Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/20—Spiro-condensed systems

Definitions

• Examples of substituted d-C 6 alkyl therefore include CF 3 , CH 2 CF 3 , CH 2 CN, CH 2 OH and CH 2 CH 2 OH.
• d-d alkynyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon atoms and at least one triple bond.
• alkenyl groups include ethynyl, propynyl, 2- propynyl, 1-butynyl, 2-butynyl and 1-hexynyl.
• d-d alkynyl within the definitions of Q 1 and within the definition of substituents for R 2 , may be unsubstituted or substituted with one or more of the substituents defined herein.
• the alkoxy may be linked through carbon to the remainder of the molecule, for example, -CH 2 CH 2 OCH 3 , or alternatively, the alkoxy is linked through oxygen to the remainder of the molecule, for example -OCi_ 6 alkyl. In one instances, the alkoxy is linked through oxygen to the remainder of the molecule but the alkoxy group contains a further oxygen atom, for example - OCH 2 CH 2 OCH 3 .
• Ci-C 6 alkoxy and Ci-C 3 alkoxy within the definitions R le , R lf , Q 1 , and within the definition of substituents for R 2 may be unsubstituted or substituted with one or more of the substituents defined herein. Examples of substituted Ci-C 6 alkoxy therefore include OCF 3 , OCHF 2 , OCH 2 CF 3 , CH 2 CH 2 OCH 3 and CH 2 CH 2 OCH 2 CH 3 .
• a bicyclic heteroaryl is one in which the entire fused ring system is aromatic.
• a bicyclic heteroaryl can have the at least one heteroatom in either of the fused rings.
• a bicyclic ring with an aromatic ring fused to a partially saturated ring may contain the at least one heteroatom in the aromatic ring or the partially saturate ring.
• Attachment of the bicyclic ring to the group it is a substituent of may be via either a heteroatom containing ring or a carbon only containing ring.
• the point of attachment of heteroaryl to the group it is a substituent of can be via a carbon atom or a heteroatom (e.g. nitrogen).
• heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (e.g. 2,3- dihydrofuranyl, 2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g.
• Pharmaceutically acceptable salts of the compounds of the invention include but are not limited to addition salts (for example phosphates, nitrates, sulphates, borates, acetates, maleates, citrates, fumarates, succinates, methanesulphonates, benzoates, salicylates and hydrohalides), salts derived from organic bases (such as lithium, potassium and sodium), salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine and proline), inorganic bases (such as triethylamine, hydroxide, choline, thiamine and N-N'-diacetylethylenediamine).
• Other pharmaceutically acceptable salts include ammonium salts, substituted ammonium salts and aluminium salts. Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of the invention.
• the invention relates to these compounds prepared as isomeric mixtures or racemates whether present in an optically pure form or as mixtures with other isomers.
• Enantiomers differ only in their ability to rotate plane-polarized light by equal amounts in opposite directions and are denoted as the (+) / (S) or (-) / (R) forms respectively.
• Individual enantiomers or isomers may be prepared by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation e.g. chiral HPLC, or an asymmetric synthesis approach).
• compounds of the invention exist as alternative tautomeric forms e.g. keto/enol, amide/imidic acid
• the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
• a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise.
• a reference to an alkyl group such as an ethyl group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group).
• isotopically labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes i.e. H and 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• isotopes such as "C, F, 1J 0 and 1J N, can be useful in Positron Emission Topography (PET) studies for examining receptor occupancy.
• Isotopically labelled compounds of formula (I) can generally be
• the compounds of formula (I) may exist in crystalline or amorphous form and some of the crystalline forms may exist as polymorphs, which are included within the scope of the present invention.
• Polymorphic forms of compounds of formula (I) may be characterised and differentiated using a number of conventional analytical techniques, including, but not limited to, infra-red spectra, Raman spectra, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis and solid state nuclear magnetic resonance.
• the invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.
• 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 invention relates to pharmaceutically functional derivatives of compounds as defined herein including ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound of the invention.
• ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound of the invention.
• prodrugs of compounds as defined herein also includes prodrugs of compounds as defined herein.
• Prodrugs of compounds may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
• Prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively.
• prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elsevier, New York-Oxford (1985).
• Metabolites of compounds of formula (I) are also within the scope of the present invention.
• the term 'metabolites' refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal. Preferably the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions.
• alkyl 3 each represent hydrogen.
• the alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF 5 , in particular fluorine.
• R lf may represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, or an optionally substituted 5 or 6 membered heteroaryl or aryl ring.
• the alkyl and alkoxy may be substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF 5 .
• the heteroaryl or aryl ring may be unsubstituted or substituted with halogen, cyano, oxo, nitro, amino, hydroxy, Ci-C 6 alkyl or C 1 -C3 alkyl, Ci-C 6 alkoxy or C 1 -C3 alkoxy, aryl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, Ci_ 3 alkylamino, C 2 -e alkenylamino,
• R lf can represent hydrogen, fluorine, unsubstituted or substituted C 1 -C3 alkyl or unsubstituted or substituted C 1 -C3 alkoxy.
• R lf can represent hydrogen or methyl.
• R lf can represent
• the cycloalkyl rings within the definitions of R la , R lb , R lc , R ld , R le and R lf may be unsubstituted or substituted with one or more substituents selected from halogen, cyano, oxo, nitro, amino, hydroxy, C 1 -C3 alkyl, C 1 -C3 alkoxy, Ci_ 3 alkylamino, C 2 -e alkenylamino, C 1 -C3 acylamino, carboxy, C 1 -C3 alkoxycarbonyl, carboxamidyl, carbamoyl, mono-Ci-3 carbamoyl and di-Ci-3 carbamoyl wherein any hydrocarbyl moiety may itself be substituted by one or more halogen, hydroxyl, cyano, amino, nitro or SF 5 , in particular fluorine.
• the cycloalkyl ring may be unsubstituted or substituted with one or two substituents selected from halogen, cyano, oxo, nitro, amino, hydroxy, C 1 -C3 alkyl and C 1 -C3 alkoxy, wherein the alkyl and alkoxy may be substituted with one or more halogen, in particular fluorine.
• the compounds may be in the form where R la , R lb , R lc , R ld , R le and R lf each represent hydrogen. In such cases the compounds may be of formula:
• Ring A may be monocyclic or bicyclic. Where the ring is bicyclic, the second ring (i.e. the ring not directly attached to the pyrrolidine ring) may be aromatic, saturated or may be partly saturated. Preferably, the second ring is aromatic.
• Ring A may represent a 5 or 6 membered heterocyclyl ring which may be optionally further substituted with one or more (e.g. one, two, three or four) of -Q ⁇ R 2 ) ⁇
• ring A may represent a 9, 10 or 1 1 membered fused bicyclic heterocyclic ring which may be optionally further substituted with one or more (e.g. one, two, three or four) of -Q ⁇ R 2 ) ⁇
• Ring A may comprise one or more (e.g. 1, 2 or 3) heteroatoms in addition to the amide nitrogen, wherein the additional heteroatom(s) are independently selected from nitrogen, oxygen and sulphur.
• ring A may further comprise one or more additional heteroatoms selected from nitrogen and oxygen.
• the additional heteroatoms may be in first ring (i.e. the ring containing -NH-C(O)-) and/or the second ring (i.e. the fused ring portion not containing -NH-
• Ring A may be selected from piperidin-2-one, indoline-2-one, piperazine-2-one, pyrrolidin-2-one, 3 ,4-dihydroquinolin-2( lH)-one, lH-pyrido [2,3 -b] [ 1 ,4]oxazin-2(3H)-one, 3 ,4-dihydropyrido [2,3 - 6]pyrazine-2( lH)-one, 1 ,5 -diydrobenzo [e] [ 1 ,4] oxazepin-2(3H)-one, 3 ,4-dihydro- 1 ,5 -naphthyridin- 2(lH)-one, 3,4-dihydro-l,6-naphthyridin-2(lH)-one, 3,4-dihydro-l,7-naphthyridin-2( lH)-one, 3,4- dihydr
• ring A may be further substituted with one or more -( ⁇ -(R 2 ), ! wherein each occurrence of-Q 1 - ⁇ 2 ⁇ is the same or different, and wherein:
• n 0 or 1
• Q 1 may be selected from halogen (e.g. fluorine, chlorine or bromine),
• Q 1 is selected from halogen, cyano, oxo, nitro, hydroxyl, -SR 3 , -NR R 4 , - CONR R 4 , -NR COR 4 , -NR CONR 4 R 4a , -COR 3 , -C(0)OR 3 , -S0 2 R 3 , -S0 2 NR R 4 , -NR S0 2 R 4 , NR S0 2 NR 4 R 4a , -NR C(0)OR 4 , optionally substituted -C 1 -C4 alkyl, optionally substituted Ci-C 2 alkyl, optionally substituted -Ci-C 6 alkoxy, optionally substituted -C 2 -C 6 alkenyl, optionally substituted -C 2 -C 6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -OR 5 -, -SO-, -S0 2 -,
• Q 1 may represent oxo, methyl, ethyl, CF 3 , methoxy, halogen (e.g. fluorine or chlorine), -C(0)NR R 4 , wherein R 3 and R 4 are each independently represent hydrogen or methyl.
• ring A is substituted with a further ring either directly or via a linker, i.e. ring A is substituted with at least one -Q ⁇ R 2 ), ! wherein n is 1.
• R 2 represents a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring.
• R 2 may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadia
• R 2 may represent an optionally substituted 5 or 6 membered monocyclic heterocyclyl, cycloalkyl, heteroaryl or aryl ring.
• R 2 is selected from phenyl, pyrazolyl, indazolyl, pyridinyl, benzothiazolyl and pyrimidinyl. More particularly, R 2 is phenyl.
• R 2 may be optionally substituted with one or more substituents selected from halogen, cyano, oxo, nitro, hydroxyl -SR 6 , -NR 6 R 7 , -CONR 6 R 7 , -NR 6 COR 7 , -NR 6 CONR R 7a , - COR 6 , -C(0)OR 6 , -S0 2 R 6 , -S0 2 NR 6 R 7 , -NR 6 S0 2 R 7 , NR 6 S0 2 NR 7 R 7a , -NR 6 C(0)OR 7 , -d-C 6 alkyl, - Ci-Ce alkoxy,-C 2 -C 6 alkenyl, -C 2 -C 6 , -Q 2a -R 8 , -Q 2b -NR 6 CONR R 7a , -Q 2b -NR 6 CONR 7a , -Q 2b -NR 6 CONR 7 -Q 2c -R
• Q 2a represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -S0 2 -, -CO-, optionally substituted Ci-C 6 alkylene or optionally substituted C 2 -C 6 alkenylene;
• Q 2b and Q 2c each independently represent a covalent bond, optionally substituted Ci-C 6 alkylene or optionally substituted C 2 -C 6 alkylenylene;
• R 6 , R 7 and R 7a each independently represent hydrogen or optionally substituted Ci-C 6 alkyl
• R 8 represents optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl.
• R 2 may be substituted with one or more substituents selected from halogen (e.g. chlorine or fluorine), cyano, oxo, methyl, /-propyl, OMe, OCF 3 , O-z-propyl, -C(0)NHMe, - C(0)N(CH 3 ) 2 , -NHC(0)Me, piperidinyl ,-NHS0 2 -cyclopropyl, Q 2a -phenyl wherein Q 2a is a covalent bond, an oxygen atom or methyleneoxy, Q 2a -piperazinyl wherein Q 2a is a covalent bond or -CO- and Q 2a -morpholinyl wherein Q 2a is -CO- or -S0 2 -.
• halogen e.g. chlorine or fluorine
• R 2 is unsubstituted, mono-substituted or disubstituted.
• R 2 may be selected from phenyl, pyrazolyl, indazolyl, pyridinyl, benzothiazolyl and pyrimidinyl, wherein the ring is unsubstituted or substituted with one or more (e.g. one, two or three)
• R la , R lb , R lc and R ld are each independently selected from hydrogen and C 1 -C 3 alkyl which may be optionally substituted with fluorine;
• Ring A is selected from pyrrolidin-2-one, piperazine2-one, 3,4-dihydroquinolin-2(lH)-one, 1H- pyrido[2,3-6][l,4]oxazin-2(3H)-one, 3,4-dihydropyrido[2,3-6]pyrazine-2(lH)-one, 1,5- dihydrobenzo[e][l,4]oxazepin-2(3H)-one and 1,2,3, 5-tetrahydro-4H-pyrido[2,3-b][l,4]diazepin-4- onewherein the ring is optionally further substituted with one, two or three of -( ⁇ -(R 2 ), ! wherein Q 1 , R 2 and n are as defined herein.
• R la , R lb , R lc , R ld , R le and R lf each represent hydrogen
• Ring A represents a monocyclic or bicyclic 5 to 10 membered heterocyclyl ring which is optionally further substituted with one, two or three of -Q ⁇ iR 2 ) ⁇ wherein
• Examples of the monocyclic and bicyclic heterocyclyl ring represented by A include those shown below:
• novel compounds of formula I include:
• R la - R lf and A are as defined elsewhere.
• composition comprising a compound of the invention.
• compositions of this invention comprise any of the compounds of the invention combined with any pharmaceutically acceptable carrier, adjuvant or vehicle.
• pharmaceutically acceptable carriers are known to those skilled in the art and include but are not limited to preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms.
• the compositions may be in the form of, for example, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups and liquid preparations including suspensions and solutions.
• a compound of formula (I) or pharmaceutical composition thereof for use in therapy there is provided a compound of formula (I) or pharmaceutical composition thereof for use in therapy.
• the compounds of the invention have use in the treatment of cancer and more particularly in the treatment of cancer linked to DUB activity.
• Compounds of the invention may be useful against any DUB enzyme, including but not limited to Cezanne 1 and USP30.
• the compounds described herein may be used in the manufacture of a medicament for the treatment of cancer linked to DUB activity.
• a method of treatment or prevention of cancer linked to Cezanne 1 or USP30 activity comprising administering a pharmaceutically effective amount of a compound of the invention or a pharmaceutical composition thereof to an individual suffering from cancer linked to Cezanne 1 or USP30 activity.
• cancer or “tumour” include but are not limited to breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone or other cancers of tissue organs and
• cancers of the blood cells such as lymphomas and leukaemias.
• Particular cancers include lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma.
• the compounds of the invention may be useful in the treatment of disorders and diseases related to USP30 inhibition.
• the compounds of the invention may therefore be useful in the treatment of disorders or diseases having a component relating to mitochondrial dysfunction.
• Mitochondrial dysfunctions result from defects of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondria fail, less and less energy is generated within the cell and cell injury or even cell death will follow. If this process is repeated throughout the body the life of the subject in whom this is happening is severely compromised. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.
• the condition involving mitochondrial dysfunction may be a CNS disorder, for example a neurodegenerative disease.
• Neurodegenerative diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, ischemia, stroke, dementia with Lewy bodies, and frontotemporal dementia.
• compositions of the invention may be designed for administration by the oral, parenteral or mucosal route and the choice or the specific form of composition is dependent on the administration route.
• the composition may be in the form, for example, of tablets, lozenges, dragees, films, powders, elixirs, syrups, liquid preparations including dispersions, suspensions, emulsions, solutions or sprays, cachets, granules, capsules, etc.
• the composition may be in the form of sprays, inhalants, dispersions, suspensions, emulsions, solutions, gels, patches, films, ointments, creams, lotions, suppositories etc.
• composition is in the form of a liquid preparation such as a solution, dispersion, emulsion or suspension including liposome compositions.
• Preparations according to the invention for parenteral administration include sterile aqueous, aqueous- organic, and organic solutions, suspensions and emulsions.
• Such dosage forms are prepared according to techniques known in the art of pharmaceutical formulation.
• the pharmaceutical compositions When in the form of sprays or inhalants the pharmaceutical compositions may be administered nasally. Suitable formulations for this purpose are known to those skilled in the art.
• compositions of the invention may be administered by injection and may be in the form of a sterile liquid preparation for injection, including liposome preparations.
• the pharmaceutical compositions of the invention may also be in the form of suppositories for rectal administration. These are formulated so that the pharmaceutical composition is solid at room temperature and liquid at body temperature to allow release of the active compound.
• the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the remit of the person skilled in the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimal dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached.
• the magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden.
• the daily dose range is about lC ⁇ g to about 100 mg per kg body weight of a human and non- human animal and in general may be around 10 ⁇ g to 30mg per kg body weight per dose. The above dose may be given from one to three times per day.
• Step a To a stirred solution of methyl (tert-butoxycarbonyl)-L-serinate (CAS Number 2766-43-0; 30 g, 136.9 mmol) in DCM (600 ml) was added pyridine (27.03 g, 342.1 mmol) at -50°C. Benzyl chloroformate (23.35 g, 136.9 mmol) was added slowly to the reaction mixture at -50°C and the reaction mixture was stirred at rt for 16 h. The resulting mixture was poured into 10% citric acid solution (1500 ml) and the organic phase was separated and aqueous phase was re-extracted with DCM (2 x 300 ml).
• Step b To a stirred solution of methyl 0-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-serinate (22.0 g, 62.3 mmol) in DMF (150 ml) was added K 2 C0 3 (17.2 g, 124.6 mmol) at rt and the reaction mixture was stirred at 65°C for 1 h. The mixture was cooled to rt, poured into water (2000 ml) and extracted with EtOAc (2 x 500 ml). The combined organic phase was separated, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step c To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (11 g, 54.726 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (CAS Number 93102-05-7; 12.97 g, 54.7 mmol) in DCM (250 ml) was added TFA (0.3 ml) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was diluted with DCM (200 ml) and washed with saturated NaHC0 3 solution (1500 ml). The organic layer separated and aqueous layer was re-extracted with DCM (2 x 200 ml).
• Step d To a stirred solution of methyl l-benzyl-3-((tert-butoxycarbonyl)amino)pyrrolidine-3- carboxylate (0.8 g, 2.39 mmol) in DCM (15 ml) was added TFA (4 ml) at 0°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and azeotropically distilled using DCM (2 x 20 ml). The resulting residue was dissolved into EtOAc (50 ml) and washed with saturated NaHC0 3 solution (3 x 50 ml).
• Reagents and conditions a) NBS, AIBN, CC1 4 , 76°C, 16h b) LiHMDS, THF, -78°C, lh; rt, 16h c) Fe, NH 4 C1, THF/water, 60°C,16 h.
• Step a To a mixture of 4-bromo-l-methyl-2-nitro-benzene (60 g, 277 mmol, 1.0 eq) and NBS (59.3 g, 333 mmol, 1.2 eq) in CC1 4 (600 mL) was added AIBN (5.47 g, 33.3 mmol, 0.12 eq) at rt under N 2 . The mixture was stirred at 76°C for 16 h. The reaction mixture was filtered and the filtrate was washed with 2M NaHC0 3 (2 x 250 ml) and brine (400 ml), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue.
• AIBN 5.47 g, 33.3 mmol, 0.12 eq
• Step b To a mixture of l-(tert-butyl ) 3-methyl pyrrolidine-l,3-dicarboxylate (31.1 g, 135 mmol, 1.0 eq) in THF (450 ml) was added dropwise LiHMDS (1 M, 203 ml, 1.5 eq) at -78°C under N 2 . The mixture was stirred at -78°C for 30 min, then a solution of 4-bromo-l-(bromomethyl)-2-nitro-benzene (40 g, 135 mmol, 1.0 eq) in THF (150 ml) was added dropwise at -78°C.
• Step c To a mixture of 1 -(tert-butyl) 3-methyl 3-[(4-bromo-2-nitro-phenyl)methyl]pyrrolidine-l,3- dicarboxylate (15 g, 33.8 mmol, 1.0 eq) in THF (250 ml) and water (250 ml) was added Fe (18.9 g, 338 mmol, 10.0 eq) and NH 4 Cl (18.1 g, 338 mmol, 11.8 ml, 10.0 eq) at 0°C. The mixture was stirred at 60°C for 16 h. The reaction mixture was filtered, and the filtrate was diluted with water (50 ml) and extracted with EtOAc (5 x 50 ml).
• Reagents and conditions a) NaCN, NaHC0 3 , Et 2 0, water; b) HC1, 1,4-dioxane, water; c) Boc 2 0, EtOAc, NaHC0 3 (aq); d) Cs 2 C0 3 , DMF; e) Fe, NH 4 C1, THF, water; f) TFA, DCM; g) CNBr, K 2 C0 3 , THF
• Step b To a stirred solution of tert-butyl 3-cyano-3-hydroxypyrrolidine-l-carboxylate (4.2 g, 19.8 mmol) in MeOH (10.5 ml) was added 4M HC1 in 1,4-dioxane (42 ml) at 0°C. The reaction mixture was stirred at rt for 3 h. The excess of solvent was distilled under reduced pressure yielding methyl 3- hydroxypyrrolidine-3-carboxylate HC1 salt (4.2 g, quantitative). This material was used directly for the next step without further purification.
• LCMS Method 3, 1.140 min, MS: ES+ 146.07.
• Step c To a stirred solution of methyl 3-hydroxypyrrolidine-3-carboxylate HC1 salt (4.2 g, 23.204 mmol) in EtOAc (42 ml) was added saturated NaHC0 3 solution (42 ml) at rt. Boc anhydride (10.12 g, 46.4 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured into saturated NaHC0 3 (200 ml) and extracted with EtOAc (2 x 100 ml). The combined organic phase was dried over Na 2 S0 , filtered and concentrated under reduced pressure.
• Step b To a stirred solution of 1 -(tert-butyl) 3-methyl 3-((5-bromo-3-nitropyridin-2- yl)oxy)pyrrolidine-l,3-dicarboxylate (0.8 g, 1.793 mmol) in THF:water (1 : 1; 8 ml), was added iron powder (1.0 g, 17.927 mmol) and ammonium chloride (0.957 g, 17.93 mmol) at rt. The reaction mixture was heated at 70°C for 18 h. The resulting reaction mixture was cooled to rt and combined with one other batch on the same scale prepared by an identical method. The reaction mixture was filtered through celite hyflow.
• Step c To a stirred solution of an approximately 2:3 mixture of tert-butyl 7-bromo-2-oxo-l,2- dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-r-carboxylate and 1 -(tert-butyl) 3-methyl 3- ((3-amino-5-bromopyridin-2-yl)oxy)pyrrolidine-l,3-dicarboxylate (0.7 g, 1.689 mmol) in THF (20 ml) was added l,5,7-triazabicyclo[4.4.0]dec-5-ene (0.235 g, 1.689 mmol) at rt.
• reaction mixture was stirred at rt for 3 h.
• the resulting reaction mixture was combined with one other batch prepared on the same scale by an identical method.
• the obtained reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography (25% EtOAc in hexane) yielding tert- butyl 7-bromo-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-r-carboxylate (1.3 g, 3.618 mmol).
• Step a To a solution of Boc-L-serine methyl ester (CAS Number 2766-43-0; 30.0 g, 136.9 mmol) in DCM (300 ml) was added pyridine (28.8 ml, 342 mmol) at -50°C and stirred for 15 minutes. Benzyl chloroformate (25.67 g, 150.5 mmol) was added dropwise to the reaction mixture at -50°C. The temperature of the reaction mixture was gradually increased to rt. The resulting reaction mixture was stirred at rt for 15 h.
• Step c To a solution of 2-((tert-butoxycarbonyl)amino)acrylate (10.3 g, 51.24 mmol) in DCM (103 ml) was added TFA (0.26 ml) at 0°C. N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (13.35 g, 56.37 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 15 min and then stirred at rt for 15 h.
• N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (3.64 g, 15.373 mmol) was slowly added to the reaction mixture at 0°C.
• the reaction mixture was stirred at rt for a further 15 h.
• the resulting reaction mixture was poured into water (250 ml) and basified using Na 2 C0 3 .
• the resulting mixture was extracted with DCM (2 x 150 ml) and the combined organic phase was washed with brine solution (50 ml), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Reagents and conditions a) i) LiHMDS, hexane, THF; b) 10% Pd/C, H 2 , MeOH OR Fe, NH 4 C1, THF, water; c) TFA, DCM; d) CNBr, K 2 C0 3 , THF
• Step a To a stirred solution of tert-butyl methyl pyrrolidine- 1, 3 -dicarboxylate (CAS Number 122684- 33-7; 1.0 g, 4.367 mmol) in dry THF (15 ml) was added 1M LiHMDS in hexane (1.08 g, 6.55 mmol) at -78°C. The reaction mixture was stirred at -78°C for 0.5 h then 2-nitrobenzyl bromide (1.03 g, 4.803 mmol) was added at -78°C. The resulting reaction mixture was warmed to rt and stirred for 16 h.
• Step b To a stirred solution of 1 -(tert-butyl) 3-methyl 3-(2-nitrobenzyl)pyrrolidine-l,3-dicarboxylate (0.2 g, 0.549 mmol) in MeOH (10 ml) was added 10% dry Pd/C (0.2 g) at rt. The reaction mixture was purged with H 2 gas at rt for 0.5 h. The resulting reaction mixture was carefully filtered through celite hyflow and concentrated under reduced pressure to afford tert-butyl 2'-oxo-r,4'-dihydro-2'H- spiro[pyrrolidine-3,3'-quinoline]-l-carboxylate (0.14 g, 0.463 mmol).
• Step c To a stirred solution of tert-butyl 2'-oxo-r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-l- carboxylate (0.13 g, 0.43 mmol) in DCM (1 ml) was added TFA (1 ml) at rt. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was concentrated under reduced pressure yielding r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one TFA salt (0.09 g, 0.285 mmol). This material was used directly for the next step without further purification. LCMS: Method 1, 1.46 min, MS: ES+
• Step d To a stirred solution of r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one TFA salt (0.08 g, 0.253 mmol) in THF (10 ml) was added K 2 C0 3 (0.174 g, 1.265 mmol) at rt. Cyanogen bromide (0.032 g, 0.304 mmol) was added to the reaction mixture at rt and the mixture was stirred at rt for 0.5 h. The resulting reaction mixture was filtered and excess THF was removed under reduced pressure.
• Reagents and conditions a) ArB(OH) 2 , Cs 2 C0 3 , Pd(PPh 3 ) 4 , 1,4-dioxane, water; b) TFA, DCM or HC1/ EtOAc; c) CNBr, K 2 C0 3 , THF or CNBr, NaHC0 3 , EtOH
• Step a To a stirred solution of tert-butyl 7'-bromo-2'-oxo-r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]-l-carboxylate (Intermediate B; 0.25 g, 0.655 mmol) in l,4-dioxane:water (8:2, 10 ml) was added phenylboronic acid (0.16 g, 1.311 mmol) and Cs 2 C0 3 (0.427 g, 1.31 1 mmol) at rt.
• the reaction mixture was degassed for 20 min at rt before addition of Pd(PPh 3 ) 4 (0.075 g, 0.065 mmol).
• the reaction mixture was heated at 80°C for 8 h.
• the resulting reaction mixture was cooled to rt, poured into water (30 ml) and extracted with EtOAc (5 x 25 ml).
• the combined organic phase was separated and washed with brine (2 x 20 ml).
• the organic phase was separated, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step a To a solution of tert-butyl 7'-bromo-2'-oxo-r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]-l-carboxylate (Intermediate B; 0.2mmol), (5-isopropyl-2-methoxyphenyl)boronic acid (0.2 mmol) and Cs 2 C0 3 (0.6 mmol, 3eq) in 1,4-dioxane (1 ml) and water (0.2 ml) were added Pd(PPh 3 ) 4 (0.2 eq) at rt under nitrogen. The reaction mixture was stirred at 100°C for 16h. The resulting mixture was concentrated under reduced pressure.
• Step a To a stirred solution of tert-butyl 7'-bromo-2'-oxo-r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]-l-carboxylate (Intermediate B; 0.75 g, 1.967 mmol) in MeOH (20 ml) were added sodium acetate (0.81 g, 9.837 mmol) and PdCl 2 (dppf) DCM complex (0.32 g) at rt in an autoclave. The reaction mixture was heated at 120°C under 30 kg carbon monoxide pressure for 4 days.
• Steps a-e The title compound was synthesised following a procedure similar to Example 46 using methylamine (2M in THF) in step c.
• Step e To a stirred solution of l-benzyl-7'-bromo-l', 4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]- 2'-one pyridine (0.300 g, 0.801 mmol) and 5 -methyl- lh-indazol-4-ylboronic acid (CAS Number 1245816-10-7; 0.214 g, 1.216 mmol) in l,4-dioxane:water (4: 1, 12 ml) was added Cs 2 C0 3 (0.528 g, 1.624 mmol) at rt.
• the reaction mixture was degassed for 15 min before addition of Pd(PPh 3 ) 4 (0.046 g, 0.039 mmol) at rt.
• the reaction mixture was heated at 80°C for 16 h.
• the resulting mixture was cooled to rt, diluted with water (20 ml) and extracted with EtOAc (5 x 50 ml).
• the combined organic phase was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step a To a stirred solution of 2-chloro-3-nitropyridine (CAS Number 5470-18-8; 0.5 g, 3.154 mmol) in DMF (10 ml) was added l-(tert-butyl) 3-methyl 3-hydroxypyrrolidine-l,3-dicarboxylate (Intermediate C; 0.62 g, 2.524 mmol) and Cs 2 C0 3 (3.08 g, 9.463 mmol) at rt. The reaction mixture was stirred at 60°C for 16 h. The resulting reaction mixture was poured into ice cold water (100 ml) and extracted with EtOAc (2 x 70 ml). The combined organic phase was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step d To a stirred solution of spiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidin]-2(lH)-one TFA salt (0.08 g, 0.25 mmol) in THF (5 ml) was added K 2 C0 3 (0.17 g, 1.253 mmol) at 0°C. The reaction mixture stirred at 0°C for 5 min. Cyanogen bromide (0.032 g, 0.301 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 15 min. The resulting reaction mixture filtered and excess of THF was distilled under reduced pressure.
• Step a To a stirred solution of tert-butyl 7-bromo-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine- 3,3'-pyrrolidine]-l'-carboxylate (Intermediate D; 0.25 g, 0.651 mmol) in l,4-dioxane:water (4: 1; 10 ml) was added Cs 2 C0 3 (0.423 g, 1.301 mmol) at rt.
• the reaction mixture was degassed for 20 min before addition of Pd(PPh 3 ) 4 (0.075 g, 0.065 mmol) and phenylboronic acid (0.158 g, 1.301 mmol) at rt.
• the reaction mixture was heated at 90°C for 18 h.
• the resulting reaction mixture was cooled to rt, poured into water (20 ml) and extracted with EtOAc (3 x 30 ml).
• the combined organic phase was separated and washed with brine (20 ml).
• the combined organic phase was separated, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step b To a stirred solution of tert-butyl 2-oxo-7-phenyl-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine- 3,3'-pyrrolidine]-l '-carboxylate (0.21 g, 0.551 mmol) in DCM (10 ml) was added TFA (1.05 ml) at rt. The reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was concentrated under vacuum. The obtained residue was azeotropically distilled with DCM (2 x 20 ml).
• Step c To a stirred solution of 7-phenylspiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidin]-2(lH)-one TFA salt (0.2 g, 0.506 mmol) in THF (10 ml) was added K 2 C0 3 (0.208, 1.517 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min. Cyanogen bromide (0.063 g, 0.607 mmol) at 0°C. The reaction mixture was stirred at rt for 30 min. The resulting reaction mixture was poured into water (10 ml) and extracted with EtOAc (3 x 30 ml).
• Example 140 7-(l-(2-Methoxyethyl)-lH-indazol-4-yl)-2-oxo-l, 2-dihydrospiro[pyrido[2, 3- b][l,4 ]oxazine-3, 3 '-pyrrolidine ]-l '-carbonitrile
• Example 141 1 '-Cyano-N-(4-fluorophenyl)-2-oxo-l, 2-dihydrospiro[pyrido[2, 3-b ] [l, 4]oxazine-3, 3 '- pyrrolidine ]-6-carboxamide
• Step a To a solution of tert-butyl 6-bromo-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'- pyrrolidine]-l'-carboxylate (Intermediate G; 0.300 g, 0.783 mmol) in dry MeOH (5 ml) was added NaOAc (0.322 g, 3.912 mmol) at rt prepared in auto clave. The reaction mixture was degassed for 30 min before addition of PdCl 2 (dppf) DCM complex (0.046 g, 0.039 mmol) at rt and 25 kg/cm 2 H 2 pressure was applied in the autoclave.
• dppf PdCl 2
• Step b To a solution of l'-(tert-butyl) 6-methyl 2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine- 3,3'-pyrrolidine]-l',6-dicarboxylate (0.400 g, 1.102 mmol) in THF:water (1 : 1, 5 ml) was added NaOH (0.088 g, 2.203 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was poured in to water (50 ml) and acidified using saturated citric acid solution. The resulting mixture was extracted in EtOAc (3 x 50 ml).
• Step c This was carried out using a similar procedure to step a of Example 4 using phenylboronic acid.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (21)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=55859019

Family Applications (1)

Country Status (19)

Cited By (28)

Families Citing this family (3)

Citations (4)

Family Cites Families (20)

• 2016
  • 2016-03-04 GB GBGB1603779.8A patent/GB201603779D0/en not_active Ceased
• 2017
  • 2017-03-02 KR KR1020187028269A patent/KR102384139B1/ko active Active
  • 2017-03-02 MA MA043701A patent/MA43701A/fr unknown
  • 2017-03-02 AU AU2017225371A patent/AU2017225371B2/en active Active
  • 2017-03-02 CN CN201780010388.5A patent/CN108602823B/zh active Active
  • 2017-03-02 MY MYPI2018001499A patent/MY196836A/en unknown
  • 2017-03-02 RU RU2018133279A patent/RU2730552C2/ru active
  • 2017-03-02 MX MX2018008271A patent/MX382562B/es unknown
  • 2017-03-02 JP JP2018546518A patent/JP6959247B2/ja active Active
  • 2017-03-02 SG SG11201807301SA patent/SG11201807301SA/en unknown
  • 2017-03-02 CA CA3016370A patent/CA3016370C/en active Active
  • 2017-03-02 US US16/078,518 patent/US10654853B2/en active Active
  • 2017-03-02 BR BR112018017086-0A patent/BR112018017086B1/pt active IP Right Grant
  • 2017-03-02 WO PCT/GB2017/050565 patent/WO2017149313A1/en not_active Ceased
  • 2017-03-02 EP EP22172828.0A patent/EP4067355A1/en not_active Withdrawn
  • 2017-03-02 EP EP17709766.4A patent/EP3423454B1/en active Active
  • 2017-03-02 ES ES17709766T patent/ES2919549T3/es active Active
• 2018
  • 2018-06-12 ZA ZA2018/03910A patent/ZA201803910B/en unknown
  • 2018-09-02 IL IL261552A patent/IL261552B/en active IP Right Grant
  • 2018-09-04 CO CONC2018/0009275A patent/CO2018009275A2/es unknown
• 2020
  • 2020-04-08 US US16/843,408 patent/US11236092B2/en active Active
• 2021
  • 2021-09-29 JP JP2021158986A patent/JP7280928B2/ja active Active
  • 2021-12-14 US US17/550,071 patent/US20220106315A1/en not_active Abandoned

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events