WO2023007181A1 - Antipsychotiques à base de phénothiazine pour utilisation dans le traitement du glioblastome - Google Patents

Antipsychotiques à base de phénothiazine pour utilisation dans le traitement du glioblastome Download PDF

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Publication number
WO2023007181A1
WO2023007181A1 PCT/GB2022/052006 GB2022052006W WO2023007181A1 WO 2023007181 A1 WO2023007181 A1 WO 2023007181A1 GB 2022052006 W GB2022052006 W GB 2022052006W WO 2023007181 A1 WO2023007181 A1 WO 2023007181A1
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alkyl
compound
optionally substituted
group
mmol
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Hans-Rene BJØRSVIK
Rolf Bjerkvig
Lukas PETERSEN
Eirin ALME
Stephanie SCHWAB
Katarina SARNOW
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Louise Golding
Vestlandets Innovasjonsselskap AS
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Louise Golding
Vestlandets Innovasjonsselskap AS
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    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds for use in the treatment of cancer, in particular for use in the treatment of glioblastoma. It further relates to certain novel compounds, to pharmaceutical compositions containing them, and to their use in such treatment. Background to the invention
  • Glioblastoma also known as glioblastoma multiforme or “GBM” is an incurable form of brain cancer. It is particularly difficult to treat due to its location and highly aggressive characteristics, however it can be treated for reiief and prolongation of life.
  • Conventional treatment involves highly invasive (open brain) surgery, followed by radiation treatment and chemotherapy. Treatment may also involve Gamma Knife radiosurgery in which beams of radiation are highly focused on the tumour thereby minimising radiation damage to surrounding healthy tissues. Surgery is performed to remove as much of the tumour as possible, in high-risk areas of the brain, however, it may not be possible to remove all of the tumour by surgery alone.
  • Radiotherapy is used to kill remaining tumour ceils after surgery and can also reduce tumour size, as well as the rate of tumour growth.
  • radiotherapy does not have a major effect on tumours such as GBM due to its tendency to spread and the radio-resistance of the cancer cells.
  • radiotherapy is not specific in destroying cancerous cells versus normal tissues.
  • chemotherapy may also be used although there are relatively few chemotherapeutics in clinical use for the treatment of GBM.
  • Temozolomide and the nitrogen mustard ⁇ -chloro-nitrosourea carmustine which are both alkylating agents, can be used as a first line treatment but these are mainly cytostatic as the cancer cells eventually develop resistance and render the treatment no longer effective.
  • Temozolomide is a prodrug which is activated by a first pass metabolic decomposition process in the liver that produces methyl diazonium ions which can penetrate the blood-brain barrier. Its mechanism of action involves alkylation of the guanine groups of DNA by the methyl diazonium ions.
  • GBM is usually accompanied by recurrence with re- growth of tumours which requires repeated treatment.
  • the poor prognosis of GBM is mainly due to the tumour’s high degree of invasiveness and the development of chemotherapy resistance. Tumours such as GBM thus remain particularly difficult to treat and existing therapies only offer a minimal increase in survival rates.
  • Thioridazine (Mellaril) is a known antipsychotic drug belonging to the phenothiazine group of drugs. It has the following structure: Thioridazine 10-[2-[(RS)-1-methylpiperidin-2-yl]ethyl]-2-methylsulfanyl-phenothiazine Thioridazine has primarily been used in the treatment of schizophrenia, but also for various psychiatric indications in patients with dementia. However, severe side- effects such as cardiac arrhythmias have been observed leading to its discontinued use. Its serious side-effects suggest that the agent possesses poor selectivity towards its drug target.
  • the invention relates to a compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer: (I) wherein: X is CH, S, N or NH; Z is C or N; A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g.
  • each R 1 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g. -CH 3 ), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2-6 alkynyl (preferably C 2-4 alkynyl), C 1-6 haloalkyl (e.g. -CF 3 ), -O-C 1-6 alkyl (preferably -O-C 1-3 alkyl, e.g. -OCH 3 ), -S-C 1-6 alkyl (preferably -S-C 1-3 alkyl, e.g. -SCH 3 ), -OH, -SH, halogen (e.g.
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; R 3 and R 4 are each independently selected from: hydrogen, C 2-6 alkenyl (preferably C 2-4 alkenyl), and C 2-6 alkynyl (preferably C 2-4 alkynyl), or R 3 and R 4 , together with the intervening ring carbon atoms, form an optionally substituted aryl ring (e.g. an optionally substituted phenyl ring); and represents an optional bond between two adjacent carbon atoms in the ring.
  • aryl group e.g. optionally substituted phenyl
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2
  • R 3 and R 4 are each independently selected from: hydrogen, C 2-6 alkenyl (preferably C 2-4 alkenyl), and C 2-6 alkynyl (preferably C 2-4 alkynyl), or R 3 and R 4 , together with the intervening
  • the invention relates to a compound of formula (Ia), (Ib) or (Ic) as herein described, a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • the invention relates to the use of a compound of formula (I), (Ia), (Ib) or (Ic), a stereoisomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer.
  • the invention relates to a method of treatment of cancer, said method comprising the step of administering to a subject in need thereof (e.g.
  • the invention relates to novel compounds of formula (II), their stereoisomers and their pharmaceutically acceptable salts: (II) wherein: A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system, preferably an optionally substituted carbocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g.
  • each R 1 and R 2 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g. -CH 3 ), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2-6 alkynyl (preferably C 2-4 alkynyl), C 1-6 haloalkyl (e.g. -CF 3 ), -O-C 1-6 alkyl (preferably -O-C 1-3 alkyl, e.g. -OCH 3 ), -S-C 1-6 alkyl (preferably -S-C 1-3 alkyl, e.g. -SCH 3 ), -OH, -SH, halogen (e.g.
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; and m is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; with the proviso that the compound is other than thioridazine.
  • the invention relates to a compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in therapy or for use as a medicament.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • alkyl refers to a saturated hydrocarbon group and is intended to cover both straight-chained and branched alkyl groups.
  • Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
  • An alkyl group preferably contains from 1-6 carbon atoms, more preferably 1-4 carbon atoms, e.g.1-3 carbon atoms. Unless otherwise specified, any alkyl group may be substituted in one or more positions with a suitable substituent.
  • substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds and includes both straight-chained and branched alkenyl groups.
  • C 2-6 alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms and one or more (e.g. one or two) double bonds.
  • any alkenyl group mentioned herein may optionally be substituted by one or more groups, which may be identical or different.
  • Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds and includes both straight-chained and branched alkynyl groups. Unless otherwise stated, any alkynyl group mentioned herein may optionally be substituted by one or more groups, which may be identical or different. Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • the term “carbocyclic ring system” as used herein refers to a monovalent, saturated or unsaturated cyclic carbon system. Such systems may include one or more carbon-containing rings.
  • any carbocyclic ring system may be substituted in one or more positions with a suitable substituent. Where more than one substituent group is present, these may be the same or different. Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • the term “heterocyclic ring system” as used herein refers to a monovalent, saturated or unsaturated cyclic carbon system in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen or sulfur, preferably nitrogen.
  • Such systems may include one or more rings in which at least one ring contains at least one heteroatom. Where more than one ring is present the rings may be linked by a bond or they may be fused. Unless otherwise specified, any heterocyclic ring system may be substituted in one or more positions with a suitable substituent. Where more than one substituent group is present, these may be the same or different. Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • cycloalkyl refers to a monovalent, saturated cyclic carbon system. It includes monocyclic, bicyclic and polycyclic (e.g.
  • Monocyclic rings may contain from 3 to 8 carbon atoms, bicyclic rings may contain from 7 to 14 carbon atoms, and tricyclic rings may contain from 10 to 14 carbon atoms. Where these contain more than one ring, the rings may be fused or bridged. In fused compounds, two rings share two adjacent atoms. In bridged compounds, two rings share three or more atoms thereby forming a bridge which contains at least one atom.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • bicyclic cycloalkyl groups include, but are not limited to, norbornyl.
  • tricyclic cycloalkyl groups include, but are not limited to, adamantyl.
  • any cycloalkyl group may be substituted in one or more positions with a suitable substituent. Where more than one substituent group is present, these may be the same or different.
  • Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • cycloalkenyl refers to a monovalent, partially unsaturated cyclic carbon system.
  • any cycloalkenyl group may be substituted in one or more positions with a suitable substituent. Where more than one substituent group is present, these may be the same or different. Suitable substituents include -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • alkylene refers to a linking alkyl group and is intended to cover any straight-chained or branched alkylene group.
  • Such groups include methylene, ethylene, ethane-1,1-diyl, propylene, propane-2,2-diyl, 1- methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2- dimethylethylene, etc.
  • Such groups may optionally be substituted by one or more groups selected from -O-C 1-3 alkyl and halogen atoms (e.g. F, Cl or Br).
  • halogen or “halogen atom” as used herein refers to -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group as defined herein in which at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably F, Cl or Br. Examples of such groups include -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , -CHCl 2 , -CH 2 CF 3 , etc.
  • aryl refers to aromatic ring systems. Such ring systems may be monocyclic or bicyclic and contain at least one unsaturated aromatic ring. Where these contain bicyclic rings, these may be fused. Preferably such systems contain from 6-20 carbon atoms, e.g. either 6 or 10 carbon atoms.
  • heterocyclic ring refers to a saturated or partially unsaturated, 4- to 6-membered (preferably 5- or 6-membered) carbocyclic system in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon.
  • the heterocyclic ring structure may be linked to the remainder of the molecule through a carbon atom or through a nitrogen atom.
  • heterocyclic rings include, but are not limited to, tetrahydrofuran, piperidine, pyrrolidine, dioxane, morpholine, etc.
  • any heterocyclic ring mentioned herein may optionally be substituted by one or more groups, which may be identical or different, for example hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, cyano, or nitro groups, or halogen atoms (e.g. F, Cl or Br).
  • halogen atoms e.g. F, Cl or Br.
  • all substituents are independent of one another. In the case where a subscript is the integer 0 (i.e. zero), it is intended that the group to which the subscript refers is absent.
  • stereoisomer refers to compounds which have identical chemical constitution but which differ in respect of the spatial arrangement of the atoms or groups. Examples of stereoisomers are enantiomers and diastereomers.
  • enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • diastereoisomers refers to stereoisomers with two or more stereocenters which are not mirror images of one another.
  • the invention is considered to extend to diastereomers and enantiomers, as well as racemic mixtures and enantioenriched mixtures in which the ratio of enantiomers is other than 1:1.
  • the compounds herein described may be resolved into their enantiomers and/or diastereomers. For example, where these contain only one chiral center, these may be provided in the form of a racemate or racemic mixture (a 50:50 mixture of enantiomers) or may be provided as pure enantiomers, i.e. in the R- or S-form. Any of the compounds which occur as racemates may be separated into their enantiomers by methods known in the art, such as column separation on chiral phases or by recrystallization from an optically active solvent.
  • Those compounds with at least two asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallization, and where these compounds are obtained in racemic form, they may subsequently be resolved into their enantiomers.
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable organic or inorganic salt of any of the compounds herein described.
  • a pharmaceutically acceptable salt may include one or more additional molecules such as counter-ions.
  • the counter-ions may be any organic or inorganic group which stabilises the charge on the parent compound. If the compound is a base, a suitable pharmaceutically acceptable salt may be prepared by reaction of the free base with an organic or inorganic acid.
  • a suitable pharmaceutically acceptable salt may be prepared by reaction of the free acid with an organic or inorganic base.
  • suitable salts are described herein.
  • pharmaceutically acceptable means that the compound or composition is chemically and/or toxicologically compatible with other components of the formulation or with the patient to be treated.
  • a pharmaceutical composition is meant a composition in any form suitable to be used for a medical purpose.
  • cancer refers to cells undergoing abnormal proliferation. Growth of such cells typically causes the formation of a tumor. Cancerous cells may be benign, pre-malignant or malignant. Such cells may be invasive and/or have the ability to metastasize to other locations in the body.
  • cancer includes cancerous growths, tumours, and their metastases.
  • tumor refers to an abnormal mass of tissue containing cancerous cells.
  • metastasis refers to the spread of malignant tumour cells from one organ or part of the body to another non-adjacent organ or part of the body. Cancer cells may break away from a primary tumour, enter the lymphatic and blood systems and circulate to other parts of the body (e.g. to normal tissues). Here they may settle and grow within the normal tissues. When tumour cells metastasize, the new tumours may be referred to as a “secondary” or metastatic cancer or tumour.
  • treatment includes any therapeutic application that can benefit a human or non-human animal (e.g. a non-human mammal). Both human and veterinary treatments are within the scope of the present invention, although primarily the invention is aimed at the treatment of humans. Where not explicitly stated, treatment encompasses prevention.
  • a “pharmaceutically effective amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effect, i.e. an amount of the agent which is effective to achieve its intended purpose. While individual subject (e.g. patient) needs may vary, determination of optimal ranges for effective amounts of the active agent(s) herein described is within the capability of one skilled in the art.
  • the dosage regimen for treating a disease, condition or disorder with any of the compounds described herein may be selected by those skilled in the art in accordance with a variety of factors including the nature of the condition and its severity.
  • the term “subject” refers to any individual who is the target of the administration or treatment.
  • the subject may be, for example, a mammal.
  • the subject may be a human or non-human animal.
  • the term “patient” refers to a subject under the treatment of a clinician.
  • the subject will be a human.
  • the invention relates to a compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer:
  • X is CH, S, N or NH; Z is C or N; A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl); each R 1 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g.
  • C 2-6 alkenyl preferably C 2-4 alkenyl
  • C 2-6 alkynyl preferably C 2-4 alkynyl
  • C 1-6 haloalkyl e.g. -CF 3
  • -O-C 1-6 alkyl preferably -O-C 1-3 alkyl, e.g. -OCH 3
  • -S-C 1-6 alkyl preferably -S-C 1-3 alkyl, e.g. -SCH 3
  • an optionally substituted aryl group e.g.
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; R 3 and R 4 are each independently selected from: hydrogen, C 2-6 alkenyl (preferably C 2-4 alkenyl), and C 2-6 alkynyl (preferably C 2-4 alkynyl), or R 3 and R 4 , together with the intervening ring carbon atoms, form an optionally substituted aryl ring (e.g. an optionally substituted phenyl ring); and represents an optional bond between two adjacent carbon atoms in the ring.
  • the compounds for use according to the invention are those of formula (I) in which R 3 and R 4 are both hydrogen.
  • the compounds for use according to the invention are those of formula (I) in which R 3 and R 4 , together with the intervening ring carbon atoms, form an optionally substituted aryl group.
  • the aryl group which is formed can be an optionally substituted phenyl ring.
  • the compounds for use according to the invention are those of formula (Ia), their stereoisomers, or pharmaceutically acceptable salts thereof: (Ia) wherein X, Z, A, L, R 1 and n are as herein defined; represents an optional bond between two adjacent carbon atoms in the ring; R 2 is selected from any of the groups defined herein for R 1 ; and m is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2.
  • the compounds for use according to the invention are those of formula (I) or (Ia) in which X is CH or S, preferably S.
  • the compounds for use according to the invention are those of formula (I) or (Ia) in which X is S and Z is N.
  • the compounds for use according to the invention are based on a phenothiazine scaffold.
  • Such compounds are those of formula (Ib), their stereoisomers, or pharmaceutically acceptable salts thereof: (Ib) wherein A, L, R 1 , R 2 , n and m are as herein defined.
  • the compounds for use according to the invention are those of formula (I) or (Ia) in which X is CH and Z is C.
  • the compounds for use according to the invention are based on an anthracene scaffold.
  • Such compounds are those of formula (Ic), their stereoisomers, and pharmaceutically acceptable salts thereof: (Ic) wherein A, L, R 1 , R 2 , n and m are as herein defined.
  • group A may be an optionally substituted amine.
  • group A may be a group of the formula -NR a R b wherein R a and R b are independently selected from H, optionally substituted C 1-6 alkyl, and optionally substituted aryl.
  • group A may be an optionally substituted carbocyclic or heterocyclic ring system.
  • Such ring systems may comprise from 3 to 14 ring atoms, preferably from 5 to 12 ring atoms, e.g. from 6 to 14 ring atoms.
  • group A is an optionally substituted carbocyclic ring system.
  • group A may be an optionally substituted cycloalkyl or cycloalkenyl group.
  • Such groups may be mono-, bi- or tricyclic. Where more than one ring is present, these may be bridged or fused.
  • A is a cycloalkyl group containing two or three rings which are fused or bridged.
  • A is an optionally substituted aryl group. For example, it may be an optionally substituted phenyl ring.
  • A is an optionally substituted heterocyclic group.
  • Such groups may be mono-, bi- or poly-cyclic. Where more than one ring is present, these may be bridged or fused. Such groups may be saturated or unsaturated.
  • Non-limiting examples of group A include adamantyl, phenyl, quinuclidinyl (1- azabicyclo[2.2.2]octanyl), DABCO (1,4-diazabicyclo[2.2.2]octanyl), tropanyl (N- methyl-8-azabicyclo[3.2.1]octanyl), nortropanyl (8-azabicyclo[3.2.1]octanyl), norbornyl, norbornenyl, norbornadienyl, bornyl, pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, azepanyl (azacycloheptanyl), decahydroquinolyl, azonanyl, octahydrocyclopenta[c]pyrrolyl, azecanyl, octahydropyrrolo[3,4-c]pyrrolyl
  • group A is selected from substituted or unsubstituted adamantyl, phenyl, quinuclidinyl, piperidinyl and azepanyl. In another embodiment, group A is substituted or unsubstituted adamantyl or piperidinyl, preferably substituted or unsubstituted adamantyl. In one embodiment, group A is unsubstituted adamantyl. Group A may be bonded to group L either through a ring carbon or ring nitrogen atom. In one embodiment, group A is bonded to the group L via a ring carbon atom. Group A may be substituted or unsubstituted.
  • substituent groups may be present on the ring.
  • Each substituent may, independently of one another, be linked either to a ring carbon atom or to a ring nitrogen atom.
  • group A is substituted by one or more groups independently selected from -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • Preferred substituents include, but are not limited to, methyl, ethyl, n-propyl and isopropyl groups.
  • group A is not substituted at any ring carbon atom.
  • group A is not substituted at any point on the ring, i.e. it is unsubstituted.
  • the presence of a hydrogen atom on a ring nitrogen atom is not considered to be a “substituent”.
  • Preferred examples of group A include the following (where denotes the point of attachment to the rest of the molecule):
  • Linking group L serves to link the group A to the remainder of the molecule.
  • Group L may be an optionally substituted, straight-chained or branched C 1-6 alkylene group.
  • L is an optionally substituted, straight-chained or branched C 1-3 alkylene group.
  • linking group L is an unsubstituted, straight-chained C 1-6 alkylene group, preferably an unsubstituted, straight-chained C 1-3 alkylene group, such as methylene or ethylene.
  • L may be an optionally substituted C 1-6 alkylene group, preferably C 2-6 alkylene group, in which one or more -CH 2 - groups of the alkylene chain are replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl).
  • L may be an optionally substituted C 2-6 alkylene, C 3-6 alkylene or C 4-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain are replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl).
  • R’ is H or C 1-3 alkyl, e.g. methyl
  • the alkylene chain is straight-chained.
  • group L may be propylene or butylene in which one or two of the -CH 2 - groups are replaced by a group -NR’-, preferably by a group -NH- or -N(CH 3 )-.
  • group L may be pentylene in which one or two of the -CH 2 - groups are replaced by a group -NR’-, preferably by a group -NH- or -N(CH 3 )-.
  • one or more -CH 2 - groups of the alkylene chain in group L are replaced by a group -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl).
  • one or two -CH 2 - groups of the alkylene chain are replaced by such a group.
  • linking group L include the following (where denotes the point of attachment to the rest of the molecule):
  • Other examples of linking group L include the following (where denotes the point of attachment to the rest of the molecule):
  • substituent groups R 1 and R 2 may be the same or different.
  • each R 1 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g. -CH 3 ), C 1-6 haloalkyl (e.g. -CF 3 ), -O-C 1-6 alkyl (preferably -O-C 1-3 alkyl, e.g.
  • each R 1 is independently selected from C 1-3 alkyl (e.g. -CH 3 ), -CF 3 , -O-C 1-3 alkyl (e.g. -OCH 3 or -OCH 2 CH 3 ), -S-C 1-3 alkyl (e.g. -SCH 3 or -SCH 2 CH 3 ), F, Cl, Br and phenyl.
  • each R 1 is independently selected from -CH 3 , -CF 3 , -OCH 3 , -SCH 3 , and -SCH 2 CH 3 .
  • n is selected from 0, 1 or 2, preferably 0 or 1.
  • each R 2 where present, is independently selected from C 1-3 alkyl (e.g. -CH 3 ), -CF 3 , -O-C 1-3 alkyl (e.g. -OCH 3 or -OCH 2 CH 3 ), -S-C 1-3 alkyl (e.g. -SCH 3 or -SCH 2 CH 3 ), F, Cl, Br and phenyl.
  • each R 2 is independently selected from -CH 3 , -CF 3 , -OCH 3 , -SCH 3 , and -SCH 2 CH 3 .
  • m is selected from 0, 1 or 2, preferably 0 or 1. Examples of compounds for use in accordance with the invention include, but are not limited to, the following, their stereoisomers, and their pharmaceutically acceptable salts:
  • the present invention provides compounds of formula (II), their stereoisomers and their pharmaceutically acceptable salts: (II) wherein: A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g.
  • each R 1 and R 2 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g. -CH 3 ), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2-6 alkynyl (preferably C 2-4 alkynyl), C 1-6 haloalkyl (e.g. -CF 3 ), -O-C 1-6 alkyl (preferably -O-C 1-3 alkyl, e.g. -OCH 3 ), -S-C 1-6 alkyl (preferably -S-C 1-3 alkyl, e.g. -SCH 3 ), -OH, -SH, halogen (e.g.
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; and m is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2; with the proviso that the compound is other than thioridazine.
  • the compound of formula (II) is other than 10-((1- methylpiperidin-2-yl)methyl)-2-(methylthio)-10H-phenothiazine or 10-(2-(piperidin-1- yl)ethyl)-10H-phenothiazine.
  • the invention provides compounds of formula (II), their stereoisomers and their pharmaceutically acceptable salts, in which A is an optionally substituted carbocyclic ring system.
  • A is an optionally substituted cycloalkyl group, for example an optionally substituted cycloalkyl group containing two or three rings which are fused or bridged.
  • A is substituted or unsubstituted adamantyl, for example unsubstituted adamantyl.
  • the invention relates to a compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in therapy or for use as a medicament.
  • the invention relates to a pharmaceutical composition comprising a compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any of the compounds herein described may be converted into a salt thereof, particularly into a pharmaceutically acceptable salt thereof with an inorganic or organic acid or base.
  • Acids which may be used for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, methane sulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, acetic acid, trifluoroacetic acid and ascorbic acid.
  • Bases which may be suitable for this purpose include alkali and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or cesium hydroxide, ammonia and organic amines such as diethylamine, triethylamine, ethanolamine, diethanolamine, cyclohexylamine and dicyclohexylamine.
  • Procedures for salt formation are conventional in the art.
  • the compounds described herein may exist in various stereoisomeric forms, including enantiomers, diastereomers, and mixtures thereof.
  • the invention encompasses all optical isomers of the compounds described herein and mixtures of optical isomers. Hence, compounds that exist as diastereomers, racemates and/or enantiomers are within the scope of the invention.
  • the compounds for use in the invention are either known in the art, or can be prepared by methods known to those skilled in the art using readily available starting materials. Some of the compounds for use in the invention may be commercially available.
  • R 1 , R 2 , A and n are as herein defined, and w is an integer from 0-5.
  • R 1 , R 2 , R 3 , R 4 , A, L and n are as herein defined.
  • R 1 , R 2 , R 3 , R 4 , A, L and n are as herein defined; and X is a halogen atom.
  • Cancers which may be treated in accordance with the invention include, but are not limited to, any of the following: leukemias, lymphomas, colon cancer (e.g. colorectal cancer), breast cancer, glioblastoma, pancreatic cancer, bladder cancer, lung cancer and skin cancer.
  • Metastatic disease arising from any of these tumours may also be treated using any of the compounds herein described.
  • the invention finds particular use in the treatment of deep lying cancerous lesions that are difficult to access non-invasively.
  • Treatment of gliomas forms a preferred aspect of the invention.
  • the compounds described herein find use in the treatment of glioblastoma in a subject or patient and, in particular, in the treatment or prevention of astrocytomas, oligodendrogliomas or ependymomas.
  • the compounds described herein can be used in the treatment of astrocytomas, such as pliocytic astrocytoma, diffuse or low grade astrocytoma, anaplastic astrocytoma or grade 4 astrocytoma.
  • astrocytomas such as pliocytic astrocytoma, diffuse or low grade astrocytoma, anaplastic astrocytoma or grade 4 astrocytoma.
  • the compounds described herein also find particular use in the treatment of skin cancers, for example in the treatment of basal cell carcinoma, squamous cell carcinoma, and melanoma.
  • a “subject” or “patient” encompasses any animal, preferably a mammal. Examples of mammalian subjects include, without limitation, humans, dogs, cats, rodents (e.g.
  • the compounds of the invention are suitable for preventing and/or retarding cancer cell proliferation, differentiation and/or survival, or for preventing and/or retarding metastasis of cancer cells.
  • proliferation refers to cells undergoing mitosis.
  • retarding proliferation indicates that the compounds inhibit proliferation of a cancer cell.
  • "retarding proliferation” indicates that DNA replication is at least 10% less than that observed in untreated cells, more preferably at least 25% less, yet more preferably at least 50% less, e.g.75%, 90% or 95% less than that observed in untreated cancer cells.
  • the compounds herein described will typically be formulated as a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers, excipients or diluents. Acceptable carriers, excipients and diluents for therapeutic use are well known in the art and can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • compositions will be adapted for oral or parenteral administration, for example by intradermal, subcutaneous, intraperitoneal, or intravenous injection.
  • these may be formulated in conventional oral administration forms, e.g.
  • compositions may be prepared using conventional techniques, such as dissolution and/or mixing procedures. Where parenteral administration is employed this may, for example, be by means of intravenous, subcutaneous, intraperitoneal or intramuscular injection. For this purpose, sterile solutions containing the active agent may be employed, such as an oil-in-water emulsion.
  • an appropriate buffer system e.g., sodium phosphate, sodium acetate or sodium borate
  • an appropriate buffer system e.g., sodium phosphate, sodium acetate or sodium borate
  • Compounds having a partition coefficient, Log P, greater than or equal to 3 and less than or equal to 5 are particularly suitable for oral administration due to their ability to cross the blood brain barrier.
  • any pharmaceutical formulation may be administered locally (e.g. by injection or topically) at or near the affected site.
  • Topical pharmaceutical formulations include gels, creams, ointments, sprays, lotions, salves, sticks, powders, solutions and any of the other conventional pharmaceutical forms in the art.
  • Ointments, gels and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Any thickening or gelling agents used should be non-toxic and non-irritant.
  • Lotions may be formulated with an aqueous or oily base and will, in general, also contain one or more emulsifying, dispersing, suspending, thickening or colouring agents. Powders may be formed with the aid of any suitable powder base.
  • Sprays and solutions may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing, solubilising or suspending agents.
  • the formulations herein described may be prepared using conventional techniques, such as dissolution and/or mixing procedures, tableting, etc.
  • the dosage required to achieve the desired activity of the compounds herein described will depend on various factors, such as the compound selected, its mode and frequency of administration, whether the treatment is therapeutic or prophylactic, and the nature and severity of the disease or condition, etc.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon factors such as the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, the mode and time of administration, and the severity of the particular condition.
  • the compound and/or the pharmaceutical composition may be administered in accordance with a regimen from 1 to 10 times per day, such as once or twice per day.
  • the daily dosage level of the agent may be in single or divided doses.
  • Suitable daily dosages of the compounds herein described may readily be determined by those skilled in the art, but are expected to be in the range from 0.1 mg to 1 g of the compound; 1 mg to 500 mg of the compound; 1 mg to 300 mg of the compound; 5 mg to 100 mg of the compound, or 10 mg to 50 mg of the compound.
  • a “daily dosage” is meant the dosage per 24 hours.
  • Embodiments of the invention include, but are not limited to, the following: Embodiment 1: A compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer: (I) wherein: X is CH, S, N or NH; Z is C or N; A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g.
  • each R 1 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g. -CH 3 ), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2-6 alkynyl (preferably C 2-4 alkynyl), C 1-6 haloalkyl (e.g. -CF 3 ), -O-C 1-6 alkyl (preferably -O-C 1-3 alkyl, e.g. -OCH 3 ), -S-C 1-6 alkyl (preferably -S-C 1-3 alkyl, e.g. -SCH 3 ), -OH, -SH, halogen (e.g.
  • n is an integer from 0 to 4, preferably 0 to 2, e.g.0, 1, or 2;
  • R 3 and R 4 are each independently selected from: hydrogen C 2-6 alkenyl (preferably C 2-4 alkenyl), and C 2-6 alkynyl (preferably C 2-4 alkynyl), or R 3 and R 4 , together with the intervening ring carbon atoms, form an optionally substituted aryl ring (e.g. an optionally substituted phenyl ring); and represents an optional bond between two adjacent carbon atoms in the ring.
  • Embodiment 2 A compound for use as described in embodiment 1, wherein R 3 and R 4 , together with the intervening ring carbon atoms, form an optionally substituted aryl group.
  • Embodiment 3 A compound for use as described in embodiment 1 or embodiment 2 which is a compound of formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof: (Ia) wherein X, Z, A, L, R 1 and n are as defined in embodiment 1; represents an optional bond between two adjacent carbon atoms in the ring; each R 2 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g.
  • C 2-6 alkenyl preferably C 2-4 alkenyl
  • C 2-6 alkynyl preferably C 2-4 alkynyl
  • C 1-6 haloalkyl e.g. -CF 3
  • -O-C 1-6 alkyl preferably -O-C 1-3 alkyl, e.g. -OCH 3
  • -S-C 1-6 alkyl preferably -S-C 1-3 alkyl, e.g. -SCH 3
  • an optionally substituted aryl group e.g.
  • Embodiment 4 A compound for use as described in any one of embodiments 1 to 3, wherein X is CH or S, preferably S.
  • Embodiment 5 A compound for use as described in embodiment 4 which is a compound of formula (Ib), a stereoisomer, or a pharmaceutically acceptable salt thereof: wherein A, L, R 1 and n are as defined in embodiment 1; and R 2 and m are as defined in embodiment 3.
  • Embodiment 6 A compound for use as described in any one of embodiments 1 to 3 which is a compound of formula (Ic), a stereoisomer, or a pharmaceutically acceptable salt thereof: wherein A, L, R 1 and n are as defined in embodiment 1; and R 2 and m are as defined in embodiment 3.
  • Embodiment 7 A compound for use as described in any one of embodiments 1 to 6, wherein A is an optionally substituted carbocyclic or heterocyclic ring system.
  • Embodiment 8 A compound for use as described in embodiment 7, wherein A is an optionally substituted cycloalkyl or cycloalkenyl group, preferably an optionally substituted cycloalkyl group containing two or three rings which are fused or bridged.
  • Embodiment 9 A compound for use as described in embodiment 7, wherein A is an optionally substituted heterocyclic group.
  • Embodiment 10 A compound for use as described in embodiment 8 or embodiment 9, wherein A is selected from substituted or unsubstituted adamantyl, phenyl, quinuclidinyl, piperidinyl and azepanyl.
  • Embodiment 11 A compound for use as described in any one of embodiments 1 to 10, wherein A is substituted by one or more groups independently selected from -OH, C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 haloalkyl, and halogen atoms (e.g. F, Cl or Br).
  • halogen atoms e.g. F, Cl or Br
  • Embodiment 12 A compound for use as described in any one of embodiments 1 to 11, wherein A is selected from the following: .
  • Embodiment 13 A compound for use as described in any one of embodiments 1 to 12, wherein L is an optionally substituted, straight-chained or branched C 1-6 alkylene group.
  • Embodiment 14 A compound for use as described in any one of embodiments 1 to 12, wherein L is an optionally substituted C 1-6 alkylene group, preferably C 2-6 alkylene group, in which one or more -CH 2 - groups of the alkylene chain are replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl).
  • Embodiment 15 A compound for use as described in any one of embodiments 1 to 14, wherein L is selected from the following:
  • Embodiment 16 A compound for use as described in any one of embodiments 1 to 15, wherein each R 1 is independently selected from C 1-3 alkyl (e.g. -CH 3 ), -CF 3 , -O- C 1-3 alkyl (e.g. -OCH 3 or -OCH 2 CH 3 ), -S-C 1-3 alkyl (e.g. -SCH 3 or -SCH 2 CH 3 ), F, Cl, Br and phenyl.
  • Embodiment 17 A compound for use as described in any one of embodiments 1 to 16, wherein n is 0, 1 or 2, preferably 0 or 1.
  • Embodiment 18 A compound for use as described in any one of embodiments 3 to 17, wherein each R 2 is independently selected from C 1-3 alkyl (e.g. -CH 3 ), -CF 3 , -O- C 1-3 alkyl (e.g. -OCH 3 or -OCH 2 CH 3 ), -S-C 1-3 alkyl (e.g. -SCH 3 or -SCH 2 CH 3 ), F, Cl, Br and phenyl.
  • Embodiment 19 A compound for use as described in any one of embodiments 3 to 18, wherein m is 0, 1 or 2, preferably 0 or 1.
  • Embodiment 20 A compound for use as described in embodiment 1 which is selected from the following compounds, their stereoisomers, and their pharmaceutically acceptable salts:
  • Embodiment 21 A compound for use as described in any one of embodiments 1 to 20, wherein said cancer is selected from the group consisting of: leukemias, lymphomas, colon cancer, breast cancer, glioblastoma, pancreatic cancer, bladder cancer, lung cancer and skin cancer.
  • Embodiment 22 A compound for use as described in embodiment 21 in the treatment of glioblastoma, preferably in the treatment of an astrocytoma, oligodendroglioma or ependymoma.
  • Embodiment 23 A compound for use as described in embodiment 21 in the treatment of basal cell carcinoma, squamous cell carcinoma, or melanoma.
  • Embodiment 24 A compound of formula II, a stereoisomer or a pharmaceutically acceptable salt thereof: (II) wherein: A is an optionally substituted amine or an optionally substituted carbocyclic or heterocyclic ring system; L is a linking group which is an optionally substituted C 1-6 alkylene group in which one or more -CH 2 - groups of the alkylene chain may be replaced by a group independently selected from -O-, -S- and -NR’- (where R’ is H or C 1-3 alkyl, e.g. methyl); each R 1 and R 2 is independently selected from: C 1-6 alkyl (preferably C 1-3 alkyl, e.g.
  • C 2-6 alkenyl preferably C 2-4 alkenyl
  • C 2-6 alkynyl preferably C 2-4 alkynyl
  • C 1-6 haloalkyl e.g. -CF 3
  • -O-C 1-6 alkyl preferably -O-C 1-3 alkyl, e.g. -OCH 3
  • -S-C 1-6 alkyl preferably -S-C 1-3 alkyl, e.g. -SCH 3
  • an optionally substituted aryl group e.g.
  • Embodiment 25 A pharmaceutical composition comprising a compound of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof as described in embodiment 24, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Figure 1 Monitoring cell growth and morphology during treatment with 4 ⁇ M Compound EA01 after treatment for 72 h.
  • A Left: Normal Human Astrocytes (NHA) (DMEM alt), right: NHA with 4 ⁇ M Compound EA01.
  • B Left: U87-MG Control (DMEM alt), right: U87-MG with 4 ⁇ M Compound EA01.
  • C Left: U251 Control (DMEM alt), right: U251 with 4 ⁇ M Compound EA01.
  • B 72 h values of change fold confluency.
  • Step 1 – method A The 10H-phenothiazine derivative (1 eq.) 1 was treated with chloroacetyl chloride (2.7 eq.) 2 under microwave irradiation. When the microwave reaction was finished, water was added and the mixture was extracted with ethyl acetate, the extracts were combined and washed with brine. The organic layer was dried over Na 2 SO 4 , filtered, and the solvent removed in vacuo. The compound 3 was purified by recrystallization in methanol.
  • Step 1 – method B The 10H-phenothiazine derivative (1 eq.) 1 and toluene were added to a round bottle flask equipped with a magnetic stirring bar. The mixture was then placed in an ice-water bath and stirred while chloroacetyl chloride (1.5 eq.) 2 was carefully added by a syringe. The mixture was heated and left stirring. The mixture was then cooled to room temperature and the solvent was removed in vacuo. The compound 3 was then purified by recrystallization in methanol.
  • Step 2 The 2-chloro-1-(10H-phenothiazin-10-yl)ethan-1-one derivative (1 eq.) 3 and dry THF were added to a dry round bottle flask equipped with a magnetic stirring bar. The mixture was flushed with nitrogen, put in an ice water bath and BF 3 •Et 2 O (1.5 eq.) carefully added by syringe while stirring. NaBH 4 (1.2 eq.) was added and the mixture was stirred before it was put in an ultrasonic bath. After removing the mixture from the ultrasonic bath, it was quenched with NaHCO 3 and extracted with ethyl acetate.
  • Step 3 – method A The 10-(2-chloroethyl)-10H-phenothiazine derivative (1 eq.) 4, KI (1 eq.), amine (5 eq.) and DMF were added to a round bottle flask equipped with a magnetic stirrer. The mixture was heated and left stirring. When the reaction was finished it was cooled to room temperature and an aqueous solution of NH 4 Cl was added, before it was extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried over NaSO 4 . The organic extracts were filtered, and the solvent removed in vacuo.
  • the compound 5 was purified using flash column chromatography.
  • Step 3 – method B The 10-(2-chloroethyl)-10H-phenothiazine derivative (1 eq.) 4, amine (5 eq.), K 2 CO 3 (5.5 eq.), KI (1 eq.) and THF were added to a round bottle flask equipped with a condenser and a magnetic stirrer. The mixture was heated to reflux and stirred. When the reaction was finished it was cooled to room temperature and water added before it was extracted with ethyl acetate. The organic extracts were dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The compound 5 was purified using flash column chromatography.
  • Example 1 Synthesis of N-(2-(10H-Phenothiazin-10-yl)ethyl)adamantan-1-amine (Compound EA01) Synthesis of 2-chloro-1-(10H-phenothiazin-10-yl)ethan-1-one: 10H-phenothiazine (0.373 g, 1.87 mmol) and 5 mL of chlorobenzene were added to a microwave vial (20 mL) together with a magnetic stirrer bar. Chloroacetic chloride (0.40 mL, 5.02 mmol), was carefully added while stirring.
  • the mixture was then split into two round bottle flasks (25 mL) and placed in an ultrasonic bath for 4 h. After removing the mixtures from the ultrasonic bath, they were quenched with NaHCO 3 and combined. The combined mixtures were extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure resulting in a dark thick oil with a yield of 69% (0.448 g, 1.54 mmol).
  • Example 8 Synthesis of 2-Chloro-10-((1-methylpiperidin-2-yl)methyl)-10H- phenothiazine (Compounds EA09, EA10) 2-(Chloromethyl)-1-methylpiperidine (150 mg, 1.02 mmol) was dissolved in DMSO (4 mL), 2-chloro-10H-phenothiazine (240 mg, 1.02 mmol), KOH (170 mg, 3.05 mmol) and KI (a spatula tip) were added. The mixture was heated under reflux overnight.
  • Example 10 Synthesis of 10-(2-(Piperidin-1-yl)ethyl)-10H-phenothiazine (Compound EA17) 10-(2-Chloroethyl)-10H-phenothiazine (0.165 g, 0.63 mmol) KI (0.222 g, 1.32 mmol), piperidine (0.28 ml, 2.85 mmol) and DMF (5 mL) were added to a 50 mL round bottle flask equipped with a magnetic stirrer. The mixture was heated to 100°C and stirred overnight. An NH 4 Cl solution (5 mL) was added and then extracted with ethyl acetate (10 mL x 3).
  • Example 11 Synthesis of 10-(2-(Azepan-1-yl)ethyl)-10H-phenothiazine (Compound EA20) 10-(2-Chloroethyl)-10H-phenothiazine (0.206, 0.78 mmol), azepane (0.43 ml, 3.82 mmol), K 2 CO 3 (0.600 g, 4.34 mmol), KI (0.128, 0.77 mmol) and THF (20 mL) were added to a round bottle flask (100 mL) equipped with a condenser and a magnetic stirrer bar. The mixture was heated to reflux and stirred overnight.
  • Compound EA20 10-(2-Chloroethyl)-10H-phenothiazine (0.206, 0.78 mmol), azepane (0.43 ml, 3.82 mmol), K 2 CO 3 (0.600 g, 4.34 mmol), KI (0.128, 0.77 mmol) and THF (20
  • Example 12 Synthesis of N-(4-(10H-phenothiazin-10-yl)butyl)adamantan-1-amine (Compound EA22)
  • EA22 Synthesis of 10-(4-chlorobutyl)-10H-phenothiazine: Phenothiazine (1.436 g, 7.21 mmol), anhydrous DMF (10 mL) and NaH (0.260 g, 10.8 mmol) were added to a dry round bottle flask (50 mL) equipped with a magnetic stirring bar. The flask was placed in an ice-water bath and 1-bromo-4- chlorobutane (0.82 ml, 7.11 mmol) was added to the flask.
  • Example 13 Synthesis of N-(3-(10H-phenothiazin-10-yl)propyl)adamantan-1- amine (Compound EA23)
  • EA23 Synthesis of 3-chloro-1-(10H-phenothiazin-10-yl)propan-1-one: 10H-phenothiazine (5.00 g, 25.09 mmol) and 80 ml toluene were added to a round bottle flask (500 mL) equipped with a magnetic stirring bar. The mixture was immersed into an ice-water bath and stirred before 3-chloropropanoyl chloride (3.60 mL, 37.64 mmol) was carefully added by syringe.
  • the mixture was heated to 100°C and stirred for 24 h. 15 ml of a saturated aqueous solution of NH 4 Cl were added, in addition to 50 ml water before it was extracted with (50 ml x 3) ethyl acetate. The organic extracts were combined, washed with brine and dried over NaSO 4 . The organic extracts were filtered, and solvent removed in vacuo, to obtain a dark coloured sticky compound. The compound was purified using flash column chromatography (ethyl acetate: hexane 9:1 and 1% Et 3 N), to obtain a brown waxy compound in a yield of 41% (0.401 g, 1.03 mmol).
  • Example 14 Synthesis of N-(adamantan-1-yl)methyl)-2-(10H-phenothiazin-10- yl)ethan-1-amine
  • Compound EA24 10-(2-Chloroethyl)-10H-phenothiazine (0.507 g, 1.94 mmol), KI (0.324 g, 1.95 mmol) 1-adamantanemethylamine (0.5 mL, 2.82 mmol) and DMF (10 ml) were added to a round bottle flask (50 mL) equipped with a magnetic stirrer bar. The mixture was then heated at 100°C and stirred for 24 h.
  • Example 15 In vitro activity in cell lines Method: Cells from various cell lines (LN18, T98G, U87-MG, U251, NHA, SV80, P3XX) were seeded 20-24 h before the treatment in a 96-well plate to approximately 30% confluency and kept at 37°C in a humidified 5% CO 2 atmosphere.
  • the glioblastoma cell lines U87-MG and U251 show reduced cell viability and proliferation assessed via percentage of confluency when treated with 4 ⁇ M EA01 compared to cells grown in media only (DMEM alt).
  • the control cell line NHA (see Figure 1A) is not affected by treatment with 4 ⁇ M EA01.
  • Temozolomide is not adding to the treatment effect of EA01 and EA02. Both compounds lead to reduced proliferation and cell death for the tested glioblastoma cell lines U87-MG and U251 in lower concentrations compared to normal human astrocytes (NHA) as control cell line.
  • Example 16 - Cell Viability Assay Method The effect of the compounds EA01-EA10, EA16, EA17, EA20 and EA22 on the viability of various cell lines (LN18, T98G, U87-MG, U251, NHA, SV80, P3XX) was assessed using the WST-1 Assay (Roche, 11644807001).
  • Cells were seeded at a concentration of 5000 cells ⁇ well -1 (or 10000 cells ⁇ well -1 for P3XX) in 96-well plates 20-24 h prior to treatment and kept at 37°C in a humidified 5% CO 2 atmosphere.
  • the cells were treated with various concentrations of the compounds for 72 h before the WST-1 reagent was added in a 1:10 ratio dependent on the well media volume.
  • a 30 second-shaking period on a linear shaker was followed by an incubation for 3 hours at 37°C.
  • the proliferation rate was determined by measuring the absorbance at 450 nm with a microplate photometer (Multiskan FC, ThermoFisher Scientific).
  • LC 50 values were determined for the different cell lines using the WST1 assay.
  • Tumor spheroids of the stem-cell like cell lines P3, P3-GFP, BG5, BG5-GFP, BG7 and BG7-GFP were obtained by seeding 5000 cells per well in U-bottom 96-well plates. After centrifugation at 2000 rpm and 37°C for 90 min, cells were incubated at standard conditions. FRBO and tumor spheroids were treated with various concentrations of the compounds for 72 h before the WST-1 protocol was performed. Results: LC 50 values for treatment of the different primary glioblastoma cell lines derived from patient material are displayed in Table 2, with and without GFP-labelling. EA01 has a higher toxicity than EA02 in all studied stem-cell like cell lines.
  • Example 19 Colony formation assay Method: LN18, U251 and NHA cells (125 cells per well) were seeded in 6-well culture plates in triplicate and incubated at 37°C in a humidified chamber of 5% CO 2 for up 14 days. Colonies were washed with PBS, fixed in methanol for 10 min and stained with crystal violet for 10 min at room temperature. Colonies were counted when they were formed by more than 50 cells. Results: As shown in Figure 5, the control cell line NHA tolerated higher concentrations of EA01 compared to the glioblastoma cell lines (LN18, LN229, U251).

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Abstract

L'invention concerne des composés de formule (I), des stéréoisomères et des sels pharmaceutiquement acceptables de ceux-ci pour une utilisation dans le traitement du cancer : formule (I) dans laquelle : X représente CH, S, N ou NH ; Z représente C ou N ; A représente une amine éventuellement substituée ou un système cyclique carbocyclique ou hétérocyclique éventuellement substitué ; L représente un groupe de liaison qui est un groupe alkylène en C1-6 éventuellement substitué dans lequel un ou plusieurs groupes -CH2 de la chaîne alkylène peuvent être remplacés par un groupe choisi indépendamment parmi -O-, -S- et -NR'- (où R' représente H ou un groupe alkyle en C1-3) ; chaque R1 est choisi indépendamment parmi : C1-6 alkyle, C2-6 alcényle, C2-6 alcynyle, C1-6 haloalkyle, -O-C1-6 alkyle, -S-C1-6 alkyle, -OH, -SH, halogène, et un groupe aryle éventuellement substitué ; n est un entier de 0 à 4 ; R3 et R4 sont chacun indépendamment choisis parmi : l'hydrogène, un alcényle en C2-6 et un alcynyle en C2-6, ou R3 et R4, conjointement avec les atomes de carbone intermédiaires du cycle, forment un cycle aryle éventuellement substitué ; et représente une liaison éventuelle entre deux atomes de carbone adjacents du cycle. Les composés de formule (I), leurs stéréoisomères et leurs sels pharmaceutiquement acceptables trouvent une utilisation particulière dans le traitement du glioblastome.
PCT/GB2022/052006 2021-07-30 2022-07-29 Antipsychotiques à base de phénothiazine pour utilisation dans le traitement du glioblastome Ceased WO2023007181A1 (fr)

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