Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
  • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
  • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

• the present invention relates to neuronal gap junction blocking compounds having improved pharmacokinetic properties, the compounds being useful for the treatment or prevention of a range of conditions including migraine, epilepsy, non-epileptic seizures, brain injury (including stroke, intracranial haemorrhage and trauma induced) or cardiovascular disease including myocardial infarction, coronary revascularization or angina.
• Cortical spreading depolarization is a wave of depolarisation with consequent depressed electrical activity which spreads across the surface of the cerebral cortex (at a rate of 2-6 mm/min) usually followed by hyperaemia and neuronal hyperpolarisation.
• the reduction in electrical activity is a consequence of neuron depolarisation and swelling, with K+ efflux, Na and Ca influx and electrical silence.
• This abnormal neuronal activity is associated with delayed neuronal damage in a number of pathological states including cerebral ischaemia (arising from e.g.
• the conditions triggering this abnormal response in experimental models are high extracellular levels of K+ and low NO availability. These conditions are typically seen in ischaemic areas of the brain, and clusters of CSD waves in these circumstances result in spreading ischaemia (see Dreier 2011). Of particular importance is the spreading ischaemia seen after sub-arachnoid haemorrhage (SAH), in the penumbra of an infarct and after traumatic brain injury where delayed neuronal damage can have a significant effect on clinical outcomes (Dreier et al., 2006, 2012; Hartings et al., 2011a, 2011b; Fabricius et al., 2006).
• SAH sub-arachnoid haemorrhage
• Gap junctions are comprised of connexin proteins of which there are 21 in the human genome. Each Gap junction is made of two hemichannels, each comprising six connexin monomers.
• Gap junctions are also implicated in a number of other disease states including hereditary diseases of the skin and ear (e.g. keratitis-ichthyosis deafness syndrome, erythrokeratoderma variabilis, Vohwinkel's syndrome, and hypotrichosis-deafness syndrome).
• Blockade of gap junction proteins has been shown to beneficial in some preclinical models of pain (e.g. Spataro et al., 2004 J Pain 5, 392-405, Wu et al., 2012 J Neurosci Res. 90, 337-45). This is believed to be a consequence of gap junction blockade in the spinal cord resulting in a reduction in the hypersensitivity of the dorsal horn to sensory nerve input.
• gap junctions and their associated hemichannels have been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's Disease, Huntington's Disease and amyotrophic lateral sclerosis (Takeuchi et al 2011 PLoS One.; 6, e21108).
• Tonabersat (SB-220453/PRX201145) is a gap junction blocker (Silberstein, 2009; Durham and Garrett, 2009) which binds selectively and with high affinity to a unique stereo-selective site in rat and human brains. Consistent with its action on gap junctions Tonabersat also inhibits high K+ evoked CSD in cats (Smith et al., 2000; Read et al., 2000; Bradley et al., 2001) and rats (Read et al., 2001).
• Tonabersat is a crystalline solid with a high melting point (152-153 C) and with a relatively high lipophilicity (log P 3.32).
• the compound has no readily ionisable groups and consequently has a low aqueous solubility of 0.025 mg/ml over a range of pH values including pH of 7.4.
• the low aqueous solubility of Tonabersat makes both intravenous (IV) and oral (PO) modes of administration problematic.
• gap junction blocker compounds having improved physiochemical properties thus improving the utility of these agents in treating a range of disease states.
• the present invention makes available three classes of compounds, each class having one or more solubilising pro-drug groups.
• the present invention makes available a class of compounds of formula (I) or a hydrate, solvate, or pharmaceutically acceptable salt thereof:
• Z 1 , Z 2 , and Z 3 are each independently selected from H, F, or Cl,
• R 2 is H
• A is a direct bond, —C(O)O*—, —C(R 3 )(R 4 )O*—, —C(O)O—C(R 3 )(R 4 )O*—, or —C(R 3 )(R 4 )O—C(O)O*— wherein the atom marked * is directly connected to R 1 ,
• R 3 and R 4 are selected independently from H, fluoro, C 1-4 alkyl, or C 1-4 fluoroalkyl, or
• R 3 and R 4 together with the atom to which they are attached form a cyclopropyl group
• R 1 is selected from groups [1], [2], [2A], [2B][3], [4], [5] or [6] wherein the atom marked ** is directly connected to A:
• R 5 and R 6 are each independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, or benzyl;
• R 7 is independently selected from H, C 1-4 alkyl, or C 1-4 fluoroalkyl
• R 8 is selected from:
• R 9 is selected from H, —N(R 11 )(R 12 ), or —N + (R 11 )(R 12 )(R 13 )X ⁇ —, or —N(R 11 )C(O)R 14 wherein R 11 , R 12 , and R 13 are independently selected from H, C 1-4 alkyl, or C 1-4 fluoroalkyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring,
• R 14 is H, C 1-4 alkyl, or C 1-4 fluoroalkyl
• R 10 and R 15 are independently selected from C 1-4 alkyl or C 1-4 fluoroalkyl
• X ⁇ is a pharmaceutically acceptable anion.
• the present invention makes available a class of compounds of formula (II) or a hydrate, solvate, or pharmaceutically acceptable salt thereof:
• Z 1 , Z 2 , and Z 3 are each independently selected from H, F, or Cl,
• A is a direct bond and R 1 is H
• R 2 is B—R 21 wherein,
• B is a direct bond, —C(O)O*—, —C(R 23 )(R 24 )O*—, —C(O)O—C(R 23 )(R 24 )O*—, or —C(R 23 )(R 24 )O—C(O)O*— wherein the atom marked * is directly connected to R 21 ,
• R 23 and R 24 are selected independently from H, fluoro, C 1-4 alkyl, or C 1-4 fluoroalkyl, or
• R 23 and R 24 together with the atom to which they are attached form a cyclopropyl group
• R 21 is selected from groups [21], [22], [22A], [22B], [23], [24], [25] and [26] wherein the atom marked ** is directly connected to B:
• R 25 and R 26 are each independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl or benzyl;
• R 27 is independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl
• R 28 is selected from:
• R 29 is selected from H, —N(R 31 )(R 32 ), or —N + (R 31 )(R 32 )(R 33 )X ⁇ , or —N(R 31 )C(O)R 34 wherein R 31 , R 32 , and R 33 are independently selected from H, C 1-4 alkyl, or C 1-4 fluoroalkyl, or R 31 and R 32 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring,
• R 34 is H, C 1-4 alkyl, or C 1-4 fluoroalkyl
• X ⁇ is a pharmaceutically acceptable anion
• R 30 and R 35 are independently C 1-4 alkyl or C 1-4 fluoroalkyl.
• the present invention makes available a class of compounds of formula (IIIa) or (IIIb), or a hydrate, solvate, or pharmaceutically acceptable salt thereof:
• Z 1 , Z 2 , and Z 3 are each independently selected from H, F, or Cl;
• R 2 and -A-R 1 are both H;
• R 41 and R 42 are independently H, C 1-4 fluoroalkyl or optionally substituted C 1-4 alkyl, or
• R 41 and R 42 together with the carbon atom to which they are attached form a 5-8 membered heterocycle, any carbon atom of which is optionally substituted; or
• Q is an oxime of formula ⁇ NHOR 43 , wherein R 43 is
• a 300 is a direct bond, —C(O)O*—, —C(R 3 )(R 4 )O*—, —C(O)O—C(R 3 )(R 4 )O*—, or —C(R 3 )(R 4 )O—C(O)O*— wherein the atom marked * is directly connected to R 300 ,
• R 3 and R 4 are selected independently from H, fluoro, C 1-4 alkyl, or C 1-4 fluoroalkyl, or
• R 3 and R 4 together with the atom to which they are attached form a cyclopropyl group
• R 300 is selected from groups [1], [2], [2A], [2B], [3], [4], [5] or [6] wherein the atom marked ** is directly connected to A 300 :
• R 5 and R 6 are each independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, or benzyl;
• R 7 is independently selected from H, C 1-4 alkyl, or C 1-4 fluoroalkyl
• R 8 is selected from:
• R 9 is selected from H, —N(R 11 )(R 12 ), or —N + (R 11 )(R 12 )(R 13 )X ⁇ , or —N(R 11 )C(O)R 14 wherein R 11 , R 12 , and R 13 are independently selected from H, C 1-4 alkyl, or C 1-4 fluoroalkyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring,
• R 14 is H, C 1-4 alkyl, or C 1-4 fluoroalkyl
• R 10 and R 15 are independently selected from C 1-4 alkyl or C 1-4 fluoroalkyl
• X ⁇ is a pharmaceutically acceptable anion.
• R 43 is C 1-4 alkyl optionally substituted with a phosphate group (—P(O)OR 61 R 62 ).
• OR 43 is —OCH 2 P(O)OR 61 OR 62 , wherein R 61 and R 62 are independently H or C 1-4 alkyl.
• R 43 is an amino acid derivative having the structure —C(O)CH(R 100 )NH 2 wherein the group R 100 is the side chain of a natural or unnatural amino acid.
• OR 43 is —OC(O)CH(CH(CH 3 ) 2 )NH 2 .
• (C a -C b )alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
• a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
• (C a -C b )fluoroalkyl has the same meaning as “(C a -C b )alkyl” except that one or more of the hydrogen atoms directly connected to the carbon atoms forming the alkyl group is replaced by the corresponding number of fluorine atoms.
• Carbocyclic refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
• cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond.
• Illustrative of such radicals are phenyl, biphenyl and napthyl.
• heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond.
• Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl and indazolyl.
• heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in addition means a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
• radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
• substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, halo (including fluoro, bromo and chloro), fully or partially fluorinated (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or (C 1 -C 3 )alkylthio such as trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (—CN), oxo, phenyl, phenoxy, monocyclic heteroaryl or heteroaryloxy
• substituent is phenyl, phenoxy or monocyclic heteroaryl or heteroaryloxy with 5 or 6 ring atoms
• the phenyl or heteroaryl ring thereof may itself be substituted by any of the above substituents except phenyl, phenoxy, heteroaryl or heteroaryloxy.
• An “optional substituent” may be one of the foregoing substituent groups.
• salt includes base addition, acid addition and quaternary salts.
• Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
• bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl pipe
• Those compounds of formula (I), (II), (IIIa) or (IIIb) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
• inorganic acids e.g. hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
• organic acids e.g. acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric,
• solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
• solvent molecules for example, ethanol.
• hydrate is employed when said solvent is water.
• Compounds with which the invention is concerned which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomers with R or S stereochemistry at each chiral axis.
• the invention includes all such enantiomers and diastereoisomers and mixtures thereof.
• the carbon atom to which the groups R 7 and R 7 are attached may be in either the R or the S configuration.
• the compounds of the invention include compounds of formula (I), (II), (IIIa) or (IIIb) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I), (II), (IIIa) or (IIIb).
• metabolites of compounds of formula (I), (II), (IIIa) or (IIIb), that is, compounds formed in vivo upon administration of the drug include:
• the groups Z 1 , Z 2 , and Z 3 are each independently selected from H, F, or Cl. In an embodiment Z 1 is Cl, Z 2 is F, and Z 3 is H. In another embodiment Z 1 is Cl, Z 2 and Z 3 are H. In another embodiment Z 1 is H, Z 2 is F, and Z 3 is H. In another embodiment Z 1 is F, Z 2 is H, and Z 3 is F.
• the above definitions of Z 1 , Z 2 , and Z 3 is H are applicable to compounds of formula (I), (II), (IIIa), and (IIIb). As an illustration, the preferred definition of Z 1 , Z 2 , and Z 3 applied to the compounds of formula (I) is as follows:
• Z 1 is Cl
• Z 2 is F or H
• Z 3 is H
• the group Q is an oxygen atom
• the group R 2 is a hydrogen atom
• the group A is a direct bond, —C(O)O*—, —C(R 3 )(R 4 )O*—, —C(O)O—C(R 3 )(R 4 )O*—, or —C(R 3 )(R 4 )O—C(O)O*— wherein the atom marked * is directly connected to R 1 .
• R 3 and R 4 are selected independently from H, fluoro, C 1-4 alkyl such as methyl, ethyl, propyl or isopropyl, or C 1-4 fluoroalkyl such as trifluoromethyl, or R 3 and R 4 together with the atom to which they are attached form a cyclopropyl group,
• A is a direct bond. In another embodiment A is —CH 2 O*—, or —CH(CH 3 )O*—, or C(CH 3 ) 2 O*—.
• the group R 1 is selected from groups [1], [2], [2A], [2B], [3], [4], [5] or [6] wherein the atom marked ** is directly connected to A:
• R 5 and R 6 are each independently selected from H, C 1-4 alkyl such as methyl, ethyl, propyl or isopropyl, C 1-4 fluoroalkyl such as trifluoromethyl, or benzyl. In an embodiment R 5 and R 6 are hydrogen.
• R 7 is independently selected from H, C 1-4 alkyl such as methyl, ethyl, propyl or isopropyl, or C 1-4 fluoroalkyl such as trifluoromethyl.
• R 7 and R 8 are both hydrogen, or R 7 is hydrogen and R 8 is methyl, or both R 7 and R 8 are methyl.
• R 7 , R 8 and R 9 are hydrogen.
• R 7 is hydrogen.
• the group R 8 is selected from:
• R 7 and R 8 together with the atom to which they are attached form a C 3-7 carbocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
• side chain of a natural or non-natural alpha-amino acid refers to the group R 100 in a natural or non-natural amino acid of formula NH 2 —CH(R 100 )—CO 2 H.
• group -AR 1 is selected from the following groups wherein the atom marked ** is directly connected to the oxygen atom of the parent drug:
• side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ⁇ -aminoadipic acid, ⁇ -amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, ⁇ -methylserine, ornithine, pipecolic acid, and thyroxine.
• Natural alpha-amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups in their characteristic side chains include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine.
• R 8 in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.
• carboxyl groups may be esterified (for example as a C 1 -C 6 alkyl ester), amino groups may be converted to amides (for example as a NHCOC 1 -C 6 alkyl amide) or carbamates (for example as an NHC( ⁇ O)OC 1 -C 6 alkyl or NHC( ⁇ O)OCH 2 Ph carbamate), hydroxyl groups may be converted to ethers (for example an OC 1 -C 6 alkyl or a O(C 1 -C 6 alkyl)phenyl ether) or esters (for example a OC( ⁇ O)C 1 -C 6 alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thio
• side chains of non-natural alpha amino acids include: an optional substituent, C 1 -C 6 alkyl, phenyl, 2, -3-, or 4-hydroxyphenyl, 2, -3-, or 4-methoxyphenyl, 2, -3-, or 4-pyridylmethyl, benzyl, phenylethyl, 2-, 3-, or 4-hydroxybenzyl, 2, -3-, or 4-benzyloxybenzyl, 2, -3-, or 4-C 1 -C 6 alkoxybenzyl, and benzyloxy(C 1 -C 6 alkyl)-groups, wherein any of the foregoing non-natural amino acid side chains is optionally substituted in the alkyl, phenyl or pyridyl group; or
• Alk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R 51 )— groups [where R 51 is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1, and R 50 is an optionally substituted cycloalkyl or cycloalkenyl group; or
• a heterocyclic(C 1 -C 6 )alkyl group either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoromethyl (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylphenylmethyl; and
• the group R 9 is selected from H, —N(R 11 )(R 12 ) such as —NH 2 , NH(CH 3 ), —NH(CH 3 ) 2 , or —N + (R 11 )(R 12 )(R 13 )X ⁇ such as —N + (CH 3 ) 3 X ⁇ , or —N(R 11 )C(O)R 14
• R 11 , R 12 , and R 13 are independently selected from H, C 1-4 alkyl such as methyl, ethyl, propyl or isopropyl, or C 1-4 fluoroalkyl such as trifluoromethyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring such as pyrrolidine, piperidine, piperazine, morpholine or homomorpholine.
• R 11 and R 12 are both methyl.
• R 14 is H, C 1-4 alkyl such as methyl, ethyl, propyl or isopropyl, or C 1-4 fluoroalkyl such as trifluoromethyl
• R 10 and R 15 are independently selected from C 1-4 alkyl or C 1-4 fluoroalkyl.
• the counterion X ⁇ is a pharmaceutically acceptable anion such as chloride, or any other anion fromed by removal of one or more protons from an inorganic acid, e.g. hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, or from an organic acids e.g. acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
• hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
• organic acids e.g. acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulph
• the compounds of formula (I), (II), (IIIa) or (IIIb) may be further modified by adding one or more of the prodrug groups Q, -AR 1 or R 2 .
• the compounds of formula (I) or (ii) may be modified by exchanging the oxygen atom Q for a prodrug Q group as defined in (IIIa) or (IIIb).
• the compounds of formula (I) could be modified by replacing the hydrogen atom R2 by the prodrug group R2 as defined in formula (II), and vice versa.
• the present invention makes available a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), (II), (IIIa) or (IIIb) together with one or more pharmaceutically acceptable carriers and/or excipients.
• the present invention makes available a compound of formula (I), (II), (IIIa) or (IIIb) for use in medicine.
• the inventions encompasses the use of a compound of formula (I), (II), (IIIa) or (IIIb) treatment of a disease or medical condition which benefits from inhibition of gap junction activity.
• Inhibition of gap junction activity may be achieved by blocking the gap junction as a whole or by blocking one or more hemichannels.
• the inventions encompasses a method of treatment of a disease or medical condition which benefits from inhibition of gap junction activity, comprising administering to a subject suffering from such disease or condition and effective amount of a compound of formula (I), (II), (IIIa) or (IIIb).
• the disease or condition which benefits from inhibition of gap junction activity is selected from among migraine, aura with or without migraine, epilepsy, non-epileptic seizures, cerebrovascular accidents including stroke, intracranial haemorrhage (including traumatic brain injury, epidural hematoma, subdural hematoma and subarachnoid haemorrhage), and intra-cerebral haemorrhage, spinal cord vascular accidents arising from trauma, epidural hematoma, subdural hematoma or subarachnoid haemorrhage, pain including pain arising from hyperalgesia caused by damage to sensory neurons (i.e.
• neuropathic pain including but not limited to diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia, myofascial pain, post herpetic neuralgia, spinal stenosis, HIV pain, post-operative pain, post-trauma pain) or inflammation (including pain associated with osteoarthritis, rheumatoid arthritis, sciatica/radiculopathy, pancreatitis, tendonitis), neurodegenerative disease (including but not limited to Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis) and cardiovascular disease including myocardial infarction, coronary revascularization or angina.
• diabetic neuropathy including but not limited to diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia, myofascial pain, post herpetic neuralgia, spinal stenosis, HIV pain, post-operative pain, post-trauma pain) or inflammation (including pain associated with osteoarthritis, rheuma
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art.
• the total daily dose of the compounds of the invention may typically be in the range 1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 10 mg to 1000 mg, while an intravenous dose may only require from 1 mg to 500 mg.
• the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60 kg to 100 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly, and especially obese patients.
• the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. Suitable routes for administration include oral, intravenous, buccal, intranasal, inhalation, rectal, and intradermal.
• the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• non-aqueous vehicles which may include edible oils
• almond oil fractionated coconut oil
• oily esters such as glycerine, propylene
• the pro-drug may also be administered parenterally in a sterile medium.
• the drug can either be suspended or dissolved in the vehicle.
• adjuvants such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the person skilled in the art is aware of many excipients useful for IV formulation.
• the compounds of formula (I) above may be prepared by, or in analogy with, conventional methods.
• the preparation of intermediates and compounds according to the Examples of the present invention may in particular be illuminated by the following Schemes. Definitions of variables in the structures in Schemes herein are commensurate with those of corresponding positions in the formulas delineated herein.
• Compounds of general formula (I) can easily be prepared from the alcohols of general formula (IV) by either using the alcohol directly or pre-forming the alkoxide using a suitable base/reagent (e.g. NaH) and coupling to a suitably activated A-R or R group (or protected A-R or R group).
• a suitable base/reagent e.g. NaH
• Activated A-R or R group functionalities typically used for the formation of phosphates, esters, carbonates and carbamates include, but not limited to, phosphoryl chlorides, acid chlorides, activated carboxylic acids, chloroformates, activated carbonates and isocyanates.
• the formation of (la) from (IV) using dimethylaminoacetyl chloride as an activated R group is representative of this approach.
• P 1 is a suitable protecting group or functionality that can be readily chemically modified/utilised to append R 1 .
• compounds of general formula (I) can easily be prepared in a more step wise manner from the alcohol of general formula (IV) by using either the alcohol directly or pre-forming the alkoxide using a suitable base/reagent (e.g. NaH) and coupling to a suitably activated A-P 1 group.
• a suitable base/reagent e.g. NaH
• the compound of general formula (I) has an A group defined as —C(R 3 )(R 4 )O*— or C(R 3 )(R 4 )OC(O)O*—
• activated forms of A-P 1 including, but not limited to, alkylchlorides, alkylbromides, alkyliodides, mesylates and tosylates.
• the compound of general formula (I) has an A group defined as —C(O)O*— or C(O)OC(R 3 )(R 4 )O*— these may be prepared using activated forms of A-P 1 including, but not limited to, chloroformates and activated carbonates. Then using methods known to those skilled in the art the intermediates of general formula (V) can be chemically modified to provide functionality that facilitates the final coupling step to afford compounds of general formula (I). The formation of (Ic) from (IV) via the methylsulfanyl methoxy intermediate (Va) is representative of this approach.
• Tonabersat The synthesis of Tonabersat, and other structurally related compounds, is disclosed in WO 95/34545.
• the present invention encompasses compounds prepared by applying the pro-drug groups -AR 1 , R 2 and Q taught herein to the specific Examples disclosed in WO 95/34545.
• the methods proposed for the synthesis of compounds of general formula (I) are known to those skilled in the art, for example in Rautio et al., Nature Reviews Drug Discovery, 7, 255-270, 2008.
• a compound of formula (I) can also be transformed into another compound of formula (I) in one or more synthetic steps.
• N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide (1.00 g, 2.55 mmol) was dissolved in DME (10 mL) and added to a suspension of sodium hydride (60% dispersion in oil, 112 mg, 2.81 mmol) in DME (10 mL). The reaction mixture was stirred for 10 min then sodium iodide (421 mg, 2.81 mmol) was added followed by chloromethyl methyl sulfide (232 ⁇ L, 2.81 mmol).
• N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide (2.00 g, 5.10 mmol) was dissolved in methylethyl ketone (50 mL). Pyridine (1.62 mL, 20.4 mmol) and POCl 3 (1.50 mL, 16.3 mmol) were added and the reaction mixture was stirred for 16 h.
• N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide 200 mg, 0.51 mmol was slurried in toluene (2.0 mL) with acetic anhydride (50 ⁇ L, 0.51 mmol), N-hydroxysuccinimide (18 mg, 0.15 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol). The reaction mixture was heated to 80° C. for 195 min to give a colourless solution and then cooled to ambient temperature overnight.
• Boc-Sar-OSu (full name: tert-butyl N- ⁇ 2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-hydroxyethyl ⁇ -N-methylcarbamate) (292 mg, 1.02 mmol), DIPEA (196 ⁇ L, 1.12 mmol) and DMAP (6 mg, 0.05 mmol) were added and the reaction mixture was stirred overnight at 70° C. The THF was evaporated in vacuo and the residue suspended between EtOAc (10 mL) and 10% aqueous citric acid solution (5 mL). The organic phase was washed with water (10 mL) and concentrated in vacuo.
• the product was extracted into 10% aqueous sodium carbonate solution (30 mL).
• the aqueous phase was separated, adjusted to pH1-2 with 2N HCl in ice and the product extracted into EtOAc (15 mL).
• the organic phase was washed with water (3 ⁇ 10 mL) until pH 4 and then concentrated in vacuo.
• the residue was partitioned between EtOAc (20 mL) and 5% aqueous sodium carbonate solution (20 mL).
• the aqueous phase was separated, adjusted to pH 1 with 2N HCl in ice, loaded onto a preconditioned column of Amberlite XAD-4 resin (5 g) and the product eluted with water/MeCN mixtures.
• Boc-Leu-OH full name: (2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -4-methylpentanoic acid
• HOBt hydrate 429 mg, 2.80 mmol
• EDC.HCl 537 mg, 2.80 mmol
• DMAP 733 mg, 6.00 mmol
• N-Boc-N-isopropylamino-acetic acid (520 mg, 2.39 mmol), HOBt hydrate (441 mg, 2.88 mmol), EDC.HCl (552 mg, 2.88 mmol) and DMAP (733 mg, 6.00 mmol) were dissolved in DCM (10 ml) and the reaction mixture was stirred for 30 min.
• N-[(3S,4S)-6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl]-3-chloro-4-fluorobenzamide (784 mg, 2.00 mmol) was added and the reaction mixture was stirred for 20 h and concentrated in vacuo.
• Compounds of general formula (IIa) can easily be prepared from the alcohols of general formula (IVa) by protecting the hydroxyl functionality with a suitable protecting group P 2 to give compounds of general formula (VI) and then coupling the prodrug functionality onto the amide nitrogen atom in one or more steps using synthetic strategies analogous to those used for the synthesis of compounds of general formula (I). The final step is to remove the protecting group P 2 to give compounds of general formula (IIa).
• the general mode of action of the claimed pro-drugs is as follows.
• IV administration the high solubility conferred by the solubilising pro-moiety to the parent Tonabersat-like drug is expected to allow a rapid bolus injection whereupon the pro-drug will be quickly cleaved by in vivo esterases/phosphatases to reveal the parent drug.
• PO administration the preferred mode of action is where the solubilising pro-drug is predominantly cleaved in the gut by esterases/phosphatases prior to absorption of the parent drug into the systemic circulation.
• Example prodrugs were dosed either intravenously or orally to fasted male Sprague Dawley rats. The rats underwent surgery for jugular vein cannulation 48 hrs prior to dosing. Following dosing, 0.25 mL blood samples were taken via the cannulae at 0, 5, 10, 20, 30, 45, 60, 120, 240 & 360 minutes in EDTA coated tubes. Tubes were spun at 13,000 rpm for 4 minutes and 100 ul of supernatant taken immediately and stored at ⁇ 80° C. prior to analysis.
• Plasma samples were analysed by LC-MS/MS following extraction by protein precipitation, and levels of parent prodrug and tonabersat were measured by MRM (Multiple Reaction Monitoring) analysis against an extracted calibration curve of plasma samples spiked with the Example prodrug and tonabersat.
• MRM Multiple Reaction Monitoring
• Example 2 was dosed according to this protocol at 0.95 mg/kg IV. Plasma levels of Example 2 were found to decline from 730 ng/mL at 5 min to ⁇ 5 ng/mL at 6 hrs. Plasma levels of tonabersat were determined to be 130 ng/mL at 5 min and 115 ng/mL at 6 hrs clearly showing conversion of the prodrug to tonabersat over this timecourse following intravenous dosing.
• Example 2 was dosed according to this protocol at 6.10 mg/kg PO. Plasma levels of Example 2 were found to decline from 38 ng/mL at 5 min to ⁇ 5 ng/mL at 6 hrs. Plasma levels of tonabersat were determined to be 63 ng/mL at 5 min and 900 ng/mL at 6 hrs clearly showing conversion of the prodrug to tonabersat over this timecourse following oral dosing.

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• 2013
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