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WO2019185882A1 - Composés pharmaceutiques - Google Patents

Composés pharmaceutiques Download PDF

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Publication number
WO2019185882A1
WO2019185882A1 PCT/EP2019/058041 EP2019058041W WO2019185882A1 WO 2019185882 A1 WO2019185882 A1 WO 2019185882A1 EP 2019058041 W EP2019058041 W EP 2019058041W WO 2019185882 A1 WO2019185882 A1 WO 2019185882A1
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compound
hyd
hydrogen
group
hydrocarbon group
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Andrew David Morley
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Opal Oncology Ltd
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Opal Oncology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application describes compounds, compositions, uses and methods for therapy, especially cancer therapy.
  • the application relates to compounds for use in the treatment of cancer generally, and in particular gliomas.
  • Chemotherapy drugs for the treatment of cancer are generally directed to inhibiting the reproduction of malignant cells and killing malignant cells, thereby preventing tumour growth or reducing tumour size.
  • Some of the most commonly used cancer chemotherapy drugs include alkylating drugs, anthracycline antibiotics, taxanes, alkaloids, and topoisomerase inhibitors.
  • Alkylating drugs are the oldest anti-cancer drugs and are used to treat many types of cancer. Alkylating drugs are typically methylating agents or chloroethylating agents which cause apoptosis in malignant cells.
  • Temozolomide (brand name, Temodar®, Schering- Plough Corp.), is an oral alkylating agent used in the treatment of brain cancer (1-3), e.g. glioblastoma multiforme and oligodendroglioma, and of melanoma (4, 5). It has also been used to treat prostate cancer, pancreatic carcinoma, soft tissue sarcoma, and renal cell carcinoma (6-12). Temozolomide inhibits cell reproduction by inhibiting DNA replication (13).
  • Temodar® has unique characteristics compared with other alkylating agents. For example, it is administered orally, forms a small lipophilic molecule that crosses the blood-brain barrier, is less toxic than other alkylating agents, does not chemically cross- link DNA, and is effective on a wide variety of cancers.
  • Temodar® is the current chemotherapeutic standard for treating brain tumours, as many as 50% of brain tumours are resistant to Temodar® therapy (14, 15). Resistance to Temodar® is also found in melanoma (16, 17).
  • Anthracycline antibiotics include doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin and are commonly used to treat most types of cancers, e.g. leukemias, Hodgkin's lymphoma, cancers of the bladder, breast, stomach, lung, ovaries, and thyroid, soft tissue sarcoma, multiple myeloma, and others.
  • Doxombicin acts by intercalating into DNA and preventing transcription and DNA synthesis (18).
  • Doxorubicin is also a topoisomerase I inhibitor (19) and Pa poison (20).
  • Topoisomerase inhibiting drugs include doxorubicin, etoposide, and teniposide, and are generally used to treat leukemia, lung, ovarian, and gastrointestinal cancers (21 , 22). These drugs act by inhibiting topoisomerase I or topoisomerase Pa or Pb, thereby preventing DNA replication, recombination, transcription and chromosome segregation (23, 24).
  • tumour cells have, or may, develop resistance to them.
  • topoisomerase inhibitors for example, endogenously produced ganglioside GM3 was shown to be involved in etoposide and doxombicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cell line (25).
  • Primary non-malignant and malignant brain and central nervous system tumours are expected to occur in more than 64,000 people in the United States in 201 1 (26). Gliomas represent 31% of all primary brain and central nervous system tumours, and over 80% of gliomas are malignant (26). The mortality rate of primary malignant brain and CNS tumours is high; approximately 22,020 new adult cases of brain and other nervous system cancers and 13,140 deaths occurred in 2010 (27). Malignant brain tumours account for 1.4% of all primary malignant cancers, and 2.2% of all cancer related deaths (28).
  • barbituric acid derivatives have value as therapeutic agents.
  • they have been employed for their central nervous system depressant activity, finding use inter alia as sedatives and anti-convulsants. Due to their toxicity, they have largely been replaced by benzodiazepines in such treatments.
  • Ciustea et al. discloses inter alia barbiturates for treating the vaccinia virus (smallpox) ("Identification of non-nucleoside DNA synthesis inhibitors of vaccinia virus by high throughput screening", J. Med. Chem., 51 , 6563-6570, 2008).
  • WO 01/93841 discloses certain barbituric acid analogues as therapeutic agents which inhibit HIF-1 activity. This may be used to treat proliferative conditions, such as cancer.
  • merocyanine dyes compounds related to thiobarbiturates
  • This treatment involves the use of the dye to photosensitize leukemic cells, followed by exposure to light.
  • Merocyanine 540 has also been shown to have apoptotic activity (Chen Yen-Chou et al., "Photodynamic anticancer agent merocyanine 540 inhibits cell growth by apoptosis”. Anticancer Research, 16, 5 A, 2781- 2788, 1996; D. L.
  • WO2013/024447 discloses barbiturate and thiobarbiturate compounds for use in treating cancers.
  • JPS 50125978 A discloses a series of thiomorpholine derivatives, including 2-cinnamylidene-3-thiomorpholinone-1 -oxide having the formula:
  • JPS 50125978 A does not disclose or suggest that the thiomorpholine derivaties described therein may be useful in the treatment of cancers.
  • barbiturates and their analogues have received attention, there is still considerable room for improvement in their anti-cancer properrties.
  • the present inventors have surprisingly discovered a class of barbiturate analogues and related compounds which may provide therapies, such as treatments for cancer, especially for cancers that are resistant to current drugs such as Temodar®, and for cancers that are resistant to radiation. These compounds may be used to improve treatments for various forms of cancer.
  • Q is SO or SO2
  • n 1 or 2
  • R 1 is selected from hydrogen and a non-aromatic C1-6 hydrocarbon group
  • R 1 together with R 2 forms a C2- 4 alkylene linker which is optionally substituted with one or more substituents selected from a C1-4 hydrocarbon group, halogen, hydroxy and amino;
  • R 4 and R 5 are independently selected from hydrogen and a non-aromatic (e.g. saturated) C1-6 hydrocarbon group; or R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropane-1 ,1-diyl group or a cyclobutane-1 ,1-diyl group;
  • Ar 1 is selected from phenyl, thiophenyl and furanyl each optionally substituted with one or more substituents R 6 ;
  • R 1 is selected from hydrogen and a non-aromatic C1-5 hydrocarbon group; or together with R 2 forms a C2- 4 alkylene linker which is optionally substituted with one or more substituents selected from a C1-4 hydrocarbon group (e.g alkyl, cycloalkyl or cyclopropylmethyl), halogen, hydroxy and amino.
  • a C1-4 hydrocarbon group e.g alkyl, cycloalkyl or cyclopropylmethyl
  • a Ci -4 hydrocarbon group e.g alkyl, cycloalkyl or cyclopropylmethyl
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) Ci -4 hydrocarbon group; or together with R 2 forms a C2- 4 alkylene linker which is optionally substituted with one or more substituents selected from a C1-2 hydrocarbon (e.g. alkyl) group or halogen.
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) Ci -4 hydrocarbon group; or together with R 2 forms a C2- 4 alkylene linker which is optionally substituted with one or more substituents selected from a C1-2 hydrocarbon (e.g. alkyl) group or halogen.
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) Ci -4 hydrocarbon group;
  • R 2 and R 3 are independently selected from hydrogen and a C1-2 hydrocarbon (e.g. alkyl) group; or R 1 together with R 2 forms a C2- 4 alkylene linker;
  • R 1 is selected from hydrogen and a Ci -4 alkyl, cycloalkyl or cycloalkylalkyl group;
  • R 2 and R 3 are independently selected from hydrogen and methyl
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) Ci- 6 hydrocarbon group.
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) C1-5 hydrocarbon group.
  • R 1 is selected from hydrogen and a non-aromatic (e.g. saturated) Ci -4 hydrocarbon group.
  • R 1 is hydrogen or, if it is a non-aromatic hydrocarbon group, the non-aromatic hydrocarbon group is selected from alkyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyl group.
  • R 1 is selected from hydrogen, methyl, ethyl, n-propyl, iso- propyl cyclopropyl, cyclopropylmethyl, n-butyl, iso butyl and tert- butyl.
  • R 1 is selected from hydrogen, methyl, ethyl, iso- propyl cyclopropyl and cyclopropylmethyl.
  • C2- 4 alkylene linker which is optionally substituted with one or more substituents selected from methyl, ethyl and fluorine.
  • a compound according to any one of Embodiments 1.1 to 1.5 and 1.1 1 to 1.22 wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a carbonyl group (C 0), a cyclopropane-1 , 1-diyl or a cyclobutane-1 , 1-diyl group.
  • a compound according to any one of Embodiments 1.1 to 1.5 and 1.11 to 1.22 wherein R 2 and R 3 are independently selected from hydrogen, methyl, ethyl, n-propyl, iso propyl and cyclopropyl or, together with the carbon atom to which they are attached, form a carbonyl group (C 0), a cyclopropane-1 , 1-diyl or a cyclobutane-1 , 1-diyl group.
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropane- 1 , 1-diyl group or a cyclobutane-1 ,1-diyl group.
  • R 4 and R 5 are independently selected from hydrogen, methyl, ethyl, n-propyl, iso- propyl and cyclopropyl or, together with the carbon atom to which they are attached, form a cyclopropane-1 , 1-diyl or a cyclobutane-1 ,1-diyl group.
  • cyclobutane-1 ,1-diyl group is present in the compound.
  • 1.71 A compound according to Embodiment 1.70 wherein R 6 is selected from halogen, cyano, Hyd and O-Hyd.
  • R 6 is selected from fluorine, chlorine, bromine, cyano, Hyd and O-Hyd.
  • R 6 is selected from fluorine, chlorine, cyano, Hyd and O-Hyd.
  • R 6 is selected from fluorine, chlorine, Hyd and O-Hyd.
  • Hyd is an optionally fluorinated C1-5 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).
  • Hyd is an optionally fluorinated C1-4 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).
  • Hyd is an optionally fluorinated C 1-3 hydrocarbon group (e.g. a saturated optionally fluorinated hydrocarbon group).
  • Hyd is an optionally fluorinated C1-2 hydrocarbon (e.g. alkyl) group.
  • Hyd is an optionally fluorinated alkyl group.
  • Hyd is an unsubstituted hydrocarbon group, a perfluorinated saturated hydrocarbon group, or a saturated hydrocarbon group substituted with 1 to 5 fluorine atoms.
  • Hyd is selected from methyl, ethyl, iso- propyl, cyclopropyl, cyclopropylmethyl, tert- butyl, difluoromethyl and
  • R 6 is absent or is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, iso- propyl, cyclopropyl, tert- butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy and acetyl.
  • Ar 1 is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-6- fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,5- difluorophenyl, 2-trifluorophenyl, 2,3-diflu
  • Ar 1 is selected from 2- chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl,
  • Q is SO or SO2
  • n 1 or 2
  • R 1 is selected from hydrogen, methyl, ethyl, iso-propyl, cyclopropyl and
  • R 2 and R 3 are independently selected from hydrogen and methyl
  • R 4 and R 5 independently selected from hydrogen or methyl
  • Ar 1 is a phenyl group optionally substituted with one or two subsitutents R 6 ;
  • R 6 is selected from fluorine, chlorine, methyl, tert- butyl, trifluoromethyl and
  • 1 .108 A compound according to any one of Embodiments 1 .1 to 1.106 which is other than a compound wherein, in combination, Q is SO, n is 2 and R 1 is other than hydrogen.
  • 1 .109 A compound according to any one of Embodiments 1 .1 to 1.106 which is other than a compound wherein, in combination, Q is SO and n is 2.
  • 1.109A A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, Q is SO and Ar 1 is an unsubstituted phenyl group.
  • 1.109C A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, n is 1 and Ar 1 is an unsubstituted phenyl group.
  • 1.109D A compound according to any one of Embodiments 1.1 to 1.106 which is other than a compound wherein, in combination, Q is SO, n is 1 and Ar 1 is an unsubstituted phenyl group.
  • hydrocarbon refers to aliphatic, alicyclic and aromatic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated.
  • hydrocarbon groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups.
  • Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein.
  • non-aromatic hydrocarbon refers to a hydrocarbon moiety that does not have aromatic character.
  • the non-aromatic hydrocarbon can contain only carbon-carbon single bonds or it may contain one or more double or triple bonds.
  • saturated as used herein in relation to hydrocarbon groups means that there ae no multiple (e.g. double or triple) bonds present in the hydrocarbon group.
  • alkylene e.g. as in Ci -4 straight chain or branched chain alkylene
  • alkanediyl group i.e. a divalent saturated acyclic straight chain or branched chain hydrocarbon group.
  • straight chain alkylene groups include methylene (CH2), ethylene (CH2CH2) and propylene ((CH2CH2CH2).
  • branched chain alkylene groups include CH(CH3), CH2CH(CH3)CH2 and
  • Embodiments 1.1 to 1.1 12A may be presented in the form of salts, when the compound contains a salt-forming moiety
  • the salts referred to above are typically acid addition salts.
  • the salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • the salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et ai, 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.
  • salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts.
  • Such non-pharmaceutically acceptable salts forms which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • Geometric isomers and tautomers The compounds of the invention may exist in a number of different geometric isomeric, and tautomeric forms and references to the compounds of formula (1 ) as defined in Embodiments 1.1 to 1.118 include all such forms.
  • the compounds of formula (1 ) can exist in both E and Z isomeric forms.
  • references to the compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
  • optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the“R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, New York, 1992, pages 109-1 14, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.
  • Optical isomers can be separated by a number of techniques including chiral
  • optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.
  • chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic
  • compositions containing a compound having one or more chiral centres wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (1 ) is present as a single optical isomer (e.g.
  • 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1 ) may be present as a single optical isomer (e.g. enantiomer or
  • the compounds of the invention as defined in any one of Embodiments 1.1 to 1.118 may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 0 and 18 0.
  • the isotopes may be radioactive or non-radioactive.
  • the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
  • Solvates Compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 may form solvates (as defined in Embodiments 1.117 and 1.1 18).
  • Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
  • TGE thermogravimetric analysis
  • DSC differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • the solvates can be stoichiometric or non-stoichiometric solvates.
  • Particularly preferred solvates are hydrates, and examples of hydrates include
  • Prodruqs The compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 18 may be presented in the form of a pro-drug.
  • prodrugs is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1 ), as defined in any one of Embodiments 1.1 to 1.1 18.
  • esters may be formed by esterification, for example, of any hydroxyl groups present in the parent compound with, where
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.) ⁇
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • complexes e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals
  • Biological Activity Compounds of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.118 have been shown to have cytotoxic effects on glioma cell lines. As such, they may be useful in preventing or treating cancers and in particular gliomas.
  • the invention provides:
  • Embodiments 2.4 to 2.9 include, but are not limited to carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias,
  • myelodysplastic syndrome or promyelocytic leukaemia
  • thyroid follicular cancer tumours of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma
  • tumours of the central or peripheral nervous system for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
  • gliomas are a common type of primary brain tumour that originate in the glial cells in the brain, and account for about 30% of all primary brain and central nervous system tumours, and about 80% of all malignant brain tumours. Gliomas typically arise from three different types of cells that are normally found in the brain, namely astrocytes,
  • gliomas include ependymomas (associated with ependymal cells), astrocytomas (associated with astrocytes),
  • oligodendrogliomas associated with oligodendrocytes
  • brainstem glioma which develops in the brain stem
  • optic nerve glioma which develops in or around the optic nerve
  • mixed gliomas which contain cells from different types of glia.
  • Ependymomas are rare, accounting for only about 2-3% of primary brain tumours. However, they account for about 8-10% of brain tumours in children and occur most often in children younger than 10 years of age.
  • Astrocytomas originate in the star-shaped glial cells (astrocytes) in the cerebrum.
  • Astrocytomas do not usually spread outside the brain and spinal cord and do not usually affect other organs but they are the most common glioma and can occur in most parts of the brain and occasionally in the spinal cord.
  • Two broad classes of astrocytoma are generally recognised, namely those with narrow zones of infiltration (mostly invasive tumours; e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), that often are clearly outlined on diagnostic images; and those with diffuse zones of infiltration (e.g., high-grade astrocytoma, anaplastic astrocytoma, glioblastoma).
  • Glioblastoma multiforme is a malignant astrocytoma and the most common primary brain tumour among adult humans.
  • oligodendrogliomas is a type of glioma that develops from oliogodendrocytes, which are the supportive tissue cells of the brain, and are usually found in the cerebrum. About 4% of primary brain tumours are oliogodendrogliomas and they are most common in young and middle-aged adults. Seizures are a very common symptom of these gliomas, as well as headache, weakness, or changes in behavior or sleepiness.
  • Brain stem gliomas are tumours found in the brain stem. Most brain stem tumours cannot be surgically removed because of the remote location and delicate and complex function this area controls. Brain stem gliomas occur almost exclusively in children, typically in school-age children.
  • a mixed glioma is a malignant glioma made up of more than one type of glial cell. This type of glioma may also be referred to as an oligoastrocytoma.
  • Mixed gliomas are often found in the cerebrum, but may metastasize to other parts of the brain. Only about 1% of primary brain tumours are mixed gliomas and they are most commonly found in adult men.
  • An optic nerve glioma is a type of malignant glioma (brain tumour) found in the optic chiasm.
  • Optic nerve gliomas often surround the optic nerves, and are frequently found in people who have neurofibromatosis.
  • a person suffering from an optic nerve glioma typically experiences loss of vision, and may also suffer from hormone disturbances as the tumours are often found at the base of the brain where the structures responsible for hormonal control are located.
  • Optic nerve gliomas are typically difficult to treat because of the sensitivity of the surrounding brain structures.
  • gliomas In addition to being classified according to the type of glial cell from which they originate or the region of the brain in which they develop, gliomas can also be classified according to their“grade”, which is a measure of the growth potential and aggressiveness of the tumour.
  • gliomas are most often referred to as “low-grade” or “high-grade” gliomas, the grade being determined by pathological evaluation of the tumour.
  • Tumours can be further graded according to the World Health Organization (WHO) grading system, under which tumours are graded from I (least advanced disease— best prognosis) to IV (most advanced disease— worst prognosis).
  • WHO World Health Organization
  • Gliomas can also be classified according to whether they are located above or below the tentorium membrane which tentorium separates the cerebrum (above) region of the brain from the cerebellum (below).
  • Supratentorial gliomas i.e. tumours located above the tentorium in the cerebrum
  • infratentorial gliomas tumors located below the tentorium, in the cerebellum
  • a further class of gliomas consists of those tumours found in the pons of the brainstem.
  • the brainstem has three parts (pons, midbrain and medulla); the pons controls critical functions such as breathing, making surgery on pontine gliomas extremely dangerous.
  • the invention provides:
  • glioma is an oligodendroglioma.
  • glioma is a brainstem glioma.
  • glioma is a high- grade glioma.
  • glioma is a supratentorial glioma.
  • the invention also provides processes for the preparation of a compound of the formula (1 ) and salts and tautomers thereof.
  • the invention provides a process for preparing a compound as defined in any one of Embodiments 1.1 to 1.1 18, which process comprises:
  • LG-R 1 is a suitable alkylating agent.
  • LG may be, for example, a halide or sulphonate (e.g.
  • LG-R 1 may be an alkyl iodide such as methyl iodide.
  • the reaction is typically carried out in the presence of a base in a polar aprotic solvent such as dimethylformamide.
  • the base must be capable of deprotonating the amide hydrogen in the compound of formula (12) and suitable bases include metal hydrides (e.g. NaH).
  • the reaction is typically carried out at temperatures of less than 25°C, for example, less than 10°C, for a period of up to 1 hour.
  • step (a) 2-aminoalkanethiol (13) is reacted with ethyl chloroacetate (14) to form lactam (15).
  • the reaction is typically carried out in a polar solvent, for example a polar protic solvent, such as an alcohol (e.g. methanol).
  • a base is also typically added, for example a metal alkoxide (e.g. d-hONa).
  • the lactam (15) may be alkylated as shown in step (b) in Scheme 1 to give alkylated lactam (16).
  • LG-R 1 is a suitable alkylating agent.
  • LG may be, for example, a halide or sulphonate (e.g. aryl sulphonate or alkyl sulphonate).
  • R 1 is an alkyl group (such as methyl)
  • LG-R 1 may be an alkyl iodide such as methyl iodide.
  • the reaction is typically carried out in the presence of a base in a non-aqueous polar solvent such as dimethylformamide.
  • a base must be capable of deprotonating the amide hydrogen in the compound of formula (12) and suitable bases include metal hydrides (e.g. NaH).
  • suitable bases include metal hydrides (e.g. NaH).
  • the reaction is typically carried out at temperatures of less than 25°C, for example, less than 10°C for a period of up to 1 hour.
  • step (c) the lactam (15) can be used directly in step (c).
  • step (c) the lactam (15) or (16) is oxidised with an oxidising agent such as hydrogen peroxide to form the sulphoxide.
  • the reaction can be carried out in a polar solvent, for example an alcohol such as methanol, and is advantageously carried out in the presence of a Montmorillonite catalyst (e.g. Montmorillonite K).
  • step (d) the sulphoxide (17) is then reacted with aldehyde (1 1 ) to form a compound of formula (1 ) using the conditions described above in relation to process variant (I).
  • Lactams (15) and (16) can be prepared as described in relation to Scheme 1 above.
  • a stronger oxidising agent such as a
  • peroxymonosulphate salt for example, potassium peroxymonosulphate
  • step (c) peroxymonosulphate salt
  • the oxidation may be carried out in a polar, protic solvent, for example water, an alcohol (such as t-BuOH) or mixtures thereof.
  • the oxidation is typically carried out at temperatures of less than 5°C for a period of up to 2 hours.
  • Sulphone (18) can then be reacted with aldehyde (11 ) in step (d) to form a compound of formula (1 ) using the conditions described above in relation to process variant (I).
  • the aldehyde compounds of formula (11 ) can be prepared according to Scheme 3 shown below.
  • an aromatic aldehyde Ar 1 -CHO is reacted with a Wittig reagent to give the aldehyde of formula (11 ).
  • the reaction is typically carried out in an aprotic solvent such as dichloromethane at or around room temperature.
  • one compound of the formula (1 ), or a protected derivative thereof can be converted into another compound of the formula (1 ) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic
  • a pharmaceutical composition comprising at least one compound as defined in any one of Embodiments 1.1 to 1 .1 18 together with a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be, for example, a carrier (e.g. a solid, liquid or semi-solid carrier), a diluent or bulking agent, a granulating agent, coating agent, binding agent, disintegrant, lubricating agent, preservative, antioxidant, buffering agent, suspending agent, thickening agent, flavouring agent, sweetener, taste masking agent or any other excipient conventionally used in pharmaceutical compositions.
  • a carrier e.g. a solid, liquid or semi-solid carrier
  • a diluent or bulking agent e.g. a diluent or bulking agent
  • a granulating agent e.g. a granulating agent
  • coating agent e.g. a granulating agent
  • binding agent e.g. a granulating agent
  • disintegrant e.g. a granulating agent
  • lubricating agent e.g. granulating agent
  • preservative
  • compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient.
  • aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels,
  • compositions for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201 -230).
  • a drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pK a is sufficiently away from the formulation pH value.
  • the acceptable range is pH 2-12 for intravenous and intramuscular administration, but subcutaneously the range is pH 2.7-9.0.
  • the solution pH is controlled by either the salt form of the drug, strong acids/bases such as hydrochloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to buffering solutions formed from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, tris(hydroxymethyl)-aminomethane (TRIS), or carbonate.
  • the combination of an aqueous solution and a water-soluble organic solvent/surfactant is often used in injectable formulations.
  • the water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N- methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60, and polysorbate 80.
  • Such formulations can usually be, but are not always, diluted prior to injection.
  • Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic water-miscible solvents and surfactants used in commercially available injectable formulations and can be used in combinations with each other.
  • the resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • the pharmaceutical formulation can be prepared by lyophilising a compound of Formula (1 ) or acid addition salt thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms. A typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials).
  • vials they are partially stoppered with lyo-stoppers.
  • the formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry lyophile formulation.
  • the composition will typically have a low residual water content, e.g. less than 5% e.g. less than 1 % by weight based on weight of the lyophile.
  • the lyophilisation formulation may contain other excipients for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters.
  • Typical buffers include phosphate, acetate, citrate and glycine.
  • antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxyl anisole, and
  • Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of para-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride.
  • the buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.
  • Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake.
  • Bulking agent means a freely water soluble, solid particulate diluent that when co-lyophilised with the compound or salt thereof, provides a physically stable lyophilized cake, a more optimal freeze-drying process and rapid and complete reconstitution.
  • the bulking agent may also be utilised to make the solution isotonic.
  • the water-soluble bulking agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation.
  • Such bulking agents include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol or mannitol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.
  • the ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.
  • dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process.
  • the supplied formulation may require further dilution or preparation before delivery for example dilution into suitable sterile infusion packs.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. In another preferred embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
  • compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • excipients are well known and do not need to be discussed in detail here.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
  • a protective film coating e.g. a wax or varnish
  • the coating e.g. a EudragitTM type polymer
  • the coating can be designed to release the active component at a desired location within the gastro-intestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound.
  • Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.
  • the compound as defined in any one of Embodiments 1.1 to 1.118, or a prodrug thereof, may be formulated with a carrier and administered in the form of nanoparticles.
  • Nanoparticles offer the possibility of direct penetration into the cell.
  • Nanoparticle drug delivery systems are described in“Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13 th March 2006. Nanoparticles for drug delivery are also described in J.
  • the pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.
  • compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
  • compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
  • formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.
  • Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • Embodiment 4.1 A pharmaceutical composition according to Embodiment 4.1 which is in a form for oral or parenteral administration.
  • Embodiment 4.2 A pharmaceutical composition according to Embodiment 4.2 which is in a form for oral administration.
  • a pharmaceutical composition according to Embodiment 4.3 which is selected from tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
  • a pharmaceutical composition according to Embodiment 4.3 which is selected from tablets and capsules.
  • a pharmaceutical composition according to Embodiment 4.6 which is formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection or infusion.
  • a pharmaceutical composition according to Embodiment 4.6 or Embodiment 4.7 which is selected from aqueous and non-aqueous sterile injection solutions; and aqueous and non-aqueous sterile suspensions.
  • a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient.
  • particular sub- ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
  • a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • the invention provides:
  • a pharmaceutical composition according to any one of Embodiments 4.1 to 4.9 which is in unit dose form and contains from 1 nanogram to 2 grams of a compound of any one of Embodiments 1.1 to 1.118.
  • Embodiment 4.9 which contains from 0.1 milligrams to 2 grams of a compound of any one of Embodiments 1.1 to 1.1 18.
  • Embodiment 4.10 A pharmaceutical composition according to Embodiment 4.10 which contains from 10 milligrams to 1 gram of a compound of any one of Embodiments 1.1 to 1.118.
  • Embodiment 4.1 1 which contains from 50 milligrams to 500 milligrams of of a compound of any one of Embodiments 1.1 to 1.1 18.
  • a pharmaceutical composition according to Embodiment 4.9 which contains from 1 microgram to 20 milligrams of a compound of any one of Embodiments 1.1 to 1.1 18.
  • Embodiment 4.9 which contains from 1 microgram to 10 milligrams of a compound of any one of Embodiments 1.1 to 1.118.
  • Embodiment 4.9 which contains from 0.1 milligrams to 2 milligrams of a compound of any one of Embodiments 1.1 to 1.118. Methods of T reatment
  • Embodiments 1.1 to 1.1 18 will be useful either as sole chemotherapeutic agents or, more usually, in combination therapy with
  • chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions are set out above.
  • Embodiments 4.1 to 4.15) and a chemotherapeutic agent are provided.
  • chemotherapeutic agents that may be co-administered with the compounds of Embodiments 1.1 to 1.1 18 (e.g. in accordance with Embodiment 5.1 ) include:
  • mTOR inhibitors e.g. Everolimus
  • PI3K pathway inhibitors e.g. PI3K, PDK1 .
  • Alkylating Agents e.g. temozolomide, cyclophosphamide
  • hypoxia triggered DNA damaging agents e.g. Tirapazamine
  • Aromatase inhibitors • Anti Her2 antibodies, (see for example
  • HER2 small molecule inhibitors e.g. lapatinib
  • CDK4/6 inhibitor e.g. Ibrance
  • Taxanes e.g. paclitaxel, docetaxel, cabazitaxel
  • Platinum agents e.g. cisplatin, carboplatin, oxaliplatin
  • Anthracyclines e.g. Doxorubicin
  • Inhibitors of Bcl-2 family proteins e.g. ABT263 (navitoclax), a Bcl-2/Bcl-extra large
  • the compounds may also be administered in conjunction with radiotherapy.
  • the compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.
  • the compounds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect.
  • the "effective amount” can be a quantity of compound which, when administered to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and/or increases longevity.
  • the amount of the compound of the invention administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.
  • the compounds are generally administered to a subject in need of such administration, for example a human or animal subject), preferably a human.
  • a typical daily dose of the compound of any of Embodiments 1.1 to 1.118 can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required.
  • the compound can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21 , or 28 days for example.
  • a patient will be given an infusion of a compound for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.
  • a patient may be given an infusion of a compound for periods of one hour daily for 5 days and the treatment repeated every three weeks.
  • a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.
  • a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.
  • the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
  • 2-pyrolidinylmethanol (3g, 0.029 mole) was dissolved in dry toluene (100ml_) under an N2 atmosphere. Carbonyldiimidazole (9.6g, 0.059 mole) and 4-dimethylaminopyridine (0.36g, 0.002 mole) were added and the reaction mixture was refluxed at 100°C for 2 hours. The crude reaction mixture was cooled to room temperature and concentrated. The crude solid was diluted with dichloromethane (200ml_) and washed with water (100ml_) follow by 1 M HCI(100ml_). The organic layer was dried over Na 2 S0 4 and concentrated to give the crude tetrahydro-1 H,3H-pyrrolo[1 ,2-c]oxazol-3-one (1.4g, 37.83%) which was used without further purification.
  • Hexahydro-1 H-pyrrolo[2,1 -c]thiomorpholin-4-one Sodium metal (0.5g, 0.021 mole) was added portion-wise to propan-2-ol (280ml_) under N 2 atmosphere and the resulting mixture was then stirred at room temperature until a homogeneous solution was formed. Methyl thioglycolate (3.48g, 0.032 mole) was added and the resulting mixture was stirred for 1 hour at room temperature. Tetrahydro-1 H,3H- pyrrolo[1 ,2-c]oxazol-3-one(1.4g,0.010 mole) was added and the resulting mixture was heated for 2 hours at 1 10°C. The crude reaction mixture was cooled to room temperature and partially concentrated under reduced pressure. The resulting suspension was extracted with EtOAc (300ml_). The organic layer was dried over Na 2 S0 4 and
  • Step 1 Methyl thioglycolate (5.4g, 0.050 mole) was dissolved in dry methanol (80ml). To this was added 2-bromo-2-methylpropionamide (5.0g, 0.030 mole) followed by NaOMe (4.9g, 0.090 mole). The resulting mixture was refluxed for 16 hours. The crude reaction mixture was cooled to room temperature and concentrated. The resulting crude product was used directly in the next step.
  • Step 2 Step 1 product (1 7g) was dissolved in dry DMF (10ml_). The resulting solution was heated at 110°C in sealed tube for 16 hours. The crude reaction mixture was cooled to room temperature, and the reaction mixture quenched with 1 M HCI (50ml). The resulting mixture was extracted using EtOAc. The organic layer was dried over Na2S04 and concentrated. The crude product was used directly in the next step.
  • Human glioblastoma cell lines (U87-MG_ATCC HTB-14, T98G_ATCC CRL-1690, CCF- STTG1_CRL-1718) were obtained from the American Type Culture Collection (ATCC). The cells were maintained in DMEM (Gibco #1 1885-076) containing 10% FBS (Gemini #100-106) and 1X Penicillin-Streptomycin-Glutamine (Gibco #10378-0167). The cells were cultured at 37 °C under CO2 in a cell culture incubator.
  • the cells were plated into clear flat bottom 96-well cell culture plates with a low
  • evaporation lid (Denville #T1096) using XL3000i multichannel pipettes (Denville #P3971- 9A) to be 4,000 cells per well in 100 pL except blank wells. The cells were then cultured overnight at 37 °C under CO2 in a cell culture incubator.
  • the cells were subjected to a Sulforhodamine B (SRB) cytotoxicity assay. After shaking out the medium into a sink, the cells were washed once with cold PBS and then 200 pL of 10% trichloroacetic acid (TCA) (Sigma #T0699) solution was added to each well. The TCA treated cells were incubated at 4 °C for over 1 hour. Following shake out the TCA into the sink, cells were rinsed 3 times with tap water. After the final wash, the plates were left to dry upside-down.
  • SRB Sulforhodamine B
  • a tablet composition containing a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 may be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.
  • BP lactose
  • a capsule formulation is prepared by mixing 100 mg of a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.
  • a parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.
  • a parenteral composition for injection is prepared by dissolving in water a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.1 16 (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.
  • a formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving. vi) Injectable formulation IV
  • a formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving.
  • a buffer e.g. 0.2 M acetate pH 4.6
  • a composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1 ) as defined in any one of Embodiments 1.1 to 1.116 with pharmaceutical grade corn oil to give a concentration of 5 mg/ml.
  • the composition is sterilised and filled into a suitable container. viii) Lyophilised formulation
  • compositions are frozen using a one-step freezing protocol at (-45 °C).
  • the temperature is raised to -10 °C for annealing, then lowered to freezing at -45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 °C.
  • the pressure during primary and secondary drying is set at 80 millitor.
  • CBTRUS 201 I .CBTRUS Statistical Report: NPCR and SEER data from 2004-2007, in: Central Brain Tumour Registry of the United States.

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Abstract

L'invention concerne des composés de formule (1) ou des sels ou des tautomères de ceux-ci ; dans la formule : Q représente SO ou SO2 ; n vaut 1 ou 2 ; R1 est choisi parmi l'hydrogène et un groupe hydrocarboné en C1-6 non aromatique ; R2 et R3 sont indépendamment choisis parmi l'hydrogène et un groupe hydrocarboné en C1-6 ; ou R2 et R3 conjointement avec l'atome de carbone auquel ils sont attachés forment un groupe carbonyle (C=O), un groupe cyclopropane-1,1-diyle ou un groupe cyclobutane-1,1-diyle ; ou R conjointement avec R2 forment un lieur alkylène en C2-4 éventuellement substitué par un ou plusieurs substituants choisis parmi un groupe hydrocarboné en C1-4 , halogène, hydroxy et amino ; R4 et R5 sont indépendamment choisis parmi l'hydrogène et un groupe hydrocarboné en C1-6 non aromatique ; ou R4 et R5 forment ensemble avec l'atome de carbone auquel ils sont attachés un groupe cyclopropane-1,1-diyle ou un groupe cyclobutane-1,1-diyle ; et Ar1 est choisi parmi phényle, thiophényle et furanyle, chacun étant éventuellement substitué. Ces composés sont utiles en médecine, par exemple dans le traitement de maladies, telles que le cancer.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50125978A (fr) * 1974-03-22 1975-10-03
WO2003074497A1 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceutical, Inc. Composes de modulation de pin1 et methodes d'utilisation associees
WO2010025436A2 (fr) * 2008-08-29 2010-03-04 Triad Multitech Pharmaceuticals, Inc. Dérivés hétérocycliques contenant de l’azote et du soufre
WO2013024447A1 (fr) * 2011-08-18 2013-02-21 Nuhope, Llc Composés pour utilisation dans la thérapie du cancer

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Publication number Priority date Publication date Assignee Title
JPS50125978A (fr) * 1974-03-22 1975-10-03
WO2003074497A1 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceutical, Inc. Composes de modulation de pin1 et methodes d'utilisation associees
WO2010025436A2 (fr) * 2008-08-29 2010-03-04 Triad Multitech Pharmaceuticals, Inc. Dérivés hétérocycliques contenant de l’azote et du soufre
WO2013024447A1 (fr) * 2011-08-18 2013-02-21 Nuhope, Llc Composés pour utilisation dans la thérapie du cancer

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