Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • 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
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to new compounds, to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy.
• the present invention also relates to processes for the preparation of said compounds.
• the current treatment regimes for pain conditions utilise compounds which exploit a very limited range of pharmacological mechanisms.
• One class of compounds, the opioids stimulates the endogenous endorphine system; an example from this class is morphine.
• Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability.
• the second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-I or COX-2 types also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-I inhibitors cause ulcers of the mucosa.
• Mechanisms of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.
• Local anesthetics that are known to block most types of sodium channels in nerves, are useful for relieving pain in small areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular heart toxicity, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for more selective modulators of sodium channels involved in pain signal conduction.
• neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.
• NaV 1.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states ⁇ Acta Neurochirurgica 2002, 144, 803-810).
• ectopic activity in the injured nerve corresponds to the behavioral signs of pain.
• intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).
• sodium channel blockers In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). DISCLOSURE OF THE INVENTION
• R is hydrogen; Ci_ 3 alkyl, optionally substituted by one or more substituents independently selected from hydroxy, C1.3 alkoxy andfluoro; Ci_3alkoxy, optionally substituted by one or more fluoro; cyano; hydroxy or halo;
• n 1,2 or 3;
• Het is C5-6 heteroaryl substituted by 1 or 2 substituents R 2 ;
• R 2 is Ci_ 4 alkyl; d_ 4 haloalkyl; d_ 4 haloalkoxy; halo; Ci_ 4 alkoxy; or C3_7 cycloalkyloxy, optionally substituted by one or more fluoro;
• D is C 5 _ 6 heteroaryl; C 3 _ 7 heterocycloalkyl; or C 3 _ 7 cycloalkyl; wherein each D may optionally be substituted by one or more JC;
• One embodiment of the invention relates to a compound of formula I, wherein
• R 1 is hydrogen; m is 1;
• R 2 is Ci_4alkyl, Ci_4haloalkoxy, halo, Ci_4alkoxy or C3_7Cycloalkyloxy; and wherein said Ci-jcycloalkyloxy is optionally substituted by one or morefluoro;
• Het is C 5 _ 6 heteroaryl where at least one atom is taken from N or S;
• D is C5-6 heteroaryl, C ⁇ heterocycloalkyl or C3-7cycloalkyl, each optionally and independently substituted by one or more JC;
• X 4 is halo, -C(O)-O-C(CH 3 ) 3 or -C(O)-O-CH(CH 3 ) 2 ;
• Li is a Ci_4alkylene or a bond; and L 2 is C i_ 3 alkylene.
• One embodiment of the invention is related to a compound of formula I, wherein R 1 is hydrogen.
• Still an embodiment of the invention is a compound of formula I, wherein m is 1.
• One embodiment of the invention is related to a compound of formula I, wherein R 2 is -0-CH 2 -CF 3 .
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is -0-CH 2 -CH(CHs) 2 .
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is -O-CHF2.
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is methyl.
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is -CH 2 -CH(CH 3 ) 2 .
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is iso-propyl.
• Yet an embodiment of the invention is a compound of formula I, wherein R 2 is chloro.
• One embodiment of the invention is related to a compound of formula I, wherein Li is a bond.
• Still an embodiment of the invention is related to a compound of formula I, wherein Li is ethylene.
• Still an embodiment of the invention is related to a compound of formula I, wherein Li is -CH(CH 3 )-CH 2 -.
• One embodiment of the invention is related to a compound of formula I, wherein L 2 is methylene.
• Still an embodiment of the invention is related to a compound of formula I, wherein L 2 is -CH(CH 3 )-.
• One embodiment of the invention is related to a compound of formula I, wherein Het is pyridinyl or thiophenyl.
• Yet an embodiment of the invention is related to a compound of formula I, wherein Het is thiophenyl.
• One embodiment of the invention is related to a compound of formula I, wherein D is pyridinyl.
• Yet an embodiment of the invention is related to a compound of formula I, wherein D is tetrahy dropyr any 1.
• Yet an embodiment of the invention is related to a compound of formula I, wherein D is piperidinyl.
• Yet an embodiment of the invention is related to a compound of formula I, wherein D is azetidinyl.
• Yet an embodiment of the invention is related to a compound of formula I, wherein D is cyclohexyl.
• One embodiment of the present invention is a related to a compound of formula I, wherein X 4 is fluoro. Yet an embodiment of the present invention is a related to a compound of formula I, wherein X 4 is -C(O)-O-C(CH 3 ) 3 .
• Yet an embodiment of the present invention is a related to a compound of formula I, wherein X 4 is -C(O)-O-CH(CH 3 ) 2 .
• alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.
• Ci_4alkyl as used herein is defined as a straight, branched or cyclic (cyclic where at least three carbon atoms are present) alkyl chain, having from 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl or tert-butyl.
• Ci_3 alkyl as used herein is defined as a straight, branched or cyclic alkyl chain (cyclic when three carbon atoms are present), having from 1 to 3 carbon atoms, namely: methyl, ethyl, n-propyl, iso-propyl, or cyclopropyl.
• Ci_4alkylene as used herein for I4 may be a straight, branched or cyclic alkylene group, and includes but is not limited to methylene, ethylene, n-propylene, iso-propylene, cyclopropylene and n-butylene hydrocarbon chain.
• Ci_3alkylene as used herein for L 2 may be a straight, branched or cyclic alkylene group, and includes a methylene, ethylene, n-propylene, i-propylene and cyclopropylene hydrocarbon chain.
• alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
• the term "Ci- ⁇ alkoxy” may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
• C 1-3 alkoxy as used herein may include, but is not limited to methoxy, ethoxy, or propoxy.
• C1-4 alkoxy as used herein may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy.
• C1-3 alkoxy may be substituted by one or more fluoro atoms whereby one or more hydrogen atoms in the alkoxy group is replaced by one or more fluoro atoms such as -0-CH 2 -CF 3 ; -0-CH 2 -CH 2 -CF 3 ; -0-CHF 2 ;
• Ci_ 3 alkyl-O-Ci_ 3 alkyl or “Ci_ 4 alkyl-O-Ci_ 4 alkyl, unless stated otherwise, refers to an ether group with the general formula R-O-R, wherein R is selected from a hydrocarbon radical.
• haloalkyl means an alkyl group as defined above, which is substituted with halo as defined above.
• C 1-4 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fluorochloromethyl.
• haloalkoxy means an alkoxy group as defined above, which is substituted with halo as defined above.
• Ci_4 haloalkoxy may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
• cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
• C 3 _ 7 cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• Cs_6 cycloalkyl is defined as cyclopentyl or cyclohexyl.
• cycloalkyloxy- refers to a cycloalkyl group attached to the rest of the molecule via the 0-atom of the oxy-group. Examples of C ⁇ . ⁇ cycloalkyloxy as used herein, are without limitation -O-cyclohexyl, -O-cyclopropyl, O-cyclobutyl, and -O-cyclopentyl.
• heterocycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system and which further comprises one or more heteroatoms selected from O, N or S.
• C 3 _ 7 heterocycloalkyl may be, but is not limited to, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrrolidinyl-2-on, azetidinyl, piperidinyl.
• aryl used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring.
• aromatic character e.g., 4n + 2 delocalized electrons
• C 6 -ioaryl may be, but is not limited to phenyl, naphthyl and the like.
• aryl group may be substituted by one or more substituents including -OH, halo, cyano, nitro, C ⁇ alkyl, Ci_6alkoxy or sulfamoyl.
• substituents including -OH, halo, cyano, nitro, C ⁇ alkyl, Ci_6alkoxy or sulfamoyl.
• aryl is preferably substituted by between one and three substitutents.
• heteroaryl used alone or as suffix or prefix, refers to an aromatic ring in which at least one atom in the ring are elements other than carbon, such as N, S and O. Each heteroaryl may be bonded to the rest of the molecule either via a carbon atom of said heteroaryl, or via one nitrogen atom of said heteroaryl.
• Cs_6 heteroaryl as used herein is an aromatic ring having from 5 to 6 ring atoms and wherein at least one of said 5 to 6 ring atoms is a heteroatom selected from N, S and O.
• Examples of such "Cs_ 6 heteroaryl” are pyridinyl, thiophenyl, imidazolyl, pyrazolyl.
• a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid.
• a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
• useful salts in accordance with the invention are an acetate, fumarate, maleate, tartrate, citrate, hydrochloride, hydrobromide, sulphate and phosphate salt.
• the compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
• the compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
• Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
• the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
• the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
• a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
• the pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.
• parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
• a sterile solution suspension or emulsion
• topical administration e.g. as an ointment, patch or cream
• rectal administration e.g. as a suppository.
• compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
• a suitable daily dose of a compound of the invention in the treatment of a mammal, including man is approximately from 5 to 100 mg/kg bodyweight at peroral administration and from about 0.01 to 250 mg/kg bodyweight at parenteral administration.
• the typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
• Compounds according to the present invention are contemplated to be useful in therapy.
• Compounds of formula I as herein described and claimed, or a pharmaceutically acceptable salt thereof, as well as their corresponding active metabolites, exhibit a high degree of potency at the sodium channel NaVl .7 and also selectivity for this channel compared with other essential sodium channels. Accordingly, compounds of the present invention are expected to be useful in the treatment of conditions associated with upregulation of NaVl.7 and other sodium channels present in C-f ⁇ bers.
• Compounds of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.
• One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in the manufacture of a medicament for the treatment of NaV 1.7 mediated disorders.
• Compounds of formula I according to the invention are expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
• a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as
• Still an aspect of the invention is the use of a compound of formula I, for the treatment of a vascular headache such as migraine.
• Yet an aspect of the invention is the use of a compound of formula I, for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.
• Still an embodiment of the present invention is the use of a compound of formula I, for the treatment of epilepsy.
• One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.
• One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in therapy.
• Still an embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
• a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain
• Still an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.
• Yet an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.
• Still an embodiment of the present invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of of epilepsy.
• Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout; whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
• pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromy
• Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
• Yet an aspect of the invention is a method for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
• Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby a compound of formula I as hereinbefore defined is administered to a subject in need of such treatment.
• an embodiment of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
• a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, viscer
• Still an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a vascular headache such as migraine.
• Yet an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder. Still an embodiment of the present invention is a compound of formula I as hereinbefore defined, for use in the treatment of epilepsy.
• the term “therapy” and “treatment” includes prevention and prophylaxis, unless there are specific indications to the contrary.
• the terms “treat'V'therapeutic” and “therapeutically” should be construed accordingly.
• inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.
• disorder means any condition and/or disease associated with NaVl .7 activity.
• Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy.
• Such therapy may for example include in combination with a compound of the present invention, one or more of the following categories of pain-relieving ingredients:
• opioid analgesics for example morphine, ketobemidone or fentanyl
• analgesics of the NSAID or COX- 1/2 class for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups
• analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine
• NMDA antagonists for example ketamine or dextrometorfan
• sodium channel blocking agents for example lidocaine
• anticonvulsants for example carbamazepine, topiramate or lamotrigine
• anticonvulsant/analgesic amino acids such as gabapentin or pregabalin
• cannabinoids cannabinoids.
• Each active compound of such a combination may be administered simultaneously, separately or sequentiallly.
• An aspect of the present invention provides a process for the preparation of a compound of formula I or a salt thereof.
• room temperature and “ambient temperature” shall mean, unless otherwise specified, a temperature between 16 and 25 0 C.
• One embodiment of the invention relates to processes for the preparation of the compound of formula I according to Methods A and B, wherein R ⁇ R 2 , L 1 , L 2 , D, m and n unless otherwise specified, are defined as in formula I.
• a compound of formula I may be prepared by a 3-component Ugi reaction (Journal of Organic Chemistry (1999), 64(3), 1074-1076) using appropriately substituted 2- formylbenzoic acid, amine and isonitrile reacting in a protic solvent, for example methanol at ambient temperature.
• a protic solvent for example methanol at ambient temperature.
• a compound of formula I may be prepared by an amide coupling reaction using appropriately substituted indolone carboxylic acid II and amine III and a suitable activator, for example but not limited to, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, O-benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate or O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate reacting in precence of an organic base such as triethylamine, N ,N- diisopropylamine or 4-(dimethylamino)pyridine in an aprotic solvent such as DMF, acetonitrile, tetrahydrofuran or dioxane at 0-45 0 C.
• carboxylic acids II are available via procedures described in the literature, for example: Othman, M. and Decroix, B., Synthetic communications 1996, 26 (15), 2803- 2809 and Othman, M. et. al, Tetrahedron 1998, 54 (30), 8737-8744 where a homophtalic ester is brominated by for example N-bromosuccinimide (NBS) in carbontetrachloride and then ring closed with an amine in precence of an organic base such as triethylamine, N ,N- diisopropylamine or 4-(dimethylamino)pyridine in a solvent such as acetonitrile at 0-25 °C, as shown below.
• NBS N-bromosuccinimide
• a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 85 ELS detector and a ZQ single quadrupole mass spectrometer.
• the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode.
• the capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively.
• the mass spectrometer scanned between m/z 100-700 with a scan time of 0.3 s.
• the diode array detector scanned from 200-400 nm.
• the temperature of the ELS detector was adjusted to 40 0 C and the pressure was set to 1.9 bars.
• a LC-MS system consisting of a Waters sample manager 2111 C, a Waters 1525 ⁇ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA 2996 diode array detector and a Sedex 85 ELS detector.
• the mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device.
• APCI atmospheric pressure chemical ionisation
• APPI atmospheric pressure photo ionisation
• the mass spectrometer scanned in the positive mode, switching between APCI and APPI mode.
• the mass range was set to m/z 120-800 using a scan time of 0.3 s.
• the APPI repeller and the APCI corona were set to 0.86 kV and 0.80 ⁇ A, respectively.
• the desolvation temperature (300 0 C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode. Separation was performed using a Gemini column C 18, 3.0 mm x 50 mm, 3 ⁇ m, (Phenomenex) and run at a flow rate of 1 ml/min. A linear gradient was used starting at 100 % A (A: 10 mM ammonium acetated in 5 % methanol) and ending at 100% B (methanol). The column oven temperature was set to 40 0 C.
• a LC-MS system consisting of a Waters Alliance 2795 HPLC and a Waters Micromass ZQ detector operating at 120 0 C.
• the mass spectrometer was equipped with an electrospray ion source (ES) operated in a positive or negative ion mode.
• the mass spectrometer was scanned between m/z 100-1000 with a scan time of 0.3 s.
• the LC system used was 75 % acetonitrile and 25 % of a 0.1 % formic acid solution in water.
• the PDA was scanned from 210-350 nm.
• the ZQ mass spectrometer was run with ESI in positive mode.
• the Capillary Voltage was 3kV and the Cone Voltage was 30V. Mixed triggering, UV and MS signal, determined the fraction collection.
• An Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315C Diode Array Detector.
• the column used was a Gemini Cl 8 3.0 x 50, 3 ⁇ m (Phenomenex) run at a flow rate of 1.0 ml/min.
• the purity method consisted of three parts: firstly a 3 -minute column wash was applied, secondly a blank run was performed and finally the sample was analysed.
• a linear gradient was used for both the blank and the sample, starting at 100 % A (A: 10 mM ammonium acetate in 5 % acetonitrile) and ending at 100 % B (B: acetonitrile) after 3.5 minutes.
• the blank run was subtracted from the sample run at the wavelengths 220 nm, 254 nm and 290 nm.
• a Waters 600 Controller system with a Waters 717 Plus Autosampler and a Waters 2996 Photodiode Array Detector was used. The column used was an ACE C 18 , 5 ⁇ m, 6O x 150 mm. A linear gradient was applied, starting at 95 % A (A: 0.1 % H 3 PO 4 in water) and ending at 55 % B (B: acetonitrile) in 20 min run. The column was at ambient temperature with the flow rate of 1.0 mL/min. The Diode Array Detector was scanned from 200-400 nm.
• NMR spectra were recorded on a Varian Mercury Plus 400 NMR Spectrometer, operating at 400 MHz and equipped with a Varian 400 ATB PFG probe; or on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 5 mm BBO probe with Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI 1 HZD- 13 C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 4-nucleus probe with Z-gradients.
• Diastereomers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
• the reaction mixture was dissolved in ethyl acetate (100 mL) and washed with water, sat. sodium bicarbonate, and finally with brine. The organic layer was dried over magsesium sulfate and concentrated in vacuo.
• the crude was purified by column chromatography using a gradient of chloroform/methanol/7 M ammonia in methanol 90/9/1, in chloroform (0-60 %). The fractions containing the product were pooled and concentrated in vaccum to yield the title compound as yellow oil, 2.08 g (67 %).
• the methanol was evaporated in vacuo.
• the waterphase was acidified to pH 2 with 1 M
• the titled compound was synthesized according to the procedure described for intermediate 1 from ethyl 2-(l-bromo-2-ethoxy-2-oxoethyl)benzoate (3.0 g, 9.5 mmol), 1- methyl-2-pyridin-2-yl-ethylamine (1.95 g, 14.3 mol) and triethylamine (2.13 rnL, 15.3 mmol) in acetonitrile (25 rnL) to yield the product, 1.9 g (62 %).
• Zinc cyanide (1.21 g, 10.4 mmol) followed by Pd(PPh 3 ) 4 (0.477 g, 0.415 mmol) were added to a solution of 5 -bromo-2-(difluoromethoxy)pyridine (1.16 g, 5.19 mmol) in DMF (25 mL) at room temperature. The mixture was heated at 100 0 C for 16 hours. The cold mixture was diluted with ethyl acetate (30 mL), filtered through a short bed of celite and concentrated under reduced pressure.
• Example 1 (general procedure 1) 3-Oxo-2-(2-pyridin-2-ylethyl)-N-rr6-(2,2,2-trifluoroethoxy)pyridin-3-yllmethyll-lH- isoindole-1-carboxamide
• the titled compound was prepared according to the general procedure 1 , described in example 1, from 3-oxo-2-(tetrahydro-2H-pyran-4-yl)isoindoline-l-carboxylic acid (78 mg,
• the title compound was prepared according to the general procedure 1 , described in example 1, from 3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindoline-l-carboxylic acid (71 mg, 0.25 mmol) and (6-isopropoxypyridin-3-yl)methanamine (125 mg, 0.75 mmol). Solid, 13 mg (12 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-l-carboxylic acid (56 mg, 0.20 mmol) and (6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanamine (44 mg, 0.20 mmol). Solid, 24 mg (25 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindo line- 1-carboxylic acid (30 mg, 0.10 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine (52 mg, 0.25 mmol) to yield 12 mg (25 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindo line- 1-carboxylic acid (30 mg, 0.10 mmol) and (2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methanamine (55 mg, 0.25 mmol) to yield 13 mg (27 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindo line- 1-carboxylic acid (30 mg, 0.10 mmol) and (6-isobutoxypyridin-3-yl)methanamine (45 mg, 0.25 mmol) to yield 12 mg (27 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindo line- 1-carboxylic acid (30 mg, 0.10 mmol) and (6-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine (55 mg, 0.25 mmol) to yield 6 mg (12 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and ((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (52 mg, 0.25 mmol) to yield 11 mg (23 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from of 2-(4,4-difluorocyclohexyl)-3-oxoisoindoline-l-carboxylic acid (74 mg, 0.25 mmol) and ((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (103 mg, 0.50 mmol) to yield a white solid, 13 mg (11 %).
• the title compound was prepared according to the general procedure 1 , described in example 1, from 2-(l-methyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-l-carboxylic acid (30 mg, 0.10 mmol) and (6-(4,4-difluorocyclohexyloxy)pyridin-3-yl)methanamine (61 mg, 0.25 mmol) to yield 14 mg (27 %).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 2-formylbenzoic acid (35 mg, 0.23 mmo), 2-(pyridin-2-yl)ethanamine (28 mg, 0.23 mmol) and 2-chloro-5-(isocyanomethyl)thiophene (33 mg, 0.21 mmol) to yield 39 mg (41 %).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 2-formylbenzoic acid (75 mg, 0.50 mmol), 2-(pyridin-2-yl)ethanamine (61 mg, 0.50 mmol) and 2-(difluoromethoxy)-5-(isocyanomethyl)pyridine (93 mg, 0.50 mmol).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 2-formylbenzoic acid (60 mg, 0.40 mol), 2-(pyridin-3-yl)ethanamine (49 mg, 0.40 mmol) and 2-(difluoromethoxy)-5-(isocyanomethyl)pyridine (74 mg, 0.40 mmol) and. Pale yellow solid, 128 mg (73 %).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 2-formylbenzoic acid (60 mg, 0.40 mmol), tert-butyl 4-aminopiperidine- 1-carboxylate (80 mg, 0.40 mmol) and 5-(isocyanomethyl)-2-isopropylpyridine (64 mg, 0.40 mmol). Pale yellow solid, 40 mg (25 %).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 4,4-difluorocyclohexylaminium chloride (69 mg, 0.40 mmol), triethylamine (0.11 mL), 2-formylbenzoic acid (60 mg, 0.40 mmol) and 5- (isocyanomethyl)-2-isopropylpyridine (64 mg, 0.40 mmol). Pale yellow solid, 39 mg (23 %).
• the title compound was synthesized according to the general procedure 2, described in example 12, from 2-formylbenzoic acid (60 mg, 0.40 mmol), 2-(pyridin-3-yl)ethanamine (49 mg, 0.40 mmol) and 5-(isocyanomethyl)-2-isopropoxypyridine (70.4 mg, 0.40 mmol). Solid, 60 mg (34.9 %).
• the title compound was synthesized according to general procedure 2, described in example 12, from 2-formylbenzoic acid (0.051 g, 0.34 mmol), tert-butyl 3-aminoazetidine- 1-carboxylate (0.059 g, 0.34 mmol) and 5-(isocyanomethyl)-2-isopropoxypyridine (0.060 g, 0.34 mmol). Dry film, 18 mg (11 %).
• the title compound was synthesized according to general procedure 2, described in example 12, from 2-formylbenzoic acid (542 mg, 3.61 mmol), tert-butyl 3-aminoazetidine- 1-carboxylate (0.621 mL, 3.61 mmol) and 5-(isocyanomethyl)-2-(2,2,2- trifluoroethoxy)pyridine (780 mg, 3.61 mmol).
• White solid 1.128 g (60 %).
• Step 1 tert-Butyl 3-(l-oxo-3-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methylcarbamoyl)isoindolin- 2-yl)azetidine-l-carboxylate (390 mg, 0.75 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL, 26.05 mmol) was added. The resulting mixture was stirred under argon at room temperature for 16 hours. Saturated aqueous NaHCO 3 solution was carefully added until effervescence ceased and the resulting mixture was extracted twice with dichloromethane and twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the amine intermediate as solid, 197 mg (62.5 %).
• Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art.
• the so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.
• Li+ influx assay The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells.
• a suitable Na- free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO 4 0.81, CaCl 2 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min.
• a buffer rich in LiCl for 60 min at 37 0 C.
• the LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells.
• Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO 4 0.81, CaCl 2 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition.
• an effective concentration for example 100 ⁇ M
• the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener may be added to the medium to enhance signal detection.
• an effective concentration for example 10 ⁇ g/ml
• suitable scorpion venom may also be added to the medium to delay channel inactivation.
• the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.
• the described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format.
• the described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.
• the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-trans fection or through establishment of a stable co-transfected cell line.
• a suitable potassium leak ion channel for example TREK-I
• the successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp.
• a cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.
• Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.
• Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform.
• the cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms.
• Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms.
• a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest.
• a suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV or -65 mV, but may also have other suitable parameters.
• Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature.
• cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.
• a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.
• This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tj ⁇ lsen et al. Pain 1992, 51, 5/ It can therefore be inferred that a compound of the present invention is usefulas a therapeutic agent to relieve pain of various origins.
• Compounds of formula I may show analgesic activity in the intraarticular FCA (Freund's complete adjuvant) test in the rat, a model of inflammatory pain (Iadarola et al. Brain Research 1988, 455, 205-12) and in the Chung nerve lesion test in the rat, a model for neuropathic pain (Kim and Chung. Pain 1992, 50, 355).
• the analgesic effects in the animal models may be obtained after doses that do not produce tissue concentrations leading to conduction block in nerve fibers. Thus, the analgesic effects can not be explained by the local anesthetic properties of the compounds mentioned in the publication by Kornet and Thio.
• Analgesic efficacy after systemic administration is not a general property of drugs with local anesthetic effects (Scott et al. British Journal of Anaesthesia 1988, 61, 165-8).
• compounds of the invention are active in the Whole-cell voltage clamp electrophysiology assay above with IC50 values less than 10 ⁇ M. In one aspect of the invention, the IC 50 value is less than 1 ⁇ M.
• IC50 represents the compound concentration required for 50% inhibition. Specimen results are shown in the following table as pIC50 values, i.e. -log (IC50). Thus the larger the pIC50 the more potent the compound. For example, a pIC50 of 6.5 indicates an IC50 of 10 ' M.

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