP-65), Src kinases, MAP kinases, and
PI3-K. These events are followed by PLC-γ activation that leads to IP3 generation and sustained Ca2+ flux, and subsequently activation of transcription factors. PLC-γl has been suggested as a direct substrate for Itk.
In T cells, Itk (and Tec) may also mediate signalling through the CD28 co-receptor.
Furthermore, Itk has in T cells been implicated in the activation of β-integrin.
Signalling from Tec -family kinases can also be regulated by PH domain-mediated plasma membrane localization, and by Src-family-mediated phosphorylation of critical tyrosine residues. Interestingly, Itk, Btk and Txk have recently been shown to translocate to the nucleus after activation.
From studies using Itk-/- mice, it has been proposed that Itk is required for Th2 but not Thl cell development. This was demonstrated in the N. brasiliensis and L. major infection models where the Itk-/- animals are protected in the Leishmania model indicating an intact Thl response, whereas they are susceptible to infection with N. Brasiliensis that requires an intact Th2 response for resolution of the infection. This indicates that modulation of Itk activity may prove useful for treatment of Th2-driven disorders and conditions.
We have identified the critical role of Itk in regulating important mast cell and basophil functions and it is shown that the activity of mast cells or basophils may be inhibited through inhibition of Itk. Thus Itk inhibitors may be used as pharmaceutical agents for the treatment of mast cell-driven or basophil-driven conditions or diseases. In particular, we have identified Itk as a target for inhibiting several key events in both acute and late phase allergic reactions common to allergic rhinitis and asthma.
Certain 2-(2-hydroxyphenyl)benzothiazole derivatives have been previously disclosed in the literature but no such compounds have been disclosed to have utility as kinase inhibitors, particularly not as inhibitors of the kinase Itk. The present invention discloses certain 2-aryl benzothiazole derivatives that have activity as Itk inhibitors and are thereby useful as pharmaceuticals.
Disclosure of the Invention
The present invention provides the use of a compound of formula (I)
Figure imgf000004_0001
(I)
wherein:
A and D independently represent CH or N; and
either B represents CH and X represents O;
or B represents N and X represents NH;
R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy;
R represents hydroxy, amino, CI to 6 alkyl, CI to 6 alkoxy, carbamoyl
3 4 (-CONR R ) or -COOH; said alkyl or alkoxy group being optionally further substituted by one or more groups independently selected from hydroxy and NR R ; R , R , R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected
7 8 independently from hydroxy, CI to 6 alkoxy, NR R and CI to 6 alkoxycarbonyl;
or the group NR R or the group NR R may together represent a 5 to 7 membered
9 azacyclic ring optionally incorporating one further heteroatom selected from O and NR ;
7 8 7 8
R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further
9 heteroatom selected from O and NR ;
9 R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
or a pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which inhibition of kinase Itk activity is beneficial.
The compounds of formula (I) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
Compounds of formula (I) may also exist in various tautomeric forms. All possible tautomeric forms and mixtures thereof are included within the scope of the invention.
In one embodiment, B represents CH and X represents O.
In another embodiment, A and D each represent CH.
In another embodiment, R represents hydrogen, halogen or CI to 6 alkoxy. In another embodiment, R represents -CONR R or CI to 6 alkyl substituted by NR R
2 In one embodiment, the substituent R is located at the 5- or 6-position of the
2 benzothiazole ring system. In another embodiment, the substituent R is located at the
6-position of the benzothiazole ring system.
In one embodiment, the invention provides the use of a compound of formula (I) wherein
A and D each represent CH; B represents CH and X represents O; R represents hydrogen,
2 3 4 halogen or CI to 6 alkoxy, R represents -CONR R or CI to 6 alkyl substituted by
NR R ; and the substituent R is located at the 5- or 6-position of the benzothiazole ring system.
The present invention specifically includes the use of the following compounds: 2-(4-chloro-2-hydroxyphenyl)-l ,3-benzothiazole-6-carboxylic acid;
2-(2-hydroxy-6-methoxyphenyl)- 1 ,3-benzothiazole-6-carboxylic acid;
2-(2-hydroxy-5-methoxyphenyl)- 1 ,3-benzothiazole-6-carboxylic acid;
2-(4-chloro-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3-benzothiazole-6- carboxamide; 5-chloro-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol;
2-(4-chloro-2-hydroxyphenyl)-N-(3-mo holin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
2-(4-chloro-2-hydroxyphenyl)-N-(2-pyrrolidin- 1 -ylethyl)-l ,3-benzothiazole-6- carboxamide; 5-chloro-2-(6-{[4-(2-methoxyethyl)piperazin-l-yl]carbonyl}-l,3-benzothiazol-2- yl)phenol;
2-(2-hydroxy-5-methoxyphenyl)-N-(3-morpholin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
4-methoxy-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol; 2-(5-bromo-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3-benzothiazole-6- carboxamide;
4-fluoro-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol;
5-methoxy-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol; methyl N-{ [2-(2-hydroxyphenyl)-l,3-benzothiazol-6-yl]carbonyl}serinate;
2-[6-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol;
2-(5-chloro-2-hydroxyphenyl)-N-(3-morpholin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
3-methoxy-2-[6-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol; N,N-diethyl-2-(2-hydroxy-4-methoxyphenyl)- 1 ,3-benzothiazole-6-carboxamide;
N-[2-hydroxy-l-(hydroxymethyl)ethyl]-2-(2-hydroxy-4-methoxyphenyl)-l ,3- benzothiazole-6-carboxamide;
2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridin-3-ol; methyl 4-{[2-(6-{ [[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-l,3-benzothiazol-2- yl)-3 -hydroxyphenoxy] methyl } benzoate ;
5-ethoxy-4-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridin-3-ol;
N-[2-(dimethylamino)ethyl]-2-(4-hydroxy- 1 , 1 '-biphenyl-3-yl)-N-methyl- 1 ,3- benzothiazole-6-carboxamide;
N-[2-(dimethylamino)ethyl]-2-(4-hydroxy-3'-methoxy- 1 , 1 '-biphenyl-3-yl)-N-methyl- 1 ,3- benzothiazole-6-carboxamide;
5-chloro-2-(6-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-l,3-benzothiazol-2- yl)phenol;
5-chloro-2-(6-{ [4-(2-methoxyethyl)piperazin-l-yl]methyl}-l,3-benzothiazol-2-yl)phenol;
5-chloro-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol; 4-fluoro-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
2-[6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol;
3-methoxy-2-[6-(pyrrolidin- 1-ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol;
4-methoxy-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
4-bromo-2-[6-(ρyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol; 5-methoxy-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol; 4-chloro-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
2- { 6-[(diethylamino)methyl]- 1 ,3-benzothiazol-2-yl }-5-methoxyphenol;
5-ethoxy-4-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]pyridin-3-ol;
4-chloro-2-(6-{[(3-morpholin-4-ylpropyl)amino]methyl}-l,3-benzothiazol-2-yl)phenol; 2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]pyridin-3-ol;
2-[5-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
5-chloro-2-[6-(piperidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
5-chloro-2-[6-(4-methylpiperazin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol;
5-chloro-2-{6-[(diethylamino)methyl]-l,3-benzothiazol-2-yl}phenol; 5-chloro-2-{6-[(dimethylamino)methyl]-l,3-benzothiazol-2-yl}phenol;
2-[6-(hydroxymethyl)-l,3-benzothiazol-2-yl]phenol;
2-(6-amino- 1 ,3-benzothiazol-2-yl)-4-methoxyphenol;
NN-dimethyl-2-(2-hydroxy-4-methoxyphenyl)-l,3-benzothiazole-6-carboxamide;
N,N-dimethyl-2-(2-hydroxyphenyl)-l,3-benzothiazole-6-carboxamide; 3-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyrazin-2-amine;
2-(4-chloro-2-hydroxyphenyl)-l,3-benzothiazol-6-ol;
5-chloro-2-[6-(2-hydroxy-3-pyrrolidin-l-yl-propoxy)-l,3-benzothiazol-2-yl]-phenol;
5-chloro-2-[5-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol;
2-[5-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol; N,N-dimethyl-2-(2-hydroxyphenyl)- 1 ,3-benzothiazole-5-carboxamide;
5-chloro-2-[5-(pyrrolidin-l -ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol;
2-{5-[(dimethylamino)methyl]-l ,3-benzothiazol-2-yl Jphenol;
2-(2-hydroxyphenyl)-Ν-(3-moφholin-4-ylpropyl)-l,3-benzothiazole-7-carboxamide; and pharmaceutically acceptable salts thereof.
Unless otherwise indicated, the term "CI to 6 alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. Unless otherwise indicated, the term "CI to 6 alkoxy " referred to herein denotes an oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, i-butoxy and s-butoxy.
Unless otherwise indicated, the term "halogen" referred to herein denotes fluorine, chlorine, bromine and iodine.
Unless otherwise indicated, the term "aryl" referred to herein denotes a C6 to 10 carbocyclic aromatic ring system. Examples include phenyl, naphthyl and indanyl.
Examples of a 5 to 7 membered azacyclic ring optionally incorporating one further
9 heteroatom selected from O and NR include pyrrolidine, piperidine, morpholine and piperazine
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
A more particular aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). According to the invention there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of kinase Itk activity is beneficial, which comprises administering to a person suffering from or at risk of said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
More particularly, there is also provided a method of treating, or reducing the risk of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), which comprises administering to a person suffering from or at risk of said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Examples of these conditions are:
(1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; sinusitis, chronic rhinosinusitis, nasosinusal polyposis; pulmonary fibrosis;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, for example, migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (ALUS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; tuberculosis;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
We are particularly interested in Th2-driven and/or mast cell-driven and/or basophil-driven conditions or diseases.
Thus, a more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of Th2-driven and/or mast cell-driven and/or basophil driven diseases or conditions; and a method of treating, or reducing the risk of, Th2-driven and/or mast cell-driven and/or basophil driven diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a preferred aspect of the invention, we provide a method for the treatment or prevention of a reversible obstructive airway disease, especially asthma, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a human that is suffering from or susceptible to the disease. We also provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a reversible obstructive airway disease, especially asthma.
In another preferred aspect of the invention, we provide a method for the treatment or prevention of rhinitis which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a human that is suffering from or susceptible to rhinitis, especially allergic rhinitis. We also provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of rhinitis, especially allergic rhinitis.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
For the above mentioned therapeutic indications, the dose of the compound to be administered will depend on the compound employed, the disease being treated, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient). The compounds of formula (I) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
In another aspect the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of diseases or conditions in which inhibition of kinase Itk activity is beneficial.
In a more particular aspect, the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
According to the invention, there is provided a pharmaceutical formulation comprising preferably less than 95% by weight and more preferably less than 50% by weight of a compound of formula (I) in admixture with a pharmaceutically acceptable diluent or carrier.
We also provide a method of preparation of such pharmaceutical formulations that comprises mixing the ingredients. The compounds may be administered topically, for example, to the lungs and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler® ; or systemically, for example, by oral administration in the form of tablets, pills, capsules, syrups, powders or granules; or by parenteral administration, for example, in the form of sterile parenteral solutions or suspensions; or by rectal administration, for example, in the form of suppositories.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or an other polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.
For oral administration the active compound may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
Certain compounds of formula (I) are novel.
Therefore a further aspect of the invention provides a compound of formula (la):
Figure imgf000016_0001
(la)
wherein:
A and D independently represent CH or N; and
either B represents CH and X represents O;
or B represents N and X represents NH;
R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy;
2 R , which is attached to the 5- or 6-position of the benzothiazole ring, represents
3 4 CONR R or CI to 6 alkyl or CI to 6 alkoxy; said alkyl or alkoxy group being further substituted by one or more groups independently selected from hydroxy and NR R ;
.3 4 NR R represents a 5 to 7 membered azacyclic ring optionally incorporating one further
9 heteroatom selected from O and NR ;
R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from
7 8 hydroxy, CI to 6 alkoxy, NR R and CI to 6 alkoxycarbonyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally
9 incorporating one further heteroatom selected from O and NR ;
7 8 7 8 R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further
9 heteroatom selected from O and NR ;
9 R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
or a pharmaceutically acceptable salts thereof.
In one embodiment, B in formula (la) represents CH and X represents O.
In another embodiment, A and D in formula (la) each represent CH.
In another embodiment, R in formula (la) represents hydrogen, halogen or CI to 6 alkoxy.
2 3 4 In another embodiment, R in formula (la) represents -CONR R or CI to 6 alkyl substituted by NR R .
2 In another embodiment, the substituent R in formula (la) is located at the 6-position of the benzothiazole ring system.
In one embodiment, the invention provides a compound of formula (la) wherein A and D each represent CH; B represents CH and X represents O; R represents hydrogen, halogen or CI to 6 alkoxy, R represents -CONR R or CI to 6 alkyl substituted by NR R ; and
2 the substituent R is located at the 6-position of the benzothiazole ring system. Particular novel compounds of formula (la) include those described within the Examples section of the present specification, either as such, or as the corresponding free bases, or as pharmaceutically acceptable salts thereof.
According to the invention there is also provided a compound of formula (la) or a pharmaceutically acceptable salt thereof for use as a medicament.
In a further aspect the invention provides a process for the preparation of a compound of formula (la) which comprises:
(a) reaction of a compound of formula (II)
Figure imgf000018_0001
(ii) wherein R , A, B, D and X are as defined in formula (la), with a compound of formula (πi)
Figure imgf000018_0002
(HI)
wherein R is as defined in formula (la); or (b) oxidative cyclisation of a compound of formula (IN)
Figure imgf000019_0001
(iv)
.1 2 wherein R , R , A, B, D and X are as defined in formula (la);
and where desired or necessary converting the resultant compound of formula (la), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (la) into another compound of formula (la); and where desired converting the resultant compound of formula (la) into an optical isomer thereof.
In process (a), the reaction may be achieved by heating together a mixture of compounds (II) and (HI) in an oxidizing solvent, for example, nitrobenzene, at an elevated temperature, for example, at about 185 °C.
In process (b), the reaction may be achieved by suspending the compound of formula (IN) in aqueous base and then heating it together with a suitable oxidising agent such as potassium ferricyanide.
2 3 4
Compounds of formula (la) in which R represents -COΝR R may be prepared by reacting a compound of formula (N)
Figure imgf000020_0001
(V)
wherein R , A, B, D and X are as defined in formula (la), with an amine of the general formula (NI) HΝR3R4 (NI)
3 4 in which R and R are as defined in formula (la).
Methods that are suitable for the reaction of a compound of formula (N) with a compound of general formula (NI) will in general be well known to the man skilled in the art. For example, the two compounds may be coupled together in the presence of a coupling agent, for example, HATU.
Compounds of formula (la) in which R
Figure imgf000020_0002
may be prepared by reduction of corresponding compounds in which R represents -CONR R with a reducing agent such as, for example, lithium aluminium hydride.
Compounds of formula (IN) may be prepared from corresponding compounds of formula (VI):
Figure imgf000020_0003
(VI) 1 2 wherein R , R , A, B, D and X are as defined in formula (la), with a sulphurising agent such as Lawesson's reagent or phosphorus pentasulphide under conditions that will be readily apparent to the man skilled in the art.
Compounds of formulae (II), (III), (V) and (VI) are either commercially available, or are previously described in the chemical literature, or may be prepared using standard methods that are well known in the art.
Salts of compounds of formula (la) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxan, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may be a metathetical process or it may be carried out on an ion exchange resin.
Compounds of formula (la) and intermediate compounds thereto may be prepared as such or in protected form. The protection and deprotection of functional groups is, for example, described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999).
The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (la) may exist in enantiomeric or diastereoisomeric forms or mixtures thereof, all of which are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC. Alternatively, the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions that will not cause racemisation.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures thereof.
According to a further aspect of the invention we provide a compound of formula (la) or a pharmaceutically acceptable salt thereof, for use as a medicament.
The compounds of formula (la), and their pharmaceutically acceptable salts, are useful because they possess pharmacological activity in animals. The compounds of formula (la) have activity as pharmaceuticals, in particular as modulators of kinase activity, especially Itk kinase activity, and as such are predicted to be useful in therapy. They may be used in the treatment or prophylaxis of allergic, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immune-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
Examples of these medical conditions are disclosed above.
The compounds of formula (la) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of formula (la) in admixture with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
In another aspect the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (la) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
The following Examples are intended to illustrate, but in no way limit the scope of the invention.
General methods
All reactions were performed in dried glassware in an argon atmosphere at room temperature, unless otherwise noted. All reagents and solvents were used as received. Merck Silica gel 60 (0.040-0.063 mm) was used for preparative silica gel chromatography. A Kromasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water at a flow rate of 10 ml/min were used for preparative HPLC. Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150 x 4.6 mm) and a gradient (containing 0.1% trifluoroacetic acid) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 60 °C. Products were dried under reduced pressure at about 40 °C.
1H-NMR spectra were recorded on a Varian Inova 400 MHz or Narian Mercury 300 MHz instrument. The central solvent peak of chloroform-<i (6H 7.27 ppm), dimethylsulfoxide- ό (5H 2.50 ppm) or methanol-<i4 (6H 3.35 ppm) were used as internal references. Low resolution mass spectra obtained on a Hewlett Packard 1100 LC-MS system equipped with a APCI ionisation chamber.
General procedure for the preparation of 2-arylbenzothiazole-6-carboxyIic acids (Method 1)
A mixture of 4-amino-3-mercaptobenzoic acid (J. Med. Chem. 1997, 40, 105) (5 mmol) and an aromatic aldehyde (5.1 mmol) were dissolved in acetic acid (5 ml) and nitrobenzene (15 ml). The solution was heated at 185 °C for 15 minutes. After cooling the reaction mixture was made alkaline by the addition of 1M sodium hydroxide solution and extracted with ethyl acetate. Following acidification with cone, hydrochloric acid, the water phase was extracted with ethyl acetate. Drying and evaporation of the solvent gave the title compound. General procedure for preparation of 2-arylbenzothiazoles (Method 2) N-Aryl-thiobenzamides : The N-aryl-benzamide, which was synthesised by known methods (see, for example, J. Med. Chem. 1999, 42, 4172) (53.6 mmol) was dissolved in dry toluene (200 mL). Lawesson's reagent (32.2 mmol) was added and the reaction mixture was heated to 80 °C for 1 h under an inert atmosphere. TLC (toluene : ethyl acetate, 2: 1) showed a distinct yellow spot from the product. The reaction mixture was evaporated to dryness and purified via column chromatography (toluene : ethyl acetate, 9:1) and used directly in the next step.
2-Arylbenzothiazoles : N-Aryl-thiobenzamide (40 mmol) was suspended in 1.5M sodium hydroxide solution (270 mL, 400 mmol). The suspension was slowly added (30 minutes) to a warm (80 °C) 1.8M aqueous solution of K3[Fe(CN)6] (160 mmol). The reaction mixture was stirred for another 30 minutes before it was diluted with water (500 mL) and extracted with ethyl acetate. After evaporation of the solvent, the crude product was purified by column chromatography (toluene : ethyl acetate, 10: 1) and recrystallised.
Following the protocol for the preparation of 2-arylbenzothiazole-6-carboxylic acids (Method 1), the following compounds (Examples 1 to 3) were synthesised:
Example 1 2-(4-Chloro-2-hvdroxyphenyl)- 1 ,3-benzothiazole-6-carboxyIic acid
The title compound was isolated in 44% yield.
1H-NMR (400 MHz, DMSO-d6): δ 12.00 (IH, brs); 8.76 (IH, s); 8.32 (IH, d); 8.11-8.05
(2H, m); 7.16 (IH, d); 7.09 (IH, dd). APCI-MS m/z: 306 [MH+].
Example 2 2-(2-Hydroxy-6-methoxyphenylVl,3-benzothiazole-6-carboxylic acid
The title compound was isolated in 44% yield. 1H-NMR (400 MHz, DMSO-d6): δ 8.78 (IH, s); 8.18-8.08 (2H, m); 7.45 (IH, t); 6.77 (IH, d); 6.73 (IH, d). APCI-MS m/z: 302.1 [MH+].
Example 3 2-(2-Hydroxy-5-methoxyphenyl)- 3-benzothiazole-6-carboxylic acid
The title compound was isolated in 64% yield.
1H-NMR (400 MHz, DMSO-d6): δ 11.16 (IH, brs); 8.74 (IH, s); 8.12-8.04 (2H, m); 7.80
(IH, d); 7.11-7.04 (2H, m); 3.80 (3H, s). APCI-MS m/z: 302.1 [MH+].
General procedure for the amidation of 2-arylbenzothiazole-6-carboxylic acids
A mixture of 2-arylbenzothiazole-6-carboxylic acid (1 mmol), HATU (1.2 mmol) and N,N-diisopropylethylamine (5 mmol) were dissolved in Ν,Ν-dimethylformamide (20 ml). After stirring for 5 minutes at room temperature, the amine (2 mmol) was added and the mixture stirred at room temperature overnight. Dichloromethane (50 ml) was added and the solution was washed with IM sodium hydrogen carbonate solution and then water.
Drying and evaporation of the solvent yielded the crude title product which was purified by column chromatography (methanol : dichloromethane, 5:95).
Following the above protocol for the amidation of 2-arylbenzothiazole-6-carboxylic acid (and the general procedure for the synthesis of the acids), the compounds of Examples 4 to 20, 46 and 47 were synthesized:
Example 4 2-(4-Chloro-2-hydroxyphenyl)-N-r2-(dimethylamino)ethyl1-N- methyl- 1 ,3-benzothiazole-6-carboxamide From 2-(4-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.062 g, 0.203 mmol) and NNN'-trimethylethylenediamine (0.051 ml, 0.392 mmol), the title compound was isolated (0.030 g, 38%).
APCI-MS m/z: 390 [MH+]. Example 5 5-Chloro-2-r6-φyrrolidin-l-ylcarbonyl -1.3-benzothiazol-2- yll phenol
From 2-(4-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.060 g, 0.196 mmol) and pyrrolidine (0.033 ml, 0.395 mmol), the title compound was isolated (0.067 g, 95%).
1H-NMR (400 MHz, CD2C12): δ 8.13 (IH, d); 8.04 (IH, d); 7.71-7.68 (2H, m); 7.15 (IH, d); 7.01 (IH, dd); 3.73-3.42 (4H, m); 2.04-1.87 (4H, m).
APCI-MS m/z: 359 [MH+].
Example 6 2-(4-Chloro-2-hydroxyphenyl)-N-(3-moφholin-4-ylpropyl)- 1 ,3- benzothiazole-6-carboxamide
From 2-(4-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.060 g, 0.196 mmol) and 3-morpholin-4ylpropan-l-amine (0.058 ml, 0.394 mmol), the title compound was isolated (0.025 g, 29%). APCI-MS m/z: 432 [MH+].
Example 7 2-(4-Chloro-2-hvdroxyphenyl)-N-(2-pyrrolidin- 1 -ylethyl)- 1.3- benzothiazole-6-carboxamide
From 2-(4-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.059 g, 0.193 mmol) and 2-pyrrolidin-l-ylethanamine (0.050 ml, 0.395 mmol), the title compound was isolated (0.018 g, 23%).
APCI-MS m/z: 402.1 [MH+].
Example 8 5-Chloro-2-(6-{ r4-(2-methoxyethyl)piperazin- 1 -yllcarbonyl 1-1,3- benzothiazol-2-yl)phenol
From 2-(4-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.061 g, 0.200 mmol) and l-(2-methoxyethyl)piperazine (0.062 g, 0.430 mmol), the title compound was isolated (0.061 g, 70%).
APCI-MS m/z: 432.1 [MH+]. Example 9 2-(2-Hvdroxy-5-methoxyphenyl)-N-(3-moφholin-4-ylpropyD- 1.3- benzothiazole-6-carboxamide
From 2-(2-hydroxy-5-methoxyphenyl)benzothiazole-6-carboxylic acid (0.059 g, 0.196 mmol) and 3-moφholin-4ylpropan-l-amine (0.059 ml, 0.400 mmol), the title compound was isolated (0.047 g, 56%).
1H-NMR (400 MHz, acetone-d6): δ 11.61 (IH, s); 8.66 (IH, s); 8.40 (IH, brs); 8.18-8.08
(2H, m); 7.35 (IH, d); 7.13 (IH, dd); 7.05 (IH, d); 3.87 (3H, s); 3.86-3.72 (2H, m); 3.67- 3.55 (8H, m); 3.15-2.62 (2H, m); 2.04-1.95 (2H, m).
APCI-MS m/z: 428 [MH+].
Example 10 4-Methoxy-2-r6-(pyrroIidin-l -ylcarbonyl)- 1 -benzothiazol-2- yllphenol
From 2-(2-hydroxy-5-methoxyphenyl)benzothiazole-6-carboxylic acid (0.060 g, 0.199 mmol) and pyrrolidine (0.033 ml, 0.395 mmol), the title compound was isolated (0.054 g, 77%).
Η-NMR (400 MHz, CD2C12): δ 8.13 (IH, d); 8.04 (IH, d); 7.69 (IH, dd); 7.23 (IH, dt); 7.06 (2H, brs); 3.87 (3H, s); 3.69-3.43 (4H, m); 2.04-1.87 (4H, m).
APCI-MS m/z: 355 [MH+].
Example 11 2-(5-Bromo-2-hvdroxyphenyl)-N-r2-(dimethylamino)ethyll-N- methyl- 3-benzothiazole-6-carboxamide
From 2-(5-bromo-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.396 g, 1.13 mmol) and NNN'-trimethylethylene diamine (0.300 ml, 2.31 mmol), the title compound was isolated (0.324 g, 66%). APCI-MS m/z: 433.9 [MH+].
Example 12 4-Fluoro-2-[6-(pyrrolidm-l -ylcarbonyl)- 1 ,3-benzothiazol-2- yllphenol
From 2-(5-fluoro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.098 g, 0.339 mmol) and pyrrolidine (0.058 ml, 0.691 mmol), the title compound was isolated (0.097 g, 83%). 1H-NMR (400 MHz, DMSO-d6): δ 11.43 (IH, s); 8.34 (IH, d); 8.08 (IH, d); 8.03 (IH, dd); 7.67 (IH, dd); 7.30 (IH, dt); 7.10 (IH, dd); 3.53-3.43 (4H, m); 1.91-1.81 (4H, m). APCI-MS m/z: 343.1 [MH+].
Example 13 5-Methoxy-2-r6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2- yllphenol
From 2-(2-hydroxy-4-methoxyphenyl)benzothiazole-6-carboxylic acid (0.062 g, 0.206 mmol) and pyrrolidine (0.033 ml, 0.395 mmol), the title compound was isolated (0.059 g,
81%). 1H-NMR (400 MHz, CD2C12): δ 8.08 (IH, d); 7.97 (IH, d); 7.67-7.64 (2H, m); 6.62-6.57
(2H, m); 3.89 (3H, s); 3.70-3.45 (4H, m); 2.02-1.90 (4H, m).
APCI-MS m/z: 355 [MH+].
Example 14 Methyl N-( F2-(2-hydroxyphenyl)- 3-benzothiazol-6- yllcarbonyl } serinate
From 2-(2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.200 g, 0.737 mmol) and serine methyl ester hydrochloride (0.229 g, 1.47 mmol), the title compound was isolated (0.116 g, 42%).
1H-NMR (400 MHz, DMSO-d6): δ 8.71 (IH, d); 8.67 (IH, d); 8.26 (IH, dd); 8.12 (IH, d); 8.04 (IH, dd); 7.44 (IH, dt); 7.10 (IH, d); 7.03 (IH, t); 5.08 (IH, t); 4.62-4.56 (IH, m); 3.83 (2H, t); 3.67 (3H, s).
APCI-MS m/z: 373.1 [MH+].
Example 15 2-r6-(Pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yllphenol From 2-(2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.062 g, 0.229 mmol) and pyrrolidine (0.037 ml, 0.443 mmol), the title compound was isolated (0.064 g, 86%). 1H-NMR (400 MHz, CD2C12): δ 8.12 (IH, d); 8.04 (IH, d); 7.77 (IH, dd); 7.69 (IH, dd); 7.45 (IH, dt); 7.12 (IH, d); 7.02 (IH, dt); 3.70-3.45 (4H, m); 2.05-1.90 (4H, m).
APCI-MS m/z: 325 [MH+]. Example 16 2-f 5-Chloro-2-hvdrox vphen yl)-N-(3-morpholin-4-ylpropyl)- 1 - benzothiazole-6-carboxamide
From 2-(5-chloro-2-hydroxyphenyl)benzothiazole-6-carboxylic acid (0.061 g, 0.200 mmol) and 3-moφholin-4ylpropan-l-amine (0.058 ml, 0.394 mmol), the title compound was isolated (0.059 g, 68%).
1H-NMR (400 MHz, DMSO-d6): δ 11.73 (IH, s); 9.62 (IH, brs); 8.62 (IH, d); 8.29 (IH, d); 8.14 (IH, d); 8.01 (IH, dd); 7.48 (IH, dd); 7.14 (IH, d); 3.99 (2H, d); 3.65 (2H, t); 3.24-3.00 (6H, m); 2.01-1.90 (2H, m); 1.26 (2H, t).
APCI-MS m/z: 432 [MH+].
Example 17 3-Methoxy-2-r6-(pyrrolidin-l-ylcarbonyl)- 3-benzothiazol-2- yllphenol
From 2-(2-hydroxy-6-methoxyphenyl)benzothiazole-6-carboxylic acid (0.060 g, 0.199 mmol) and pyrrolidine (0.033 ml, 0.395 mmol), the title compound was isolated (0.065 g, 92%).
1H-NMR (400 MHz, CD2C12): δ 8.15 (IH, d); 8.04 (IH, d); 7.69 (IH, dd); 7.40 (IH, t); 6.79 (IH, d); 6.61 (IH, d); 4.11 (3H, s); 3.62-3.55 (4H, m); 2.00-1.94 (4H, m).
APCI-MS m/z: 355 [MH+].
Example 18 N,N-Diethyl-2-(2-hydroxy-4-methoxyphenyl)- 1 ,3-benzothiazole-6- carboxamide
From 2-(2-hydroxy-4-methoxyphenyl)benzothiazole-6-carboxylic acid (0.061 g, 0.202 mmol) and diethylamine (0.050 ml, 0.483 mmol), the title compound was isolated (0.007 g, 10%). APCI-MS m/z: 357.1 [MH+] .
Example 19 N-r2-Hvdroxy-l-(hydroxymethyl)ethyl1-2-(2-hydroxy-4- methoxyphenyl)- 1 ,3-benzothiazole-6-carboxamide
From 2-(2-hydroxy-4-methoxyphenyl)benzothiazole-6-carboxylic acid (0.200 g, 0.664 mmol) and serinol (0.130 g, 1.43 mmol), the title compound was isolated (0.017 g, 7%). APCI-MS m z: 375.1 [MH+].
Example 20 2-r6-(Pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yllpyridin-3-ol
From 2-(3-hydroxypyridine-2-yl)benzothiazole-6-carboxylic acid (0.074 g, 0.272 mmol) and pyrrolidine (0.045 ml, 0.544 mmol), the title compound was isolated (0.055 g, 62%). 1H-NMR (400 MHz, CD2C12): δ 8.29 (IH, dd); 8.17 (IH, d); 8.09 (IH, d); 7.71 (IH, dd); 7.50 (IH, d); 7.41 (IH, dd); 3.72-3.44 (4H, m); 2.05-1.90 (4H, m).
APCI-MS m/z: 326 [MH+].
Example 21 Methyl 4-( F2-(6-( rr2-(dimethylamino)ethyl](methyl)amino1- carbonyl}-L3-benzothiazol-2-yl)-3-hvdroxyphenoxylmethyl)benzoate In dry N,N-dimethylformamide (15 ml), 2,6-dihydroxybenzaldehyde (0.293 g, 2.12 mmol) and Cs2CO3 (0.828 g, 2.54 mmol) were dissolved. Following the addition of methyl 4- (bromomethyl)benzoate (0.490 g, 2.14 mmol) the mixture was stirred at room temperature overnight. After filtration, the solvent was evaporated, the residue dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. Drying (Na2SO4) and evaporation afforded crude material that was purified by flash chromatography (ethyl acetate : heptane, 1:3), giving methyl 4-[(2-formyl-3- hydroxyphenoxy)methyl]benzoate as a white solid (0.385 g, 63%). 1H-NMR (400 MHz, DMSO-d6): δ 10.4 (IH, s); 7.99 (2H, d); 7.65 (2H, d); 7.52 (IH, t); 6.68 (IH, d); 6.55 (IH, d); 5.35 (2H, s); 3.85 (3H, s).
This aldehyde was then reacted with 4-amino-3-mercaptobenzoic acid according to General Method 1 to give the corresponding benzothiazole derivative. Further reaction with N.NN'-trimethylethylenediamine using the general amidation procedure then gave the title compound.
APCI-MS m z: 520.1 [MH+].
Example 22 5-Ethoxy-4-r6-ψyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2- yIlpyridin-3-ol A mixture of 3,5-diethoxy-4-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridine (prepared according to the general method 1) (0.200 g, 0.503 mmol) and BBr3 (1 ml, IM solution in dichloromethane) was refluxed overnight in dichloromethane (20 ml). After cooling to room temperature, water (5 ml) was added. The organic phase was washed with brine and dried (Na2SO4). The crude material isolated upon evaporation was purified by column chromatography (methanol : dichloromethane, 5:95), delivering the title product (0.046 g, 25%).
1H-NMR (400 MHz, CD2C12): δ 13.48 (IH, s); 8.23 (IH, s); 8.20 (IH, s); 8.13 (IH, d); 8.05 (IH, s); 7.74 (IH, dd); 4.46 (2H, q); 3.67 (2H, t); 3.50 (2H, t); 2.03-1.90 (4H, m); 1.72 (3H, t).
APCI-MS m/z: 370 [MH+].
Example 23 N-r2-(Dimethylamino)ethyl1-2-(4-hvdroxy-U'-biphenyl-3-yl)-N- methyl- 1 ,3-benzothiazole-6-carboxamide
A mixture of 2-(5-bromo-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3- benzothiazole-6-carboxamide (0.048 g, 0.11 mmol), phenyl boronic acid (0.039 g, 0.32 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.012 g, 0.0147 mmol) and 2M sodium carbonate solution (0.29 ml, 0.58 mmol) was heated at 100 °C in dioxane (4 ml) and ethanol (0.5 ml) overnight. After cooling to room temperature and filtration, the solution was washed with IM sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated to give the crude product. Purification by column chromatography (methanol : dichloromethane, 5:95) delivered the title product (0.015 g, 32%).
APCI-MS m/z: 432.1 [MH+].
Example 24 N-r2-(Dimethylamino)ethvn-2-(4-hydroxy-3'-methoxy-l , 1 '- biphenyl-3-yl)-N-methyl- 1 ,3-benzothiazole-6-carboxamide
A mixture of 2-(5-bromo-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3- benzothiazole-6-carboxamide (0.050 g, 0.115 mmol), 3-methoxyphenyl boronic acid (0.048 g, 0.345 mmol), [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane complex (0.010 g, 0.0122 mmol) ) and 2M sodium carbonate solution (0.29 ml, 0.58 mmol) was heated at 100 °C in dioxane (4 ml) and ethanol (0.5 ml) overnight. After cooling to room temperature and filtration, the solution was washed with IM sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated to give the crude product. Purification by column chromatography (methanol : dichloromethane, 5:95) delivered the title product (0.017 g, 32%).
APCI-MS m/z: 462.1 [MH+].
General procedure for the reduction of 2-arylbenzothiazolecarboxamides to the corresponding amines or alcohols
The 2-arylbenzothiazole-6-carboxamide (0.2 mmol) was dissolved in tetrahydrofuran. After cooling to 0 °C, a IM solution of lithium aluminium hydride in tetrahydrofuran (0.4 mmol) was added dropwise. The ice-bath was removed and the reaction mixture stirred at room temperature until completion of the reduction (LC-MS). Water (0.5 ml) was added followed by dichloromethane (30 ml). After washing with brine, drying and evaporation, the crude title product was purified by column chromatography (methanol : dichloromethane, 5:95).
Following this general procedure (and the general procedures for the synthesis of the corresponding amides), the amines of Examples 25 to 44 were synthesised:
Example 25 5-Chloro-2-(6-f rr2-(dimethylamino)ethvn(methyl)ammolmethyll- 1 ,3-benzothiazol-2-yl)phenol
From 2-(4-chloro-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl- 1 ,3- benzothiazole-6-carboxamide (0.026 g, 0.067 mmol), the title compound was isolated
(0.007 g, 28%).
1H-NMR (400 MHz, CD2C12): δ 7.97 (IH, s); 7.96 (IH, d); 7.67 (IH, d); 7.53 (IH, dd); 7.12 (IH, d); 6.98 (IH, dd); 3.69 (2H, s); 2.64-2.55 (4H, m); 2.32 (6H, s); 2.27 (3H, s).
APCI-MS m z: 376.2 [MH+].
Example 26 5-Chloro-2-(6-{ r4-(2-methoxyethyl)piperazin-l-yl1methyl 1-1,3- benzothiazol-2-yl)phenol From 5-chloro-2-(6-{ [4-(2-methoxyethyl)piperazin-l-yl]carbonyl}-l,3-benzothiazol-2- yl)phenol (0.060 g, 0.139 mmol), the title compound was isolated (0.022 g, 38%). APCI-MS m/z: 418.3 [MH+].
Example 27 5-Chloro-2-r6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-ynphenol
From 5-chloro-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol
(0.065 g, 0.181 mmol), the title compound was isolated (0.028 g, 45%).
1H-NMR (400 MHz, CD2C12): δ 12.72 (IH, brs); 8.03 (IH, s); 7.97 (IH, d); 7.68 (IH, d);
7.57 (IH, d); 7.13 (IH, d); 6.99 (IH, dd); 3.87 (2H, s); 2.74-2.60 (4H, m); 1.91-1.82 (4H, m).
APCI-MS m/z: 345.1 [MH+].
Example 28 4-Fluoro-2-r6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yllphenol
From 4-fluoro-2-[6-(pyrrolidin-l -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol (0.090 g, 0.263 mmol), the title compound was isolated (0.044 g, 51%).
1H-NMR (400 MHz, DMSO-d6): δ 8.05 (IH, s); 8.01-7.95 (2H, m); 7.49 (IH, dd); 7.27 (IH, ddd); 7.09 (IH, dd); 3.74 (2H, s); 2.53-2.44 (4H, m); 1.76-1.67 (4H, m).
APCI-MS m z: 329.2 [MH+].
Example 29 2-r6-(Pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl1phenol
From 2-[6-(pyrrolidin-l -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol (0.062 g, 0.191 mmol), the title compound was isolated (0.028 g, 45%).
1H-NMR (400 MHz, CD2C12): δ 12.43 (IH, brs); 8.01-7.95 (2H, m); 7.75 (IH, d); 7.55 (IH, d); 7.42 (IH, t); 7.10 (IH, d); 7.00 (IH, t); 3.86 (2H, s); 2.72-2.60 (4H, m); 1.90-1.82 (4H, m).
APCI-MS m/z: 311 [MH+].
Example 30 3-Methoxy-2- r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2- yllphenol
From 3-methoxy-2-[6-(pyrrolidin-l -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol
(0.063 g, 0.178 mmol), the title compound was isolated (0.035 g, 58%). 'H-NMR (400 MHz, CD2C12): δ 7.99 (IH, s); 7.96 (IH, d); 7.54 (IH, dd); 7.35 (IH, t); 6.75 (IH, dd); 6.59 (IH, dd); 4.08 (3H, s); 3.89 (2H, s); 2.75-2.67 (4H, m); 1.91-1.84 (4H, m).
APCI-MS m/z: 341.1 [MH+].
Example 31 4-Methoxy-2-r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2- yllphenol
From 4-methoxy-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol (0.052 g, 0.147 mmol), the title compound was isolated (0.033 g, 66%). 1H-NMR (400 MHz, CD2C12): δ 12.00 (IH, brs); 8.01 (IH, s); 7.97 (IH, d); 7.55 (IH, dd); 7.22 (IH, t); 7.03 (2H, d); 3.87 (2H, s); 2.72-2.64 (4H, m); 1.90-1.84 (4H, m). APCI-MS m/z: 341.1 [MH+].
Example 32 4-Bromo-2-r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-vnphenol From 4-bromo-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol (0.062 g, 0.154 mmol), the title compound was isolated (0.024 g, 40%).
1H-NMR (400 MHz, CD2C12): δ 7.99 (IH, s); 7.97 (IH, d); 7.85 (IH, d); 7.56 (IH, dd); 7.48 (IH, dd); 7.01 (IH, d); 3.83 (2H, s); 2.67-2.58 (4H, m); 1.88-1.81 (4H, m).
APCI-MS m/z: 378.9 [MH+].
Example 33 5-Methoxy-2-r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2- yllphenol
From 5-methoxy-2-[6-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]phenol (0.057 g, 0.161 mmol), the title compound was isolated (0.014 g, 26%). 1H-NMR (400 MHz, CD2C12): δ 7.96 (IH, s); 7.92 (IH, d); 7.62 (IH, d); 7.51 (IH, dd); 6.61-6.54 (2H, m); 3.98 (2H, s); 3.88 (3H, s); 2.90-2.81 (4H, m); 1.97-1.90 (4H, m).
APCI-MS m/z: 341.2 [MH+]. Example 34 4-Chloro-2-F6-ψyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-vπphenol
From 4-chloro-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol (0.063 g, 0.176 mmol), the title compound was isolated (0.035 g, 58%).
1H-NMR (400 MHz, CD2C12): δ 12.48 (IH, brs); 8.10 (IH, s); 8.00 (IH, d); 7.73 (IH, d); 7.64 (IH, d); 7.37 (IH, dd); 7.07 (IH, d); 3.95 (2H, s); 2.90-2.64 (4H, m); 1.99-1.85 (4H, m).
APCI-MS m/z: 345 [MH+].
Example 35 2- ( 6-r(Diethylamino)methyll- 1 ,3-benzothiazol-2-yl 1 -5- methoxyphenol
From N,N-diethyl-2-(2-hydroxy-4-methoxyphenyl)-l,3-benzothiazole-6-carboxamide (0.019 g, 0.053 mmol), the title compound was isolated (0.009 g, 49%). 1H-NMR (400 MHz, CDC13): δ 7.87 (IH, s); 7.85 (IH, d); 7.57 (IH, d); 7.45 (IH, d); 6.60 (IH, d); 6.53 (IH, dd); 3.86 (2H, s); 2.57 (4H, q); 1.08 (6H, t). APCI-MS m/z: 343.1 [MH+].
Example 36 5-Ethoxy-4-r6-(pyrrolidin- 1 -ylmethyl)- 1 ,3-benzothiazol-2- yllpyridin-3-ol
From 5-ethoxy-4-[6-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]pyridin-3-ol (0.038 g, 0.103 mmol), the title compound was isolated (0.011 g, 30%).
Η-NMR (400 MHz, CD2C12): δ 13.59 (IH, s); 8.28-7.98 (4H, m); 7.58 (IH, d); 4.43 (2H, q), 3.81 (2H, s); 2.64-2.52 (4H, m); 1.85-1.79 (4H, m); 1.70 (3H, t).
APCI-MS m/z: 356 [MH+].
Example 37 4-Chloro-2-(6- ( K3-moφholin-4-ylpropyl amino1methyl 1-1,3- benzothiazol-2-yl)phenol
From 2-(5-chloro-2-hydroxyphenyl)-N-(3-moφholin-4-ylpropyl)- 1 ,3-benzothiazole-6- carboxamide (0.056 g, 0.130 mmol), the title compound was isolated (0.005 g, 9%).
APCI-MS m/z: 418 [MH+]. Example 38 2- r6-(Pyrrolidin- 1 -ylmethyl)- 1 ,3 -benzothiazol-2-yllpyridin-3 -ol
From 2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridin-3-ol (0.070 g, 0.215 mmol), the title compound was isolated (0.038 g, 57%).
1H-NMR (400 MHz, CD2C12): δ 12.08 (IH, s); 8.26 (IH, dd); 8.02-7.98 (2H, m); 7.55 (IH, dd); 7.47-7.34 (2H, m); 3.81 (2H, s); 2.65-2.53 (4H, m); 1.88-1.79 (4H, m). APCI-MS m/z: 312 [MH+].
Example 39 2-r5-(Pyrrolidin- 1 -ylmethyl)- 1 , 3 -benzothiazol-2-vH phenol
From 2-[5-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]phenol (0.010 g, 0.031 mmol), the title compound was isolated (0.005 g, 52%).
APCI-MS m/z: 311 [MH+].
Example 40 5-Chloro-2-r6-(piperidin-l-ylmethyl)-l,3-benzothiazol-2-yllphenol
APCI-MS m/z: 359 [MH+].
Example 41 5-Chloro-2-r6-(4-methylpiperazin-l-ylmethyl)-l,3-benzothiazol-2- yllphenol
APCI-MS m/z: 374.1 [MH+].
Example 42 5-Chloro-2-(6-r(Diethylamino)methyll-l,3-benzothiazol-2- yll phenol
APCI-MS m/z: 347 [MH+].
Example 43 5-Chloro-2- { 6-r(dimethylamino)methvn-l ,3-benzothiazol-2- yll phenol
APCI-MS m/z: 319 [MH+].
Example 44 2-r6-(Hydroxymethyl)- 1 ,3-benzothiazol-2-vnphenol
From 2-(2-hydroxyphenyl)-N-phenyl-benzothiazole-6-carboxamide (0.042 g, 0.121 mmol), the title compound was isolated (0.003 g, 10%). APCI-MS m/z: 258.1 [MH+].
Example 45 2-(6- Amino- 1 ,3-benzothiazol-2-yl)-4-methoxyphenol
A mixture of 2-(2-hydroxy-5-methoxyphenyl)-l,3-benzothiazole-6-carboxylic acid (0.502 g, 1.67 mmol) and triethylamine (0.35 ml, 2.51 mmol) was dissolved in
N,N-dimethylformamide (10 ml). Diphenylphosphorylazide (0.54 ml, 2.51 mmol) was added via syringe. The mixture was stirred at room temperature for 3h, after which water (2 ml) was added and the solution heated at 100 °C for lh. After cooling the reaction mixture was diluted with dichloromethane (30 ml), and washed with water and IM sodium hydrogen carbonate solution. The dichloromethane solution was extracted with IM sodium hydroxide solution, the pH adjusted to 9 and the basic water phase was re-extracted with dichloromethane. After drying (Na2SO4) and filtration the title compound was isolated (0.004g, 0.9%).
Η-NMR (400 MHz, DMSO-d6): δ 11.1 1 (IH, s); 7.71 (IH, d); 7.42 (IH, s); 7.10 (IH, d); 6.96 (2H, d); 6.81 (IH, dd); 5.49 (2H, s); 3.78 (3H, s).
APCI-MS m/z: 373.1 [MH+].
Example 46 N,N-Dimethyl-2-(2-hydroxy-4-methoxyphenyl)-l,3-benzothiazole-6- carboxamide APCI-MS m z: 329.1 [MH+].
Example 47 Ν,N-Dimethyl-2-(2-hvdroxyphenyl)-l,3-benzothiazole-6- carboxamide
APCI-MS m/z: 299.1 [MH+].
Example 48 3-r6-(Pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yllpyrazin-2- amine
3-Amino-pyrazine-2-carbaldehyde: 3-Aminopyrazine-2-carboxylic acid methyl ester (3.0 g, 20 mmol) was suspended in tetrahydrofuran (100 ml) under a nitrogen atmosphere and cooled to 0 °C. Lithium aluminium hydride as a 1.0M solution in tetrahydrofuran (20 ml, 20 mmol) was added dropwise over 30 minutes whereupon the solution was stirred for another 30 minutes. Saturated aqueous ammonium chloride solution (100 ml) was carefully added (evolution of gas) and the resulting mixture acidified (pH 1) with 4M hydrochloric acid, shaken (5 minutes) and then basified again (pH 10) with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with diethyl ether (3 x 150 ml) and the combined organic phase dried (MgSO4) and concentrated in vacuo. The yellow oily residue was applied to column chromatography (silica gel/dichloromethane/methanol) and the first fraction was concentrated in vacuo to yield the aldehyde as pale yellow crystals (689 mg, 28 %).
1H-NMR (400 MHz, DMSO-d6): δ 9.90 (IH, s); 8.31 (IH, d); 8.02 (IH, d); 7.67 (2H, bs). APCI-MS m z: 124 (MH+). Following the protocol for the preparation of 2-arylbenzothiazole-6-carboxylic acids
(Method 1), 3-amino-pyrazine-2-carbaldehyde and 4-amino-3-mercaptobenzoic acid were reacted together to give 2-(3-aminopyrazin-2-yl)-benzothiazole-6-carboxylic acid in 19% yield. This product (136 mg, 0.5 mmol) and pyrrolidine (360 mg, 5 mmol) were mixed in N,N-dimethylformamide (3 ml). HBTU (209 mg, 0.55 mmol) was added and the resulting mixture heated (50 °C) for lh. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (2 x 20 ml) and brine (10 ml). The organic phase was concentrated in vacuo and the residue chromatographed on silica using ethyl acetate as eluent. This afforded the amide as an off- white powder (33 mg, 20%). 1H-NMR (400 MHz, CDC13): δ 8.15 (IH, s); 8.10-8.08 (2H, m); 7.98 (IH, s); 7.70 (IH, d); 7.62 (0.5H, s); 7.59 (0.25H, s); 7.47 (0.25 H, s); 4.4 (IH, bs); 3.7-3.4 (4H, m); 2.0-1.9 (4H, m).
Example 49 2-(4-Chloro-2-hydroxyphenyl)- 1 ,3-benzothiazol-6-ol 2-(4-Chloro-2-methoxyphenyl)-6-methoxybenzothiazole (2.48 g, 8.1 mmol) [prepared starting from 4-methoxyaniline and 4-chloro-2-hydroxybenzoic acid by the general Method 2 described above], was dissolved in dichloromethane (200 ml) and BBr3 (IM in dichloromethane, 49 ml) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (300 ml) and brine (300 ml). The organic layer was dried (Na2SO ) and evaporated to dryness. Recrystallization from dichloromethane/methanol yielded the title compound (1.955 g, 87%).
APCI-MS m/z: 278.0 , 280.0 [MH+].
Example 50 5-Chloro-2-r6-(2-hvdroxy-3-pyrrolidin-l-yl-propoχy)-l,3- benzothiazol-2- yll -phenol
a) 5-Chloro-2-r6-(2,3-epoxypropoxy)-l,3-benzothiazol-2-ynphenol 2-(4-Chloro-2-hydroxyphenyl)-6-hydroxy-l,3-benzothiazole (60 mg, 0.22 mmol) was dissolved in dry tetrahydrofuran (10 ml) and sodium hydride (60% in mineral oil, 24 mg, 1.67 mmol) was added followed by epibromohydrin (22 μl, 0.26 mmol). The reaction mixture was stirred for 24h at 55 °C before it was quenched with water (200 μl), diluted with ethyl acetate (50 ml) and washed with 1.5 % hydrochloric acid (50 ml) followed by saturated aqueous sodium hydrogen carbonate solution (50 ml). Purification by HPLC-C18 yielded the title epoxide (6 mg, 8%).
1H-NMR (400 MHz, DMSO-d6): 5 11.87 (IH, bs); 8.16 (IH, d); 7.95 (IH, d); 7.72 (IH, d) ; 7.17(1H, dd); 7.10 (IH, d); 7.05 (IH, dd); 4.43 (IH, dd); 3.95 (lH,dd); 3.39 (IH, m); 2.87 (IH, t); 2.75 (IH, dd).
APCI-MS m/z: 333.9 , 335.9 [MH+].
5-Chloro-2-r6-(2-hydroxy-3-pyrrolidin-l-yl-propoxy)-l,3-benzothiazol-2-yll-phenol 5-Chloro-2-[6-(2,3-epoxypropoxy)-l,3-benzothiazol-2-yl]phenol (6 mg, 0,018 mmol) was dissolved in dioxane (2 ml) and diluted with ethanol (30 ml). Pyrrolidine (100 μl, 1.2 mmol) was added and the mixture was stirred at 70 °C for 2h. After evaporation of the solvent and excess reagent the product was purified by HPLC-Cι8. Yield 7 mg (95%).
APCI-MS m/z: 405.1 , 407.1 [MH+]. Example 51 5-Chloro-2-l5-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2- yll phenol
a) 2-(4-Chloro-2-hydroxyphenyl)- 1 ,3-benzothiazole-5-carboxyIic acid This compound was prepared by the general method described above. The regioisomers were separated by HPLC-C18.
1H-NMR (400 MHz, DMSO-d6): δ 13.14 (IH, bs); 11.93 (IH, bs); 8.54 (IH, s); 8.31 (IH, d); 8.28 (IH, d); 7.98 (IH, dd); 7.11 (2H, m).
APCI-MS m/z: 306.1 [MH+]. b) 5-Chloro-2-[5-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yllphenol
2-(4-Chloro-2-hydroxyphenyl)-l,3-benzothiazole-5-carboxylic acid (25 mg, 0.082 mmol) was dissolved in NMP (1.5 ml) and mixed with HBTU (34 mg, 0,090 mmol), DIEA (28 μl, 0.16 mmol) and pyrrolidine (10 μl, 0.16 mmol). The mixture was stirred at room temperature overnight. Purification was made by HPLC-C18 and yielded the title compound (7mg, 23%).
APCI-MS m z: 359.2 , 361.2 [MH+].
Example 52 2- r5-(Pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yllphenol
The title compound was prepared by a route analogous to that used for Example 51. APCI-MS m/z: 325.2 [MH+].
Example 53 N,N-Dimethyl-2-(2-hydroxyphenyl)- 1 ,3-benzothiazole-5- carboxamide
The title compound was prepared by a route analogous to that used for Example 51. APCI-MS m/z: 299.2 [MH+].
Example 54 5-Chloro-2-r5-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yllphenol
5-Chloro-2-[5-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]phenol (5 mg, 0.014 mmol) was dissolved in dry tetrahydrofuran (2 ml) under an inert atmosphere at 0 °C. Lithium aluminium hydride (28 μl, IM in tetrahydrofuran) was added and the mixture was stirred for 1 h before it was quenched with methanol (100 μl). The product was purified by HPLC-Cis giving the title compound (2 mg, 41%).
APCI-MS m/z: 345.1 , 347.1 [MH+].
Example 55 2-{5-r(Dimethylamino)methyn-l,3-benzothiazol-2-yllphenol
The title compound was prepared by a route analogous to those used for Examples 51 and 54.
APCI-MS m/z: 285.1 [MH+].
Example 56 2-(2-Hvdroxyphenyl)-N-(3-moφholin-4-ylpropyl)- 1,3- benzothiazole-7-carboxamide
a) 2-(2-Hydroxyphenyl)-l,3-benzothiazole-7 -carboxylic acid
This compound was prepared according to the general method described above. The regioisomers were separated by HPLC-C18.
1H-NMR (400 MHz, DMSO-d6): δ 13.71(1H, bs); 11.56 (IH, bs); 8.30 (IH, d); 8.23 (IH, d); 8.08 (IH, d); 7.67 (IH, t); 7.43 (IH, dt); 7.10 (IH, d); 7.02 (IH, t).
APCI-MS m/z: 272.1 [MH+]. b) 2-(2-Hydroxyphenyl)-N-(3-moφholin-4-ylpropyl)- 1 ,3-benzothiazole-7-carboxamide The title compound was prepared by the same route as Example 51(b). APCI-MS m/z:
398.2 [MH+].
Screen
Itk LANCE TRF assay
The Itk kinase assay utilized recombinant human Itk kinase domain fused with GST (Glutathione S-Transf erase). The protein was expressed in High five insect cells, purified in one step on an affinity chromatography glutathione column and stored in 50 mM Tris/HCl (pH 7.6), 150 mM NaCl, 5% (w/v) mannitol, 1 mM DTT, 30% glycerol at -70 °C. The kinase substrate used in the assay was a biotinylated peptide derived from the Src- optimal substrate (Nair et al, J. Med. Chem., 38: 4276, 1995; biotin- AEEEIYGEFEAKKKK). The assay additions were as follows: Test compounds (or controls; 1 μL in 100% DMSO) were added to black 96-well flat-bottomed plates (Greiner 655076) followed by 20 μL Itk in assay buffer and the reaction was started by adding 20 μL ATP and peptide substrate in assay buffer. The assay buffer constitution during phosphorylation was: 50 mM HEPES (pH 6.8), 10 mM MgCl2, 0.015% Brij 35, 1 mM DTT, 10% glycerol, 160 ng/well Itk, 2 μM peptide substrate and 50 μM ATP. The assay was stopped after 50 minutes (RT) by adding ,150 μL ice-cold Stop solution (50 mM Tris/HCl, pH 7.5, 10 mM EDTA, 0.9% NaCl and 0.1% BSA) together with LANCE reagents (2 nM PT66-Eu3+, Wallac AD0069 and 5 μg/ml Streptavidin-APC, Wallac AD0059. Both concentrations were final in stopped assay solution). The plates were measured on a Wallac 1420 Victor 2 instrument with TRF settings after lh incubation, and the ratio (665 signal/615 signal)*10000 was used to calculate the inhibition values. IC50 values were determined using XLfit.
When tested in the above screens, the compounds of Examples 1 to 56 gave IC50 values for inhibition of Itk activity of less than 25 μM, indicating that the compounds of the invention are expected to possess useful therapeutic properties. Representative results are shown in the following Table:
Figure imgf000042_0001

Claims

Claims
1. The use of a compound of formula (I)
Figure imgf000043_0001
(I)
wherein:
A and D independently represent CH or N; and
either B represents CH and X represents O;
or B represents N and X represents NH;
R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy;
R represents hydroxy, amino, CI to 6 alkyl, CI to 6 alkoxy, carbamoyl
.3. 4
(-CONR R ) or -COOH; said alkyl or alkoxy group being optionally further substituted by
5„6 one or more groups independently selected from hydroxy and NR R
R , R , R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected
7 8 independently from hydroxy, CI to 6 alkoxy, NR R and CI to 6 alkoxycarbonyl; or the group NR R or the group NR R may together represent a 5 to 7 membered
9 azacyclic ring optionally incoφorating one further heteroatom selected from O and NR ;
7 8 7 8
R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incoφorating one further
9 heteroatom selected from O and NR ;
9 R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
or a pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which inhibition of kinase Itk activity is beneficial.
2. The use according to Claim 1 of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of Th2-driven and/or mast cell-driven and/or basophil driven diseases or conditions.
3. The use according to Claim 2 wherein the disease is asthma.
4. The use according to Claim 2 wherein the disease is allergic rhinitis.
5. The use according to any one of Claims 1 to 4 wherein B in formula (I) represents CH and X represents O.
2 6. The use according to any one of Claims 1 to 5 wherein R in formula (I) represents
-CONR R or R represents CI to 6 alkyl substituted by NR R .
7. The use according to any one of Claims 1 to 4 wherein the compound of formula (I) is:
2-(4-chloro-2-hydroxyphenyl)- 1 ,3-benzothiazole-6-carboxylic acid;
2-(2-hydroxy-6-methoxyphenyl)- 1 ,3-benzothiazole-6-carboxylic acid; 2-(2-hydroxy-5-methoxyphenyl)-l,3-benzothiazole-6-carboxylic acid;
2-(4-chloro-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3-benzothiazole-6- carboxamide;
5-chloro-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol;
2-(4-chloro-2-hydroxyphenyl)-N-(3-moφholin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
2-(4-chloro-2-hydroxyphenyl)-N-(2-pyrrolidin- 1 -ylethyl)- 1 ,3-benzothiazole-6- carboxamide;
5-chloro-2-(6- { [4-(2-methoxyethyl)piperazin- 1 -yljcarbonyl } - 1 ,3-benzothiazol-2- yl)phenol; 2-(2-hydroxy-5-methoxyphenyl)-N-(3-moφholin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
4-methoxy-2- [6-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol ;
2-(5-bromo-2-hydroxyphenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-l,3-benzothiazole-6- carboxamide; 4-fluoro-2-[6-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol;
5-methoxy-2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]phenol; methyl N- { [2-(2-hydroxyphenyl)- 1 ,3-benzothiazol-6-yl]carbonyl } serinate;
2-[6-(pyrrolidin- 1 -ylcarbonyl)- 1 ,3-benzothiazol-2-yl]phenol ;
2-(5-chloro-2-hydroxyphenyl)-N-(3-moφholin-4-ylpropyl)-l,3-benzothiazole-6- carboxamide;
3-methoxy-2-[6-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]phenol;
N,N-diethyl-2-(2-hydroxy-4-methoxyphenyl)-l,3-benzothiazole-6-carboxamide;
N- [2-hy droxy- 1 - (hydroxymethyl)ethyl] -2-(2-hydroxy-4-methoxyphenyl)- 1,3- benzothiazole-6-carboxamide; 2-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridin-3-ol; methyl 4-{ [2-(6-{ [[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-l,3-benzothiazol-2- yl)-3-hydroxyphenoxy]methyl}benzoate; 5-ethoxy-4-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyridin-3-ol;
N-[2-(dimethylamino)ethyl]-2-(4-hydroxy-l,r-biphenyl-3-yl)-N-methyl-l,3- benzothiazole-6-carboxamide;
N-[2-(dimethylamino)ethyl]-2-(4-hydroxy-3'-methoxy-l, -biphenyl-3-yl)-N-methyl-l,3- benzothiazole-6-carboxamide;
5-chloro-2-(6-{ [[2-(dimethylamino)ethyl](methyl)amino]methyl}-l,3-benzothiazol-2- yl)phenol;
5-chloro-2-(6- { [4-(2-methoxyethyl)piperazin- 1 -yljmethyl } - 1 ,3-benzothiazol-2-yl)phenol;
5-chloro-2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]phenol; 4-fluoro-2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]phenol;
2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
3-methoxy-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
4-methoxy-2-[6-(ρyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
4-bromo-2-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol; 5-methoxy-2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]phenol;
4-chloro-2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]phenol;
2-{ 6-[(diethylamino)methyl]- 1 ,3-benzothiazol-2-yl } -5-methoxyphenol;
5-ethoxy-4-[6-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]pyridin-3-ol;
4-chloro-2-(6- { [(3-moφholin-4-ylpropyl)amino]methyl } - 1 ,3-benzothiazol-2-yl)phenol; 2-[6-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]pyridin-3-ol;
2-[5-(pyrrolidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
5-chloro-2-[6-(piperidin-l-ylmethyl)-l,3-benzothiazol-2-yl]phenol;
5-chloro-2-[6-(4-methylpiperazin- 1 -ylmethyl)- 1 ,3-benzothiazol-2-yl]phenol;
5-chloro-2-{6-[(diethylamino)methyl]-l,3-benzothiazol-2-yl}phenol; 5-chloro-2- { 6- [(dimethylamino)methyl] - 1 ,3-benzothiazol-2-yl } phenol ;
2-[6-(hydroxymethyl)-l,3-benzothiazol-2-yl]phenol;
2-(6-amino- 1 ,3-benzothiazol-2-yl)-4-methoxyphenol;
N,N-dimethyl-2-(2-hydroxy-4-methoxyphenyl)- 1 ,3-benzothiazole-6-carboxamide;
N,N-dimethyl-2-(2-hydroxyphenyl)-l,3-benzothiazole-6-carboxamide; 3-[6-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yl]pyrazin-2-amine;
2-(4-chloro-2-hydroxyphenyl)- 1 ,3-benzothiazol-6-ol;
5-chloro-2-[6-(2-hydroxy-3-pyrrolidin-l-yl-propoxy)-l,3-benzothiazol-2-yl]-phenol; 5-chloro-2-[5-(pyrrolidin-l-ylcarbonyl)-l,3-benzothiazol-2-yljphenol; 2-[5-(pyrrolidin-l -ylcarbonyl)- l,3-benzothiazol-2-yl]phenol; N,N-dimethyl-2-(2-hydroxyphenyl)-l,3-benzothiazole-5-carboxamide; 5-chloro-2-[5-(pyrrolidin-l -ylmethyl)- l,3-benzothiazol-2-yl]phenol; 2-{ 5-[(dimethylamino)methyl]- 1 ,3-benzothiazol-2-yl } phenol; 2-(2-hydroxyphenyl)-Ν-(3-moφholin-4-ylpropyl)-l,3-benzothiazole-7-carboxamide;
or a pharmaceutically acceptable salt of any one thereof.
8. A compound of formula (la)
Figure imgf000047_0001
(la)
wherein:
A and D independently represent CH or N; and
either B represents CH and X represents O;
or B represents N and X represents NH;
R represents hydrogen, halogen, CI to 6 alkyl, CI to 6 alkoxy, aryl or benzyloxy; said aryl or benzyloxy group being optionally further substituted by a group selected from CI to 6 alkyl, CI to 6 alkoxy, halogen and carbomethoxy; 2 R , which is attached to the 5- or 6-position of the benzothiazole ring, represents
3 4 CONR R or CI to 6 alkyl or CI to 6 alkoxy; said alkyl or alkoxy group being further substituted by one or more groups independently selected from hydroxy and NR R ;
3 4 NR R represents a 5 to 7 membered azacyclic ring optionally incoφorating one further
9 heteroatom selected from O and NR ;
R and R each independently represent hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from
7 8 hydroxy, CI to 6 alkoxy, NR R and CI to 6 alkoxycarbonyl;
or the group NR R together represents a 5 to 7 membered azacyclic ring optionally
9 incoφorating one further heteroatom selected from O and NR ;
7 8 7 8 R and R independently represent hydrogen or CI to 6 alkyl; or the group NR R together represents a 5 to 7 membered azacyclic ring optionally incoφorating one further
9 heteroatom selected from O and NR ;
9 R represents hydrogen or CI to 6 alkyl; said alkyl group being optionally further substituted by CI to 6 alkoxy;
or a pharmaceutically acceptable salts thereof.
9. A compound of formula (la), according to Claim 8, for use as a medicament.
10. A pharmaceutical formulation comprising a compound of formula (la), as defined in Claim 8, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable diluent or carrier.
11. A process for the preparation of a compound of formula (la), as defined in Claim 8, and optical isomers, racemates and tautomers thereof and pharmaceutically acceptable salts thereof, which comprises: (a) reaction of a compound of formula (II)
Figure imgf000049_0001
(II) wherein R , A, B, D and X are as defined in Claim 8, with a compound of formula (DI)
Figure imgf000049_0002
(III)
2 wherein R is as defined in Claim 8; or
(b) oxidative cyclisation of a compound of formula (IN)
Figure imgf000049_0003
(IV) wherein R , R , A, B, D and X are as defined in Claim 8; and where desired or necessary converting the resultant compound of formula (la), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (la) into another compound of formula (la); and where desired converting the resultant compound of formula (la) into an optical isomer thereof.
PCT/SE2003/001271 2002-08-14 2003-08-13 Novel use of benzothiazole derivatives WO2004016600A1 (en)

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006026316A2 (en) * 2004-08-26 2006-03-09 Wyeth Prodrug substituted benzoxazoles as estrogenic agents
WO2007019346A1 (en) * 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Benzothiazoles and thiazolopyridines as sirtuin modulators
US7307094B2 (en) 2005-02-17 2007-12-11 Amr Technology, Inc. Benzoxazole carboxamides for treating CINV and IBS-D
WO2009053737A3 (en) * 2007-10-25 2009-07-30 Astrazeneca Ab Pyridine and pyrazine derivatives useful in the treatment of cell proliferative disorders
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7893086B2 (en) 2007-06-20 2011-02-22 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8343997B2 (en) 2008-12-19 2013-01-01 Sirtris Pharmaceuticals, Inc. Thiazolopyridine sirtuin modulating compounds
WO2013153539A1 (en) 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Tricyclic compounds as tec kinase inhibitors
WO2017040617A1 (en) 2015-08-31 2017-03-09 Pharmacyclics Llc Btk inhibitor combinations for treating multiple myeloma
WO2018085731A2 (en) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and a btk inhibitor
WO2018111049A1 (en) * 2016-12-15 2018-06-21 한국생명공학연구원 Pharmaceutical composition for preventing or treating dyrk-related diseases, containing pyridine-based compound as active ingredient
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
US10765669B2 (en) 2016-12-15 2020-09-08 Korea Research Institute Of Bioscience And Biotechnology Pharmaceutical composition for preventing or treating DYRK-related diseases, containing pyridine-based compound as active ingredient
WO2021096811A1 (en) * 2019-11-11 2021-05-20 Beyondspring Pharmaceuticals, Inc. Tucaresol derivatives and uses thereof
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
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US11633393B2 (en) 2017-01-06 2023-04-25 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
US11786523B2 (en) 2018-01-24 2023-10-17 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing thrombocytopenia
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy
US11857522B2 (en) 2016-02-08 2024-01-02 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
US11918574B2 (en) 2015-03-06 2024-03-05 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2368005T3 (en) * 2007-05-07 2011-11-11 Siemens Aktiengesellschaft CERAMIC POWDER, CERAMIC COAT AND LAYER SYSTEM WITH PIROCLORO AND OXIDE PHASES.

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3257204A (en) * 1958-08-22 1966-06-21 Azoplate Corp Electrophotographic reproduction material
GB1363691A (en) * 1970-09-11 1974-08-14 Tokyo Tanabe Co Benzothiazole derivatives
GB1363692A (en) * 1971-08-03 1974-08-14 Tokyo Tanabe Co Benzothiazolyl acetic acid derivatives
DD150059A1 (en) * 1980-04-07 1981-08-12 Horst Hartmann PROCESS FOR THE PRODUCTION OF HYDROXYARYLAZOLES
JPS62221679A (en) * 1986-03-19 1987-09-29 Santen Pharmaceut Co Ltd Benzothazoline derivative
EP0483502A1 (en) * 1990-09-27 1992-05-06 BASF Aktiengesellschaft High temperature resistant benzothiazol-groups containing polyarylether
US5552421A (en) * 1991-09-24 1996-09-03 Boehringer Ingelheim Pharmaceuticals, Inc. Leukotriene biosynthesis inhibitors
WO1999024035A1 (en) * 1997-11-10 1999-05-20 Bristol-Myers Squibb Company Benzothiazole protein tyrosine kinase inhibitors
WO2001074810A2 (en) * 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as h3 antagonists
WO2002051821A1 (en) * 2000-12-22 2002-07-04 Astrazeneca Ab Therapeutic compounds
JP2002306916A (en) * 2001-01-26 2002-10-22 Toray Ind Inc Air filter unit

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3257204A (en) * 1958-08-22 1966-06-21 Azoplate Corp Electrophotographic reproduction material
GB1363691A (en) * 1970-09-11 1974-08-14 Tokyo Tanabe Co Benzothiazole derivatives
GB1363692A (en) * 1971-08-03 1974-08-14 Tokyo Tanabe Co Benzothiazolyl acetic acid derivatives
DD150059A1 (en) * 1980-04-07 1981-08-12 Horst Hartmann PROCESS FOR THE PRODUCTION OF HYDROXYARYLAZOLES
JPS62221679A (en) * 1986-03-19 1987-09-29 Santen Pharmaceut Co Ltd Benzothazoline derivative
EP0483502A1 (en) * 1990-09-27 1992-05-06 BASF Aktiengesellschaft High temperature resistant benzothiazol-groups containing polyarylether
US5552421A (en) * 1991-09-24 1996-09-03 Boehringer Ingelheim Pharmaceuticals, Inc. Leukotriene biosynthesis inhibitors
WO1999024035A1 (en) * 1997-11-10 1999-05-20 Bristol-Myers Squibb Company Benzothiazole protein tyrosine kinase inhibitors
WO2001074810A2 (en) * 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as h3 antagonists
WO2002051821A1 (en) * 2000-12-22 2002-07-04 Astrazeneca Ab Therapeutic compounds
JP2002306916A (en) * 2001-01-26 2002-10-22 Toray Ind Inc Air filter unit

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] OTSUKA PHARMACEUTICAL CO. LTD.: "Preparation of Benzothiazoles and Benzimidazoles as blood platelet aggregation inhibitors", XP002974378, accession no. STN Database accession no. 1991:207259 *
DATABASE CAPLUS [online] SANTEN PHARMACEUTICAL CO. LTD.: "Preparation of 2-phenylbenzothiazoline derivatives as cardiovascular agents", XP002974379, accession no. STN Database accession no. 1988:167460 *
KLINE ET AL.: "Antimicrobial Effects of Novel Siderophores Linked to Beta-Lactam Antibiotics", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 8, no. 1, 2000, pages 73 - 93, XP002204722 *
STEVENS ET AL.: "Structural Studies on Bioactive Compounds. 23. Synthesis of Polyhydroxylated 2-Phenylbenzothiazoles and a Comparison of Their Cytotoxicities and Pharmacological Properties with Genistein and Quercetin", J. MED. CHEM., vol. 37, no. 11, 1994, pages 1689 - 1695, XP002236361 *

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* Cited by examiner, † Cited by third party
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WO2006026316A2 (en) * 2004-08-26 2006-03-09 Wyeth Prodrug substituted benzoxazoles as estrogenic agents
US7781430B2 (en) 2005-02-17 2010-08-24 Albany Molecular Research, Inc. Benzoxazole carboxamides for treating CINV and IBS-D
US7307094B2 (en) 2005-02-17 2007-12-11 Amr Technology, Inc. Benzoxazole carboxamides for treating CINV and IBS-D
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
WO2007019346A1 (en) * 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Benzothiazoles and thiazolopyridines as sirtuin modulators
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8163908B2 (en) 2005-08-04 2012-04-24 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8178536B2 (en) 2005-08-04 2012-05-15 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
EP2468752A1 (en) * 2005-08-04 2012-06-27 Sirtris Pharmaceuticals, Inc. Thiazolopyridine derivatives as sirtuin-modulators
US7893086B2 (en) 2007-06-20 2011-02-22 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8268862B2 (en) 2007-06-20 2012-09-18 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
WO2009053737A3 (en) * 2007-10-25 2009-07-30 Astrazeneca Ab Pyridine and pyrazine derivatives useful in the treatment of cell proliferative disorders
US8017611B2 (en) 2007-10-25 2011-09-13 Astrazeneca Ab Pyridine and pyrazine derivatives -083
US8492401B2 (en) 2008-12-19 2013-07-23 Glaxosmithkline Llc Thiazolopyridine sirtuin modulating compounds
US8343997B2 (en) 2008-12-19 2013-01-01 Sirtris Pharmaceuticals, Inc. Thiazolopyridine sirtuin modulating compounds
WO2013153539A1 (en) 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Tricyclic compounds as tec kinase inhibitors
EP4115886A1 (en) 2013-10-25 2023-01-11 Pharmacyclics LLC Methods of treating and preventing graft versus host disease
US11918574B2 (en) 2015-03-06 2024-03-05 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
WO2017040617A1 (en) 2015-08-31 2017-03-09 Pharmacyclics Llc Btk inhibitor combinations for treating multiple myeloma
US11857522B2 (en) 2016-02-08 2024-01-02 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
WO2018085731A2 (en) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and a btk inhibitor
US10765669B2 (en) 2016-12-15 2020-09-08 Korea Research Institute Of Bioscience And Biotechnology Pharmaceutical composition for preventing or treating DYRK-related diseases, containing pyridine-based compound as active ingredient
WO2018111049A1 (en) * 2016-12-15 2018-06-21 한국생명공학연구원 Pharmaceutical composition for preventing or treating dyrk-related diseases, containing pyridine-based compound as active ingredient
US11633393B2 (en) 2017-01-06 2023-04-25 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
US11786523B2 (en) 2018-01-24 2023-10-17 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing thrombocytopenia
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2021096811A1 (en) * 2019-11-11 2021-05-20 Beyondspring Pharmaceuticals, Inc. Tucaresol derivatives and uses thereof
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy

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