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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
• • 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
  • A61P25/04—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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

• W preferably represents (CH )4 or (CH 2 )5
• the group -(CH 2 ) n A(CH ) m Ar may be substituted on any carbon atom in the ring.
• W is (CH 2 )4 or (CH 2 >5 the substituent is preferably ⁇ to the ring nitrogen atom.
• n, m and A should be chosen such that the chain (CH2) n A(CH 2 ) m contains at least one atom.
• the length of the chain -(CH 2 ) n A(CH ) rn is from 2 to 6 atoms.
• Preferred values for n and m depend on the group A.
• A is oxygen the sum of n+m is from 1 to 5; for example n may be 1 or preferably 2 and m may be zero.
• A is preferably oxygen or a bond, most preferably oxygen.
• W is -(CH )5- and the substituent -(CH2) n A(CH 2 ) rn Ar is ⁇ to the ring nitrogen atom.
• A is oxygen, n is 1 or 2 and m is zero.
• a particularly preferred group of compounds according to the present invention is that of formula (IA):
• - ⁇ 3 is preferably in the 4-position relative to the -(CH ) n A(CH 2 ) m - group.
• Particular compounds according to the invention include: ( ⁇ )2- [2- ⁇ 4-(4-fluorophenylsulphone)phenoxy ⁇ ethyl]piperidine,
• compounds of the invention will have a relatively simple pharmacokinetic profile and extended durations of action in vivo. It is further believed that the compounds of the invention are particularly advantageous because they are resistant to metabolic degradation. The present compounds are also characterised by having improved solubility.
• the present invention provides a process for preparing a compound of formula (I) which process comprises: (a) for compounds of formula (I) in which A is O, S or NR 1 , reaction of a compound of formula (II):
• R ⁇ a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above.
• L(CH 2 ) m Ar can take place under conditions which depend on the nature of the group L and the value of m.
• L is preferably fluoro, such that the compound of formula (II) is reacted with a compound F-Ar.
• the reaction is preferably effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylsulphoxide or dimethylfoimamide.
• L is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero
• the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base.
• the reaction between a compound of formula (HI) and a compound of formula HA ⁇ CH ⁇ j Ar can take place under conditions which depend on the nature of L 1 and A 1 .
• L 1 is hydroxy
• m is 0
• A* is oxygen or sulphur
• the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
• the leaving group L may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy.
• the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C.
• a compound of formula (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
• a compound of formula (TV) can be prepared (for example as described below) and reduced in a One-pot' reaction, without isolation of compound (IV) itself.
• reaction between a compound of formula (V) and a compound of formula ⁇ l Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
• Reduction of a compound of formula (VI) according to process (e) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg. ethanol.
• a noble metal catalyst such as platinum, palladium or platinum oxide
• Process (f) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH 2 ) m+ ⁇ P(O)(OAlk) 2 , such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH 2 ) m+ ⁇ PPh3X ⁇ (where X" is an anion) which compounds are available commercially or can be prepared by known methods.
• the reaction may be carried out in a solvent such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5 or 18-crown-6, and in the presence of a strong base such as sodium hydride, or potassium tert-butoxide.
• Interconversion reactions according to process (g) may be effected by methods well known in the art.
• Protecting groups R ⁇ include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl.
• a protecting group R ⁇ a is preferably alkyl e.g. methyl or aralkyl e.g. benzyl. Such groups may be removed by methods which are well known in the art.
• alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such a 1-chloromethylchloroformate, aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis.
• a protecting group R ⁇ or R ⁇ a present in any of the above compounds (II) to (VII) as well as compounds (VIII) below should be chosen such that it will not be cleaved by or participate in any of the reactions that the particular compound is intended to undergo, and furthermore such that its removal will not disturb any other groups or moieties present in the molecule. Such factors can be readily ascertained by those skilled in the art, to whom appropriate protecting groups will thus be readily apparent.
• R ⁇ should be a group such as alkyl, which is not cleaved by reductive conditions.
• a compound of formula (VI) may be prepared using the general methods described in processes (a) to (d) above.
• Compounds of formula (VII) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A * is oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and
• N,O-dimethylhydroxylamine hydrochloride to give the N-methyl-N-methoxy- carboxamide, which can be reduced to the aldehyde using diisobutylaluminium hydride.
• Compounds of formula (VII) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
• aldehyde may be converted to the corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
• a compound of formula (I) When a compound of formula (I) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
• Suitable resolving agents include optically active acids such as R-(-)- or S-(+)-mandelic acid.
• a mixture of diastereomeric amides may be prepared by reacting a mixture of enantiomers of formula (I) with an optically active reagent such as S(+)- ⁇ - methoxyphenylacetic acid, in the form of a reactive derivative such as an acid chloride.
• the mixture of amides may be separated by conventional methods and then converted into the resolved amines by hydrolysis.
• An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen.
• a cascade of biochemical reactions ensues, a consequence of which is to permit the influx of calcium ions into the brain cells (neurons) via so-called Voltage Operated Calcium Channels (VOCCs) causing cell death. It is believed that agents which inhibit such calcium influx will minimise cell death and hence increase the potential for recovery.
• VOCCs Voltage Operated Calcium Channels
• Compounds of formula (I) have been found to exhibit high calcium influx blocking activity for example in neurons.
• the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
• the compounds are expected to be of use in the treatment of ischaemia including for example stroke, anoxia, and traumatic head injury. They may also be of use in the treatment of migraine, visceral pain, epilepsy, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
• a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treatment of ischaemia including for example stroke, anoxia or traumatic head injury which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof..
• the invention also provides a method of treatment of migraine, visceral pain, epilepsy, AEDS-related dementia, neurodegenerative diseases such as Alzheimer's disease, and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the compounds of the present invention are usually administered in a standard pharmaceutical composition.
• the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
• the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
• the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
• a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid ca ⁇ ier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
• a suitable liquid ca ⁇ ier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
• a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
• suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
• suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
• a composition in the form of a capsule can be prepared using routine encapsulation procedures.
• pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion.
• Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
• Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent such as Cremophor.
• the composition is in unit dose form such as a tablet, capsule or ampoule.
• Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
• the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
• the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400mg per day.
• the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg.
• the compounds will be administered for a period of continuous therapy, for example for a week or more.
• Cd?+ current can be measured in vitro using cell preparations of sensory neurons from dorsal root ganglia as described in WO92/02501 and WO92/02502, or sensory neurons from superior cervical ganglia as described in WO95/04027.
• Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
• Solvent Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol. Tablet
• Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
• CDCI3 ⁇ 1.38 (9H, s), 1.60-1.70 (12H, m), 1.85 (1H, m), 2.20 (1H, m), 2.80 (1H, m), 3.90 (3H, m), 4.47 (1H, m), 6.75 (2H, m), 7.05 - 7.30 (7H, m)
• Ci9H 22 FNO3S.HCl requires: C, 57.1, H, 5.8, N, 3.5 Found: C, 56.9, H, 5.7, N, 3.5%

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• 1994
  • 1994-06-02 GB GB9411052A patent/GB9411052D0/en active Pending
• 1995
  • 1995-05-24 WO PCT/EP1995/002002 patent/WO1995033722A1/en not_active Application Discontinuation
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