WO1995024390A1 - Novel phenyl(-alkyl/alkoxy)-1-aminoalkyl-substituted piperidines and pyrrolidines as calcium channel antagonists - Google Patents

Novel phenyl(-alkyl/alkoxy)-1-aminoalkyl-substituted piperidines and pyrrolidines as calcium channel antagonists Download PDF

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Publication number
WO1995024390A1
WO1995024390A1 PCT/EP1995/000850 EP9500850W WO9524390A1 WO 1995024390 A1 WO1995024390 A1 WO 1995024390A1 EP 9500850 W EP9500850 W EP 9500850W WO 9524390 A1 WO9524390 A1 WO 9524390A1
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Prior art keywords
formula
compound
piperidinyl
phenylpropyl
alkyl
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PCT/EP1995/000850
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French (fr)
Inventor
Thomas Henry Brown
David Gwyn Cooper
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Smithkline Beecham Plc
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Publication of WO1995024390A1 publication Critical patent/WO1995024390A1/en

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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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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

  • the present invention relates to nitrogen containing heterocyclic derivatives, processes for their preparation, pharmaceutical compositions cortaining them and their use in therapy, in particular in the treatment of ischaemic stroke.
  • Stroke is reportedly the third most common cause of death in the developed world.
  • Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
  • the present invention provides, in a first aspect, a compound of formula (I):
  • W is -CH2- or a bond; p is an integer from 3-12; NR 1R2 represents:
  • R ! and R.2 each independently represent: hydrogen, Cj.galkyl, C3_gcycloalkyl, C3_gcycloalkylC ⁇ _galkyl, arylC ⁇ alkyl, hydroxyC2-6alkyl or R ⁇ R ⁇ NC2-6alkyl (where R ⁇ and R ⁇ independently represent H or C ⁇ alkyl) provided that when one of R and R ⁇ represents hydrogen, the other does not represent hydrogen, Cj.galkyl, C3-gcycloalkylC galkyl, arylC ⁇ alkyl or hydroxy C2-6alkyl; (ii) a saturated heterocyclic ring containing 4 to 9 ring members, one of which may optionally be a further heteroatom selected from O, S or NR ⁇ , (where R ⁇ is H, Chalky!
  • W preferably represents -CH2-.
  • p is preferably from 4-8.
  • NR1R2 represents in particular a piperidine ring, which is preferably unsubstituted.
  • A is preferably oxygen or a bond.
  • the values of m and n should be chosen such that the length of the chain (CH2)nA(CH2) m is at least 2 atoms. In general the length of the chain -(CH2) n A(CH2) m is from 2 to 6 atoms. Preferred values for n and m depend on the group A. Thus for example when A is oxygen the sum of n+m is preferably from 1 to 5 for example n may be 1 or 2 and m may be 0. When A is a bond, the sum of m+ n is preferably from 2 to 4.
  • the phenyl group Ar may be substituted, for example, by a Cj- ⁇ alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cj ⁇ alkoxy, nitro, SC ⁇ alkyl, NR" R (in which R" and R ZD independently represent H or C ⁇ _4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylC ⁇ alkyl and optionally substituted phenylC ⁇ alkoxy.
  • a Cj- ⁇ alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
  • substituents selected from halogen, Cj ⁇ alkoxy, nitro, SC ⁇ alkyl, NR" R (in which R" and
  • Suitable optionally substituted phenylC ⁇ .4alkyl groups include, for example benzyl.
  • Suitable optionally substituted phenylC ⁇ alkoxy groups include, for example benzyloxy groups.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylCj_4alkyl and ph.enylCj_4alkoxy groups include for example halogen, C ⁇ alkyl, C ⁇ _4alkoxy, nitro and trifluoromethyl groups.
  • the phenyl group Ar is substituted by one or two substituents, in particular, by a phenyl, phenyl(C ⁇ _4)alkyl, phenoxy, benzoyl or phenylC ⁇ alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a C ⁇ _4alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts e.g. oxalates, may be used for example in the isolation of final products and are included within the scope of this invention.
  • This invention also includes solvates and hydrates of formula (I).
  • Particular compounds of the invention include: l,4-bis-[4-(3-phenylpropyl)piperidinyl]-butane; l,5-bis-[4-(3-phenylpropyl)piperidinyl]-pentane; l,6-bis-[4-(3-phenylpropyl)piperidinyl]-hexane; l,7-bis-[4-(3-phenylpropyl)piperidinyl]-heptane; l,8-bis-[4-(3-phenylpropyl)piperidinyl]-octane; l,12-bis-[4-(3-phenylpropyl)piperidinyl]-dodecane; l,7-bis- ⁇ 4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl] ⁇ -heptane; l-[4-(3-pheny
  • the compounds of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides in a further aspect, a process for the preparation of a compound of formula (I) which comprises:
  • R 2 Formula (II) wherein Ar, m, n, A, W, Rl, R ⁇ and p are as defined above, one of x and y is 1 and the other is zero or 1;
  • NR ⁇ R2 may also represent a pyrrolidine or piperidine ring substituted by L ⁇ (CH2) n , and L* is a group displaceable by a nucleophile), with a compound of formula HA ⁇ (CH2) m Ar, where m and Ar are as defined above and A ⁇ s O, S or NR 6 ;
  • NR ⁇ R2 may also represent a pyrrolidine or piperidine ring substituted by HAl(CH.2) n ),
  • NR*R ⁇ may also represent a pyrrolidine or piperidine ring substituted by LHCH2
  • X ⁇ Ar in which Ar is as defined above and XMs an alkali metal
  • process (a) The reduction of a compound of formula (II) according to process (a) can be effected by methods well known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a reducing agent such as lithium aluminium hydride.
  • process (b) the reaction between a compound of formula (III) and a compound of formula HA ⁇ (CH2) m Ar can take place under conditions which depend on the nature of
  • the leaving group L may be for example a halogen atom or a sulphonyloxy group e.g. 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, optionally in the presence of a base.
  • reaction between a compound of formula (IV) and a compound I--2(CH2) m Af can take place under conditions which depend on the nature of the group IX and the value of m.
  • L ⁇ is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero
  • the reaction may be carried out under standard conditions in a solvent, optionally in the presence of a base.
  • a fluoro- substituted aryl compound F-Ar is employed in process (c) (to prepare compounds where m is zero)
  • the reaction may be effected in the presence of a strong base such as sodium hydride, and in an inett organic solvent such as dimethylsulphoxide.
  • reaction between a compound of formula (V) and a compound of formula X Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
  • Alkylation according to process (e) may be effected using standard conditions well known in the art.
  • the reaction may be carried out in a suitable solvent, for example an alcohol such as ethanol, and preferably in the presence of a base, such as potassium carbonate.
  • a suitable solvent for example an alcohol such as ethanol
  • a base such as potassium carbonate.
  • one equivalent of the alkylating agent reacts with two equivalents of the compound (VI) to give a symmetrical bis-amine.
  • Interconversion reactions according to process (f) may be effected by methods well known in the art.
  • a compound of formula (II) may be prepared by reacting the appropriate amine(s) of formula (VI) and if necessary (VII) :
  • a compound of formula (II) wherein NR1R2 is a group (i) or (ii) as hereinbefore defined, such that the compound (II) contains two different amine functions an unsymmetrical compound of formula (VIII) should be employed, that is, wherein the moiety ⁇ 2(CO) u - has a different value from the moiety -(CO) v X 3 .
  • one of X ⁇ and X ⁇ may be a halogen atom (e.g. chlorine) and the other an esterifying group.
  • u may be 1 and v may be zero, in which case X ⁇ represents a halogen atom (e.g. bromine) and X ⁇ may represent a halogen atom (e.g. chlorine) or an esterifying group.
  • X ⁇ represents a halogen atom (e.g. bromine)
  • X ⁇ may represent a halogen atom (e.g. chlorine) or an esterifying group.
  • the position of the CO group i.e.
  • the values of x and y) in the resulting compound of formula (II) will depend on the precise nature of the acylating moiety X ⁇ (CO) u or (CO) v ⁇ 3 in formula (VIII) and the sequence of the reactions.
  • the first reaction will be acylation, followed by alkylation, but when an ester is employed alkylation will take place first.
  • An amine of formula (VI) may be prepared by the general methods described in WO93/15052, including processes analogous to (b), (c) and (d) described above, employing a corresponding amine of formula (IX), (X) or (XI) or an N-protected derivative thereof.
  • Protecting groups which may be employed include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; acyl groups such as acetyl, trifluoroacetyl or benzoyl; and alkoxycarbonyl or aralkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl. 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 as 1-chloromethylchloroformate, an 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 present in any of the above compounds (IX), (X) and (XI) 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.
  • 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.
  • An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen.
  • VOCCs Vo ' ⁇ e Operated Calcium Channels
  • Compounds of the invention 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 useful 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 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, 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, 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 the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal e.g. a human.
  • Compounds of the present invention will preferably be of use in the treatment of ischaemic stroke.
  • 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 carrier(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 carrier(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.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions may contain other excipients known in the pharmaceutical art, such as cyclodextrins.
  • 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 " between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 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, e.g. 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 400 mg 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. It will be appreciated that the precise dosage and timing will be at the discretion of the physician and will depend amongst other factors on the severity of the condition to be treated.
  • the first dose of a compound of the invention will preferably be administered as soon as possible following an ischaemic event, eg within 12 hours, preferably within 6 hours.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca z+ currents.
  • the external solution for recording Ca2+ channel currents contained in mM: BaCl2- 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Block by 20 ⁇ M drug was assessed 3 minutes after drug application.
  • compounds of the invention gave percentage inhibition of plateau Ca ⁇ current in the range 56 to 99% at 20 ⁇ M.
  • Co-Solvent to 5 ml 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.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch
  • Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone
  • Lubricant e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
  • Suspending agent e.g. Xanthan gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • Ethyl 6-morphoIinylhexanoate A mixture of ethyl 6-bromohexanoate (l l.l ⁇ g), morpholine (4.36g), potassium carbonate (8.29g) and ethanol (200ml) was heated at reflux for 18 hours. The mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in dilute hydrochloric acid and extracted with ether. The aqueous layer was basified with dilute sodium hydroxide and extracted with ether. This ether layer was washed with brine, dried over magnesium sulphate and the solvent was removed to give the title compound as an oil.
  • Example 2 l,5-Bis-[4-(3-phenylpropyI)piperidinyl]-pentane dihydrochloride
  • the title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with glutaryl dichloride (1.69g). Recrystallisation from methanol/ethyl acetate gave a white solid, (2.94g), m.p. softens 70 - 72 melts 215 - 217 C.
  • Example 5 l,8-Bis-[4-(3-phenylpropyl)piperidinyl]-octane dihydrochloride
  • the title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with suberoyl chloride (2.1 lg). Recrystallisation from acetonitrile gave white needles, (1.508g), m.p. 210 - 212°C.
  • Example 8 l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane dihydrochloride
  • a solution of l-oxo-l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane hydrochloride (1.594g) in chloroform (50ml) was washed with dilute sodium hydroxide and brine, dried over magnesium sulphate and the solvent was removed.
  • the resulting oil was dissolved in tetrahydrofuran (30ml) and added over 20 minutes to a solution of lithium aluminum hydride (0.89g) in tetrahydrofuran (100ml) stirred at 50 C.
  • Example 13 l-[4-(3-phenylpropyI)piperidinyl]-6-morphoIinohexane dihydrochloride
  • the title compound was prepared in a similar manner to example 9 starting from 1-oxo-l- [4-(3-phenylpropyl)piperidinyl]-6-morpholinohexane (0.75g) and lithium aluminum hydride (0.44g). Recrystallisation from acetonitrile gave white needles, (0.445g), m.p. ⁇ 217 - 218°C.
  • the title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-benzylphenol (0.52g), triphenylphosphine (0.74g), diethyl azodicarboxylate (0.49g) and tetrahydrofuran (30ml). Recrystallisation from methanol/ethyl acetate gave a white solid (0.949g), m.p. 191 - 192°C.
  • the title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-benzyloxyphenol (0.56g), triphenylphosphine (0.74g), diethyl azodicarboxylate (0.49g) and tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a white solid (0.714g), m.p. 191 - 192°C.
  • Example 17 l- ⁇ 4-[2-(4-Fluorophenoxy)ethyI]piperidinyl ⁇ -5-piperidinylpentane dihydrochloride
  • the title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-fluorophenol (0.32g), triphenylphosphine (0.74g) and diethyl azodicarboxylate (0.49g) in tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a white solid (0.305g), m.p. 228 - 230°C. Found: C, 60.99; H, 8.54; N, 6.27; Cl, 15.43%
  • Example 18 l- ⁇ 4-[2-(4-Fluorophenoxy)ethyl]piperidinyl ⁇ -6-piperidinylhexane dihydrochloride
  • the title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-6-piperidinylhexane (l.Og), 4-fluorophenol (0.378g), triphenylphosphine (0.88g), diethyl azodicarboxylate (0.58g) and tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a cream solid (0.365g), m.p. 221 - 222 C.
  • the title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-6-piperidinylhexane (l.Og), 3,4-dichlorophenol (0.55g), triphenylphosphine (0.88g), diethyl azodicarboxylate (0.58g) and tetrahydrofuran (30ml).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Compounds of formula (I) in which W is -CH2- or a bond; p is an integer from 3-12; NR1R2 represents: (i) an acyclic amino group wherein R?1 and R2¿ each independently represents: hydrogen, C¿1-8?alkyl, C3-8cycloalkyl, C3-8cycloalkylC1-8alkyl, arylC1-4alkyl, hydroxyC2-6alkyl or R?3R4NC¿2-6alkyl (where R?3 and R4¿ independently represent H or C¿1-4?alkyl) provided that when one of R?1 and R2¿ represents hydrogen, the other does not represent hydrogen, C¿1-8?alkyl, C3-8cycloalkylC1-8alkyl, arylC1-4alkyl or hydroxy C2-6alkyl; (ii) a saturated heterocyclic ring containing 4 to 9 ring members, one of which may optionally be a further heteroatom selected from 0, S or NR?5¿, (where R5 is H, C¿1-4?alkyl or arylC1-4alkyl), which ring may optionally be substituted by one or two substituents selected from C1-6alkyl and C1-6alkoxy; or (iii) when W represents a bond, NR?1R2¿ may also represent a pyrrolidine ring substituted by -(CH¿2?)nA(CH2)mAr and when W represents -CH2-, NR?1R2¿ may also represent a piperidine ring substituted by -(CH¿2?)nA(CH2)mAr to form a symmetrical compound of formula (I); n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C C-, oxygen, sulphur or NR?6¿ where R6 is hydrogen, C¿1-8?alkyl or phenylC1-4alkyl; and Ar is optionally substituted phenyl; and salts thereof are calcium antagonists with activity in neurons and are useful in the treatment of conditions such as ischaemic stroke.

Description

NOVEL PHENYL(-ALKYL/AL 0XY)- 1 -AMIN0ALKYL-SUBSTITUTED PIPERIDINES
AND PYRROLIDINES AS CALCIUM CHANNEL ANTAGONISTS **********************************
The present invention relates to nitrogen containing heterocyclic derivatives, processes for their preparation, pharmaceutical compositions cortaining them and their use in therapy, in particular in the treatment of ischaemic stroke.
Stroke is reportedly the third most common cause of death in the developed world. Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
International Applications No's WO92/02501, WO92/02502, WO92/22527 and WO93/15052 describe substituted piperidine and pyrrolidine derivatives, which compounds are said to have activity as calcium blocking agents.
We have now found a group of novel piperidine and pyrrolidine derivatives which exhibit activity as calcium channel antagonists.
The present invention provides, in a first aspect, a compound of formula (I):
Figure imgf000003_0001
Formula (I) in which
W is -CH2- or a bond; p is an integer from 3-12; NR 1R2 represents:
(i) an acyclic amino group wherein R ! and R.2 each independently represent: hydrogen, Cj.galkyl, C3_gcycloalkyl, C3_gcycloalkylCι_galkyl, arylC^alkyl, hydroxyC2-6alkyl or R^R^NC2-6alkyl (where R^ and R^ independently represent H or C^alkyl) provided that when one of R and R^ represents hydrogen, the other does not represent hydrogen, Cj.galkyl, C3-gcycloalkylC galkyl, arylC^alkyl or hydroxy C2-6alkyl; (ii) a saturated heterocyclic ring containing 4 to 9 ring members, one of which may optionally be a further heteroatom selected from O, S or NR^, (where R^ is H, Chalky! or arylC^alkyl), which ring may optionally be substituted by one or two substituents selected from C galkyl and C^alkoxy; or (iii) when W represents a bond, NR R may also represent a pyrrolidine ring substituted by -(CH2)nA(CH2)mAr and when W represents -CH2-, NR1R2 may also represent a piperidine ring substituted by -(CH2)n A(CH2)mAr' t0 form a symmetrical compound of formula (I); n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR^ where R6 is hydrogen, Ci-galkyl or phenylCι_4alkyl; and Ar is optionally substituted phenyl; and salts thereof.
It will be appreciated that when W is -CH2- the compound of formula (I) is a piperidino derivative and when W is a bond the compound of formula (I) is a pyrrolidino derivative. When W is -CH2- the substituent -(CH2)nA(CH2)mAr is preferably at the 4- position of the piperidine ring and when W is a bond the substituent -(CH2)nA(CH2)mAr is preferably at the 3-position of the pyrrolidine ring.
In the compounds of formula (I) W preferably represents -CH2-. p is preferably from 4-8.
NR1R2 represents in particular a piperidine ring, which is preferably unsubstituted.
A is preferably oxygen or a bond. The values of m and n should be chosen such that the length of the chain (CH2)nA(CH2)m is at least 2 atoms. In general the length of the chain -(CH2)nA(CH2)m is from 2 to 6 atoms. Preferred values for n and m depend on the group A. Thus for example when A is oxygen the sum of n+m is preferably from 1 to 5 for example n may be 1 or 2 and m may be 0. When A is a bond, the sum of m+ n is preferably from 2 to 4.
The phenyl group Ar may be substituted, for example, by a Cj-^alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cj^alkoxy, nitro, SC^alkyl, NR" R (in which R" and RZD independently represent H or Cι_4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylC^alkyl and optionally substituted phenylC^alkoxy.
Suitable optionally substituted phenylCι.4alkyl groups include, for example benzyl. Suitable optionally substituted phenylC^alkoxy groups include, for example benzyloxy groups.
Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylCj_4alkyl and ph.enylCj_4alkoxy groups include for example halogen, C^^alkyl, Cι_4alkoxy, nitro and trifluoromethyl groups. Preferably the phenyl group Ar is substituted by one or two substituents, in particular, by a phenyl, phenyl(Cι_4)alkyl, phenoxy, benzoyl or phenylC^alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus a Cι_4alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non- pharmaceutically acceptable salts e.g. oxalates, may be used for example in the isolation of final products and are included within the scope of this invention. This invention also includes solvates and hydrates of formula (I). Particular compounds of the invention include: l,4-bis-[4-(3-phenylpropyl)piperidinyl]-butane; l,5-bis-[4-(3-phenylpropyl)piperidinyl]-pentane; l,6-bis-[4-(3-phenylpropyl)piperidinyl]-hexane; l,7-bis-[4-(3-phenylpropyl)piperidinyl]-heptane; l,8-bis-[4-(3-phenylpropyl)piperidinyl]-octane; l,12-bis-[4-(3-phenylpropyl)piperidinyl]-dodecane; l,7-bis-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl] } -heptane; l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane; l-[4-(3-phenylpropyl)piperidinyl]-6-piperidinylhexane; l-[4-(3-phenylpropyl)piperidiny!l-7-piperidinylheptane; l-[4-(3-phenylpropyl)piperidinyl]-8-piperidinyloctane; l-[4-(3-phenylpropyl)piperidinyl]-7-morpholinoheptane; l-[4-(3-phenylpropyl)piperidinyl]-6-morpholinohexane; l-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl}-5-piperidinylpentane; 1 - { 4-[2-(4-benzylphenoxy)ethyl]piperidinyl } -5-piperidinylpentane; l-{4-[2-(4-benzyloxyphenoxy)ethyl]piperidinyl}-5-piperidinylpentane; l-{4-[2-(4-fluorophenoxy)ethyl]piperidinyl}-5-piperidinylpentane;
1 - { 4-[2-(4-fluorophenoxy)ethyl]piperidinyl } -6-piperidinylhexane; l-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl}-6-piperidinylhexane; and salts thereof.
It will be appreciated that the compounds of formula (I) may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. In addition, when A represents -CH=CH- the compounds will exist as geometric isomers, and the invention encompasses all such isomers and mixtures thereof. The compounds of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides in a further aspect, a process for the preparation of a compound of formula (I) which comprises:
(a) reduction of a compound of formula (II) :
R2
Figure imgf000006_0001
Formula (II) wherein Ar, m, n, A, W, Rl, R^ and p are as defined above, one of x and y is 1 and the other is zero or 1;
(b) to prepare a compound of formula (I) in which A is O, S or NR^, reaction of a compound of formula (III) :
Figure imgf000006_0002
Formula (III)
(wherein W, n, p, Rl and Rz are as hereinbefore defined, or NR^ R2 may also represent a pyrrolidine or piperidine ring substituted by L^(CH2)n, and L* is a group displaceable by a nucleophile), with a compound of formula HA^(CH2)mAr, where m and Ar are as defined above and A^s O, S or NR6;
(c) to prepare a compound of formula (I) in which A is O, S or NR^, reaction of a compound of formula (IV) :
Figure imgf000006_0003
Formula (IV)
(wherein W, n, p, Rl, R^ and A^ are as hereinbefore defined, or NR ^R2 may also represent a pyrrolidine or piperidine ring substituted by HAl(CH.2)n),
4 -
SUBST1TUTE SHEET (RULE 26) with a compound of formula L (CH2)mAr in which m and Ar are as defined above and L^ is a leaving group.
(d) To prepare a compound of formula (I) in which A is a bond, reaction of a compound of formula (V) :
L1(CH2)n+m
W N-(CH2) — NR1R2 L_y
Formula (V)
(wherein l , W, n, m, p, R* and R^ are as hereinbefore defined, or NR*R^ may also represent a pyrrolidine or piperidine ring substituted by LHCH2)n+ )> with a compound of formula X^Ar in which Ar is as defined above and XMs an alkali metal,
(e) to prepare a symmetrical compound (I) wherein NR * R2 represents a substituted pyrrolidino or piperidino group (iii) as hereinbefore defined, reaction of a compound of formula (VI) :
Figure imgf000007_0001
Formula (VI)
(wherein Ar, A, m, n and W, are as hereinbefore defined) with an alkylating agent Br(CH2)pBr.
(f) Interconversion of one compound of formula (I) to a different compound of formula (I), e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2-CH2-; and optionally thereafter forming a salt of formula (I).
The reduction of a compound of formula (II) according to process (a) can be effected by methods well known in the art, for example using a reducing agent such as lithium aluminium hydride. In process (b) the reaction between a compound of formula (III) and a compound of formula HA^(CH2)mAr can take place under conditions which depend on the nature of
W - and A. For example when LMs hydroxy, m is 0 and A Ms oxygen or sulphur the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1). Alternatively the leaving group L may be for example a halogen atom or a sulphonyloxy group e.g. methane-sulphonyloxy or p-toluene sulphonyloxy. In this case the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C, optionally in the presence of a base.
In process (c) the reaction between a compound of formula (IV) and a compound I--2(CH2)mAf can take place under conditions which depend on the nature of the group IX and the value of m. For example, when L^ is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero, the reaction may be carried out under standard conditions in a solvent, optionally in the presence of a base. When a fluoro- substituted aryl compound F-Ar is employed in process (c) (to prepare compounds where m is zero), the reaction may be effected in the presence of a strong base such as sodium hydride, and in an inett organic solvent such as dimethylsulphoxide.
The reaction between a compound of formula (V) and a compound of formula X Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
Alkylation according to process (e) may be effected using standard conditions well known in the art. Thus the reaction may be carried out in a suitable solvent, for example an alcohol such as ethanol, and preferably in the presence of a base, such as potassium carbonate. It will be appreciated that in this process one equivalent of the alkylating agent reacts with two equivalents of the compound (VI) to give a symmetrical bis-amine. Interconversion reactions according to process (f) may be effected by methods well known in the art. Thus for example conversion of a compound (I) wherein A represents -CH=CH- into a compound (I) wherein A represents-CF^-CFb- may be effected by catalytic reduction.
A compound of formula (II) may be prepared by reacting the appropriate amine(s) of formula (VI) and if necessary (VII) :
Figure imgf000008_0001
Formula (VI) Formula (VII)
(wherein Ar, A, m, n, W, R! and R^ are as hereinbefore defined), with an acylating agent (e.g. an acid halide or ester) of formula (VIII) :
X2(OC)u(CH2) Nu+v)(CO)vX3
Formula (VIII) wherein p is as hereinbefore defined; one of u and v is 1 and the other is zero or 1; and X^ and X^ independently represent a halogen atom or, when adjacent to a CO group may also represent an esterifying group, e.g. alkoxy. It will be appreciated that to prepare a compound of formula (II) wherein NR1R2 is a group (i) or (ii) as hereinbefore defined, such that the compound (II) contains two different amine functions, an unsymmetrical compound of formula (VIII) should be employed, that is, wherein the moiety χ2(CO)u- has a different value from the moiety -(CO)vX3. For example, when u and v in formula (VIE) both represent 1, one of X^ and X^ may be a halogen atom (e.g. chlorine) and the other an esterifying group. Alternatively u may be 1 and v may be zero, in which case X^ represents a halogen atom (e.g. bromine) and X^ may represent a halogen atom (e.g. chlorine) or an esterifying group. It will further be appreciated that when one of u and v in formula (VIII) is zero, the position of the CO group (i.e. the values of x and y) in the resulting compound of formula (II) will depend on the precise nature of the acylating moiety X^(CO)u or (CO)vχ3 in formula (VIII) and the sequence of the reactions. In general when the compound of formula (VIII) is an acid halide, the first reaction will be acylation, followed by alkylation, but when an ester is employed alkylation will take place first.
Thus, to prepare a compound of formula (II) wherein x is 1 and y is zero, a compound (VI) may first be reacted with an acid chloride of formula (VIII) (X^ = Cl, u = 1, v = zero, X^ = Br), followed by reaction with an amine of formula (VII). Alternatively, a compound (VII) may be reacted with an ester of formula (VIII) (X^ = alkoxy, u = 1 , v = zero, X^ = Br) and the product subsequently reacted with an amine (VI). Similarly, a compound (II) wherein x is zero and y is l,may be prepared either starting from an ester of formula (VIII) (X^ = Br u = 0, v = 1, χ3 = alkoxy) by reaction with an amine of formula (VI) and subsequently reacting the product with an amine of formula (VII) or when an acid chloride is used the order of amine addition is reversed such that a compound of formula (VIII) (X?- = Br u = 0, v = 1, X^ = Cl) is first treated with amine (VII) and subsequently reacting the product with an amine of formula (VI). These reactions may be carried out using standard conditions, which are well known in the art.
A compound of formula (II) wherein NR1R2 represents a substituted pyrrolidine or piperidine ring (iii) as hereinbefore defined may be prepared in an analogous manner. However, such compounds are more conveniently prepared using a symmetrical acylating agent of formula (VIII), wherein u and v represent 1 and X^ = χ , preferably a halogen atom e.g. chlorine, and the appropriate compound of formula (VI). It will be appreciated that at least two molar equivalents of the amine should be employed.
The general methods (a) and (e) described above for the preparation of compounds of formula (I) may also be employed as appropriate to prepare compounds of formulae (III), (IV) and (V) using an appropriately substituted amine of formula (IX), (X) or (XI) :
Figure imgf000010_0001
Formula (IX) Formula (X)
Figure imgf000010_0002
Formula (XI) in place of a compound (VI).
An amine of formula (VI) may be prepared by the general methods described in WO93/15052, including processes analogous to (b), (c) and (d) described above, employing a corresponding amine of formula (IX), (X) or (XI) or an N-protected derivative thereof.
Compounds of formulae (VII) and (VIII) are commercially available or may be prepared by methods well known in the art, as are alkylating agents Br(CH2)pBr employed in process (e).
Compounds of formulae (IX) or (XI) wherein L^ is hydroxy are available commercially or known in the literature or can be prepared by standard techniques, for example when W is -CH2- reduction of the corresponding hydroxyalkylpyridine. When L represents a halogen atom or a sulphonyloxy group such compounds can be prepared from the alcohol in conventional manner. Where necessary the length of the alkyl chain may be increased using methods well known in the art. Compounds of formula (X) wherein A* is oxygen are equivalent to compounds
(IX) wherein L^ is hydroxy and may be prepared as described above. When A* represents S or NR" compounds (X) may be prepared from the corresponding alcohol, via a halide according to methods well known in the art.
It will be appreciated that in some of the processes employed to prepare compounds (VI) it may be necessary or desirable to protect the amine nitrogen atom present in compounds of formulae (IX), (X), and (XI). Protecting groups which may be employed include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; acyl groups such as acetyl, trifluoroacetyl or benzoyl; and alkoxycarbonyl or aralkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl. Such groups may be removed by methods which are well known in the art. An alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such as 1-chloromethylchloroformate, an aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that a protecting group present in any of the above compounds (IX), (X) and (XI) 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.
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.
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 Vo ' ιe 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.
Compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neurons. As such 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. For example, 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 useful 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.
In a further aspect of the invention there is therefore provided a method of treatment of conditions or diseases 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. Thus for example, 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, 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, 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 the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal e.g. a human. Compounds of the present invention will preferably be of use in the treatment of ischaemic stroke.
For use in medicine, 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 carrier(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. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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. Alternatively, 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 cyclodextrins. Preferably 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 " between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 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, e.g. 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. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus 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. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. It will be appreciated that the precise dosage and timing will be at the discretion of the physician and will depend amongst other factors on the severity of the condition to be treated. However, in general the first dose of a compound of the invention will preferably be administered as soon as possible following an ischaemic event, eg within 12 hours, preferably within 6 hours.
BIOLOGICAL DATA Ca^+ Current Measurement
Cell preparations Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca-+ currents. Superior cervical ganglion neurons were isolated and cultured following a method modified from Marrion et al, Neurosci. Lett., 77, 55-60 (1987). Cells were plated onto laminin coated plastic tissue culture dishes and incubated at 37°C until just prior to recording. Electrophysiological recordings were performed from 2 to 9 days after dissociation.
Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH. Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Caz+ currents. The external solution for recording Ca2+ channel currents contained in mM: BaCl2- 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided. Compounds were dissolved in DMSO to make a 20 mM stock solution. At the drug concentration used the vehicle (0.1%) had no significant effect on Ca2+ currents. All experiments were performed at 21 to 24°C. Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784).
Ca^+ currents
Peak voltage gated Ca?+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Baz+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording C*X+ cunents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a rundown corrected control value.
RESULTS
Dorsal Root Ganglion Cells
Block by 20 μM drug was assessed 3 minutes after drug application. In this test compounds of the invention gave percentage inhibition of plateau Ca^÷ current in the range 56 to 99% at 20 μM.
Superior Cervical Ganglion Cells
Once a constant calcium current had been recorded for 4 successive pulses (1 minute) lOμM Nimodipine. a dihydropyridine, was applied to the cell to block L type calcium current. After three minutes 5 μM drug was coapplied with 10 μM Nimodipine for three minutes. Such drug application tested the block of the remaining, predominantly N type, calcium current.
In this test compounds of Examples 2, 3, 4, 9, 13, 14 ,18 and 19 gave percentage inhibition of plateau Ca-+ current in the range 45 to 99% at 5 μM. Pharmaceutical Formulations
The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
IV Infusion
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Solvent/complexing agent to 100 ml
Bolus Injection
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Co-Solvent to 5 ml 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
Compound 1 - 40 mg
Diluent/Filler * 50 - 250 mg
Binder 5 - 25 mg
Disentegrant * 5 - 50 mg Lubricant 1 - 5 mg
Cyclodextrin 1 - 100 mg
* may also include cyclodextrins
Diluent : e.g. Microcrystalline cellulose, lactose, starch
Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
Disintegrant : e.g. Sodium starch glycollate, crospovidone
Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
Compound 1 - 40 mg
Suspending Agent 0.1 - 10 mg
Diluent 20 - 60 mg Preservative 0.01 - 1.0 mg
Buffer to pH ca 5 - 8
Co-solvent 0 - 40 mg
Flavour 0.01 - 1.0 mg
Colourant 0.001 - 0.1 mg Suspending agent :e.g. Xanthan gum, microcrystalline cellulose
Diluent : e.g. sorbitol solution, typically water
Preservative : e.g. sodium benzoate
Buffer : e.g. citrate
Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
The following non-limiting examples illustrate the preparation of compounds of formula
(I).
Preparation la 5-Bromo-l-oxo-l-[4-(3-phenylpropyI)piperidinyl]pentane
A stirred solution of 4-(3-phenylpropyl)piperidine (5.08g) and triethylamine (7.51ml) in chloroform (120ml) was treated with 5-bromovaleryl chloride (5.0g) in chloroform (30ml). The solution was stirred for 2 hours and then washed with dilute hydrochloric acid, dilute sodium hydroxide and brine, dried over sodium sulphate and the solvent was removed to give the title compound (6.4g) as a straw coloured oil.
Preparation lb
6-Bromo-l-oxo-l-[4-(3-phenylpropyI)piperidinyl]hexane
Starting from 4-(3-phenylpropyl)piperidine (4.26g), 6-bromohexanoyl chloride (4.48g) and triethylamine (5.0ml) in chloroform (100ml) and using the method of Preparation la gave the title compound (8.0g) as a straw coloured oil.
Preparation lc
7-Bromo-l-oxo-l-[4-(3-phenylpropyl)piperidinyl]heptane A stirred solution of 4-(3-phenylpropyl)piperidine (2.03g), potassium carbonate (1.5g), ether (100ml) and water (50ml) was treated with 7-bromoheptanoyl chloride (2.27g) at 0 C. The solution was stirred for 1 hour and then washed with water and brine, dried over sodium sulphate and the solvent was removed to give the title compound (3.846g) as a straw coloured oil.
Preparation Id
8-Bromo-l-oxo-l-[4-(3-phenylpropyl)piperidinyl]octane
Starting from 4-(3-phenylpropyl)piperidine (4.26g), 8-bromooctanoyl chloride (5.07 g) and triethylamine (5.0ml) in chloroform (100ml) and using the method of Preparation la gave the title compound (8.59g) as a straw coloured oil.
Preparation le
5-Bromo-l-oxo-l-[4-(2-hydroxyethyl)piperidinyI]pentane
Starting from 4-(2-hydroxyethyl)piperidine (12.9g), 5-bromovaleryl chloride (20.94g) and triethylamine (20g) in dichloromethane (200ml) and using the method of Preparation la gave the title compound (23.39g) as a straw coloured oil.
Preparation If
6-Bromo-l-oxo-l-[4-(2-hydroxyethyl)piperidinyI]hexane
Starting from 4-(2-hydroxyethyl)piperidine (12.9g), 6-bromohexanoyl chloride (21.35g) potassium carbonate (1.5g), ether (100ml) and water (50ml) and using the method of Preparation lc gave the title compound (27.064g) as a straw coloured oil.
Preparation 2a l-Oxo-l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane hydrochloride A stirred solution of piperidine (15ml) in chloroform (100ml) was treated with 5-bromo-l- oxo-l-[4-(3-phenylpropyl)piperidinyl]pentane (6.0g) in chloroform (20ml). The solution was stirred for 2 days and then washed with dilute hydrochloric acid, dilute sodium hydroxide and brine, dried over sodium sulphate and the solvent was removed. The residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride and the resulting solid was collected, chromatographed on silica gel eluted with dichloromethane- methanol and recrystallised from acetonirrile to give the title compound as white plates, (3.661g), m.p. 140 - 141°C. Found: C, 71.06; H, 9.37; N, 7.05; Cl', 8.72% (C24H3gN2O.HCl) requires: C, 70.82; H, 9.66; N, 6.88; Cl", 8.71% Preparation 2b l-Oxo-l-[4-(3-phenylpropyl)piperidinyI]-6-piperidinyIhexane
A stirred solution of piperidine (10ml) in chloroform (50ml) was treated with 6-bromo-l- oxo-l-[4-(3-phenylpropyl)piperidinyl]hexane (4.0g). The solution was stirred for 18 hours and then washed with dilute hydrochloric acid, dilute sodium hydroxide and brine, dried over sodium sulphate and the solvent was removed to give the title compound (3.5 lg) as a straw coloured oil. A sample (lg) was treated with oxalic acid in methanol and recrystallised from methanol/ethyl acetate to give the oxalate salt of the title compound as a white solid (0.952g), m.p. 92 - 94°C. Found: C, 68.02; H, 8.55; N, 5.94%
(C25H40N2O.C2H2O4) requires: C, 68.32; H, 8.92; N, 5.90%
Preparation 2c l-Oxo-l-[4-(3-phenylpropyl)piperidinyl]-7-piperidinylheptane Using the method of Preparation 2b and starting from 7-bromo-l-oxo- l-[4-(3- phenylpropyl)piperidinyl]heptane (1.8g) piperidine (2ml) and chloroform (50ml) gave the title compound (0.895g) as a straw coloured oil.
Preparation 2d l-Oxo-l-[4-(3-phenylpropyI)piperidinyI]-8-piperidinyloctane
Using the method of Preparation 2b and starting from 8-bromo-l-oxo-l-[4-(3- phenylpropyl)piperidinyl] octane (4.0g) piperidine (10ml) and chloroform (100ml) gave the title compound (4.17g) as straw coloured oil. A sample (0.5g) was treated with oxalic acid in methanol and recrystallised from methanol/ethyl acetate to give the oxalate salt of the title compound as a white solid (0.441 g), m.p. 110 - 1 11°C. Found: C, 68.48; H, 8.80; N, 5.36% (C27H44N2O.C2H2O4.O.3H2O) requires: C, 68.55; H, 9.24; N, 5.51%
Preparation 2e l-Oxo-l-[4-(3-phenylpropyI)piperidinyI]-7-morphoIinylheptane
Using the method of Preparation 2b and starting from 7-bromo-l-oxo-l-[4-(3- phenylpropyl)piperidinyl]heptane (1.8g), morpholine (2ml) and chloroform (50ml) gave the title compound (1.93g) as a colourless oil. Preparation 2f l-Oxo-l-[4-(2-hydroxyethyI)piperidinyl]-5-piperidinylpentane
Using the method of Preparation 2a and starting from 5-bromo-l oxo-l-[4-(2-hydroxy- ethyl)piperidinyl]pentane (lOg), piperidine (15ml) and chloroform (150ml) gave the title compound (10.46g) as an oil.
Preparation 2g l-Oxo-l-[4-(2-hydroxyethyl)piperidinyl]-6-piperidinylhexane
Using the method of Preparation 2a and starting from 6-bromo-l-oxo-l-[4-(2-hydroxy- ethyl)piperidinyl]hexane (7.5g), piperidine (10ml) and chloroform (150ml) gave the title compound (7.59g) as an oil.
Preparation 3a
Ethyl 6-morphoIinylhexanoate A mixture of ethyl 6-bromohexanoate (l l.lόg), morpholine (4.36g), potassium carbonate (8.29g) and ethanol (200ml) was heated at reflux for 18 hours. The mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in dilute hydrochloric acid and extracted with ether. The aqueous layer was basified with dilute sodium hydroxide and extracted with ether. This ether layer was washed with brine, dried over magnesium sulphate and the solvent was removed to give the title compound as an oil.
Preparation 3b l-Oxo-l-[4-(3-phenylpropyl)piperidinyI]-6-morphoIinylhexane
A mixture of ethyl 6-morpholinylhexanoate, 4-(3-phenylpropyl)piperidine (1.42g), 80% sodium hydride in oil (0.195g) and toluene (10ml) was heated at reflux for 6 hours. Water was added and the mixture was extracted with ether. (100ml). This ether layer was washed with brine, dried over magnesium sulphate and the solvent was removed to give the title compound (0.76g) as an oil.
Preparation 4a l-[4-(2-HydroxyethyI)piperidinyI]-5-piperidinylpentane
A solution of l-oxo-l-[4-(2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (7.5g) in tetrahydrofuran (30ml) was added over 30 minutes to a solution of lithium aluminum hydride (5.0g) in tetrahydrofuran (250ml) stirred at 50 C. The mixture was stirred at 50 C for 2.5 hours, cooled, treated with dilute sodium hydroxide solution (20ml) and filtered. The filtrate was evaporated and the residue was dissolved in ether, washed with brine, dried over magnesium sulphate and the solvent was removed. The residue was Kugelrohr distilled (b.p. 219 - 220°C@ O. lmmHg) to give the title compound (3.61g) as an oil.
Preparation 4b l-[4-(2-Hydroxyethyl)piperidinyl]-6-piperidinylhexane
Using the method of Preparation 4a and starting from l-oxo-l-[4-(2- hydroxyethyl)piperidinyl]-6-piperidinylhexane (7.4g) and lithium aluminum hydride (4.52g) gave the title compound (6.70g) as a straw coloured a oil.
Example 1 l,4-Bis-[4-(3-phenylpropyI)piperidinyl]-butane dihydrochloride
A stirred solution of 4-(3-phenylpropyl)piperidine (4.26g) and triethylamine (5ml) in chloroform (100ml) was treated with succinyl chloride (1.54g) at 0 C. The solution was stirred for 2 hours and then washed with dilute hydrochloric acid and brine, dried over magnesium sulphate and the solvent was removed. The resulting oil was dissolved in tetrahydrofuran (30ml) and added over 30 minutes to a solution of lithium aluminum hydride (3.11g) in tetrahydrofuran (120ml) stirred at 50 C. The mixture was stirred at 50 C for 3 hours, cooled, treated with dilute sodium hydroxide solution (10ml) and filtered. The filtrate was evaporated and the residue was dissolved in ether, the solution washed with brine, dried over sodium sulphate and the solvent was removed. The residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride and the resulting solid was recrystallised from acetonitrile to give the title compound as white needles, (2.70g), m.p. 288 - 289°C. Found: C, 70.91; H, 9.04; N, 5.18; Cl", 13.14%
(C32H4 N2.2HCLO.3H2O) requires: C, 71.29; H, 9.40; N, 5.19; Cl", 13.15%
Example 2 l,5-Bis-[4-(3-phenylpropyI)piperidinyl]-pentane dihydrochloride The title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with glutaryl dichloride (1.69g). Recrystallisation from methanol/ethyl acetate gave a white solid, (2.94g), m.p. softens 70 - 72 melts 215 - 217 C.
Found: C, 66.34; H, 9.39; N, 4.82; Cl, 11.92%
(C33H50N2-2HC1.2.5H2O) requires: C, 66.87; H, 9.69; N, 4.72; Cl, 11.96% Example 3 l,6-Bis-[4-(3-phenylpropyI)piperidinyl]-hexane dihydrochloride
The title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with adipoyl chloride (1.83g). Recrystallisation from acetonitrile gave white needles, (2.143g), m.p. 240 - 242°C. Found: C, 68.37; H, 9.37; N, 4.88; Cl, 11.61% (C34H52N2.2HCl.2H2O) requires: C, 68.32; H, 9.78; N, 4.68; Cl, 11.86%
Example 4 l,7-Bis-[4-(3-phenylpropyl)piperidinyl]-heptane dihydrochloride
The title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with pimeloyl chloride (2.53g). Recrystallisation from methanol/ethyl acetate gave a white solid, (2.53g), m.p. softens 80 - 90, melts 199 - 201 C.
Found: C, 68.27; H, 9.42; N, 4.46: Cl, 1 1.63%
(C35H54N2.2HCL2.2H2O) requires: C, 68.31; H, 9.24; N, 4.55; Cl, 1 1.52%
Example 5 l,8-Bis-[4-(3-phenylpropyl)piperidinyl]-octane dihydrochloride The title compound was prepared in a similar manner to Example 1 by substituting succinyl chloride with suberoyl chloride (2.1 lg). Recrystallisation from acetonitrile gave white needles, (1.508g), m.p. 210 - 212°C.
Found: C. 68.86; H, 9.52; N, 4.51; Cl, 11.01%
(C36H56N2.2HC1.2H2O) requires: C, 69.09: H, 9.98; N, 4.47; Cl, 1 1.33%
Example 6 l,12-Bis-[4-(3-phenylpropyl)piperidinyl]-dodecane dihydrochloride
A mixture of 4-(3-phenylpropyl)piperidine (4.14g), 1,12-dibromododecane (3.28g) potassium carbonate (lOg) and ethanol (100ml) was heated at reflux for 18 hours. The mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in chloroform, the solution washed with dilute sodium hydroxide solution and brine, dried over magnesium sulphate and the solvent was removed. The residue was treated with ethanolic hydrogen chloride and the resulting solid was recrystallised from ethanol/water to give the title compound as an off white solid, (0.6g), m.p. 214 - 216 C. Found: C, 73.87; H, 10.53; N, 4.07%
(C40H64N2.2HC1.0.25H2O) requires: C, 73.86; H, 10.30; N, 4.31% Example 7 l,7-Bis-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyI]}-heptane dihydrochloride
The title compound was prepared in a similar manner to example 6 starting from 4-[2- (3,4-dichlorophenoxy)ethyl]piperidine (l.Og, WO94/13291), 1,7-dibromoheptane (0.387g), potassium carbonate (2.07g) and ethanol (50ml). Treatment with ethereal hydrogen chloride and recrystallisation from ethyl acetate gave a cream solid, (0.643g), m.p. 204 - 206°C
Found: C, 51.16; H, 6.46; N, 3.69; Cl, 9.16%
(C33H46N2CI4O2.2HCI.3H2O) requires: C, 51.37; H, 7.05; N, 3.63; Cl, 9.19%
Example 8 l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane dihydrochloride A solution of l-oxo-l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane hydrochloride (1.594g) in chloroform (50ml) was washed with dilute sodium hydroxide and brine, dried over magnesium sulphate and the solvent was removed. The resulting oil was dissolved in tetrahydrofuran (30ml) and added over 20 minutes to a solution of lithium aluminum hydride (0.89g) in tetrahydrofuran (100ml) stirred at 50 C. The mixture was stirred at 50 C for 2 hours, cooled, treated with dilute sodium hydroxide solution (10ml) and filtered. The filtrate was evaporated and the residue was dissolved in chloroform, the solution washed with brine, dried over sodium sulphate and the solvent was removed. The residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride and the resulting solid was recrystallised from acetonitrile to give the title compound as white needle clusters, (1.12g), m.p. 203 - 204°C.
Found: C, 66.58; H, 9.36; N, 6.58; Cl", 16.33% (C24H40N2.2HCI) requires: C, 67.1; H, 9.85; N, 6.52; Cl", 16.50%
Example 9 l-[4-(3-phenylpropyl)piperidinyl]-6-piperidinylhexane dihydrochloride
A solution of l-oxo-l-[4-(3-phenylpropyl)piperidinyl]-6-piperidinylhexane (2.3g) in tetrahydrofuran (30ml) was added over 30 minutes to a solution of lithium aluminum hydride (1.36g) in tetrahydrofuran (100ml) stirred at 50 C. The mixture was stirred at 50 C for 2.5 hours, cooled, treated with dilute sodium hydroxide solution (10ml) and filtered. The filtrate was evaporated and the residue was dissolved in ether, the solution washed with brine, dried over magnesium sulphate and the solvent was removed. The residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride and the resulting solid was recrystallised from acetonitrile to give the title compound as white needles, (2.1 g), m.p. 219.- 220°C. Found: C, 63.47; H, 9.59; N, 6.03; Cl', 15.06% (C25H42N2.2HCI.I.5H2O) requires: C, 63.81; H, 10.06; N, 5.95; Cl", 15.07%
Example 10 l-[4-(3-phenylpropyl)piperidinyl]-7-piperidinylheptane dihydrochloride
The title compound was prepared in a similar manner to Example 9 starting from 1-oxo- l-[4-(3-phenylpropyl)piperidinyl]-7-piperidinylheptane (0.8g) and lithium aluminum hydride (0.38g). Recrystallisation from acetonitrile gave white needles, (0.318g), m.p.
202 - 203°C.
Found: C, 68.11 ; H, 9.86; N, 6.16; Cl, 15.24%
(C26H44N2.2HCI) requires: C, 68.25; H, 10.13; N, 6.12; Cl, 15.50%
Example 11 l-[4-(3-phenylpropyI)piperidinyI]-8-piperidinyloctane dihydrochloride
The title compound was prepared in a similar manner to example 9 starting from 1-oxo-l- [4-(3-phenylpropyl)piperidinyl]-8-piperidinyloctane (l.lg) and lithium aluminum hydride (0.6g). Recrystallisation from ethyl acetate gave white needles (0.92g), m.p. 202 - 203 °C. Found: C, 63.56; H, 9.77; N, 5.50; Cl, 13.97% (C27H46N2.2HC1) requires: C, 63.88; H, 10.10; N, 5.51; Cl, 14.08%
Example 12 l-[4-(3-phenylpropyl)piperidinyl]-7-morphoIinoheptane dihydrochloride
The title compound was prepared in a similar manner to Example 9 starting from 1-oxo- l-[4-(3-phenylpropyl)piperidinyl]-7-morpholinoheptane (1.76g) and lithium aluminum hydride (l.Og). Recrystallisation from ethyl acetate gave a cream solid, (1.145g), m.p. n - 172°C. Found: C, 63.10; H, 9.24; N, 5.94; Cl, 15.21%
(c25H42N2o-2HC1.0.75H2O) requires: C, 63.47; H, 9.60; N, 5.92; Cl, 14.99%
Example 13 l-[4-(3-phenylpropyI)piperidinyl]-6-morphoIinohexane dihydrochloride The title compound was prepared in a similar manner to example 9 starting from 1-oxo-l- [4-(3-phenylpropyl)piperidinyl]-6-morpholinohexane (0.75g) and lithium aluminum hydride (0.44g). Recrystallisation from acetonitrile gave white needles, (0.445g), m.p. ■ 217 - 218°C.
Found: C, 63.28; H, 9.25; N, 6.18; Cl, 15.76%
(C24H40N2°.2HC1.0.5H2O) requires: C, 63.42; H, 9.53; N, 6.16; Cl, 15.60%
Example 14 l-{4-[2-(3,4-Dichlorophenoxy)ethyl]piperidinyl}-5-piperidinyIpentane dihydrochloride
A solution of l-[4-(2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (l.Og), 3,4- dichlorophenol (0.58g), and triphenylphosphine (0.92g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (0.6 lg). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate and treated with ethereal hydrogen chloride to give the title compound (0.535g) as a white crystalline solid, m.p. 222 - 223 C.
Found: C, 53.27; H, 7.27; N, 5.47; Cl, 13.68%. (c23H36cl2N2θ.2HCl.H2O) requires: C, 53.29; H, 7.77; N, 5.40; Cl, 13.67%
Example 15 l-{4-[2-(4-Benzylphenoxy)ethyl]piperidinyI}-5-piperidinylpentane dihydrochloride
The title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-benzylphenol (0.52g), triphenylphosphine (0.74g), diethyl azodicarboxylate (0.49g) and tetrahydrofuran (30ml). Recrystallisation from methanol/ethyl acetate gave a white solid (0.949g), m.p. 191 - 192°C.
Found: C, 68.04; H, 8.61; N, 5.43; Cl, 13.38%
(C30H44N2O.2HCI.O.5H2O) requires: C, 67.90; H, 8.92; N, 5.27; Cl, 13.36%
Example 16 l-{4-[2-(4-BenzyIoxyphenoxy)ethyl]piperidinyl}-5-piperidinylpentane dihydrochloride
The title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-benzyloxyphenol (0.56g), triphenylphosphine (0.74g), diethyl azodicarboxylate (0.49g) and tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a white solid (0.714g), m.p. 191 - 192°C. Found: C, 65.98; H, 8.30; N, 5.40; Cl, 12.90% (C30H44N2O2.2HCLO.3H2O) requires: C, 66.35; H, 8.21; N, 5.15; Cl, 13.06%
Example 17 l-{4-[2-(4-Fluorophenoxy)ethyI]piperidinyl}-5-piperidinylpentane dihydrochloride The title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-5-piperidinylpentane (0.8g), 4-fluorophenol (0.32g), triphenylphosphine (0.74g) and diethyl azodicarboxylate (0.49g) in tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a white solid (0.305g), m.p. 228 - 230°C. Found: C, 60.99; H, 8.54; N, 6.27; Cl, 15.43%
(C23H37FN2O.2HCI) requires: C, 61.46; H, 8.75; N, 6.23; Cl, 15.77%
Example 18 l-{4-[2-(4-Fluorophenoxy)ethyl]piperidinyl}-6-piperidinylhexane dihydrochloride The title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-6-piperidinylhexane (l.Og), 4-fluorophenol (0.378g), triphenylphosphine (0.88g), diethyl azodicarboxylate (0.58g) and tetrahydrofuran (30ml). Recrystallisation from acetonitrile gave a cream solid (0.365g), m.p. 221 - 222 C. Found: C, 61.50; H, 8.58; N, 5.96; Cl, 15.26% (C24H39FN2O.2HCLO.2H2O) requires: C, 61.71 ; H, 8.92; N, 5.99; Cl, 15.18%
Example 19 l-{4-[2-(3,4-Dichlorophenoxy)ethyl]piperidiny }-6-piperidinylhexane dihydrochloride
The title compound was prepared in a similar manner to example 14 starting from l-[4- (2-hydroxyethyl)piperidinyl]-6-piperidinylhexane (l.Og), 3,4-dichlorophenol (0.55g), triphenylphosphine (0.88g), diethyl azodicarboxylate (0.58g) and tetrahydrofuran (30ml).
Recrystallisation from acetonitrile gave a cream solid (0.30g), m.p. 225 - 226 C.
Found: C, 55.20; H, 7.44; N, 5.69%
(C24H3gCl2N2O.2HC1.0.25H2O) requires: C, 55.55; H, 7.86; N, 5.39%

Claims

Claims :
1. A compound of formula (I):
Figure imgf000026_0001
Formula (I) in which
W is -CH2" or a bond; p is an integer from 3-12;
NR1R2 represents: (i) an acyclic amino group wherein R^ and R2 each independently represent: hydrogen, Cj.galkyl, C3_gcycloalkyl, C3-gcycloalkylC galkyl, arylC^alkyl, hydroxyC2-6alkyl or R3R4NC2-6alkyl (where R^ and R^ independently represent H or Cι _4alkyl) provided that when one of R* and R2 represents hydrogen, the other does not represent hydrogen, Cj-galkyl, C3_gcycloalkylCι_galkyl, arylC^alkyl or hydroxy C2-6alkyl;
(ii) a saturated heterocyclic ring containing 4 to 9 ring members, one of which may optionally be a further heteroatom selected from O, S or NR^, (where R^ is H, C\. 4alkyl or arylC^alkyl), which ring may optionally be substituted by one or two substituents selected from C^alkyl and C^.galkoxy; or (iii) when W represents a bond, NR 1R2 may also represent a pyrrolidine ring substituted by -(CH2)nA(CH2)mAr and when W represents -CH2-, NR*R2 may also represent a piperidine ring substituted by -(CH2)nA(CH2)mAr to form a symmetrical compound of formula (I); n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR^ where R^ is hydrogen,
C galkyl or phenylC^alkyl; and
Ar is optionally substituted phenyl; or a salt thereof.
2. A compound according to claim 1 wherein W is -CH2-.
3. A compound according to claim 1 or claim 2 wherein p is from 4 to 8.
4. A compound according to any of claims 1 to 3 wherein NR R represent a saturated heterocyclic ring containing 4 to 9 ring members, one cf which may optionally be a further heteroatom selected from O, S or NR^, (where R^ is H, C^alkyl or arylCj. 4alkyl), which ring may optionally be substituted by one or two s jbstituents selected from Ci-βalkyl and C^alkoxy.
5. A compound according to claim 4 wherein NR 1R2 represents an unsubstituted piperidino group.
6. A compound according to any of claims 1 to 5 wherein the length of the chain -(CH2)nA(CH2)m is fr°m 2 to 6 atoms.
7. A compound according to any of claims 1 to 6 wherein A is oxygen, or a bond.
8. A compound according to claim 1 selected from : l,4-bis-[4-(3-phenylpropyl)piperidinyl]-butane; l,5-bis-[4-(3-phenylpropyl)piperidinyl]-pentane; l,6-bis-[4-(3-phenylpropyl)piperidinyl]-hexane; l,7-bis-[4-(3-phenylpropyl)piperidinyl]-heptane; l,8-bis-[4-(3-phenylpropyl)piperidinyl]-octane; l,12-bis-[4-(3-phenylpropyl)piperidinyl]-dodecane; l,7-bis-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl] } -heptane; l-[4-(3-phenylpropyl)piperidinyl]-5-piperidinylpentane; l-[4-(3-phenylpropyl)piperidinyl]-6-piperidinylhexane; l-[4-(3-phenylpropyl)piperidinyl]-7-piperidinylheptane; l-[4-(3-phenylpropyl)piperidinyl]-8-piperidinyloctane; l-[4-(3-phenylpropyl)piperidinyl]-7-morpholinoheptane; l-[4-(3-phenylpropyl)piperidinyl]-6-morpholinohexane; l-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl}-5-piperidinylpentane;
1 - { 4-[2-(4-benzylphenoxy)ethyl]piperidinyl } -5-piperidinylpentane; l-{4-[2-(4-benzyloxyphenoxy)ethyl]piperidinyl}-5-piperidinylpentane; l-{4-[2-(4-fluorophenoxy)ethyl]piperidinyl }-5-piperidinylpentane;
1 - { 4-[2-(4-fluorophenoxy)ethyl]piperidinyl } -6-piperidinylhexane; l-{4-[2-(3,4-dichlorophenoxy)ethyl]piperidinyl}-6-piperidinylhexane; or a salt thereof.
9. A process for the preparation of a compound of formula (I) as defined in any of claims 1 to 8 which comprises: (a) reduction of a compound of formula (II) :
Figure imgf000028_0001
Formula (II) wherein Ar, m, n, A, W, R*, R2 and p are as defined above, one of x and y is 1 and the other is zero or 1;
(b) to prepare a compound of formula (I) in which A is O, S or NR^, reaction of a compound of formula (III) :
Figure imgf000028_0002
Formula (III) (wherein W, n, p, R and R2 are as hereinbefore defined, or NR IR2 may also represent a pyrrolidine or piperidine ring substituted by L^(CH2)n, and LMs a group displaceable by a nucleophile), with a compound of formula HA^(CH2)mAr, where m and Ar are as defined above and
A s O, S or NR6; (c) to prepare a compound of formula (I) in which A is O, S or NR", reaction of a compound of formula (IV) :
Figure imgf000028_0003
Formula (IV)
(wherein W, n, p, Rl, R^ and A* are as hereinbefore defined, or NR1R2 may also represent a pyrrolidine or piperidine ring substituted by HA 1 (CH2)n), with a compound of formula L2(CH2)mAr in which m and Ar are as defined above and IX is a leaving group.
(d) To prepare a compound of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Figure imgf000029_0001
Formula (V)
(wherein L*, W, n, m, p, R* and R^ are as hereinbefore defined, or NR * R2 may also represent a pyrrolidine or piperidine ring substituted by L^(CH2)n+m)' with a compound of formula X^Ar in which Ar is as defined above and X s an alkali metal,
(e) to prepare a compound (I) wherein NR^R^ represents a substituted pyrrolidino or piperidino group (iii) as hereinbefore defined, reaction of a compound of formula (VI) :
Figure imgf000029_0002
Formula (VI)
(wherein Ar, A, m, n, W, R! and R^ are as hereinbefore defined) with an alkylating agent Br(CH2)pBr;
(f) Interconversion of one compound of formula (I) to a different compound of formula (I), e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2-CH2-; and optionally thereafter forming a salt of formula (I).
10. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
11. A compound of formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in therapy.
12. Use of a compound of formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition related to the accumulation of calcium in the brain cells of a mammal.
13. A method of treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
PCT/EP1995/000850 1994-03-11 1995-03-07 Novel phenyl(-alkyl/alkoxy)-1-aminoalkyl-substituted piperidines and pyrrolidines as calcium channel antagonists WO1995024390A1 (en)

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US7498344B2 (en) 1996-07-22 2009-03-03 Asubio Pharma Co., Ltd. Arylpiperidinol and arylpiperidine derivatives and pharmaceuticals containing the same
EP0867183A4 (en) * 1996-07-22 1999-11-17 Suntory Ltd Arylpiperidinol and arylpiperidine derivatives and drugs containing the same
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EP0867183A1 (en) * 1996-07-22 1998-09-30 Suntory Limited Arylpiperidinol and arylpiperidine derivatives and drugs containing the same
WO1999043658A1 (en) * 1998-02-27 1999-09-02 Warner-Lambert Company Heterocyclic substituted aniline calcium channel blockers
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US8044206B2 (en) 2003-03-07 2011-10-25 Astellas Pharma Inc. Nitrogen—containing heterocyclic derivatives having 2,6-disubstituted styryl
WO2005123678A1 (en) * 2004-06-15 2005-12-29 L'oréal Cosmetic use of piperidine derivatives
US7807695B2 (en) 2004-06-15 2010-10-05 L'oreal Cosmetic use of piperidine derivatives
FR2871462A1 (en) * 2004-06-15 2005-12-16 Oreal New piperidine derivatives useful as cosmetic agents to: fight against wrinkles (expression wrinkles); relax/contract the skin; and and/or smoothen the skin
US8129409B2 (en) 2004-06-15 2012-03-06 L'oreal Piperidine derivatives and cosmetic compositions thereof
EP1901746A2 (en) * 2005-06-29 2008-03-26 Merck & Co., Inc. 4-fluoro-piperidine t-type calcium channel antagonists
WO2007002884A2 (en) 2005-06-29 2007-01-04 Merck & Co., Inc. 4-fluoro-piperidine t-type calcium channel antagonists
EP1901746A4 (en) * 2005-06-29 2011-11-30 Merck Sharp & Dohme 4-fluoro-piperidine t-type calcium channel antagonists
WO2007073407A1 (en) * 2005-12-21 2007-06-28 Decode Genetics Ehf Biaryl substituted nitrogen containing heterocycle inhibitors of lta4h for treating inflammation
US7576102B2 (en) 2005-12-21 2009-08-18 Decode Genetics Ehf Biaryl substituted nitrogen containing heterocycle inhibitors of LTA4H for treating inflammation

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